GLOBAL STRATEGY FOR ASTHMA MANAGEMENTAND PREVENTION
Updated 2021 ©2021 Global Initiative for Asthma
Global Strategy for Asthma Management and Prevention
(2021 update^
The reader acknowledges that this report is intended as an evidence-based asthma management strategy, for the use of health professionals and policy-makers. It is based, to the best of our knowledge, on current best evidence and medical knowledge and practice at the date of publication. When assessing and treating patients, health professionals are strongly advised to use their own professional judgment, and to take into account local and national regulatic(Q^cind guidelines. GINA cannot be held liable or responsible for inappropriate healthcare 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, 2021. Available from: www.ginasthma.org
1
Table of contents
Tables and figures.............................................................................................................................................................5
Preface................................................................................................................................................................................7
Members of GINA committees (2019-20).........................................................................................................................8
Methodology.....................................................................................................................................................................10
What's new in GINA 2021?..............................................................................................................................................14
Advice 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
Definition of asthma...................................................................................................................................................20
Description of asthma................................................................................................................................................20
Making the initial diagnosis........................................................................................................................................21
Confirming the diagnosis of asthma in patients already taking controller treatment.................................................26
Differential diagnosis..................................................................................................................................................27
How to make the diagnosis of asthma in other contexts...........................................................................................28
Chapter 2. Assessment of asthma................................................................................................................................31
Overview....................................................................................................................................................................32
Assessing asthma symptom control..........................................................................................................................33
Assessing future risk of adverse outcomes...............................................................................................................38
Role of lung function in assessing asthma control.....................................................................................................39
Assessing asthma severity..................................................................................................................................40
Chapter 3. Treating asthma to control symptoms and minimize risk.......................................................................43
Part A. General principles of asthma management.......................................................................................................44
Long-term goals of asthma management..................................................................................................................45
The patient-health care provider partnership.............................................................................................................45
Personalized control-based asthma management....................................................................................................46
Part B. Medications and strategies for symptom control and risk reduction..................................................................49
Asthma medications...................................................................................................................................................50
Asthma treatment tracks for adults and adolescents.................................................................................................52
Step 1.........................................................................................................................................................................62
Step 2.........................................................................................................................................................................64
Step 3.........................................................................................................................................................................67
Step 4.........................................................................................................................................................................68
Step 5.........................................................................................................................................................................69
Reviewing response and adjusting treatment............................................................................................................71
Treating other modifiable risk factors.........................................................................................................................74
2
Other therapies..........................................................................................................................................................75
Non-pharmacological strategies................................................................................................................................77
Indications for referral for expert advice....................................................................................................................85
Part C. Guided asthma self-management education and skills training........................................................................86
Overview....................................................................................................................................................................86
Skills training for effective use of inhaler devices......................................................................................................86
Adherence with medications and other advice..........................................................................................................87
Asthma information....................................................................................................................................................89
Training in guided asthma self-management............................................................................................................90
Part D. Managing asthma with comorbidities and in specific populations.....................................................................92
Managing comorbidities.............................................................................................................................................92
Managing asthma in specific populations or settings................................................................................................95
Part E. Difficult-to-treat and severe asthma in adults and adolescents.......................................................................101
Definitions: uncontrolled, difficult-to-treat and severe asthma.................................................................................101
Prevalence: how many people have severe asthma?.............................................................................................102
Importance: the impact of severe asthma................................................................................................................102
Investigate and manage adult and adolescent patients with difficult-to-treat asthma.............................................108
Assess and treat severe asthma phenotypes..........................................................................................................110
Manage and monitor severe asthma treatment.......................................................................................................115
Chapter 4. Management of worsening asthma and exacerbations.........................................................................117
Overview..................................................................................................................................................................119
Diagnosis of exacerbations......................................................................................................................................120
Self-management of exacerbations with a written asthma action plan...................................................................120
Management of asthma exacerbations in primary care (adults, adolescents, chldren 6-11 years).......................124
Management of asthma exacerbations in the emergency department (adults, adolescents, children 6-11 years)127
Chapter 5. Diagnosis and initial treatment of adults with features of asthma, COPD or both ('asthma-COPD overlap')..........................................................................................................................................................................135
Objectives................................................................................................................................................................137
Background to diagnosing asthma and/or COPD in adult patients.........................................................................137
Assessment and management of patients with chronic respiratory symptoms.......................................................138
Future research........................................................................................................................................................143
SECTION 2.CHILDREN 5 YEARS AND YOUNGER.........................................................................................................145
Chapter 6. Diagnosis and management of asthma in children 5 years and younger...........................................145
Part A. Diagnosis.........................................................................................................................................................146
Asthma and wheezing in young children................................................................................................................146
Clinical diagnosis of asthma....................................................................................................................................147
Tests to assist in diagnosis......................................................................................................................................150
3
Differential diagnosis...............................................................................................................................................151
Part B. Assessment and management........................................................................................................................153
Goals of asthma management.................................................................................................................................153
Assessment of asthma............................................................................................................................................153
Medications for symptom control and risk reduction................................................................................................155
Asthma treatment steps for children aged 5 years and younger.............................................................................157
Reviewing response and adjusting treatment.........................................................................................................160
Choice of inhaler device..........................................................................................................................................160
Asthma self-management education for carers of young children.........................................................................161
Part C. Management of worsening asthma and exacerbations in children 5 years and younger...............................162
Diagnosis of exacerbations......................................................................................................................................162
Initial home management of asthma exacerbations.............................................-^tj^-..........................................^2
Primary care or hospital management of acute asthma exacerbations in children 5 years or younger..................165
Chapter 7. Primary prevention of asthma..................................................................................................................169
Factors contributing to the development of asthma in children...............................................................................170
Factors associated with increased or decreased risk of asthma in children............................................................170
Advice about primary prevention of asthma......................................................................................................173
SECTION 3. TRANSLATION INTO CLINICAL PRACTICE................................................................................................175
Chapter 8. Implementing asthma management strategies into health systems....................................................175
Introduction.....................................................-.o*^................................................................................................^
Adapting and implementing asthma clinical practice guidelines..............................................................................176
Barriers and facilitators............................................................................................................................................178
Examples of high impact implementation interventions...........................................................................................178
Evaluation of the implementation process...............................................................................................................178
How can GINA help with implementation?..............................................................................................................179
Peer-reviewed publications about the GINA report...................................................................................................180
REFERENCES....................................................................................................................................................................181
4
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 36
Box 2-3. Specific questions for assessment of asthma in children 6-11 years 37
Box 2-4. Investigating a patient with poor symptom control and/or exacerbations despite treatment 42
ASTHMA MANAGEMENT
Box 3-1. Communication strategies for health care providers 45
Box 3-2. The asthma management cycle for personalized asthma care 46
Box 3-3. Population level versus patient level decisions about asthma treatment 48
Initial treatment choices
Box 3-4A. Initial asthma treatment - recommended options for adults and adolescents 53
Box 3-4BL Selecting initial controller treatment in adults and actojescents with a diagnosis of asthma (V1) 54
Box 3-4BN. Selecting initial controller treatment in adults and adolescents with a diagnosis of asthma (V2) 55
Box 3-4C. Initial asthma treatment - recommended optioiJ§>fbr children aged 6-11 years 56
Box 3-4DL Selecting initial controller treatment in children aged 6-11 years with a diagnosis of asthma (V1) 57
Box 3-4DN. Selecting initial controller treatment in children aged 6-11 years with a diagnosis of asthma (V2) 58
Main treatment figures
Box 3-5A. Personalized management for a«Qms and adolescents to control symptoms and minimize future risk 59
Box 3-5B. Personalized management for children 6-11 years to control symptoms and minimize future risk 60
Box 3-6. Low, medium and high daily metered doses of inhaled corticosteroids (alone or with LABA) 61
Ongoing management
Box 3-7. Options for stepping down treatment once asthma is well controlled 73
Box 3-8. Treating potentially modifiable risk factors to reduce exacerbations 74
Box 3-9. Non-pharmacological interventions - summary 77
Box 3-10. Effectiveness of avoidance measures for indoor allergens 81
Box 3-11. Indications for considering referral for expert advice, where available 85
Box 3-12. Strategies to ensure effective use of inhaler devices 87
Box 3-13. Poor medication adherence in asthma 88
Box 3-14. Asthma information 89
Difficult-to-treat and severe asthma
Box 3-15. What proportion of adults have difficult-to-treat or severe asthma? 102
Box 3-16A. Decision tree - investigate and manage adult and adolescent patients with difficult-to-treat asthma 104
Box 3-16B. Decision tree - assess and treat severe asthma phenotypes 105
Box 3-16C. Decision tree - consider add-on biologic Type 2 targeted treatments 106
Box 3-16D. Decision tree - monitor and manage severe asthma treatment 107
5
EXACERBATIONS
Box 4-1. Factors that increase the risk of asthma-related death 119 Box 4-2. Self-management of worsening asthma in adults and adolescents with a written asthma action plan 123 Box 4-3.           Management of asthma exacerbations in primary care (adults, adolescents, children 6-11 years) 125
Box 4-4.           Management of asthma exacerbations in acute care facility, e.g. emergency department 129
Box 4-5.           Discharge management after hospital or emergency department care for asthma 133
ASTHMA, COPD AND ASTHMA+COPD
Box 5-1.           Current definitions of asthma and COPD, and clinical description of asthma-COPD overlap 138
Box 5-2.          Approach to initial treatment in patients with asthma and/or COPD 139
Box 5-3.           Spirometric measures in asthma and COPD 140
Box 5-4.           Specialized investigations sometimes used in distinguishing asthma and COPD 142
CHILDREN 5 YEARS AND YOUNGER
Box 6-1.           Probability of asthma diagnosis in children 5 years and younger 147
Box 6-2.           Features suggesting a diagnosis of asthma in children 5 years and younger 148
Box 6-2A.         Questions that can be used to elicit features suggestive of asthma 149
Box 6-3.           Common differential diagnoses of asthma in children 5 years and younger 151
Box 6-4.           GINA assessment of asthma control in children 5 years and yourwwj? 154
Box 6-5.           Personalized management of asthma in children 5 years and younger 159
Box 6-6.           Low daily doses of inhaled corticosteroids for children 5 years and younger 160
Box 6-7.           Choosing an inhaler device for children 5 years and younger 161
Box 6-8.           Management of acute asthma or wheezing in children 5 years and younger 164
Box 6-9.           Initial assessment of acute asthma exacerbations-tfschildren 5 years and younger 165
Box 6-10. Indications for immediate transfer to hospital for children 5 years and younger 166 Box 6-11.         Initial emergency department management of asthma exacerbations in children 5 years and younger 167
PRIMARY PREVENTION OF ASTHMA
Box 7-1. Advice about primary prevention of asthma in children 5 years and younger 173 IMPLEMENTATION STRATEGIES
Box 8-1.          Approach to implementation afcKne Global Strategy for Asthma Management and Prevention 177
Box 8-2.           Essential elements required to implement a health-related strategy 177
Box 8-3.           Examples of barriers to the implementation of evidence-based recommendations 178
Box 8-4.           Examples of high-imjgtet interventions in asthma management 178
6
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 updated annually since 2002, and publications based on the GINA reports have been translated into many languages. In 2001, GINA initiated an annual World Asthma Day, raising awareness about the bur<Qwi of asthma, and becoming a focus for local and national activities to educate families and health care professionals about effective methods to manage and control asthma.
In spite of these efforts, and the availability of effective therapies, international surveys provide ongoing evidence for suboptimal asthma control in many countries. It is clear that if recomm^dations contained within this report are to improve care of people with asthma, every effort must be made to encourage health care leaders to assure availability of, and access to, medications, and to develop means to implement and evaluate effective asthma management programs. To this end, the major revision of the GINA report published inJaray 2014 not only reflected new evidence about asthma and its treatment, but also integrated evidence into strategies that would be both clinically relevant and feasible for implementation into busy clinical practice, and presented,recommendations in a user-friendly way with extensive use of summary tables and flow-charts. For clinical utility, recommendations for clinical practice are contained in the core GINA Report, while additional resources and background supporting material are provided online at www.ginasthma.org. New recommendations about treatment of mild asthma, described in the present report, represent the outcome of more than a decade of work by GINA members and others, and may be considered the most fundamental change in asthma management in the past 30 years.
It is essential that we acknowledge the superlative work of all who have contributed to the success of the GINA program, and the many people who have p^wcipated in it; in particular, the outstanding and dedicated work of Drs Suzanne Hurd as Scientific Director and Claude Lenfant as Executive Director over the many years since GINA was first established, until their retirement in December 2015. Through their tireless contributions, Dr Hurd and Dr Lenfant fostered and facilitated the development of GINA. In January 2016, we were delighted to welcome Ms Rebecca Decker, BS, MSJ, as 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
7
Members of GINA committees (2019-20)
GINA SCIENTIFIC COMMITTEE
Helen K. Reddel, MBBS PhD, Chair
Woolcock Institute of Medical Research, University of
Sydney
Sydney, Australia
Leonard B. Bacharier, MD Vanderbilt University Medical Center Nashville, TN, USA
Eric D. Bateman, MD
University of Cape Town Lung Institute
Cape Town, South Africa
Louis-Philippe Boulet, MD Universitě Laval Quebec, QC, Canada
Christopher Brightling, FMedSci, PhD Leicester NIHR Biomedical Research Centre, University of Leicester Leicester, UK
Guy Brusselle, MD, PhD Ghent University Hospital Ghent, Belgium
Roland Buhl, MD PhD Mainz University Hospital Mainz, Germany
Liesbeth Diujts, MD MSc Phd University Medical Center Rotterdam, The Netherlands
J. Mark FitzGerald, MD University of British Columbia Vancouver, BC, Canada
Louise Fleming, MBChB MD Royal Brompton Hospital London, United Kingdom
Hiromasa Inoue, MD Kagoshima University Kagoshima, Japan
Fanny Wai-san Ko, MD
The Chinese University of Hong Kong
Hong Kong
Jerry A. Krishnan, MD PhD
University of Illinois Hospital & Health Sciences System Chicago, IL, USA
Kevin Mortimer, BA/MA, MB/BChir, PhD Liverpool School of Tropical Medicine Liverpool, UK
Paulo Pitrez, MD, PhD Hospital Moinhos de Vento Porto Alegre, Brazil
Aziz Sheikh, BSc, MBBS, MSc, MD The University of EdinbuKjSfo Edinburgh, United Kingdom
GINA BOARD OF DIRECTORS
Louis-Philippe Boulet, MD, Chair Universitě Laval Quebec, QC, Canada
Eq0). Bateman, MD
University of Cape Town Lung Institute
Cape Town, South Africa
Guy Brusselle, MD, PhD Ghent University Hospital Ghent, Belgium
Alvaro A. Cruz, MD Federal University of Bahia Salvador, BA, Brazil
J. Mark FitzGerald, MD University of British Columbia Vancouver, BC, Canada
Hiromasa Inoue, MD Kagoshima University Kagoshima, Japan
Jerry A. Krishnan, MD PhD
University of Illinois Hospital & Health Sciences System Chicago, IL, USA
Mark L. Levy, MD Locum GP London, UK
8
Members of GINA Board (continued)
Jiangtao Lin, MD China-Japan Friendship Hospital Peking University Beijing, China
Helen K. Reddel, MBBS PhD
Woolcock Institute of Medical Research, University of
Sydney
Sydney, Australia
Arzu Yorgancioglu, MD Celal Bayar University Department of Pulmonology Manisa, Turkey
GINA DISSEMINATION AND IMPLEMENTATION COMMITTEE
Arzu Yorgancioglu, MD (Chair) Celal Bayar University Department of Pulmonology Manisa, Turkey
Mark L. Levy, MD Locum GP London, UK
GINA PROGRAM
Rebecca Decker, BS, MSJ Kristi Rurey, AS
EDITORIAL ASSISTANCE
Ruth Hadfield, BSc, DPhil, GCBiostat Jenni Harman, BVSc, BA
GRAPHICS ASSISTANCE
Kate Chisnall
INFORMATION DESIGN
Tomoko Ichikawa, MS Hugh Musick, MBA
Institute for Healthcare Delivery Design University of Illinois, Chicago, USA
-O
Alvaro A. Cruz, MD Federal University of Bahia Salvador, BA, Brazil
Louis-Philippe Boulet, MD Universitě Laval Quebec, QC, Canada
Guy Brusselle, MD, PhD Ghent University Hospital Ghent, Belgium
Hiromasa Inoue, MD Kagoshima University Kagoshima, Japan
Jerry A. Krishnan, MD PhD
University of Illinois Hospital & Health Sciences System Chicago, IL, USA
Disclosures for members of GINA Board of Directors and Science Committee can be found at www.ginasthma.org
9
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
GINA processes for the review of evidence and development of recommendations for GINA reports, including handling of conflict of interest, were reviewed by the Science Committee and approved by the Board in September 2018, and are described below.
Literature search
For each meeting of the GINA Science Committee, a rolling PubMed search is performed covering approximately 18 months, using filters established by the Committee: 1) asthma, all fields, all ages, only items with abstracts, clinical trial, human; and 2) asthma and meta-analysis, all fields, all ages, only items with abstracts, human. The 'clinical trial' publication type includes not only conventional randomized controlled trials, but also pragmatic, real-life and observational studies. The respiratory community is also invited to submit to the Program Director any other peer-reviewed publications that they believe should be considered, providing an abstract and the full paper are submitted in (or translated into) English; however, because of the comprehensive process for literature review, such ad hoc submissions have rarely resulted in substantial chano&ino the report.
Screening and review
After initial screening of articles identified by^accumulative search of the literature by the Editorial Assistant and Chair of the Science Committee, each publication identified by the above search is reviewed for relevance and quality by members of the Science Committee. Eiiph publication is allocated to at least two Committee member reviewers, neither of whom may be an author (or co-author) or declare a conflict of interest in relation to the publication. All members receive a copy of all of the abstral^fs and non-conflicted members have the opportunity to provide comments during the pre-meeting review period. Members evaluate the abstract and, by their judgment, the full publication, and answer written questions about wh&tter the scientific data impact on GINA recommendations, and if so, what specific changes 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.
10
Methodology
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. The Science Committee includes systematic reviews conducted with GRADE methodology as part of its normal review process, once such reviews are published.
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.
Table A. Description of levels of evidence used in this report
Evidence Sources level          of evidence		Definition
A	Randomized controlled trials (RCTs), systematic reviews, observational evidence. Rich body of data.	Evidence is from endpojtft^ of well designed RCTs, systematic reviews of relevant studies or observational studies that provide a consistent pattern of findings in the population for which the recommendation is made. Category A requires substantial numbers of studies involving substantial numbers of participants.
B	Randomized controlled trials and systematic reviews. Limited body of data.	Evidence is from endpoints of intervention studies that include only a limited number of patients, post hoc or subgroup analysis of RCTs or systematic reviews of such RCTs. In general, Category B pertains when few randomized trials exist, they are small in size, they were undertaken in a population that differs from the target population of the recommendation, or the results are somewhat inconsistent.
C	Nonrandomized trials or observational studies.	Evidence is from non-randomized trials or observational studies.
D	Panel consensus judgment.	This category is used only in cases where the provision of some guidance was 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.
Methodology
11
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. Regulatory approvals of maintenance and reliever therapy (MART) also vary between countries.
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 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 report does not refer to recommendations being 'off-label'. However, readers are advised that when assessing and treating patients, they should use their own professional judgment and should also take into account local and national guidelines and eligibility criteria, as well as licensed drug doses.
LITERATURE REVIEWED FOR GINA 2021 UPDATE
The GINA report has been updated in 2021 following the routine twice-yearly review of the literature by the GINA Science Committee. The literature searches for 'clinical trial' publication types (see above) and meta-analyses identified a total of 2,986 publications, of which 2,219 were screened out for duplicates, relevance and/or quality. The remaining 767 publications (616 'clinical trials' and 151 'meta-analyses') were reviewed by at least two members of the Science Committee; a total of 84 were subsequently discussed at meetings of the Science Committee, which were held virtually rather than face to face because ofct£& COVID-19 pandemic. A list of key changes in GINA 2021 can be found starting on p.14, and a tracked changes copy of the report is archived on the GINA website at www.ginasthma.org/archived-reports/.
FUTURE CHALLENGES
In spite of laudable efforts to improve asthma care over the past 20 years, many patients globally have not benefited from advances in asthma treatment and often lack even the rudiments of care. Many of the world's population live in areas with inadequate medical facilities and meager financial resources. The GINA Board of Directors recognizes that 'fixed' international guidelines and 'rigid' scientific protocols will not work in many locations. Thus, the recommendations found in this report must be adapted to fit local practices and the availability of health care resources.
At the most fundamental level, patients in many areas may not have access even to low dose inhaled corticosteroids, which are the cornerstone of care for asthma patients of all severity. More broadly, medications remain the major contributor to the overall costs of asthma management, so the access to and pricing of high quality asthma medications 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
12
Methodology
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 2021?
The GINA report has been updated in 2021 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: This advice (p.17) has been updated with evidence about the risk of COVID-19 infection, and severe COVID-19 disease, and with interim advice about COVID-19 vaccination in people with asthma. The reduction in asthma exacerbations seen during 2020 in many countries may be due to the handwashing, masks and physical distancing introduced because of COVID-19, that also reduced the incidence of other respiratory viral infections.
• Mild asthma: GINA does not distinguish between so-called 'intermittent' and 'mild persistent asthma' (p.40), because this historical distinction was arbitrary and based on an untested assumption that patients with symptoms twice a week or less would not benefit from inhaled corticosteroids (ICS). However, such patients are still at risk of severe exacerbations and this risk is reduced by ICS-containing treatment.
• Severe asthma definition: This has been clarified, and is now worded without referejfe to GINA Steps, since the treatments recommended at each step have changed overtime. Severe asthma is asthma that is uncontrolled despite high dose ICS-long-acting beta2 agonist (LABA), or that requires high dose ICS^^BAto remain controlled (p.40, p.101).
• Description of populations in clinical trials and observational studies: GINA recommends that such populations should be described by the treatment they are prescribed rather than by a specific treatment 'Step', and that severity should not be imputed from current treatment (p.40).
• Treatment tracks for adults and adolescents: For clarity in clinical practice during ongoing treatment, the main treatment figure (Box 3-5A, p.59) now shows two 'tracks', based on the choice of reliever.
o Track 1, with low dose ICS-formoterol as the reliever, is the preferred approach recommended by GINA,
because of the evidence for reduction in risk of severe exacerbations compared with using a short-acting beta2 agonist (SABA) reliever, with similar symptom control and similar lung function.
o Track 2, with SABA as the reliever, is an alternative approach if Track 1 is not possible, or is not preferred by a patient with no exacerbations on their c^ent therapy. Before considering a regimen with SABA reliever, the clinician should consider whether trus^Jatient is likely to be adherent with their controller therapy, as if not, they will be exposed to the risks of SABA-<mly treatment.
o Treatment may be stepped up or down within a track using the same reliever at each step, or switched between tracks, according to the pai^wf's needs, so the two tracks are always shown together rather than separately.
o The text about treatment steps 1 to 5 has been re-organized so that options for the two treatment tracks at each step can be distinguished more easily. Additional information has been provided about the rationale for recommendations in Step 1 (p.62), Step 2 (p.64), Step 3 (p.67), Step 4 (p.68) and Step 5 (p.69). Practice points have been added, including information about dosing and mouth rinsing.
• Treatment steps for children 6-11 years: In the treatment figure (Box 3-5B, p.60), Step 1 options have been updated to be consistent with the (unchanged) recommendations in the text (p.64). Likewise, the treatment figure now also includes maintenance and reliever therapy (MART) with low dose budesonide-formoterol, which has been recommended by GINA for this age-group since 2007 based on a study showing a large reduction in severe exacerbations with MART compared with the same dose ICS-LABA or higher dose ICS (p.67).
• Long-acting muscarinic antagonists (LAMAs). Previous recommendations for adding tiotropium to ICS-LABA have been expanded to include ICS-LABA-LAMA combinations ('triple therapy') for patients aged >18 years in Step 5, i.e. with LAMA added to medium or high dose ICS-LABA. The evidence showed that adding LAMA to medium or high dose ICS-LABA provided a modest improvement in lung function (although not in symptoms), and in some studies, there was a small reduction in exacerbations. In Step 4, add-on LAMA is an "other" (i.e. non-preferred) option. For
14
Methodology
patients with exacerbations, it is important to ensure that the patient receives sufficient ICS, i.e. at least medium dose ICS-LABA, before considering adding a LAMA (p.70).
• Add-on azithromycin (adults): Evidence from a new meta-analysis, and concerns about antibiotic resistance, confirm the positioning of add-on azithromycin for patients aged >18 years with severe asthma, i.e. after referral in Step 5. No specific evidence is available about its efficacy when added to medium dose ICS-LABA. Recommendations about 'macrolides' have been changed to 'azithromycin', as all of the evidence in asthma is with azithromycin.
• Blood eosinophils for eligibility for biologic treatment. The recommendation to repeat blood eosinophils if low at first assessment in a patient with severe asthma has been confirmed by a study that found that 65% of patients on medium or high dose ICS-LABA shifted their eosinophil category over a 12-month period (p.111). For eligibility for biologic therapy, clinicians are advised to check the blood eosinophil criterion specified by their local payer. In the severe asthma decision tree, to avoid ambiguity, a second example of the eosinophil criterion used by different payers has been included ("e.g. >150 or>300/ul", p.106).
• Children 5 years and younger. The dose of ipratropium bromide for use in acute asthma exacerbations has been corrected (Box 6-8 p.164 and Box 6-11 p.167).
• Primary prevention of asthma in children: A suggestion has been added to B^v-1 (p. 173) for identification and correction of Vitamin D insufficiency in women with asthma who are pregnant or are planning pregnancy.
• Other changes include the following:
o Evidence Levels (Table A, p.VV): references to 'meta-analyses' have been replaced with 'systematic reviews'. The positioning of observational studies has been clarified, to indiesus that Level A evidence may include well-designed RCTs, systematic reviews and/or observational studies, where there is a rich body of evidence. Evidence from non-randomized trials or observational studies alone is ri^ssified as Level C.
o Advice about withholding bronchodilators before lung function testing has been updated in line with new spirometry guidelines and to allow for ultra-long-acting beta2-agonists (p.23).
o Additional evidence about the risks of over-us&pf short-acting beta2-agonists has been provided, including increased risk of asthma-related death (p.63, p.109).
o Asthma Control Questionnaire (ACQ): the interpretation of versions and cut-<points has been clarified (p.34)
o Box 3-6 (p.61), which includes examples of low, medium and high ICS doses, has been updated to reflect new evidence about mometasone do6es, and to re-emphasize that this is NOT a table of equivalence.
o Additional evidence has been included about the effects of regular physical activity (p.79) and breathing exercises (p.82). Links to online training in breathing exercises that have been used in past studies have been included
o Adverse effects of dupilumab: rare cases of eosinophilic granulomatosis with polyangiitis (EGPA) added (p.114
o
o
o
Methodology
15
Topics to be addressed in future GINA reports:
• GINA plans to review the definition of mild asthma.
• GINA is seeking evidence relevant to the assessment of symptom control in patients whose reliever is ICS-formoterol.
• During 2021, GINA plans to review evidence about subcutaneous allergen immunotherapy (SCIT) and sublingual immunotherapy (SLIT) for patients with asthma. Recommendations will be updated next year as needed.
• Chapter 6, about diagnosis, assessment and management of asthma in children 5 years and younger will be reviewed in detail.
• A pocket guide on management of severe asthma in children 6-11 years will be developed.
• Advice about COVID-19 will be updated on the GINA website in a timely manner as relevant new information becomes available.
Updates to GINA 2021 report dated 17 May, 2021
• Some minor corrections to text and references about add-on LAMA have been made on p.68 and p.69, for accuracy
• Add-on HDM SLIT has been included in the 'other controller options' in Step 4 of the main treatment figure for adults and adolescents (Box 3-5A, p.59) for consistency with the text.
16
Methodology
Advice on asthma management during the COVID-19 pandemic
COVID-19 and asthma
People with asthma do not appear to be at increased risk of acquiring COVID-19, and systematic reviews have not shown an increased risk of severe COVID-19 in people with asthma. Overall, people with asthma are not at increased risk of COVID-19-related death.5,6 However, the risk of COVID-19 death was increased for people who had recently needed oral corticosteroids for their asthma.5 Therefore, it is important to continue good asthma management (as described in the GINA report), with strategies to maintain good symptom control, reduce the risk of severe exacerbations and minimize the need for oral corticosteroids. In one study of hospitalized patients aged >50 years with COVID-19, mortality was lower among those with asthma who were using inhaled corticosteroid (ICS) than in patients without an underlying respiratory condition.7
In 2020, many countries saw a reduction in asthma exacerbations and influenza-related illness. The reasons are not precisely known, but may be due to handwashing, masks and social/physical digfaincing that reduced the incidence of other respiratory infections, including influenza.
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 pandemic. This includes ICS-containing medications (alone o^w 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.49) for information about asthma medications and regimens and non-pharmacologic strategies, and Chapter 3C (p.86) for guided asthma self-management education and skills training.
For a small proportion of patients with severe asthma, long-term OCS may sometimes be needed, and it is very dangerous to stop these suddenly. See Chapter 3E (p.101) for advice about investigation and management of difficult-to-treat and severe asthma, including addffcjpn of biologic therapy for minimizing use of OCS.
Advise patients to discuss with you bewps stopping any asthma medication.
Make sure that all patients have a written asthma action plan
An action plan tells the patient how to recognize worsening asthma, how to increase their reliever and controller medications, and when to seek medical help. A short course of OCS may be needed during severe asthma flare-ups (exacerbations). See Box 4-2 (p.123) for more information about specific action plan options for increasing controller and reliever medications, depending on the patient's usual therapeutic regimen.
At present, there is no clear evidence about how to distinguish between worsening asthma due to respiratory viral infections such as rhinovirus and influenza, and COVID-19.
Where possible, avoid use of nebulizers due to the risk of transmitting infection to other patients and to healthcare workers
Nebulizers can transmit respiratory viral particles for at least 1 meter. Use of nebulizers is mainly restricted to management of life-threatening asthma in acute care settings. Instead, to deliver short-acting beta2-agonist for acute asthma in adults and children, use a pressurized metered-dose inhaler and spacer, with a mouthpiece or tightly fitting face mask, if required. Check the manufacturer's instructions about whether a spacer can be autoclaved. If not (as is the case for many types of spacers), or if in doubt, spacers should be restricted to single patient use. If use of a nebulizer is needed, strict infection control procedures should be followed.
Interim advice about COVID-19 and asthma
17
Remind patients not to share inhaler devices or spacers with family members, to avoid transmitting infection.
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 strict infection control precautions. The U.S. Centers for Disease Control and Prevention (CDC) recommendations are found here.
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. CDC recommendations are found here.
Follow local health advice about hygiene strategies and use of personal protective equipment, as new information becomes available in your country or region.
The CDC website provides up-to-date information about COVID-19 for health professionals here, and for patients here.
The website of the World Health Organization (WHO) provides comprehensive adviCKror health professionals and health systems about prevention and management of COVID-19 here.
Asthma and COVID-19 vaccines
Many types of COVID-19 vaccines have been studied and are in use. H&i evidence about the vaccines, including in people with asthma, will emerge overtime.
In general, allergic reactions to the vaccines are rare. The current advice is that the Pfizer/BioNTech and Moderna COVID-19 vaccines should be administered in a healthcare setting where anaphylaxis can be treated if it occurs, and that they should not be administered to patients with a history of severe allergic reaction to polyethylene glycol, or any other vaccine ingredient. However, there appears to be no increased risk of anaphylaxis to these COVID-19 vaccines for patients with anaphylaxis to foods, insect venom, or other medications. More details from the U.S. Advisory Committee on Immunization Practices are here. As always, patients should speak to their healthcare provider if they have concerns.
Usual vaccine precautions apply. For example, ask if the patient has a history of allergy to any components of the vaccine, and if the patient has a fever or another infection, delay vaccination until they are well.
At present, based on the benefits and risks, and with the above caution, GINA recommends COVID-19 vaccination for people with asthma.
Current advice from the CDC is that people who have been fully vaccinated against COVID-19 should continue to wear a mask and avoid close contact with others when in public places. Further details are here.
Remind people with asthma to have an annual influenza vaccination (p.76). A gap of 14 days between COVID-19 vaccination and any other vaccination including influenza is recommended by CDC (advice here), because of a lack of data on safety and effectiveness of COVID-19 vaccine administered at the same time as other vaccines.
For people with severe asthma receiving biologic therapy, GINA suggests that biologic therapy and COVID-19 vaccine should not be given on the same day, to allow adverse effects of either to be more easily distinguished.
Global Initiative for Asthma, April 26, 2021
Additional advice about management of asthma in the context of COVID-19 will be posted on the GINA website (www.ginasthma.org) as it becomes available.
18
Interim advice about COVID-19 and asthma
SECTION 1. ADULTS, ADOLESCENTS AND CHILDREN 6 YEARS AND OLDER
Chapter 1.
Definition, description, and diagnosis of asthma
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 expiratory airflow limitation. This should be documented from bronchodilator reversibility testing or other tests.
• Test before treating, wherever possible, i.e. document the evidence for the diagnos^br asthma before starting controller treatment, as it is often more difficult to confirm the diagnosis afterwards.
• Additional strategies may be needed to confirm the diagnosis of asthma in particular populations, including patients already on controller treatment, the elderly, and those in low-resource settings.
DEFINITION OF 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.
This definition was reached by consensus, based on consideration of the characteristics that are typical of asthma before controller treatment is commenced, and that distinguish it from other respiratory conditions. However, airflow limitation may become persistent later in the S$tbrse of the disease.
DESCRIPTION OF ASTHMA
Asthma is a common, chronic respiratory disease affecting 1-18% of the population in different countries (Appendix Chapter 1). Asthma is characterized by variable symptoms of wheeze, shortness of breath, chest tightness and/or cough, and by variable expiratory airflow limitation. Both symptoms and airflow limitation characteristically vary overtime and in intensity. These variations are often triggered by factors such as exercise, allergen or irritant exposure, change in 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'.810 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.810 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.
• Asthma with persistent airflow limitation: some patients with long-standing asthmaMttvelop airflow limitation that is persistent or incompletely reversible. This is thought to be due to airway wall pe^redeling.
• Asthma with obesity: some obese patients with asthma have prominent respiratory symptoms and little eosinophilic airway inflammation.
There are limited data about the natural history of asthma after diagnosfeVbut one longitudinal study showed that approximately 16% of adults with recently diagnosed asthma may experience clinical remission (no symptoms or asthma medication for at least 1 year) within 5 years.11
Additional information can be found in Appendix Chapter 2 alaQt factors predisposing to the development of asthma, and in Appendix Chapter 3 about pathophysiological and cellular mechanisms of asthma.
MAKING THE INITIAL DIAGNOSIS
Making the diagnosis of asthma, as shown in Bex"1-1 (P-22) is based on identifying both a characteristic pattern of respiratory symptoms such as wheezing, shortness of breath (dyspnea), chest tightness or cough, and variable expiratory airflow limitation.12 The pattern ^symptoms is important, as respiratory symptoms may be due to acute or chronic conditions other than asthma. If possible, the evidence supporting a diagnosis of asthma (Box 1-2, p.23) should be documented when the patient firs£presents, as the features that are characteristic of asthma may improve spontaneously or with treatment; as a result, it is often more difficult to confirm a diagnosis of asthma once the patient has been started on controller treatment.
Patterns of respiratory symptoms that are characteristic of asthma
The following features are typical of asthma and, if present, increase the probability that the patient has asthma:12
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 overtime 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
Patient with respiratory symptoms (Box 1-2)
Are the symptoms typical of asthma ?
I
YES
Detailed history/examination for asthma
/7/sfory/examination supports asthma diagnosis?
HO
Clinical urgency, and other diagnoses unlikely
YES
Further history and tests for alternative diagnoses (Box 1-3)
Alternative diagnosis confirmed?
Perform spirometry/PEF with reversibility test (Box 1-2)
Results support asthma diagnosis?
m
Empiric initial treatment {See Boxes 3-4, A-D)
Review response
Diagnostic testing within 1-3 months (Box 1-4)
NO ■ i YES
YES
Repeat on another occasion or arrange other tests (Box 1 -2)
Confirms asthma diagnosis ■•••N   MF I lllllllll
NO
NO-
YES
Consider trial of treatment for most likely diagnosis, or refer
for further investigations
Treat for ASTHMA
(Boxes 3-4,A-D)
Treat for alternative diagnosis
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; pm: as-needed; SABA: short-acting beta2-agonist.
Bronchodilator reversibility may be lost during severe exacerbations or viral infections, and in long-standing asthma, and it usually decreases with inhaled corticosteroid treatment. 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.
22
1. Definition, description and diagnosis of asthma
Box 1 -2.  Diagnostic criteria for asthma in adults, adolescents, and children 6-11 years
1. HISTORY OF VARIABLE RESPIRATORY SYMPTOMS	
Feature	Features that support the diagnosis
Wheeze, shortness of breath, chest tightness and cough (Descriptors may vary between cultures and by age)	• Generally more than one type of respiratory symptom (in adults, isolated cough is seldom due to asthma) • Symptoms occur variably over time and vary in intensity • Symptoms are often worse at night or on waking • Symptoms are often triggered by exercise, laughter, allergens, cold air • Symptoms often appear or worsen with viral infections
2. CONFIRMED VARIABLE EXPIRATORY AIRFLOW LIMITATION	
Feature	Considerations, definitions, criteria
2.1 Documented expiratory airflow limitation	At a time when FEVi is reduced, confirm that FEVi/FVC is reduced (it is usually >0.75-0.80 in adults, >0.90 in children13)
AND	
2.2 Documented excessive variability in lung function* (one or more of the following):	The greater the variations, or the more occasions excess variation is seen, the more confident the diagnosis. If initially negative, tests can be repeated during symptoms or in the early morning.
• Positive bronchodilator (BD) reversibility test	Adults: increase in FEVi of£c12% and >200 mL (greater confidence if increase is >15% and >400 mL). Cl^ilren: increase in FEVi of >12% predicted Change measured lcGl5 minutes after 200-400 meg salbutamol (albuterol) or equivalent, compacea with pre-BD readings. Positive test more likely if BD withheld before test: SABV>4 hours, twice-daily LABA 24 hours, once-daily LABA 36 hours
• Excessive variability in twice-daily PEF over 2 weeks	Adults: average daily diurnal PEF variability >10%* Children: average daily diurnal PEF variability >13%*
• Significant increase in lung function after 4 weeks of anti-inflammatory treatment	Adults: increase in FEVi by >12% and >200 mL (or PEF* by >20%) from baseline after 4 weeks of treatment, outside respiratory infections
• Positive exercise challenge test	Adults: fall in FEVi of >10% and >200 mL from baseline Children: fall in FEVi of >12% predicted, or PEF >15%
• Positive bronchial challenge test (usually only for adults)	Fall in FEVi from baseline of >20% with standard doses of methacholine, or>15% with standardized hyperventilation, hypertonic saline or mannitol challenge
• Excessive variation in lung function between visits (good specificity but poor sensitivity)	Adults: variation in FEVi of >12% and >200 mL between visits, outside of respiratory infections Children: variation in FEVi of >12% in FEVi or>15% in PEFt between visits (may include respiratory infections)
BD: bronchodilator (SABA or rapid-acting LABA); FEVi: 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. 'Daily diurnal PEF variability is calculated from twice daily PEF as (day's highest minus day's lowest) divided by (mean of day's highest and lowest), averaged over one week. fFor 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," and airflow limitation may become persistent overtime. 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.
1. Definition, description and diagnosis of asthma
23
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.15
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
Physical examination in people with asthma is often normal. The most frequent abnormality is expiratory wheezing (rhonchi) on auscultation, but this may be absent or only heard on forced expiration. Wheezing may also be absent during severe asthma exacerbations, due to severely reduced airflow (so called 'silent chest'), but at such times, other physical signs of respiratory failure are usually present. Wheezing may also be heard with inducible laryngeal obstruction, chronic obstructive pulmonary disease (COPD), respiratory infections, tracheomalacia, or inhaled foreign body. Crackles (crepitations) and inspiratory wheezing are not features of asthma. Examination of the nose may reveal signs of allergic rhinitis or nasal polyposis.
Lung function testing to document variable expiratory airflow limitation
Asthma is characterized by variable expiratory airflow limitatj/bn, i.e. expiratory lung function varies overtime and in magnitude, to a greater extent than in healthy populations. In asthma, lung function may vary between completely normal and severely obstructed in the same patient. Poorly controlled asthma is associated with greater variability in lung function than well-controlled asthma.14
Lung function testing should be carried out by well-trained operators with well-maintained and regularly calibrated equipment.16 Forced expiratory volume in 1 second (FEVi) from spirometry is more reliable than peak expiratory flow (PEF). If PEF is used, the same meter should be used each time, as measurements may differ from meter to meter by up to 20%.17
A reduced FEVi may be found with many other lung diseases (or poor spirometric technique), but a reduced ratio of FEVi to forced vital capacity (FEVi/FVC), compared with the lower limit of normal, indicates expiratory airflow limitation. Many spirometers now inclutre multi-ethnic age-specific predicted values.13
In clinical practice, once an obstructive defect has been confirmed, variation in airflow limitation is generally assessed from variation in FEVi 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')16 generally refers to rapid improvements in FEVi (or PEF), measured within minutes after inhalation of a rapid-acting bronchodilator such as 200-400 meg salbutamol,18 or more sustained improvement over days or weeks after the introduction of effective controller treatment such as ICS.18
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
24
1. Definition, description and diagnosis of asthma
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.19 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 FEVi 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 weeks. The upper 95% confidence limit of diurnal variability (amplitude percent mean) from twice daily readings is 9% in healthy adults,20 and 12.3% in healthy children,21 so in general, diurnal variability >1^Tor adults and >13% for children is regarded as excessive.
If FEVi is within the predicted normal range when the patient is experiencing symptoms, this reduces the probability that the symptoms are due to asthma. However, patients whose baseline FEVi is >80% predicted can have a clinically important increase in lung function with bronchodilator or controller treatment. Predicted normal ranges (especially for PEF) have limitations, so the patient's own best reading ('personal best') is recommended as their 'normal' value.
When can variable expiratory airflow limitation be documented?
If possible, evidence of variable expiratory airflow limitation Stteuld be documented before treatment is started. This is because variability usually decreases with treatment as lung function improves. In addition, any increase in lung function after initiating controller treatment can help to confirm the diagnosis of asthma. Bronchodilator reversibility may not be present between symptoms, during viral infectionsjjnf the patient has used a beta2-agonist within the previous few hours; and in some patients, airflow limitation rtfaybecome persistent or irreversible overtime.
If spirometry is not available, or variable expiratory airflow limitation is not documented, a decision about whether to investigate further or start controller treatment immediately depends on clinical urgency and access to other tests. Box 1-3 (P-27) describes how to confirm the diagnosis of asthma in a patient already taking controller treatment.
Other tests
Bronchial provocation tests
One option for documenting variable expiratory airflow limitation is to refer the patient for bronchial provocation testing to assess airway hyperresponsiveness. Challenge agents include inhaled methacholine,22 histamine, exercise,23 eucapnic voluntary hyperventilation or inhaled mannitol. These tests are moderately sensitive for a diagnosis of asthma but have limited specificity.22,23 For example, airway hyperresponsiveness to inhaled methacholine has been described in patients with allergic rhinitis,24 cystic fibrosis,25 bronchopulmonary dysplasia26 and COPD.27 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 considered.
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 (slgE) 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 slgE 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
1. Definition, description and diagnosis of asthma
25
anaphylaxis.28 The presence of a positive skin test or positive slgE, 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.29 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 inflammation30 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 bronchoconstriction31 and the early phases of allergic response;32 it may be increased or decreased during viral respiratory infections.31 See Chapter 3B, p.51 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 should be sought. Many patients (25-35%) with a diagnosis of asthma in primary care cajOjot be confirmed as having
asthma.15,3336
The process for confirming the diagnosis in patients already on controller treatment depends on the patient's symptoms 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 treatment. If the diagnosis of asthma cannot be confirmed, refer the patient 1<Q)expert investigation and diagnosis. For 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.
Box 1-3. Steps for confirming the diagnosis of asthma in a patient already taking controller treatment
Current status	Steps to confirm the diagnosis of asthma
Variable respiratory symptoms and variable airflow limitation	Diagnosis of asthma is confirmed. Assess the level of asthma control (Box 2-2, p.36) and review controller treatment (Box 3-^p!"59).
Variable respiratory symptoms but no variable airflow limitation	Repeat spirometry after withholding BD (4 hrs for SABA, 24 hrs for twice-daily ICS+LABA, 36hrs for once-daily ICS+LABA) or during symptoms. Check between-visit variability of baseline FEVi, and bronchodij^tor reversibility. If still normal, consider alternative diagnoses (Box 1-5, p.27). IfFEVi isa$$o predicted: consider a bronchial provocation test. If negative, consider stepping down ceJyroller treatment (see Box 1-5) and reassess in 2-4 weeks. IfFd&i is <70% predicted: consider stepping up controller treatment for 3 months (Box 3-5), then reassess symptoms and lung function. If no response, resume previous treatment and refer patient for diagnosis and investigation.
Few respiratory symptoms, normal lung function, and no variable airflow limitation	Repeat BD reversibility test again after withholding BD as above or during symptoms. If normal, consider alternative diagnoses (Box 1-5, p.27). Consider stepping down controller treatment (see Box 1-5): • If symptoms emerge and lung function falls: asthma is confirmed. Step up controller treatment 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 breath and persistent airflow limitation	Consider stepping up controller treatment for 3 months (Box 3-5, p.59), then reassess symptoms and lung function. If no response, resume previous treatment and refer patient for diagnosis and investigation. Consider asthma-COPD overlap (Chapter 5, p.135).
BD: bronchodilator; LABA: long-acting beta2-agonist; SABA: short-acting beta2-agonist. 'Variable airflow limitation' refers to expiratory airflow.
26 1. Definition, description and diagnosis of asthma
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.36) 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.123) 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.a. LABA, leukotriene receptor antagonist) if being used (Box 3-7, p.73). Schedule a review visit for 2-4 weeks.
3. REVIEW RESPONSE__
• Repeat assessment of asthma control and lung function tests in 2-4 weeks (Box 1-2, p.23).
• If symptoms increase and variable expiratory airflow limitation is confirmed after stepping down treatment, the diagnosis of asthma is confirmed. The controller dose should be returned to the lowest previous effective dose.
• If, after stepping down to a low dose controller treatment, symptoms do not worsen and there is still no evidence of variable expiratory airflow limitation, consider ceasing controller treatment and repeating asthma control assessment and lung function tests in 2-3 weeks, but follow the patient for at least 12 months
DIFFERENTIAL DIAGNOSIS
The differential diagnosis in a patient with sutepected asthma varies with age (Box 1-5). Any of these alternative diagnoses may also be found together with asthma.
Box 1-5. Differential diagnosis of asthma in adults, adolescents and children 6-11 years
Age	Symptoms	Condition
6-11	Sneezing, itchwQblocked nose, throat-clearing	Chronic upper airway cough syndrome
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 symptoms	Cystic fibrosis
continuec	next page)	
1. Definition, description and diagnosis of asthma
27
Box 1-5 (continued). Differential diagnosis of asthma in adults, adolescents and children 6-11 years
Age	Symptoms	Condition
12-39 years	Sneezing, itching, blocked nose, throat-clearing Dyspnea, inspiratory wheezing (stridor) Dizziness, paresthesia, sighing Productive cough, recurrent infections Excessive cough and mucus production Cardiac murmurs Shortness of breath, family history of early emphysema Sudden onset of symptoms	Chronic upper airway cough syndrome Inducible laryngeal obstruction Hyperventilation, dysfunctional breathing Bronchiectasis Cystic fibrosis Congenital heart disease Alphai-antitrypsin deficiency Inhaled foreign body
40+ years	Dyspnea, inspiratory wheezing (stridor) Dizziness, paresthesia, sighing Cough, sputum, dyspnea on exertion, smoking or noxious exposure Productive cough, recurrent infections Dyspnea with exertion, nocturnal symptoms, ankle edema Treatment with angiotensin converting enzyme (ACE) inhibitor Dyspnea with exertion, non-productive cough, finger clubbing Sudden onset of dyspnea, chest pain Dyspnea, unresponsive to bronchodilators	Inducible laryngeal obstruction Hyperventilation, dysfunctional breathing COPD* Bronchiectasis Cardiac failure Medication-related cough Parenchymal lung disease Pulmonary embolism Central airway obstruction
All ages	Chronic cough, hemoptysis, dyspnea; and/or fatigue, fever, (night) sweats, anorexia, weight loss	Tuberculosis
*For more detail, see Chapter 5 (p.135). Any of the above conditions may also contribute to respiratory symptoms in patients with confirmed asthma.
AT
HOW TO MAKE THE DIAGNOSIS OF ASTHMA IN OTHER CONTEXTS
Patients presenting with persistent non-productive cough as the only respiratory symptom
Diagnoses to be considered are chronic upper airway cough syndrome (often called 'postnasal drip'), cough induced by angiotensin converting enzyme (ACE) inhibitors, gastroesophageal reflux, chronic sinusitis, and inducible laryngeal obstruction.37,38 Patients with so-called 'cough-variant asthma' have persistent cough as their principal or only symptom, associated with airway hypsctesponsiveness. It is often more problematic at night. Lung function may be normal, and for these patients, documentation of variability in lung function (Box 1-2, p.23) is important.39 Cough-variant asthma must be distinguished from eosinophilic bronchitis in which patients have cough and sputum eosinophilia but normal spirometry and airway responsiveness.39
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.40,41
An estimated 5-20% of new cases of adult-onset asthma can be attributed to occupational exposure.40 Adult-onset asthma requires a systematic inquiry about work history and exposures, including hobbies. Asking patients whether their symptoms improve when they are away from work (weekends or vacation) is an essential screening question.42 It is important to confirm the diagnosis of occupational asthma objectively as it may lead to the patient changing their
28
1. Definition, description and diagnosis of asthma
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.98) and in specific guidelines.40
Athletes
The diagnosis of asthma in athletes should be confirmed by lung function tests, usually with bronchial provocation testing.43 Conditions that may either mimic or be associated with asthma, such as rhinitis, laryngeal disorders (e.g. inducible laryngeal obstruction38), dysfunctional breathing, cardiac conditions and over-training, must be excluded.44
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.97).45 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.^
The elderly
Asthma is frequently undiagnosed in the elderly,46 due to poor perception of airflow limitation; acceptance of dyspnea as being 'normal' in old age; lack of fitness; and reduced physical activity. Th^resence of comorbid diseases also complicates the diagnosis. In a large population based survey of asthma patients older than 65 years, factors associated with a history of asthma hospitalization included co-diagnosis of COE®, coronary artery disease, depression, diabetes mellitus, and difficulty accessing medications or clinical care became of cost.47 Symptoms of wheezing, breathlessness and cough that are worse on exercise or at night can also be caused by cardiovascular disease or left ventricular failure, which are common in this age group. A careful history and physical examination, combined with an electrocardiogram and chest X-ray, will assist in the diagnosis.48 Measurement of plasma brain natriuretic polypeptide (BNP) and assessment of cardiac function with echocardiography-may also be helpful.49 In older people with a history of smoking or biomass fuel exposure, COPD and overlapping asKfma and COPD (asthma-COPD overlap) should be considered (Chapter 5, p.135).
Smokers and ex-smokers
Asthma and COPD may be difficult to distinguish in clinical practice, particularly in older patients and smokers and ex-smokers, and these conditions may overlap (asthma-COPD overlap). The Global Strategy for Diagnosis, Management and Prevention of COPD (GOLD)50 defines COPD on the basis of chronic respiratory symptoms, exposure to a risk factor such as smoking, andjfrest-bronchodilator FEWFVC <0.7. Clinically important bronchodilator reversibility (>12% and >200 mL) is often found in COPD.51 Low diffusion capacity is more common in COPD than asthma. The history and pattern of symptoms and past records can help to distinguish these patients from those with long-standing asthma who have developed persistent airflow limitation (see Chapter 5, p.135). Uncertainty in the diagnosis should prompt early referral for specialized investigation and treatment recommendations, as patients with asthma-COPD overlap have worse outcomes than those with asthma or COPD alone.52
Obese patients
While asthma is more common in obese than non-obese people,53 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 expiratory 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).33 Another study found both over- and under-diagnosis of asthma in obese patients.54
1. Definition, description and diagnosis of asthma
29
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.12,55
Variable expiratory 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.56
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.57
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.58,59 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 fro<ns5'4% under-diagnosis to 34% over-diagnosis.60 Poverty is commonly associated with restrictive spirometry, so wfere possible, both FEVi and FVC should be recorded.61 These observations demonstrate how important it is to build capacity of primary care physicians for asthma diagnosis and management.
30
1. Definition, description and diagnosis of asthma
SECTION 1. ADULTS, ADOLESCENTS AND CHILDREN 6 YEARS AND OLDER
Assessment of asthma
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 short-acting beta2 agonist (SABA) use, and from activity limitation. Symptom control tools include Asthma Control Test and Asthma Control Questionnaire.
• Assess the patient's future risk for exacerbations, even when symptom control is good. Risk factors for exacerbations that are independent of symptom control include a history of >1 exacerbation in the previous year, socioeconomic problems, poor adherence, incorrect inhaler technique. |Q/ forced expiratory volume in 1 second (FEVi), smoking, and blood eosinophilia.
• 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 .
• Once the diagnosis of asthma has been made, the main role of lung function testing is in the assessment of future risk. It should be recorded at diagnosis, 3-6 months af(§r starting treatment, and periodically thereafter.
• Investigate further if there are few symptoms but imftejred lung function, or frequent symptoms and good lung function.
OVERVIEW
For every patient, assessment of asthma should include the assessment of asthma control (both symptom control and future risk of adverse outcomes), treatmert&ssues particularly inhaler technique and adherence, and any comorbidities that could contribute to symptom burden and poor quality of life (Box 2-1, p.33). Lung function, particularly FEVi as a percentage of predicted, is an impottóm part of the assessment of future risk.
The use of digital technology, telemedicine and telehealthcare in the monitoring of patients with asthma is rapidly increasing, particularly during the COVID-19 pandemic. However, the types of interactions are diverse, and high-quality studies are needed to evaluate their utility and effectiveness. See Appendix section on Telehealthcare.
What is meant by 'asthma control'?
The level of asthma control is the extent to which the manifestations of asthma can be observed in the patient, or have been reduced or removed by treatment.20,62 It is determined by the interaction between the patient's genetic background, underlying disease processes, the treatment that they are taking, environment, and psychosocial factors.62
Asthma control has two domains: symptom control and future risk of adverse outcomes (Box 2-2, p.36). 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.
32
2. Assessment of asthma
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.
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.62,63 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^?? side-effects (Box 2-2B).
• Measure lung function at diagnosis/start of treatment, 3-6 months after starting controller treatment, then periodically, e.g. at least once every 1-2 years, but more often in a^risx patients and those with severe asthma.
2. Assess treatment issues
• Document the patient's current treatment step (Box 3-5, p.59).
• Watch inhaler technique, assess adherence and side-effects.
• Check that the patient has a written asthma action plan.
• Ask about the patient's attitudes and goals for their asthma and medications.
3. Assess comorbidities
• Rhinitis, rhinosinusitis, gastroesophageal reflux, obesity, obstructive sleep apnea, depression and anxiety can contribute to symptoms and poor quality of life, and sometimes to poor asthma control.
ASSESSING ASTHMA SYMPTOM CONTROL
Asthma symptoms such as wA^eze, chest tightness, shortness of breath and cough typically vary in frequency and intensity, and contribute to the burden of asthma for the patient. Poor symptom control is also strongly associated with an increased risk of asthma exacerbations.6466
Asthma symptom control should be assessed at every opportunity, including during routine prescribing or dispensing. Directed questioning is important, as the frequency or severity of symptoms that patients regard as unacceptable or bothersome may vary from current recommendations about the goals of asthma treatment, and differs from patient to patient. For example, despite having low lung function, a person with a sedentary lifestyle may not experience bothersome symptoms and so may appear to have good symptom control.
To assess symptom control (Box2-2A) 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 SABA reliever use for relief of symptoms. In general, do not include reliever taken before exercise, because some people take this routinely without knowing whether they need it. Our current view is that frequency of as-needed inhaled corticosteroid (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. This issue will be reviewed again next year.
2. Assessment of asthma
33
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.67,68 It can be used, together with a risk assessment (Box 2-2B), to guide treatment decisions (Box 3-5, p.59). Other examples are the Primary Care Asthma Control Screening Tool (PACS),69 and the 30-second Asthma Test, which also includes time off work/school.70
Categorical symptom control tools: e.g. the consensus-based 'Royal College of Physicians (RCP) Three Questions' tool,71 which asks about difficulty sleeping, daytime symptoms and activity limitation due to asthma in the previous month. The Asthma APGAR tool 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.72
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 scalable. These scores may be useful for assessing patient progress; they are commonly used in clinical research, buKpay be subject to copyright restrictions. Numerical asthma control tools are more sensitive to change in symptom control than categorical tools.67
Examples of numerical asthma control tools for assessing symptom control are:
• Asthma Control Questionnaire (ACQ):7374 Scores range from 0-6 (higher is worse). The ACQ score is the average of 5, 6 or 7 items: all versions include five symptom questions; ACQ-6 includes SABA reliever use; and ACQ-7, pre-bronchodilator FEW The authors stated that ACQ <0.75 indicated a high probability that asthma was well-controlled; 0.75-1.5 as a 'grey zone'; and >1.5 a high probability that asthma was poorly controlled, based on concepts of asthma control at the time; the authors later added that the crossover point between 'well-controlled' and 'not well-controlled' asthma was close to 1.00.75 The minimum clinically important difference for all three versions of ACQ is 0.5.76 GINA prefers ACQ-5 over ACQ-6 or 7 because ACQ has not been validated with ICS-formoterol as the reliever, and if ACQ is used in adjustment oftf^aftment, inclusion of FEVi in the composite score could lead to repeated step-up in ICS dose for patients with persistent airflow limitation.
• Asthma Control Test (ACT):68 77 78 Scores range from 5-25 (higher is better). Scores of 20-25 are classified as well-controlled; 16-19 as not well-controlled; and 5-15 as very poorly controlled asthma. The ACT has four symptom/ reliever questions plus patient selfjassessed control. The minimum clinically important difference is 3 points.78
When different systems are used for assessing asthma symptom control, the results correlate broadly with each other, but are not identical. Respiratory symptoms may be non-specific so, when assessing changes in symptom control, it is important to clarify that symptoms are due to asthma.
Asthma symptom control tools for children 6-11 years of age
In children, as in adults, assessment of asthma symptom control is based on symptoms, limitation of activities and use of rescue medication. Careful review of the impact of asthma on a child's daily activities, including sports, play and social life, and on school absenteeism, is important. Many children with poorly controlled asthma avoid strenuous exercise so their asthma may appear to be well controlled. This may lead to poor fitness and a higher risk of obesity.
Children vary considerably in the degree of airflow limitation observed before they complain of dyspnea or use their reliever therapy, and marked reduction in lung function is often seen before it is recognized by the parents. Parents may 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.
34
2. Assessment of asthma
Several numeric asthma control scores have been developed for children. These include:
• Childhood Asthma Control Test (c-ACT)79 with separate sections for parent and child to complete
• Asthma Control Questionnaire (ACQ)80,81
Some asthma control scores for children include exacerbations with symptoms. These include:
• Test for Respiratory and Asthma Control in Kids (TRACK)82 84
• Composite Asthma Severity Index (CASI)85
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.
2. Assessment of asthma
35
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
Uncontrolled
In the past 4 weeks, has the patient had:
Well controlled
Partly controlled
YesD Nod YesD Nod YesD Nod YesD Nod J
- None of these
1-2 of these
3-4 of these
• Daytime asthma symptoms more than twice/week?
• Any night waking due to asthma?
• SABA reliever for symptoms more than twice/week?*
• Any activity limitation due to asthma?
B. Risk factors for poor asthma outcomes
Assess risk factors at diagnosis and periodically, particularly for patients experiencing exacerbations.
Measure FEVi 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.
Having uncontrolled asthma symptoms is an important risk factor for exacerbations.86
Additional potentially modifiable risk factors for flare-ups (exacerbations), even in patients with few symptoms1' include:
• Medications: high SABA use (associated with increased risk of exacerbations123,87 and mortality particularly if >1 x200-dose canister per month88,89); inadequate ICS: not prescribed ICS; poor adherence;90 incorrect inhaler technique91/^
• Other medical conditions: obesity;92,93 chronic rhinosinusitis;93 GERD;93 confirmed food allergy;94 pregnancy95
• Exposures: smoking;96 allergen exposure if sensitized;96 air pollution97"
• Context: major psychological or socioeconomic problems100
• Lung function: low FEVi, especially <60%^dieted96,101; high BD reversibility93,102,103
• Othertests in patients with Type 2 inflammation: blood eosinophils;93,104,105 elevated FeNO (in adults with allergic asthma taking ICS)106
Other major independent risk factors for flare-ups (exacerbations)
• Ever intubated or in intensivej^ffe unit for asthma107
• >1 severe exacerbation in last 12 months108,109
Having any of these risk factors increases the patient's risk of exacerbations even if they have few asthma symptoms
Risk factors for developing persistent airflow limitation
• History: preterm birth, low birth weight and greater infant weight gain;110 chronic mucus hypersecretion111,112
• Medications: lack of ICS treatment in patients who had a severe exacerbation113
• Exposures: tobacco smoke;111 noxious chemicals; occupational exposures40
• Investigations: low initial FEVi;112 sputum or blood eosinophilia112
Risk factors for medication side-effects
• Systemic: frequent OCS; long-term, high dose and/or potent ICS; also taking P450 inhibitors114
• Local: high dose or potent ICS;114,115 poor inhaler technique116
BD: bronchodilator; FEV<: 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.37. See Box 3-8, p.74 for specific risk reduction strategies. ^Independent' risk factors are those that are significant after adjustment for the level of symptom control.
36
2. Assessment of asthma
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.
Risk factors for adverse outcomes	
Exacerbations	Ask: How do viral infections affect the child's asthma? Do symptoms interfere with school or sports? How long do the symptoms last? How many episodes rra&|?occurred since their last medical review? Any urgent doctor/emergency department visits? Is there a written action plan? Risk factors for exacerbations include a history of exacerbations, poor symptom control, poor adherence and poverty,109 and persistent bronchodilator reversibility even if the child has few symptoms.103
Lung function	Check curves and technique. Main focus is on FEVi and FEWFVC ratio. Plot these values as percent predicted to see trends over timp^
Side-effects	Check the child's height at least yearly, as poorly controlled asthma can affect growth,117 and growth velocity may be lower in the first 1-2 years of ICS treatment.118 Ask about frequency and dose of ICS and OCS.
Treatment factors	
Inhaler technique	Ask the child to show how they use their inhaler. Compare with a device-specific checklist.
Adherence	Is there any controJtprnedication in the home at present? On how many days does the child use their controllerjQ&week (e.g. 0, 2, 4, 7 days)? Is it easier to remember to use it in the morning or evening? Where is inhaler kept - is it in plain view to reduce forgetting? Check date on inhaler.
Goals/concerns	Does the child or their parent/carer have any concerns about their asthma (e.g. fear of medication, side-e^teas, interference with activity)? What are the child's/parent's/carer's goals for treatment?
Comorbidities	
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 death94)
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 (laboratory)	Provides information about airway hyperresponsiveness and fitness (Box 1-2, p.23). Only undertake a challenge if it is otherwise difficult to assess asthma control.
FEV,: forced expiratory volume in 1 second; FVC: forced vital capacity; ICS: inhaled corticosteroids; OCS: oral corticosteroids.
2. Assessment of asthma
37
ASSESSING FUTURE RISK OF ADVERSE OUTCOMES
The second component of assessing asthma control (Box 2-2B, p.36) 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 treatments119,120 or by inappropriate use of long-acting beta2-agonist (LABA) alone,121 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.38
• 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.
Risk factors for exacerbations
Poor asthma symptom control itself substantially increases the risk of exacerbations.6466 However, several additional independent risk factors have been identified, i.e. factors, that, when present, increase the patient's risk of exacerbations even if symptoms are few. These risk factors (Box2-2B) include a history of >1 exacerbation in the previous year, poor adherence, incorrect inhaler technique, chronic sinusitis and smoking, alLe^which can be assessed in primary care.122 The risk of severe exacerbations and mortality increases incrementally with higher SABA use, independent of treatment step.89 Prescribing of three or more 200-dose SABA inhalers in a yeaVcorresponding to more than daily use, is associated with an increased risk of severe exacerbations89,123 and, in one study, increased mortality.89
In children, the risk of exacerbations is greatly increased if thfite is a history of previous exacerbations; it is also increased with poor symptom control, suboptimal drug regimen, comorbid allergic disease and poverty.109
Risk factors for development of persistent airflow limitation
The average rate of decline in FEVi in non-srnpfcing healthy adults is 15-20 mL/year.124 People with asthma may have an accelerated decline in lung function andxfSwelop airflow limitation that is not fully reversible. This is often associated with more persistent dyspnea. Independent risk factors that have been identified for persistent airflow limitation include exposure to cigarette smoke or noxious agents, chronic mucus hypersecretion, and asthma exacerbations in patients not taking ICS113 (see Box2-2B). Children with persistent asthma may have reduced growth in lung function, and some are at risk of accelerated decline in lung function in early adult life.125
Risk factors for medication side-effects
Choices with any medication are based on the balance of benefit and risk. Most people using asthma medications do not experience any side-effects. The risk of side-effects increases with higher doses of medications, but these are 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,114,115 and, for local side-effects, with incorrect inhaler technique.116
38
2. Assessment of asthma
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 adults126 or children.127 In some asthma control tools, lung function is numerically averaged or added with symptoms,73,128 but if the tool includes several symptom items, these can outweigh clinically important differences in lung function.129 In addition, low FEVi 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 FEVi; 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 Box2-2B). 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,20 but preferably the same conditions should apply at each visit.
How to interpret lung function test results in asthma
A low FEVi percent predicted:
• Identifies patients at risk of asthma exacerbations, independent of symptom levels, especially if FEVi is <60% predicted96101130131
• Is a risk factor for lung function decline, independent of symptom levels112
• If symptoms are few, suggests limitation of lifestyle, on&or perception of airflow limitation,132 which may be due to untreated airway inflammation.133
A 'normal' or near-normal FEVi in a patient with frequenrtcspiratory symptoms (especially when symptomatic):
• Prompts consideration of alternative causes for the symptoms; e.g. cardiac disease, or cough due to post-nasal drip or gastroesophageal reflux disease (Box 1-3, p.26).
Persistent bronchodilator reversibility:
• Finding significant bronchodilator reversibility (increase in FEVi >12% and >200 mL from baseline18) in a patient taking controller treatment, orytfty nas taken a short-acting beta2-agonist within 4 hours, or a LABA within
12 hours (or 24 hours for a once-daily LABA), suggests uncontrolled asthma.
In children, spirometry cannot be reliably obtained until age 5 years or more, and it is less useful than in adults. Many children with uncontrolled asthma have normal lung function between flare-ups (exacerbations).
How to interpret changes in lung function in clinical practice
With regular ICS treatment, FEVi starts to improve within days, and reaches a plateau after around 2 months.134 The patient's highest FEVi reading (personal best) should be documented, as this provides a more useful comparison for clinical practice than FEVi percent predicted. If predicted values are used in children, measure their height at each visit.
Some patients may have a faster than average decrease in lung function, and develop persistent (incompletely reversible) airflow limitation. While a trial of higher dose ICS-LABA and/or systemic corticosteroids may be appropriate to see if FEVi can be improved, high doses should not be continued if there is no response.
The between-visit variability of FEVi (<12% week to week or 15% yearto year in healthy individuals18) limits its use in adjusting asthma treatment in clinical practice. The minimal important difference for improvement and worsening in FEVi based on patient perception of change has been reported to be about 10%.135,136
2. Assessment of asthma
39
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.137 Average PEF continues to increase, and diurnal PEF variability to decrease, for about 3 months.126,137 Excessive variation in PEF suggests suboptimal asthma control, and increases the risk of exacerbations.138
Long-term PEF monitoring is now generally only recommended for patients with severe asthma, or those with impaired perception of airflow limitation133'139142 (Appendix Chapter 4). For clinical practice, displaying PEF results on a standardized chart may improve accuracy of interpretation.143
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.20'62,144 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:20,144
• Mild asthma is currently defined as asthma that is well controlled uijtrnStep 1 or Step 2 treatment (Box 3-5,
p.59), i.e. with as-needed ICS-formoterol alone, or with low-intensity maintenance controller treatment such as low dose ICS, leukotriene receptor antagonists orchromones. For patients prescribed as-needed ICS-formoterol, the frequency of use that should be considerable- represent well-controlled asthma has not yet been determined. GINA does not distinguish between so-called 'intermittent' and 'mild persistent asthma', because this historical distinction was arbitrary not evidence-based, and was based on an untested assumption that patients with symptoms twice a week or less would not benefit from ICS. However, patients with so-called 'intermittent' asthma can still have severe exacerbations, and this risk is reduced by ICS-containing treatment.145 GINA is currently reviewing the definitionjSJKmlld asthma.
• Moderate asthma is asthma that is welfeentrolled with Step 3 or Step 4 treatment e.g. low or medium dose ICS-LABA.
• Severe asthma is asthma that remains 'uncontrolled' despite optimized treatment with high dose ICS-LABA, or that requires high dose ICS-LABA to prevent it from becoming 'uncontrolled'. While many patients with uncontrolled asthma mayia^ajfficultto treat due to inadequate or inappropriate treatment, or persistent problems with adherence or comorbidities such as chronic rhinosinusitis or obesity, the European Respiratory Society/American Thoracic Society Task Force on Severe Asthma considered that the definition of severe asthma should be reserved for patients with refractory asthma and those in whom response to treatment of comorbidities is incomplete.144 See Chapter 3E (p.101) for more detail about the assessment of patients with difficult to treat or severe asthma.
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.62 It is important that health professionals communicate clearly to patients what they mean by the word 'severe'.
Likewise, patients may perceive their asthma as mild if they have symptoms that are easily relieved by SABA, or that are infrequent.62 It is important to communicate clearly that patients with mild or infrequent symptoms can still have severe or even fatal exacerbations, and that this risk is substantially reduced with ICS-containing treatment.146
40
2. Assessment of asthma
How to describe populations in observational studies and clinical trials
It has been common practice in reports of clinical trials and observational studies to describe patients as having mild, moderate or severe asthma based on their prescribed treatment step.147 For example, patients are often described as having mild asthma if prescribed Step 1 or 2 treatment; or moderate asthma if prescribed Step 3-4 treatment; and moderate-severe asthma if prescribed Step 4-5 treatment. This approach assumes that patients are receiving appropriate treatment, and that those prescribed more intense treatment are likely to have more severe underlying disease. However, this practice causes confusion since many studies also require participants to have uncontrolled symptoms (when severity cannot generally be assessed). In addition, the recommended treatment at each step may change overtime.
Instead, GINA recommends stating the relevant controller treatment rather than the treatment step, and recommends avoiding imputation of asthma severity. For example, if a study population or subset comprises patients taking (or prescribed) medium dose ICS-LABA, this should be stated, rather than the population being described as being on Step 4 treatment, or having moderate asthma; and patients characterized only by taking SABA (without ICS) should not be described as being on 'Step 1' treatment or as having mild asthma.
Other definitions of severity
For low resource countries that do not currently have access to medications such as ICS, the World Health Organization definition of severe asthma148 includes a category of 'untreated severe astbisnV. This category corresponds to other classifications of uncontrolled asthma in patients not taking controller trealliient.
'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.62
How to distinguish between uncontrolled asthma and severe asthma
Although most asthma patients can achieve good symptom control and minimal exacerbations with ICS-containing controller treatment, some patients will not achieve one or both of these goals even with maximal therapy.128 In some patients this is due to truly refractory severe asttmia, 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.101) about investigation and management of difficult-to-treat and severe asthma, including referral to a respiratory physician or severe asthma clinic whorepossible. The most common problems that need to be excluded before a diagnosis of severe asthma can be rnelse are:
• Poor inhaler technique (up to 80% of community patients)91 (Box 3-12, p.87)
• Poor medication adherence149 (Box 3-13, p.88)
• 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.92)93
• Ongoing exposure to sensitizing or irritant agents in the home or work environment.
2. Assessment of asthma
41
Box 2-4. Investigating a patient with poor symptom control and/or exacerbations despite treatment
Watch patient using their inhaler Discuss adherence and barriers to use	• Watch patient use their inhaler{s), check against inhaler checklist. Show correct method, and recneck, up to 3 times. Re-check each visit. • Have empathic discussion to identify poor adherence, e.g. "Many patients don't use their inhaler as prescribed In the last 4 weeks, how many days a wee k have you taken it?" (0 days, 1, 2, 3 etc) and/or: "Do you find it easier to remember your inhaler in the morning or the evening?' Ask about beliefs, cost of medications, and refiU frequency.
♦	
Confirm the diagnosis of asthma	* ff no evidence of variable airflow limitation on spirometry or other testing (Box 1-2), consider halving ICS dose and repeating lung function after 2-3 weeks (Box 1-5), check patient has action plan. Consider referring for challenge test
♦	
If possible remove potential risk factors Assess and manage comorbidities	• Check for risk factors or inducers such as smoking, beta-blockers or NSAIDs, or — occupational or domestic allergen exposure (Box 2-2), and address as possible (Box 3-8). • Check for and manage comorbidities (e.g. rhinitis, obesity, GERD, obstructive sleep apnea, depression/anxiety) that may contribute to symptoms
i                                   i ~~	
Consider treatment step-up	• Consider step up to next treatment level or alternative option on present level (Box 3-5A). • Use shared decision-making, and balance potential benefits and risks
	
Refer to a specialist or severe asthma clinic	* ff asthma still uncontrolled after 3-6 months on high dose ICS-LABA, or with ongoing risk factors, refer to a specialist or severe asthma clinic (Box 3-14). • Refer earlier than 6 months if asthma very severe or difficult to manage, or if doubts about diagnosis.
42
2. Assessment of asthma
SECTION 1. ADULTS, ADOLESCENTS AND CHILDREN 6 YEARS AND OLDER
Chapter 3.
Treating asthma to control symptoms and minimize risk
This chapter is divided into five parts:
Part A.    General principles of asthma management (p.44)
Part B.    Medications and strategies for asthma symptom control and risk reduction
• Medications, including treatment steps (p.49)
• Treating modifiable risk factors (p.74)
• Non-pharmacological therapies and strategies (p.74)
Part C.    Guided asthma self-management education and skills training (p.86)
• Information, inhaler skills, adherence, written asthma action plan, self-monitoring, regular review Part D.    Managing asthma with comorbidities and in special populations (p.92)
Part E.    DifficuIt-to-treat and severe asthma in adults and adolescents (including decision tree) (p.101)
Management of worsening and acute asthma is described in Chapter 4 (p.117).
PART A. GENERAL PRINCIPLES OF ASTHMA MANAGEMENT
KEY POINTS
--
Goals of asthma management
• The long-term goals of asthma management are to achieve good symptom control, and to minimize future risk of asthma-related mortality, exacerbations, persistent airflow limitation add side-effects of treatment. The patient's own goals regarding their asthma and its treatment should also be identified.
The patient-health professional partnership
• Effective asthma management requires a partnership between the person with asthma (or the parent/carer) and their health care providers.
• Teaching communication skills to health care providers may lead to increased patient satisfaction, better health outcomes, and reduced use of health care resources.
• The patient's 'health literacy' - that is, the pern's ability to obtain, process and understand basic health information to make appropriate health deKfetons - should be taken into account.
Making decisions about asthma treatment
• Asthma treatment is adjusted in a continuous cycle of assessment, treatment, and review of the patient's response in both symptom control and future risk (of exacerbations and side-effects), and of patient preferences.
• For population-level decisions about asthma treatment in Steps 1-4, the 'preferred' options represent the best treatments for most patients. These recommendations are based on evidence from randomized controlled trials, meta-analyses and observational studies about safety, efficacy and effectiveness, with a particular emphasis on symptom burden and exacerbation risk. For Steps 1-5, there are different population-level recommendations for different age-groups (adults/adolescents, children 6-11 years, children 5 years and younger). In Step 5, there are also different population-level recommendations depending on the inflammatory phenotype, Type 2 or non-Type 2.
• 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, medication access and cost to the patient).
44
3. Treating to control symptoms and minimize future risk
LONG-TERM GOALS OF ASTHMA MANAGEMENT
The long-term goals of asthma management from a clinical perspective 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.
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.150 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 adults151 (Evidence A) and children152 (Evidence A).
There is emerging evidence that shared decision-making is associated with improved outcomes.153 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 outcomes154156 (Evidence B). Teaching health care providers to improve their communication skills (Box 3-1) can result in increased patient satisfaction, better health outcomes, and reduced use of health care resources154-156 without lengthening consultation times.157 It can also enhance patient adherence.157 Training patients to give information clearly, seek information, and check their understanding of information provided is also assafiafed with improved adherence with treatment recommendations.157
Box 3-1. Communication strategies for health care providers Key strategies to facilitate good communication155156
• A congenial demeanor (friendless, humor and attentiveness)
• Allowing the patient to express their goals, beliefs and concerns
• Empathy, reassurance, and prompt handling of any concerns
• Giving encouragem^jjrand praise
• Giving appropriate (personalized) information
• Providing feedback and review
How to reduce the impact of low health literacy158
• 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
45
Health literacy and asthma
There is increasing recognition of the impact of low health literacy on health outcomes, including in asthma.158'159 Health literacy means much more than the ability to read: it is defined as 'the degree to which individuals have the capacity to obtain, process and understand basic health information and services to make appropriate health decisions'.158 Low health literacy is associated with reduced knowledge and worse asthma control.160 In one study, low numeracy among parents of children with asthma was associated with higher risk of exacerbations.159 Interventions adapted for cultural and ethnicity perspectives have been associated with improved knowledge and significant improvements in inhaler technique.161 Suggested communication strategies for reducing the impact of low health literacy are shown in Box 3-1.
PERSONALIZED CONTROL-BASED ASTHMA MANAGEMENT
Asthma control has two domains: symptom control and risk reduction (see Box 2-2, p.36). 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 guidelines162,163 or practical tools for implemHNtation of control-based management strategies.153,164 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 o«asthma symptom control, but also on personalized management of the patient's modifiable 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
For many patients in primary care, symptom control is a good guide to a reduced risk of exacerbations.165 When inhaled corticosteroids (ICS) were introduced into asthma management, large improvements were observed in symptom control and lung function, and exacerbations and asthma-related mortality decreased.
However, with other asthma therapies (including ICS-long-acting beta2-agonists [LABA]166,167) or different treatment regimens (such as as-needed ICS-formoterol in mild asthma168-171 and ICS-formoterol maintenance and reliever therapy172,173), and in patients with mild or severe asthma, there may be discordance between responses for symptom control and exacerbations.
Confirmation of diagnosis if necessary Symptom control & modifiable risk factors (including lung function) Comorbidities
Inhaler technique & adherence Patient (and parent) preferences and goals
Symptoms Exacerbations Side-effects Lung function Patient (and parent) satisfaction
Treatment of modifiable risk factors and comorbidities Non-pharmacological strategies Asthma medications (adjust down/up/ between tracks) Education & skills training
46
3. Treating to control symptoms and minimize future risk
In particular, patients with apparently mild asthma and few or intermittent symptoms may be still at risk of severe exacerbations145 (Box2-2B, p.36). 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.36) should be taken into account when choosing asthma treatment and reviewing the response.20,62
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.174 The benefits have primarily been seen in patients with frequent exacerbations and severe asthma.174 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.174
• 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 alg©tfhms make comparisons and conclusions difficult.175 Results of FeNO measurement at a single point in time should be interpreted with caution (see p.26).31,176 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 to -0.06] per year) compared with guidelines-based treatment177 (Evidence A); similar differences were seen in comparisonsHjtetween FeNO-guided treatment and non-guidelines-based algorithms.177 However, in non-smoking adults with asthma, no significant reduction in risk of exacerbations and in exacerbation rates was observed when compared to guideline-based treatment; a difference was only seen in studies with other (non-typical) comparator app^rches.178 No significant differences were seen in symptoms or ICS dose with FeNO-guided treatment compared with other strategies.177,178
Sputum-guided treatment is recommended for adult patients with moderate or severe asthma who are managed in (or can be referred to) centers experienced in this technique144,174 (Evidence A). In children, FeNO-guided treatment significantly reduces exacerbation rates compared with guidelines-based treatment (Evidence A).177 However, further studies are needed to identify the populations most likely to benefit from sputum-guided174 or FeNO-guided treatment,177,178 and the optimal frequency of FeNO monitoring.
There is a need for evidence-basjfd corticosteroid de-escalation strategies in patients with asthma. In a randomized controlled trial (RCT) of patients taking high dose ICS-LABA, a strategy based on a composite of Type 2 biomarkers only vs. an algorithm base^on ACQ-7 and history of recent exacerbation was inconclusive because a substantial proportion of patients di<Wiot follow recommendations for treatment change.179 Until more definitive evidence for a specific strategy is available, GINA continues to recommend a clinical evaluation that includes patient-reported symptoms as well as modifiable risk factors, comorbidities and patient preferences when making treatment decisions. Further evidence on the role of biomarkers in such decisions in Steps 1-4 is needed.
Choosing between asthma treatment options
At each treatment step in asthma management, different medication options are available that, although not of identical efficacy, may be alternatives for controlling asthma. Different considerations apply to recommendations or choices made for broad populations compared with those for individual patients (Box 3-3, p. 48), as follows:
• Population-level medication choices: Population-level medication choices are often applied by bodies such as national formularies or managed care organizations. Population-level recommendations aim to represent the best option for most patients in the particular population. At each treatment step, 'preferred' medications (controller and/or reliever) are recommended that provide the best benefit-to-risk ratio for both symptom control and risk reduction. Choice of the preferred controller and preferred reliever is based on evidence from efficacy studies
3. Treating to control symptoms and minimize future risk
47
(highly controlled studies in well-characterized populations) and effectiveness studies (from pragmatically controlled studies, or studies in broader populations, or strong observational data),180 with a particular focus on symptoms and exacerbation risk. Safety and relative cost are also taken into account. In Step 5, there are different population-level recommendations depending on the inflammatory phenotype, Type 2 or non-Type 2. In GINA 2021, the recommendations for adults and adolescents have been clarified in the treatment figure (Box 3-5A, p.59) by showing treatment options in two 'tracks' based on the choice of reliever. Track 1, with as-needed low dose ICS-formoterol as the reliever, is the preferred approach for most patients, based on evidence of overall lower exacerbation risk and similar symptom control compared with treatments in Track 2 in which the reliever is short-acting beta2 agonist (SABA) (for more details, see Chapter 3B, p.49).
• 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 outcome^N$6st and available resources. At present, most evidence and research activity about individualized treatment is focused on severe asthma181,182 (see Chapter 3E, p. 101).
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^ryst patients, based on:
• Efficacy
• Effectiveness    - Mainly based on evidence about symptoms and exacerbations (from
• Safety randomized controlled trials^jyagmatic studies and strong observational data)
• Availability and cost at the population level
For Steps 1-5, there are different population-level recommendations by age-group (adults/adolescents, children 6-11 years, children 5 years and younger). In Step 5, there are also different population-level recommendations depending on the inflammatory phenotype, Type 2 or non-Type 2.
Choosing between controller options for individual patients
Use shared decision-making with the patient/parent/carer to discuss the following:
1. Preferred treatment (as above) for symptom control and risk reduction
2. Patient characteristics or phenotype
• Does the patient have any features that predict differences in their future risk or treatment response compared with other patients (e.g. smoker; history of exacerbations, blood eosinophilia)?
• Are there any modifiable risk factors or comorbidities that may affect outcomes?
3. Patient preference
• What are the patient's goals, beliefs and concerns about asthma and medications?
4. Practical issues
• Inhaler technique - can the patient use the inhaler correctly after training?
• Adherence - how often is the patient likely to take the medication?
• Cost to patient - can the patient afford the medication?
48
3. Treating to control symptoms and minimize future risk
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.
Treatment tracks for adults and adolescents
• For clarity, the treatment figure for adults and adolescents now shows two 'tracks', based on the choice of reliever. Treatment may be stepped up or down within a track using the same reliever at each step, or treatment may be switched between tracks, according to the individual patient's needs.
• Track 1, in which the reliever is low dose ICS-formoterol, is the preferred approach recommended by GINA. When a patient at any step has asthma symptoms, they use low dose ICS-formoterol as needed for symptom relief. In Steps 3-5, they also take ICS-formoterol as regular daily treatment. This approach is preferred because it reduces the risk of severe exacerbations compared with using a SABA reliever.
• Track 2, in which the reliever is a SABA, is an alternative if Track 1 is not possibl^or is not preferred by a patient with no exacerbations on their current therapy. In Step 1, the patient takes a SABA and a low dose ICS together for symptom relief (in combination, or with the ICS taken right after the SABA). In Steps 2-5, the reliever is a SABA. Before considering a SABA reliever, consider whether the patient is likely>ro be adherent with their ICS-containing controller therapy, as otherwise they would be at higher risk of exacerbations.
Steps 1 and 2
• 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^ABA-only treatment, and is non-inferior to daily low dose ICS for severe exacerbations, with no clinically important difference in symptom control.
• Treatment with regular daily low dose ICS, with asfl»&eded SABA, is highly effective in reducing asthma symptoms and reducing the risk of asthma-related exacerbations, hospitalization and death. However, adherence with ICS in the community is poor, leaving patients taking SABA alone and at increased risk of exacerbations.
Stepping up if asthma remains uncontrolled despite good adherence and inhaler technique
• Before considering any step up, first check for common problems such as inhaler technique, adherence, persistent allergen exposure and comorbidities.
• For adults and adolescents, the preferred Step 3 treatment is low dose ICS-formoterol as maintenance and reliever therapy (MART). This reduces the risk of severe exacerbations compared with maintenance ICS-LABA controller plus as-needed SABA,      similar or better symptom control. If needed, the maintenance dose of ICS-formoterol can be increased to medium (i.e. Step 4). MART is also a preferred treatment option for children 6-11 years.
• Other Step 3 options for adults, adolescents and children include maintenance ICS-LABA plus as-needed SABA or, for children 6-11 years, medium dose ICS plus as-needed SABA.
• For children, try other controller options at the same step before stepping up.
• ICS-formoterol should not be used as the reliever for patients taking a different ICS-LABA maintenance treatment, since clinical evidence for safety and efficacy is lacking.
Stepping down to find the minimum effective dose
• Consider step down once good asthma control has been achieved and maintained for about 3 months, to find the patient's lowest treatment that controls both symptoms and exacerbations
• Provide the patient with a written asthma action plan, monitor closely, and schedule a follow-up visit.
• Do not completely withdraw ICS unless this is needed temporarily to confirm the diagnosis of asthma.
3. Treating to control symptoms and minimize future risk
49
For all patients with asthma, provide asthma education and training in essential skills
• Provide inhaler skills training: this is essential for medications to be effective, but technique is often incorrect
• Encourage adherence with controller medication, even when symptoms are infrequent.
• 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.
For patients with one or more risk factors for exacerbations
• Prescribe ICS-containing medication, preferably from Track 1 options, i.e. with as-needed ICS-formoterol as reliever; 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, over-use of SABA).
• Consider non-pharmacological strategies and interventions to assist with symptom control and risk reduction, (e.g. smoking cessation advice, breathing exercises, some avoidance strategies).
Difficult-to-treat and severe asthma (see section 3E, p.101)
• Patients with poor symptom control and/or exacerbations despite medium or high dose ICS-LABA treatment should be assessed for contributing factors, and asthma treatment optimized.
• If the problems continue or diagnosis is uncertain, refer to a specialist centec&r phenotypic assessment and consideration of add-on therapy including biologies.
For all patients, use your own professional judgment, and always check local eligibility and payer criteria
ASTHMA MEDICATIONS
Categories of asthma medications
When compared with medications used for other chronkHjIi^eases, 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 medicatic<fecontain ICS and are used to reduce airway inflammation, control symptoms, and reduce future risks sa§ffas exacerbations and related decline in lung function.113 In patients with mild asthma, controller treatment may be delivered through as-needed low dose ICS-formoterol, taken when symptoms occur and before exercise. The dose and regimen of controller medications should be optimized to minimize the risk of medication side-effects, including risks of needing oral corticosteroids (OCS).
• Reliever medications: these are provided to all patients for as-needed relief of breakthrough symptoms, including during worsening astwvna or exacerbations. They are also recommended for short-term prevention of exercise-induced bronchoconstriction (EIB). Relievers include as-needed low dose ICS-formoterol (the preferred reliever, but not if the maintenance controller contains a different ICS-LABA), or as-needed SABA. Over-use of SABA (e.g. dispensing of three or more 200-dose canisters in a year, corresponding to average use more than daily) increases the risk of asthma exacerbations.123,89 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.101): these may be considered when patients have persistent symptoms and/or exacerbations despite optimized treatment with high dose controller medications (usually a high dose of ICS plus a LABA) and treatment of modifiable risk factors (see Box 3-8, p.74).
50
3. Treating to control symptoms and minimize future risk
Initial controller treatment
For the best outcomes, ICS-containing controller treatment should be initiated as soon as possible after the diagnosis of asthma is made, as the evidence suggests that:
Early initiation of low dose ICS in patients with asthma leads to a greater improvement in lung function than if symptoms have been present for more than 2-4 years.183,184 One study showed that after this time, higher ICS doses were required, and lower lung function was achieved.185
• Patients not taking ICS who experience a severe exacerbation have a greater long-term decline in lung function than those who have already started ICS.113
• For patients with occupational asthma, early removal from exposure to the sensitizing agent and early controller treatment increase the probability of resolution of symptoms, and improvement of lung function and airway hyperresponsiveness.40'41
Recommended options for initial controller treatment in adults and adolescents, based on evidence (where available) and consensus, are listed in Box 3-4A (p.53) and shown in Box 3-4B (p.54). The corresponding resources for children 6-11 years are on p.56 and p.57. The patient's response should be reviewed, and treatment stepped down once good control is achieved. Recommendations for a stepwise approach to ongoing treatment are found in Box 3-5 (p.59).
Does FeNO help in deciding whether to commence ICS?
In studies mainly limited to non-smoking patients, FeNO >50 parts per billion (ppbjvtas been associated with a good short-term response to ICS.176,186 However, these studies did not examine the longer-term risk of exacerbations. Such 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.170171
Consequently, in patients with a diagnosis or suspected diagrrssis 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.146
Personalized approach for adjusting asthma treatment in adults, adolescents and children 6-11 years old
Once asthma treatment has been commerj^d (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.^gpTtroller 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.73).
People's ethnic and racial backgrounds may be associated with different responses to treatment. These are not necessarily associated with genetic differences.187 The contributors are likely to be multifactorial, including differences in exposures, social disadvantage, diet and health-seeking behavior.
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
• Incorrect diagnosis.
3. Treating to control symptoms and minimize future risk
51
ASTHMA TREATMENT TRACKS FOR ADULTS AND ADOLESCENTS
The options for ongoing treatment for adults and adolescents have been clarified in the main treatment figure (Box 3-5A, p.59) by showing two treatment 'tracks', with the key difference being the medication that is used for symptom relief: as-needed low dose ICS-formoterol in Track 1, and as-needed SABA in Track 2.
Track 1: The reliever is as-needed low dose ICS-formoterol. This is the preferred approach recommended by GINA for adults and adolescents, because using low dose ICS-formoterol as reliever reduces the risk of severe exacerbations compared with regimens with SABA as reliever, with similar symptom control.
• With this approach, when a patient at any treatment step has asthma symptoms, they use low dose ICS-formoterol in a single inhaler for symptom relief.
• In Steps 3-5, patients also take ICS-formoterol as their daily controller treatment; together, this is called 'maintenance and reliever therapy' or 'MART'.
Track 2: The reliever is as-needed SABA. This is an alternative approach if Track 1 isoi^possible, or is not preferred by a patient with no exacerbations on their current therapy. Before prescribing a regimen with SABA reliever, consider whether the patient is likely to be adherent with their ICS-containing controller theraajPas otherwise they will be at higher risk of exacerbations.
• In Step 1, the patient takes a SABA and a low dose ICS together for symptom relief when symptoms occur (in a
combination inhaler, or with the ICS taken right after the SABA).
•  In Steps 2-5, a SABA (alone) is used for symptom relief, and the patient takes ICS-containing controller medication regularly every day.
During ongoing treatment, treatment can be stepped up or down along one track, using the same reliever at each step, or it can be switched between tracks, according to the individual patient's needs and preferences.
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.42).
52
3. Treating to control symptoms and minimize future risk
Box 3-4A. Initial asthma treatment - recommended options for adults and adolescents
Presenting symptoms	Preferred INITIAL treatment (Track 1)	Alternative INITIAL treatment (Track 2)
Infrequent asthma symptoms, e.g. less than twice a month and no risk factors for exacerbations (Box 2-2B, p.36)	As-needed low dose ICS-formoterol (Evidence B)	Low dose ICS taken whenever SABA is taken, in combination or separate inhalers (Evidence B)
Asthma symptoms or need for reliever twice a month or more	As-needed low dose ICS-formoterol (Evidence A)	Low dose ICS with as-needed SABA (Evidence A). Consider likely adherence with daily ICS.
Troublesome asthma symptoms most days; or waking due to asthma once a week or more, especially if any risk factors exist (Box 2-2B, p.36)	Low dose ICS-formoterol maintenance and reliever therapy (Evidence A)	Low dose ICS-LABA with as-needed SABA (Evidence A), OR Medium dose ICS with as-needed SABA (Evide/i^A). Consider likely adherence with^ny controller.
Initial asthma presentation is with severely uncontrolled asthma, or with an acute exacerbation	Medium dose ICS-formoterol maintenance and reliever therapy (Evidence D). A short course of orafc corticosteroids may also be needed.	High dose ICS (Evidence A) or medium dose ICS-LABA (Evidence D) with as-needed SABA. Consider likely adherence with daily controller. A short course of oral corticosteroids may also be needed.
Before starting initial controller treatment		
• Record evidence for the diagnosis of asthma. • Record the patient's level of symptom control and risk factors, including lung function (Box 2-2, p.36). • Consider factors influencing choice betwee^rvailable treatment options (Box 3-3, p.48), including likely adherence with daily controller, particularly if the reliever is SABA. • Ensure that the patient can use the ^phaler correctly. • Schedule an appointment for a te^hsw-up visit.		
After starting initial controller treatment		
• Review patient's response (Box 2-2, p.36) after 2-3 months, or earlier depending on clinical urgency. • See Box 3-5 (p.59) for recommendations for ongoing treatment and other key management issues. • Check adherence and inhaler technique frequently. • Step down treatment once good control has been maintained for 3 months (Box 3-7, p.73).		
ICS: inhaled corticosteroids; LABA: long-acting beta2-agonist; OCS: oral corticosteroids; SABA: short-acting beta2-agonist.
This table is based on evidence from available studies and consensus, including considerations of cost and likely adherence with controller therapy. See also Box 3-4B (p.54) for where to start on the main treatment figure for adults and adolescents.
3. Treating to control symptoms and minimize future risk
53
Box 3-4Bi. Selecting initial controller treatment in adults and adolescents with a diagnosis of asthma (V1)
STARTING TREATMENT
in adults and adolescents with a diagnosis of asthma
Track 1 is preferred if the patient is likely to be poorly adherent with daily controller ICS-containing therapy is recommended even if symptoms are infrequent, as it reduces the risk of severe exacerbations and need for OCS.
Confirm diagnosis
Symptom control and modifiable risk factors, including lung function
Comorbidities
Inhaler technique and adherence
Patient preferences and goals
CONTROLLER and PREFERRED RELIEVER (Track 1). Using ICS-formoterol as reliever reduces the risk of exacerbations compared with using a SABA reliever
Symptoms less than 4-5 days a week
STEPS 1-2
As-needed low dose ICS-formoterol
Symptoms most days, or waking with asthma once a week or more
STEP 3
Low dose
maintenance
ICS-formoterol
Daily symptoms, or waking with asthma once a week or more, and low lung function
STEP 4
Medium dose maintenance ICS-formoterol
RELIEVER: As-needed low-dose ICS-formoterol
CONTROLLER and ALTERNATIVE RELIEVER
(Track 2). Before considering a regimen with SABA reliever, check if the patient is likely to be adherent with daily controller therapy
Symptoms less than twice a month
STEP 1
Take ICS whenever SABA taken
Symptoms twice a month or more, but less than 4-5 days a week
STEP 2
Low dose maintenance ICS
Symptoms most days, or waking with asthma once a week or more
STEP 3
Low dose
maintenance
ICS-LABA
Daily symptoms, or waking with asthma once a week or more, and low lung function
STEP 4
Medium/high dose maintenance ICS-LABA
Short course OCS may also be needed for patients presenting with severely uncontrolled asthma
STEP 5
Add-on LAMA Refer for phenotypic assessment ± anti-lgE, anti-IL5/5R, anti-IL4R Consider high dose ICS-formoterol
Short course OCS may also be needed for patients presenting with severely uncontrolled asthma
STEP 5
Add-on LAMA Refer for phenotypic assessment ± anti-lgE, anti-IL5/5R, anti-IL4R Consider high dose ICS-LABA
RELIEVER: As-needed short-acting (32-agonist
ICS: inhaled corticosteroid; LABA: long-acting beta2-agonist; LAMA: long-acting muscarinic antagonist; MART: maintenance and reliever therapy with ICS-formoterol; OCS: oral corticosteroids; SABA: short-acting beta2-agonist
54
3. Treating to control symptoms and minimize future risk
Box 3-4BM. Selecting initial controller treatment in adults and adolescents with a diagnosis of asthma (V2)
STARTING TREATMENT
in adults and adolescents 12+ years with a diagnosis of asthma
FIRST ASSESS:
Confirmation of diagnosis
IF:
START WITH:
Daily symptoms, waking at night once a week or more and low lung function?
YES
TRACK 1 (preferred)
Medium dose ICS-formoterol maintenance and reliever (MART)
OR
TRACK 2
Medium/high dose ICS-LABA - as-needed SABA
STEP 4
Short course OCS may also be needed for patients presenting with severely uncontrolled asthma
Symptom control & modifiable risk factors (including lung function)
Comorbidities
Inhaler technique & adherence
Patient preferences & goals
NO I
Symptoms most days, or waking at night once a week or more?
I
NO
Symptoms twice a month or more?
NO
YES
I
Low dose ICS-formoterol maintenance and reliever (MART)
YES
As-needed low dose "^k lcs-formotero1
As-needed low dose ICS-formoterol
Low dose ICS-LABA + as-needed SABA
STEP 3
Low dose ICS + as-needed SABA
STEP 2
Take low dose ICS whenever SABA is taken
STEP 1
As-needed ICS-formoterol is preferred if the patient is likely to he poorly adherent with daily ICS ICS-containing therapy is recommended even if symptoms are infrequent, as it reduces the risk of severe exacerbations and need for OCS.
ICS: inhaled corticosteroid; LABA: long-acting beta2-agonist; MART: maintenance and reliever therapy with ICS-formoterol; OCS: oral corticosteroids; SABA: short-acting beta2-agonist
3. Treating to control symptoms and minimize future risk
55
Box 3-4C. Initial asthma treatment - recommended options for children aged 6-11 years
Presenting symptoms	Preferred INITIAL treatment
Infrequent asthma symptoms, e.g. less than twice a month and no risk factors for exacerbations (Box 2-2B, p.36)	As-needed SABA Other options include taking ICS whenever SABA is taken, in combination or separate inhalers.
Asthma symptoms or need for reliever twice a month or more	Low dose ICS** with as-needed SABA (Evidence A), or 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 days; or waking due to asthma once a week or more, especially if any risk factors exist (Box 2-2B)	Low dose ICS-LABA with as needed SABA (Evidence A), OR Medium dose ICS* with as-needed SABA (E^fehce A), OR Very low dose ICS-formoterol maintenance and reliever (Evidence B) Other options include low dose ICS^tyrh daily LTRA, with as needed SABA.
Initial asthma presentation is with severely uncontrolled asthma, or with an acute exacerbation	Start regular controller treatment with medium dose ICS-LABA with as-needed SABA or low dose ICS-formoterol maintenance and reliever (MART). A short course of OCS may also be needed.
Before starting initial controller treatment	
• Record evidence for the diagnosis of asthma, if possibly • Record the child's level of symptom control and risk factors, including lung function (Box 2-2, p.36, Box 2-3, p.37). • Consider factors influencing choice between available treatment options (Box 3-3, p.48). • Ensure that the child can use the inhaler correctly. • Schedule an appointment for a follow-up visit.	
After starting initial controller treatment	
• Review child's response (Box 2-2, p.36) after 2-3 months, or earlier depending on clinical urgency. • See Box 3-5B (p.60) for ra^OThmendations for ongoing treatment and other key management issues. • Step down treatment once good control has been maintained for 3 months (Box 3-7, p.73).	
ICS: inhaled corticosteroids; LABA: long-acting beta2-agonist; LTRA: leukotriene receptor antagonist; OCS: oral corticosteroids; SABA: short-acting beta2-agonist.
This table is based on evidence from available studies and consensus, including considerations of cost. See also Box 3-4D (p.57) for where to start on the main treatment figure for children 6-11 years.
56
3. Treating to control symptoms and minimize future risk
Box 3-4Di. Selecting initial controller treatment in children aged 6-11 years with a diagnosis of asthma (V1)
STARTING TREATMENT
Children 6-11 years with a diagnosis of asthma
Confirmation of diagnosis
Symptom control & modifiable risk factors (including lung function)
Comorbidities
Inhaler technique & adherence
Child and parent preferences and goals
PREFERRED
CONTROLLER
to prevent exacerbations
and control symptoms
Other
controller options
Symptoms less than twice a month
STEP 1
Low dose ICS taken whenever SABA taken
Consider daily low dose ICS
RELIEVER
Symptoms twice a month or more, but less than daily
STEP 2
Daily low dose inhaled corticosteroid (ICS) (see table of ICS dose ranges for children)
Daily leukotriene receptor antagonist (LTRA), or low dose ICS taken whenever SABA taken
Symptoms most days, or
waking with asthma once a week or more
STEP 3
Low dose ICS-LABA, OR medium dose ICS, OR very low dose* ICS-formoterol maintenance and reliever (MART)
Low dose ICS + LTRA
Symptoms most days, or waking
with asthma once a week or more, and low
lung function
STEP 4
Medium dose ICS-LABA, OR low dose* ICS-formoterol maintenance and reliever therapy (MART).
Refer for expert advice
Add tiotropium or add LTRA
STEP 5
Short course OCS may also be needed tor patients presenting with severely uncontrolled asthma
Refer for phenotypic assessment ± higher dose ICS-LABA or add-on therapy, e.g. anti-lgE
Add-on anti-IL5, or add-on low dose OCS, but consider side-effects
I
As-needed short-acting beta2-agonist (or low dose ICS-formoterol reliever for MART as above)
'Very low dose: BUD-FORM 100/6 meg
fLow dose: BUD-FORM 200/6 meg (metered doses).
BUD-FORM: budesonide-formoterol; ICS: inhaled corticosteroid; LABA: long-acting beta2-agonist; LTRA: leukotriene receptor antagonist; MART: maintenance and reliever therapy with ICS-formoterol; OCS: oral corticosteroids; SABA: short-acting beta2-agonist
3. Treating to control symptoms and minimize future risk
57
Box 3-4DM. Selecting initial controller treatment in children aged 6-11 years with a diagnosis of asthma (V2)
SUGGESTED INITIAL CONTROLLER TREATMENT
in CHILDREN 6-11 years with a diagnosis of asthma
FIRST ASSESS:
IF:
START WITH:
Confirmation of diagnosis
Symptom control & modifiable risk factors (including lung function)
Comorbidities
Inhaler technique & adherence
Child and parent preferences and goals
Symptoms most days, waking at night > once a week and low lung function?
I
NO
YES
Medium dose ICS-LABA
or low dose MART*. STEP 4 Refer for expert advice
Short course OCS may also be needed for patients presenting with severely uncontrolled asthma
Symptoms most days:or waking at night > once a week?
I
NO
I
YES
I
Low dose ICS-LABA or medium dose ICS or     STEP 3 very low dose MART*1
♦
Symptoms twice a month or more''
YES
STEP 2
NO
Take ICS whenever SABA taken
STEP 1
* Low dose: BUD-FORM 200/6 meg; fVery low dose: BUD-FORM 100/6 meg (metered doses) MART= maintenance and reliever therapy (ICS-formoterol as both maintenance and reliever)
BUD-FORM: budesonide-formoterol; ICS: inhaled corticosteroid; LABA: long-acting beta2-agonist; MART: maintenance and reliever therapy with ICS-formoterol; OCS: oral corticosteroids; SABA: short-acting beta2-agonist
58
3. Treating to control symptoms and minimize future risk
Box 3-5A. Personalized management for adults and adolescents to control symptoms and minimize future risk
Adults & adolescents 12+ years
Personalized asthma management
Assess, Adjust, Review for individual patient needs
CONTROLLER and PREFERRED RELIEVER
(Track 1). Using ICS-formoterol as reliever reduces the risk of exacerbations compared with using a SABA reliever
Symptoms Exacerbations Side-effects Lung function Patient satisfaction
Confirmation of diagnosis if necessary Symptom control & modifiable risk factors (including lung function) Comorbidities
Inhaler technique & adherence Patient preferences and goals
Treatment of modifiable risk factors and comorbidities Non-pharmacological strategies Asthma medications (adjust down/up/between tracks) Education & skills training
STEPS 1-2
As-needed low dose ICS-formoterol
STEP 3
Low dose
maintenance
ICS-formoterol
STEP4
Medium dose
maintenance
ICS-formoterol
RELIEVER: As-needed low-dose ICS-formoterol
STEP 5
Add-on LAMA Refer for phenotypic assessment ±anti-lgE. anti-IL5/5R; anti-IL4R Consider high dose ICS-formoterol
CONTROLLER and ALTERNATIVE RELIEVER
(Track 2) Before considering a regimen with SABA reliever check if the patient is likely to be adherent with daily controller
STEP 1
Take ICS whenever SABA taken
STEP2
Low dose maintenance ICS
STEP 3
Low dose
maintenance
ICS-LABA
STEP4
Medium/high dose maintenance ICS-LABA
RELIEVER: As-needed short-acting (32-agonist
STEP 5
Add-on LAMA Refer for phenotypic assessment ±anti-lgE, anti-IL5/5R; anti-IL4R Consider high dose ICS-LABA
Other controller options for either track
Low dose ICS whenever	Medium dose ICS, or	Add LAMA or LTRA or	Add azithromycin (adults) or
SABA taken, or daily LTRA,	add LTRA, or add	HDMSLIT, orswitchto	LTRA; add low dose OCS
oraddHDM SLIT	HDM SLIT	high dose ICS	but consider side-effects
HDM: house dust mite; ICS: inhaled corticosteroid; LABA: long-acting beta2-agonist; LAMA: long-acting muscarinic antagonist; 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.53) and 3-4B (p.54).
3. Treating to control symptoms and minimize future risk
59
Box 3-5B. Personalized management for children 6-11 years to control symptoms and minimize future risk
Children 6-11 years
Personalized asthma management:
Assess, Adjust, Review
Asthma medication options:
Adjust treatment up and down for individual child's needs
PREFERRED
CONTROLLER
to prevent exacerbations
and control symptoms
Other
controller options
STEP 1
Low dose ICS taken whenever SABA taken
Consider daily low dose ICS
Symptoms Exacerbations Side-effects Lung function Child and parent
satisfaction
Confirmation of diagnosis if necessary Symptom control & modifiable risk factors (including lung function) Comorbidities
Inhaler technique & adherence Child and parent preferences and goals
STEP 2
Daily low dose inhaled corticosteroid (ICS) (see table of ICS dose ranges for children)
Treatment of modifiable risk factors & comorbidities
Non-pharmacological strategies Asthma medications (adjust down or up) Education & skills training
Daily leukotriene receptor antagonist (LIRA), or low dose ICS taken whenever SABA taken
STEP 3
Low dose ICS-LABA, OR medium dose ICS, OR very low dose* ICS-formoterol maintenance and reliever (MART)
Low dose ICS + LTRA
STEP 4
Medium dose ICS-LABA, OR low dose* ICS-formoterol maintenance and reliever therapy (MART).
Refer for expert advice
Add tiotropium or add LTRA
Refer for
phenotypic assessment ± higher dose ICS-LABA or add-on therapy, e.g. anti-lgE
Add-on anti-IL or add-on low dose OCS, but consider side-effects
RELIEVER
As-needed short-acting beta2-agonist (or ICS-formoterol reliever for MART as above)
*Very low dose: BUD-FORM 100/6 meg
fLow dose: BUD-FORM 200/6 meg (metered doses).
BUD-FORM: budesonide-formoterol; ICS: inhaled corticosteroid; LABA: long-acting beta2-agonist; LTRA: leukotriene receptor antagonist; MART: maintenance and reliever therapy with ICS-formoterol; OCS: oral corticosteroids; SABA: short-acting beta2-agonist. For initial asthma treatment in children aged 6-11 years, see Box 3-4C (p.56) and Box 3-4D (p.57)
60
3. Treating to control symptoms and minimize future risk
Box 3-6. Low, medium and high daily metered doses of inhaled corticosteroids (alone or with LABA)
This is not a table of equivalence, but instead, suggested total daily doses for 'low', 'medium' and 'high' dose ICS options for adults/adolescents (Box 3-5A, p.59) and children 6-11 years (Box 3-5B, p.60), based on product information. Few data are available for comparative potency, so this table does NOT imply potency equivalence. Doses may differ by country, depending on local products, regulatory labelling and clinical guidelines or, for one product, with addition of a LAMA to an ICS-LABA.188 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, or they have ongoing exacerbations, 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. Daily doses in this table are shown as metered doses. See product information for delivered doses.			
Adults and adolescents (12 years and older)			
Inhaled corticosteroid	Total daily ICS dose (meg) - see notes above Low             Medium High		
Beclometasone dipropionate (pMDI, standard particle, HFA)	2G@£500	>500-1000	>1000
Beclometasone dipropionate (DPI or pMDI, extrafine particle, HFA)	100-200	>200-400	>400
Budesonide (DPI, or pMDI, standard particle, HFA)	200-400	>400-800	>800
Ciclesonide (pMDI, extrafine particle, HFA)	80-160	>160-320	>320
Fluticasone furoate (DPI)	100		200
Fluticasone propionate (DPI)	100-250	>250-500	>500
Fluticasone propionate (pMDI, standard particle, HFA)	100-250	>250-500	>500
Mometasone furoate (DPI)	Depends on DPI device - see product information		
Mometasone furoate (pMDI, standard D^Nicle, HFA)	200-400		>400
Children 6-11 years - see notes above (for children 5 years and younger, see Box 6-6, p. 160)			
Beclometasone dipropionate (pMDI, standard particle, HFA)	100-200	>200-400	>400
Beclometasone dipropionate (pMDI, extrafine particle, HFA)	50-100	>100-200	>200
Budesonide (DPI)	100-200	>200-400	>400
Budesonide (nebules)	250-500	>500-1000	>1000
Ciclesonide (pMDI, extrafine particle*, HFA)	80	>80-160	>160
Fluticasone furoate (DPI)	50		n.a.
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; LABA: long-acting beta2-agonist; LAMA: long-acting muscarinic antagonist; n.a. not applicable; pMDI: pressurized metered dose inhaler; ICS by pMDI should preferably be used with a spacer.
For new preparations, including generic ICS, the manufacturer's information should be reviewed carefully, as products containing the same molecule may not be clinically equivalent. For more detailed discussion see Raissy et al.114 Combination inhalers that include a long-acting muscarinic antagonist (LAMA) may have different ICS dosing - see product information.
3. Treating to control symptoms and minimize future risk
61
Choice of medication, device and dose
In clinical practice, the choice of medication, device and dose for controller and reliever 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.48). It is important to monitor the response to treatment and any side-effects, and to adjust the dose accordingly (Box 3-5, p.59). 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.101). There is currently insufficient good quality evidence to support use of extra-fine particle ICS aerosols over others.189 More detail about asthma medications is provided in Appendix Chapter 5 (adults and adolescents: Part 5A; children 6-11 years: Part5B).
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 adolescents should receive an ICS-containing controller, incorporated as part of the patients personalized asthma management. The ICS-containing medication should be taken every day or, in mild asthma, an alternative is to take as-needed low dose ICS-formoterol for symptom relief. Box 3-6 (p.61) lists suggested low, medium and high doses for several different ICS formulations.
ASTHMA TREATMENT STEPS
GINA treatment recommendations for adults, adolescents and children have been updated in 2021 after a review of evidence for Steps 1-5. The treatment figure for adults and adolescents (Box 3-5A, p.59) has been clarified by showing treatment options in two 'tracks', with the key difference between the 'tracks' being the type of reliever (low dose ICS-formoterol or SABA; see p.52). Track 1, with as-needed low dose ICS-formoterol as the reliever, is the preferred approach, based on evidence for efficacy, effectiveness and safety for lower risk of severe exacerbations, with similar symptom control compared with controller medications plus as-needed SABA in Track 2.
STEP 1
Preferred Step 1 treatment for adults and adolescents: low dose combination ICS-formoterol taken as needed for relief of symptoms, and if needed before exercise (Track 1)
GINA Step 1 recommendations are for:
• Initial asthma treatment in patients with symptoms less than twice a month and no exacerbation risk factors, a group that is rarely studied
• Step-down treatment for patients whose asthma is well-controlled on Step 2 treatment
Use of low dose ICS-formoterol as needed for symptom relief in Step 1 for adults and adolescents (Evidence B) is supported by indirect evidence for a reduction in risk of severe exacerbations compared with as-needed SABA alone, from a large double-blind study168 and an open-label study170 in patients who were eligible for Step 2 therapy (see below). Four large studies showed a similar or greater reduction in severe exacerbations compared with daily ICS, with no clinically important difference in symptom control or lung function.173'174'180,182 No new safety signals were seen with as-needed budesonide-formoterol in mild asthma.169171,190
The most important considerations for GINA in extending the recommendation for as-needed low dose ICS-formoterol to Step 1 were:
• Patients with few interval asthma symptoms can still have severe or fatal exacerbations.191 GINA recommends assessing and addressing risk factors for exacerbations as well as symptom control (Box 2-2)
• The historic distinction between so-called 'intermittent' and 'mild persistent' asthma is arbitrary, with no evidence of difference in response to ICS.145 A large reduction in risk of severe exacerbations with as-needed ICS-
62
3. Treating to control symptoms and minimize future risk
formoterol compared with as-needed SABA was seen even in patients with SABA use twice a week or less at baseline.170
• A post hoc analysis of one study found that a day with increased as-needed budesonide-formoterol reduced the short-term (21 day) risk of severe exacerbations compared to as needed SABA alone, suggesting that timing of use of ICS-formoterol is important.192
• In patients with infrequent symptoms, adherence with prescribed daily ICS is very poor,193 exposing them to risks of SABA-only treatment if they are prescribed daily ICS plus as-needed SABA
• There is a lack of evidence for the safety or efficacy of SABA-only treatment. Historic recommendations for SABA-only treatment were based on the assumption that patients with mild asthma would not benefit from ICS
• Taking SABA regularly for as little as one week significantly increases exercise-induced bronchoconstriction, airway hyperresponsiveness and airway inflammation, and decreases bronchodilator response.194 Even modest over-use of SABA (indicated by dispensing of 3 or more canisters a year) is associated with increased risk of severe exacerbations123 and, in one study, asthma mortality.89
• An important consideration for GINA was to avoid establishing patient reliance on SABA, and the priority to avoid conflicting messages in asthma education. Previously, patients were initially provided only with SABA for symptom relief, but later, despite this treatment being effective from the pa+jgrn's perspective, they were told that in order to reduce their SABA use, they needed to take a daily controller even when they had no symptoms. Recommending that all patients should be provided with a controller<ram 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 reiitence on SABA as their main asthma treatment.
Practice points for ICS-formoterol in mild asthma
The usual dose of as-needed budesonide-formoterol in mild asthma is a single inhalation of 200/6 meg (delivered dose 160/4.5), taken whenever needed for symptom relief. The maximum recommended dose of as-needed budesonide-formoterol in a single day corresponds to a total of 72 meg formoterol (54 meg delivered dose). However, in RTCs in mild asthma, such high usage was rarely seen, with average use around 3-4 doses per week.168-170
Rinsing the mouth is not needed after as-needed use of low dose ICS-formoterol, as this was not required in any of the mild asthma studies, and there was no increase in risk of oral thrush.
ICS-formoterol formulations other than tapaesonide-formoterol have not been studied for as-needed-only use, but beclometasone-formoterol may also be suitable. Both of these medications are well-established for as-needed use within maintenance and reliever therajsy in GINA Steps 3-5.173
For pre-exercise use in patientfcwith mild asthma, one 6-week study showed that use of low dose budesonide-formoterol for symptom relief and before exercise reduced exercise-induced bronchoconstriction to a similar extent as regular daily low dose ICS with SABA for symptom relief and before exercise.195 More studies are needed, but this study 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).
Alternative Step 1 treatment options for adults and adolescents (Track 2)
Low dose ICS taken whenever SABA is taken (Evidence B): There is much less evidence about the safety and efficacy of this approach than for as-needed ICS-formoterol, but it may be an option in countries where ICS-formoterol is not available or affordable. In Step 1, the evidence for this strategy is indirect, from studies with separate or combination ICS and SABA inhalers in patients eligible for Step 2 treatment (see below).196199 In making this recommendation, the most important considerations were reducing the risk of severe exacerbations, and the difficulty of achieving good adherence with regularly prescribed ICS in patients with infrequent symptoms.
Regular daily low dose ICS has been suggested by GINA since 2014 for consideration in Step 1, for patients with symptoms less than twice a month, to reduce the risk of exacerbations. This was based on indirect evidence from studies in patients eligible for Step 2 treatment145'190,200 (Evidence B). However, patients with symptoms less than twice a
3. Treating to control symptoms and minimize future risk
63
month are extremely unlikely to take ICS regularly even if prescribed, leaving them exposed to the risks of SABA-only treatment, so for feasibility reasons, this regimen is no longer recommended for general use in such patients.
Step 1 treatment options for children 6-11 years
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 in children and adolescents. One of these showed substantially fewer exacerbations compared with SABA-only treatment,197 and another showed similar outcomes as physician-adjusted treatment but with lower average ICS dose199 (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.
There have been no studies of as needed-only 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).
/<s
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,201 patients whose asth<fuk is treated with SABA alone (compared with ICS) are at increased risk of asthma-related death (Evidence A)89,202 and urgent asthma-related healthcare (Evidence A),203 even if they have good symptom control.204 The a^rof asthma exacerbations and mortality increases incrementally with higher SABA use, including in patients treated with SABA alone.89 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.205
In adults, inhaled anticholinergic agents like ipratropium are potefltfal alternatives to SABA for routine relief of asthma symptoms; however, these agents have a slower onset of ac0n than inhaled SABA. Oral SABA and theophylline have a higher risk of side-effects and are not recommended. 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,206 and reduces the risk of severe exacerbations by 15-45% compared with as-needed SABA,207 209 but use of regular or frequent LABA without ICS is strongly discouraged because of the risk of exacerbations121,210 (Evidence A).
STEP 2
Preferred Step 2 treatment for adults and adolescents: low dose ICS-formoterol, taken as-needed for relief of symptoms and, if needed, before exercise (Track 1)
The current evidence for this combination controller + reliever treatment is with low dose budesonide-formoterol:
• A large double-blind study in mild asthma found a 64% reduction in severe exacerbations compared with SABA-only treatment,168 with a similar finding in an open-label study in patients with mild asthma previously taking SABA alone.170 (Evidence A).
• Two large double-blind studies in mild asthma showed as-needed budesonide-formoterol was non-inferior for severe exacerbations compared with regular ICS.168,169
• In two open-label randomized controlled trials, representing the way that patients with mild asthma would use as-needed ICS-formoterol in real life, as-needed budesonide-formoterol was superior to maintenance ICS in reducing the risk of severe exacerbations170,171 (Evidence A).
• In all four studies, the as-needed ICS-formoterol strategy was associated with a substantially lower average ICS dose than with maintenance low dose ics.173,174,180,182
64
3. Treating to control symptoms and minimize future risk
• A post hoc analysis of one study168 found that a day with >2 doses of as-needed budesonide-formoterol reduced the short-term (21 day) risk of severe exacerbations compared to as needed terbutaline alone, suggesting that timing of use of ICS-formoterol is important.192
In making this recommendation for as-needed ICS-formoterol, the most important considerations for GINA were:
• The need to prevent severe exacerbations in patients with mild or infrequent symptoms; these can occur with unpredictable triggers such as viral infection, allergen exposure, pollution or stress.
• The desire to avoid the need for daily ICS in patients with mild asthma, who in clinical practice are often poorly adherent with prescribed ICS.
• The very small differences in FEVi, (-30-50 ml_), symptom control (difference in ACQ-5 of-0.15 vs minimal clinically important difference 0.5), and symptom-free days (mean difference 10.6 days per year)168,169 compared with regular ICS were considered to be less important. These differences were not cumulative over the 12-month studies. The primary outcome variable of one study168 was 'well-controlled asthma weeks', but this outcome was not considered reliable because it was based on an earlier concept of asthma control, and was systematically biased against the as-needed ICS-formoterol treatment group because much less ICS was permitted in a week for patients on ICS-formoterol than those on maintenance ICS before the week was classified as not well-controlled.
• FeNO 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.170,171
Because as-needed ICS-formoterol is the preferred treatment for both Steps 1 and 2 in adults and adolescents, these steps have been combined in the treatment figure (Box 3-5A, p.59§jto avoid confusion.
Practice points for as-needed ICS-formoterol in mild asthma
The usual dose of as-needed budesonide-formoterol in mild asthma is a single inhalation of 200/6 meg (delivered dose 160/4.5), taken whenever needed for symptom relief. Based on product information, the maximum recommended dose of budesonide-formoterol in a single day is a total of 72mcg formoterol (54 meg delivered dose). However, in the randomized controlled trials in mild asthma, suer|$Tigh usage was rarely seen, and average use of as-needed ICS-formoterol was around 3-4 doses per week.168171
Rinsing the mouth is not needed aftez-asMieeded use of low dose ICS-formoterol, as this was not required in any of the mild asthma studies, and there was no increase in risk of oral thrush.
Other ICS-formoterol formulations have not been studied for as-needed-only use, but beclometasone-formoterol may also be suitable. Both of these medications are well-established for as-needed use within maintenance and reliever therapy (MART) in GINA Swps 3-5.173 No new safety signals were seen in four studies with as-needed budesonide-formoterol in mild asthma.169171,190
For pre-exercise use 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.195 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).
Alternative Step 2 treatment for adults and adolescents: daily low dose ICS plus as-needed SABA (Track 2)
For regular daily low dose ICS plus as-needed SABA, the most important consideration was to reduce the risk of severe exacerbations. There is a large body of evidence from RCTs and observational studies showing that the risks of severe exacerbations, hospitalizations and mortality are substantially reduced with regular low dose ICS; symptoms and exercise-induced bronchoconstriction are also reduced190'200'202'211,212 (Evidence A). Severe exacerbations are halved with low dose ICS even in patients with symptoms 0-1 days a week.145
3. Treating to control symptoms and minimize future risk
65
However, when prescribing daily ICS for a patient with mild asthma, clinicians should be aware that adherence with maintenance ICS in the community is extremely low. They should consider the likelihood that the patient will be poorly adherent with daily ICS, exposing them to the risks of SABA-only treatment.
Over-use of SABA, indicated by dispensing of three or more 200-dose canisters of SABA in a year (i.e. average use more than daily), is associated with an increased risk of severe exacerbations89,123 and, in one study, with increased mortality,89 even in patients also taking ICS-containing controller.
Other Step 2 treatment options for adults and adolescents
Low dose ICS taken whenever SABA is used (in combination or separate inhalers) is another option if as-needed ICS-formoterol is not available, and the patient is unlikely to take regular ICS. The evidence is from two studies in adults and two studies in children and adolescents, with separate or combination ICS and SABA inhalers,196198,213 showing no difference in exacerbations compared with daily ICS.
Leukotriene receptor antagonists (LTRA) are less effective than ICS,214 particularly for exacerbations (Evidence A). 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.215
For adult or adolescent patients not previously using controller treatment, regulafyaily combination low dose ICS-LABA as the initial maintenance controller treatment reduces symptoms and improvés^lung function compared with low dose ICS alone.216 However, it is more expensive and does not further reduce the risk of exacerbations compared with ICS alone216 (Evidence A). No comparison between regular and as-needed ICS-formoterol has been studied in patients eligible for Step 2 treatment.
For patients with purely seasonal allergic asthma, e.g. with birch pollen, with no interval asthma symptoms, regular daily ICS or as-needed ICS-formoterol should be started immediately symptoms commence, and be continued for four weeks after the relevant pollen season ends (Evidence D).
Preferred Step 2 treatment for children 6-11 years
The preferred controller option for children at Step 2 is regular low dose ICS with as-needed SABA (see Box 3-6, p.61 for ICS dose ranges in children).
Alternative Step 2 treatment for children 6-11 years
Another controller option for children is taking low dose ICS whenever SABA is taken, based on the results of two studies with separate ICS and SABA inhalers in patients aged between 5 years and 17 or 18 years.197,199 Interviews with parents indicated that those whose children were randomized to as-needed ICS+SABA felt more in control of their child's asthma than those wtaQe children were randomized to physician-based adjustment.199
Another option is daily LTRA, which overall is less effective than ICS.214 The FDA warning about montelukast (above) also applies to its use in children.215
Not recommended
Sustained-release theophylline has only weak efficacy in asthma217219 (Evidence B) and side-effects are common, and may be life-threatening at higher doses.220 Chromones (nedocromil sodium and sodium cromoglycate) have a favorable safety profile but low efficacy221223 (Evidence A), and their inhalers require burdensome daily washing to avoid blockage.
66
3. Treating to control symptoms and minimize future risk
STEP 3
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.42).
Preferred Step 3 treatment for adults and adolescents: low dose ICS-formoterol maintenance and reliever therapy (Track 1)
For adults and adolescents, the 'preferred' Step 3 option is low dose ICS-formoterol as both maintenance and reliever treatment (MART). In this regimen, low dose ICS-formoterol, either budesonide-formoterol or beclometasone-formoterol, is used as both the maintenance treatment and for symptom relief.
In adult and adolescent patients with >1 exacerbation in the previous year, ICS-formoterol maintenance and reliever therapy reduced exacerbations and provided 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 SABA224-229 (Evidence A). In open-label studies that did not require a history of severe exacerbations, maintenance and reliever therapy with ICS-formoterol also significantly reduced severe exacerbations, with a lower average dose of ICS.224,230
For patients prescribed ICS-formoterol maintenance and reliever therapy, the maximum recommended dose of formoterol in a single day, based on product information, is 72 meg metered dose (54 meg delivered dose) for budesonide-formoterol and 48 meg metered dose (36 meg delivered dosepfor beclometasone-formoterol.
ICS-formoterol should not be used as the reliever for patients taking a different ICS-LABA maintenance treatment, since clinical evidence for safety and efficacy is lacking.
Alternative Step 3 treatment for adults and adolescents: maintenance ICS-LABA plus as-needed SABA (Track 2)
Maintenance ICS-LABA with as-needed SABA: For patients receiving maintenance ICS with as-needed SABA, adding LABA in a combination inhaler provides additional irqprbvements in symptoms and lung function with a reduced risk of exacerbations compared with the same dose of ICS,231,232 (Evidence A) but there is only a small reduction in reliever
use 233,234
Currently approved combination ICS-LAB^iflfialers for Step 3 maintenance treatment of asthma include low doses of fluticasone propionate-formoterol, fluticasone furoate-vilanterol, fluticasone propionate-salmeterol, beclometasone-formoterol, budesonide-formoterol, mometasone-formoterol and mometasone-indacaterol (see Box 3-6, p.61). Effectiveness of fluticasone furoate-vilanterol over usual care was demonstrated for asthma symptom control in a large real-world study; there was nq<$flerence in risk of exacerbations.235,236
Other Step 3 controller options for adults and adolescents
For adult patients with allergic rhinitis and sensitized to house dust mite, with suboptimally controlled asthma despite low to high dose ICS, consider adding sublingual allergen immunotherapy (SLIT), provided FEVi is >70% predicted.237,238 (see p.75).
Another option for adults and adolescents is to increase ICS to medium dose135 (see Box 3-6, p.61), but at a group level this is less effective than adding a LABA239,240 (Evidence A). Other less efficacious options are low dose ICS plus either LTRA241 (Evidence A) or low dose, sustained-release theophylline242 (Evidence B). See note above about the FDA warning for montelukast.215
Preferred Step 3 treatment for children 6-11 years
In children, after checking inhaler technique and adherence, and treating modifiable risk factors, there are three preferred options at a population level: to increase ICS to medium dose (see Box 3-6, p.6_l),243 (Evidence A) or change to combination low dose ICS-LABA (Evidence A),244 both with as-needed SABA reliever, or to switch to maintenance and reliever therapy with a very low dose of ICS-formoterol (Evidence B).245 In a large study of children aged 4-11 years with a history of an exacerbation in the previous year, combination ICS-LABA was non-inferior to the same dose of ICS
3. Treating to control symptoms and minimize future risk
67
alone for severe exacerbations, with no difference in symptom control or reliever use.246 In children, a single study of maintenance and reliever therapy with very low dose budesonide-formoterol (100/6 metered dose, 80/4.5 meg delivered dose for both maintenance and reliever) showed a large reduction in exacerbations compared with the same dose of budesonide-formoterol with SABA reliever, or compared with higher dose ICS.245
Individual children's responses vary, so the other controller options above should be tried before considering Step 4 treatment.
Other Step 3 treatment options for children 6-11 years
In children, there is little evidence for adding LTRA to low dose ICS.241 The FDA warning about montelukast (above) also applies to its use in children.215
STEP 4 -
Although at a group level most benefit from ICS is obtained at low dose, individual ICS <^ponsiveness varies, and some patients whose asthma is uncontrolled on low dose ICS-LABA despite good adheren^sand correct inhaler technique may benefit from increasing the maintenance dose to medium. High dose ICS is no longer recommended at Step 4.
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 asthaJfiTfeox 2-4, p.42).
Preferred Step 4 treatment for adults and adolescents: medium dose ICS-formoterol maintenance and reliever therapy (Track 1)
For adult and adolescent patients, combination 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 ICS228 (Evidence A). The greatest reduction in risk was seen in patients with a history of severe exacerbations,173 but MART was also significantly more effective than conventional best practice in opei^fabel studies in which patients were not selected for greater exacerbation risk.223 In Step 4, the MART regimen can be prescribed with medium dose budesonide-formoterol or beclometasone-formoterol maintenance treatment, but the reliever remains low dose ICS-formoterol. Based on product information, the maximum recommended total dose of formoterol in a single day is 72 meg metered dose (54 meg delivered dose) for budesonide-formoterol and 48 meg metered dose (36 meg delivered dose) for beclometasone-formoterol).
Alternative Step 4 treatment for adults and adolescents: medium or high dose ICS-LABA with as-needed SABA (Track 2)
As above, individual ICS responsiveness varies, and some patients whose asthma is uncontrolled or who have frequent exacerbations on low dose ICS-LABA despite good adherence and correct inhaler technique may benefit from medium dose ICS-LABA167 (Evidence B) with as-needed SABA, if maintenance and reliever therapy is not available. Occasionally, high dose ICS-LABA may be needed.
Other Step 4 controller options for adults and adolescents
Long-acting muscarinic antagonists (LAMA) may be considered as add-on therapy in a separate inhaler for patients aged >6 years (tiotropium), or in a combination ('triple') inhaler for patients aged >18 years (beclometasone-formoterol-glycopyrronium; fluticasone furoate-vilanterol-umeclidinium; mometasone-indacaterol-glycopyrronium) if asthma is persistently uncontrolled despite medium or high dose ICS-LABA. Adding LAMA to medium or high dose ICS-LABA modestly improved lung function188'247 251'252 (Evidence A) but with no difference in symptoms. In some studies, adding LAMA to ICS-LABA modestly reduced exacerbations compared with some medium or high dose ICS-LABA comparators.188^247-249'252
However, for patients experiencing exacerbations despite low dose ICS-LABA, the ICS dose should be increased to at least medium, or treatment switched to maintenance and reliever therapy with ICS-formoterol, before considering adding
68
3. Treating to control symptoms and minimize future risk
a LAMA. In one study, the severe exacerbation rate was lower in patients receiving high dose fluticasone furoate-vilanterol (ICS-LABA) than with low-medium dose fluticasone furoate-vilanterol-umeclidinium (ICS-LABA-LAMA).250
In Step 4, there is insufficient evidence to support ICS-LAMA over low or medium dose ICS-LABA combination; all studies were with ICS and tiotropium in separate inhalers.248 In one analysis, response to adding LAMA to medium dose ICS, as assessed by FEVi, ACQ, and exacerbations, was not modified by baseline demographics, body-mass index, FEVi, FEVi reversibility, or past vs. never smoking.253
Consider adding sublingual allergen immunotherapy (SLIT) for adult patients with allergic rhinitis and sensitization to house dust mite, with suboptimally controlled asthma despite low-high dose ICS, provided FEVi is >70% predicted.237,238 (see p.75).
For medium or high dose budesonide, efficacy may be improved with dosing four times daily254,255 (Evidence B), but adherence may be an issue. For other ICS, twice-daily dosing is appropriate (Evidence D). Other options for adults or adolescents that can be added to a medium or high dose ICS, but that are less efficacious than adding LABA, include LTRA256 260 (Evidence A), or low dose sustained-release theophylline218 (Evidence B), but neither of these has been compared with maintenance and reliever therapy with ICS-formoterol. See note above about the FDA warning for montelukast.215
Preferred Step 4 treatment for children 6-11 years
For children whose asthma is not adequately controlled by low dose maintenance ICS-LABA with as-needed SABA, treatment may be increased to medium dose ICS-LABA246 (Evidence B). For maintenance and reliever therapy with budesonide-formoterol, the maintenance dose may be increased to 100/6 meg twice daily (metered dose; 80/4.5 meg delivered dose) (Evidence D); this is still a low dose regimen.
If asthma is not well controlled on medium dose ICS (see Bojs#-6B, p.61_), the recommendation is to refer the child for expert assessment and advice.
Other Step 4 options for children 6-11 years
Other controller options include increasing to high pediatric dose ICS-LABA (Box 3-6B, p.61_), but adverse effects must be considered. Tiotropium (long-acting muscarinic antagonist) by mist inhaler may be used as add-on therapy in children aged 6 years and older; it modestly improves lung function and reduces exacerbations247 (Evidence A) largely independent of baseline IgE or blood eosinophils].261 If not trialed before, LTRA could be added (see note above about FDA warning).215 Add-on theophylline is not recommended for use in children due to lack of efficacy and safety data.
STEP 5
Preferred treatment at Step 5 in adults, adolescents and children: refer for expert assessment, phenotyping, and add-on therapy
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 asthma144 (Evidence D).
In severe asthma, as in mild-moderate asthma,262 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 regulatory studies evaluating biologic therapy.263
The GINA Pocket Guide and decision tree on Diagnosis and Management of difficuIt-to-treat and severe asthma in adolescent and adult patients are included in Chapter 3E (p.101). Treatment options that may be considered after optimization of existing therapy may include the following (always check local eligibility and payer criteria):
3. Treating to control symptoms and minimize future risk
69
Combination high dose ICS-LABA: this may be considered in adults and adolescents, but for most patients, the increase in ICS dose generally provides little additional benefit128'135,240 (Evidence A), and there is an increased risk of side-effects, including adrenal suppression.264 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 theophylline218,259 Evidence B).
Add-on long-acting muscarinic antagonists (LAMA) can be prescribed in a separate inhaler for patients aged >6 years (tiotropium), or in a combination ('triple') inhaler for patients aged >18 years (beclometasone-formoterol-glycopyrronium; fluticasone furoate-vilanterol-umeclidinium; mometasone-indacaterol-glycopyrronium) if asthma is not well controlled with medium or high dose ICS-LABA. Adding LAMA to ICS-LABA modestly improves lung function,188,247 251,252 (Evidence A) but not symptoms. In some studies, add-on LAMA modestly increased the time to severe exacerbation requiring oral corticosteroids (Evidence B).188,247-249,252 For patients with exacerbations despite ICS-LABA, it is essential that sufficient ICS is given, i.e. at least medium dose ICS-LABA, before considering adding a LAMA.
Add-on azithromycin (three times a week) can be considered after specialist referral for adult patients with persistent symptomatic asthma despite high dose ICS-LABA. Before considering add-on azithromycin, sputum should be checked for atypical mycobacteria, ECG should be checked for long QTc (and re-checked after a month on treatment), and the risk of increasing antimicrobial resistance should bt^-^OTsidered.265 Diarrhea is more common with azithromycin 500mg 3 times a week.266 Treatment for atld|st 6 months is suggested, as a clear benefit was not seen by 3 months in the clinical trials.266,505 The evidence for this recommendation includes a meta-analysis of two clinical trials266,505 in adults with persistent as$ma symptoms that found reduced asthma exacerbations among those taking medium or high dose ICS-L^pA who had either an eosinophilic or non-eosinophilic profile and in those taking high dose ICS-LABAlp. (Evidence B) The option of add-on azithromycin for adults is recommended only after specialist consultation because of the potential for development of resistance at the patient or population level.266
Add-on anti-immunoglobulin E (anti-lgE) (omafejjmab) treatment: for patients aged >6 years with moderate or severe allergic asthma that is uncontrolled on Step 4-5 treatment268,269 (Evidence A).
Add-on anti-interleukin-5/5R treatment (subcutaneous mepolizumab for patients aged >6 years; intravenous reslizumab for ages >18 years or subcutaneous benralizumab for ages >12 years), with severe eosinophilic asthma that is uncontrolled on Step 4-5 treatment (Evidence A).270 274 Efficacy data for mepolizumab in children 6-11 years are limited to one very small open label uncontrolled study.275
Add-on anti-interleukin-4R a treatment (subcutaneous dupilumab) for patients aged >12 years with severe Type 2 asthma, or requiring treatment with maintenance OCS (Evidence A).276 278
Sputum-guided treatment: for adults with persisting symptoms and/or exacerbations despite high dose ICS or ICS-LABA, treatment may be adjusted based on eosinophilia (>3%) in induced sputum. In severe asthma, this strategy leads to reduced exacerbations and/or lower doses of ICS174 (Evidence A), but few clinicians currently have access to routine sputum testing.
Add-on treatment with bronchial thermoplasty: may be considered for some adult patients with severe asthma144,279 (Evidence B). Evidence is limited and in selected patients (see p.76). 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 asthma144 (Evidence D), but are often associated with substantial side effects280 282 (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 5 treatment, and after exclusion of other contributory factors and other add-on treatments including biologies where available and affordable. Patients should be counseled about potential side-effects.281 They should be assessed and monitored for risk of adrenal suppression and
3. Treating to control symptoms and minimize future risk
corticosteroid-induced osteoporosis, and those expected to be treated for>3 months should be provided with relevant lifestyle counseling and prescription of therapy for prevention of osteoporosis (where appropriate).283
•   Maintenance and reliever therapy (MART) with ICS-formoterol: there is no direct evidence about initiating MART in patients receiving add-on treatment such as LAMA or biologic therapy, but switching a patient from MART to conventional ICS-LABA plus as-needed SABA may increase the risk of exacerbations.
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.284 In severe and chronically under-treated disease, it may take longer.285
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.286 The frequenQrofvisits depends upon the patient's initial level of control, their response to treatment, and their level of engagemeRfith 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 scheduled287 (Evidence D).
Stepping up asthma treatment
Asthma is a variable condition, and periodic treatment adjustments by the clinician and/or the patient may be needed.288
• Day-to-day adjustment: For patients whose reliever inhaler is combination budesonide-formoterol or beclometasone-formoterol (with or without maintenance ICS-formoterol), the patient adjusts the number of as-needed doses of ICS-formoterol from day to day according to their symptoms. This strategy reduces the risk of developing a severe exacerbation requiring oral corticosteroids within the next 3-4 weeks.192289290
• Short-term step up (for 1-2 weeks): A short-term increase in maintenance ICS dose for 1-2 weeks may be necessary; for example, during viral infections or seasonal allergen exposure. This may be initiated by the patient according to their written asthma action plan (Box 4-2, p.61), or by the health care provider.
• Sustained step up (for at least 2-3 months): 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 technique may benefit from increasing the maintenance dose to medium. A step up in tf4frtment may be recommended (Box 3-5, p.31) if the symptoms are confirmed to be due to asthma; inhaler technique and adherence are satisfactory; and modifiable risk factors such as smoking have been addressed (Box 3-8, p.38). Any step-up should be regarded as a therapeutic trial, and the response reviewed after 2-3 months. If there is no response, treatment should be reduced to the previous level, and alternative treatment options or referral considered.
Stepping down treatment when asthma is well controlled
Once good asthma control has been achieved and maintained for 3 months and lung function has reached a plateau, treatment can often be successfully reduced, without loss of asthma control. The aims of stepping down are:
• To find the patient's minimum effective treatment, i.e. to maintain good control of symptoms and exacerbations, 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,291 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.168,169
3. Treating to control symptoms and minimize future risk
71
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,292,293 and a low baseline FEW293 Other predictors of loss of control during dose reduction include airway hyperresponsiveness and sputum eosinophilia,294 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.
/</
How to step asthma treatment down
Decisions about treatment step-down should be made on an individual patient level. In one study of patients with well-controlled asthma on medium dose ICS-LABA, reducing the ICS dose and removirgiNie LABA had similar effects on a composite treatment failure outcome. However, stopping LABA was associated with lower lung function and more hospitalizations; and decreasing the ICS dose was inferior to maintaining a st^Ote dose of ICS-LABA.295
If treatment is stepped down too far or too quickly, exacerbation risk maWircrease even if symptoms remain reasonably controlled296 (Evidence B). To date, higher baseline FeNO has not beeOfound to be predictive of exacerbation following step-down of ICS dose.297,298 A meta-analysis of several step-dowK^saidies, most with small numbers, suggested that greater reduction in ICS dose may be able to be achieved in paijgwts with baseline FeNO <50 ppb, but the findings point to the need for further research.298
Complete cessation of ICS is associated with a significantly increased risk of exacerbations299 (Evidence A).
Step-down strategies for different controller treatments are summarized in Box 3-7, p.73; these are based on current evidence, but more research is needed. Only a s*™tl number of step-down studies have been performed in children.
72
3. Treating to control symptoms and minimize future risk
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.36), for example a history of exacerbations in the past year,292 or persistent airflow limitation, step down only with 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.36); provide clear instructions; provide a written asthma action plan (Box 4-2, p.123) 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 patients300 (Evidence A).
Current     Current medication step and dose
Options for stepping down
Evidence
Step 5	High dose ICS-LABA plus oral corticosteroids (OCS)	• Continue high dose ICS-LABA and reduce OCS dose • Use sputum-guided approach to reducing OCS • Alternate-day OCS treatment • Replace OCS with high dose ICS	D B D D
	High dose ICS-LABA plus other add-on agents	•    Refer for expert advice	D
Step 4	Moderate to high dose ICS-LABA maintenance treatment	• Continue combinatr^vTCS-LABA with 50% reduction in ICS component, by using available formulations • Discontinuing LABA may lead to deterioration301	B A
	Medium dose ICS-formoterol* as maintenance and reliever	•    Reduce maintenance ICS-formoterol* to low dose, and continue as-needed low dose ICS-formoterol* reliever	D
	High dose ICS plus second controller	•    Reduce ICS dose by 50% and continue second controller300	B
Step 3	Low dose ICS-LABA maintenance	\f   Reduce ICS-LABA to once daily •    Discontinuing LABA may lead to deterioration301	D A
	Low dose ICS-formoterol* as maintenance and ceftever	•    Reduce maintenance ICS-formoterol* dose to once daily and continue as-needed low dose ICS-formoterol* reliever	C
	Medium or high dose ICS	.    Reduce ICS dose by 50%300 •    Adding LTRA| may allow ICS dose to be stepped down302	A B
Step 2	Low dose ICS	• Once-daily dosing (budesonide, ciclesonide, mometasone)303 304 • Switch to as-needed low dose ICS-formoterol168'169'171 .    Switch to taking ICS whenever SABA is taken196'197199	A A B
	Low dose ICS or LTRA	• Switch to as-needed low dose ICS formoterol168"171 • Complete cessation of ICS in adults and adolescents is not advised as the risk of exacerbations is increased with SABA-only treatment299	A A
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 orBDP-formoterol. fNote FDA warning on neuropsychiatry effects with montelukast.215
3. Treating to control symptoms and minimize future risk
73
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.108 There is increasing research interest in identifying at-risk patients (Box2-2B, p.36), 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 potentially modifiable risk factors to reduce exacerbations
Risk factor                                             Treatment strategy Evidence		
Any patient with >1 risk factor for exacerbations (including poor symptom control)	• Ensure patient is prescribed an ICS-containing controller. • Maintenance and reliever therapy (MART) with ICS-formoteroLi^duces risk of severe exacerbations compared with if the reliever is SABA.\^ • Ensure patient has a written action plan appropriate for their health literacy. • Review patient more frequently than low-risk patients. • Check inhaler technique and adherence frequently^ • Identify any modifiable risk factors (Box 2-2, p.36).	A A A A A D
>1 severe exacerbation in last year	• ICS-formoterol maintenance and reliever re^mnen reduces risk of severe exacerbations compared with if the reliever is SABA. • Consider stepping up treatment if no modifiable risk factors. • Identify any avoidable triggers for£$ercerbations.	A A C
Exposure to tobacco smoke	• Encourage smoking cessation by patient/family; provide advice and resources. • Consider higher dose of ICS-if asthma poorly controlled.	A B
Low FEVi, especially if <60% predicted	• Consider trial of 3 months' treatment with high dose ICS. • Consider 2 weeks' OCS, but take short- and long-term risks into account • Exclude other lur^JWisease, e.g. COPD. • Refer for expert advice if no improvement.	B B D D
Obesity	• Strategies for weight reduction • Distinguish asthma symptoms from symptoms due to deconditioning, mechanical restriction, and/or sleep apnea.	B D
Major psychological problems	• Arrange mental health assessment. • MHelp patient to distinguish between symptoms of anxiety and asthma; provide advice about management of panic attacks.	D D
Major socioeconomic problems	•   Identify most cost-effective ICS-based regimen.	D
Confirmed food allergy	•   Appropriate food avoidance; injectable epinephrine.	A
Allergen exposure if sensitized	• Consider trial of simple avoidance strategies; consider cost. • Consider step up of controller treatment. • Consider adding SLIT in symptomatic adult HDM-sensitive patients with allergic rhinitis despite ICS, provided FEVi is >70% predicted.	C D B
Sputum eosinophilia (limited centers)	•   Increase ICS dose independent of level of symptom control.	A*
COPD: chronic obstructive pulmonary disease; FEV^ 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.77 for more information about non-pharmacological interventions.
74
3. Treating to control symptoms and minimize future risk
The potential for local and/or systemic side-effects of medications can be minimized by ensuring correct inhaler technique (Box 3-12, p.87), 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.73).
OTHER THERAPIES
Allergen immunotherapy
Allergen-specific immunotherapy may be a treatment option where allergy plays a prominent role, including asthma with allergic rhinoconjunctivitis.305,306 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.307
GINA plans to review evidence about allergen immunotherapy for asthma during 2021, and will update its advice based on the findings.
Subcutaneous immunotherapy (SCIT)
SCIT involves the identification and use of clinically relevant allergens, and administration of extracts in progressively higher doses to induce desensitization and/or tolerance. European physicians tend to favor single allergen immunotherapy whereas Northern American physicians often prescribe multiple allergens for treatment.308 In people with asthma and allergic sensitization, SCIT is associated with a reduction in symptom scores and medication requirements, and improved allergen-specific and non-specific airway hyperresponsiveness.308
For SCIT, analysis of pooled safety data from clinical trials and post-marketing surveillance in house dust mite allergic respiratory disease suggests the incidence of advetee'drug reactions is approximately 0.5%.309 Studies to date suggest that serious adverse effects of SCIT are uncommon, but may include life-threatening anaphylactic reactions.
Advice
• Compared to pharmacological and awsibance options, potential benefits of SCIT must be weighed against the risk of adverse effects and the inconvenience and cost of the prolonged course of therapy, including the minimum half-hour wait required after each injection (Evidence D).
Sublingual immunotherapy (SLIT)
Modest effects were ideprfSfed in a systematic review of SLIT for asthma in adults and children,306'310,311 but there was concern about the design of many of the studies.312 The evidence for important outcomes such as exacerbations and quality of life remains limited.313 There are few studies comparing SLIT with pharmacological therapy for asthma.314 A trial of SLIT for house dust mites (HDM) in patients with asthma and HDM allergic rhinitis demonstrated a modest reduction of ICS with high dose SLIT.238 In another study in patients with asthma and HDM allergic rhinitis, SLIT added to low or medium dose ICS showed increased time to exacerbation during ICS reduction in suboptimally controlled asthma.237
Side effects315317 from SLIT for inhalant allergens are predominantly limited to oral and gastrointestinal symptoms.306 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 FEVi 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.
3. Treating to control symptoms and minimize future risk
75
Vaccinations
Influenza causes significant morbidity and mortality in the general population, and contributes to some acute asthma exacerbations. In 2020, many countries saw a reduction in influenza-related illness, likely due to the handwashing, masks and social/physical distancing introduced because of the COVID-19 pandemic.
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,318 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.319. There is no evidence for an increase in asthma exacerbations after influenza vaccination compared to placebo.319 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 pneumococca^Jsease,320 but there is insufficient evidence to recommend routine pneumococcal vaccination in people with asthma.321
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).
• Advice about COVID-19 vaccination is on p.18.
• The current recommendation is for a gap of 14 days between COVID-19 vaccination and influenza vaccination. Bronchial thermoplasty
Bronchial thermoplasty is a potential treatment option at Step's in some countries for adult patients whose asthma remains uncontrolled despite optimized therapeutic regimens and referral to an asthma specialty center (Evidence B). Bronchial thermoplasty involves treatment of the airw&ys during three separate bronchoscopies with a localized radiofrequency pulse.120 The treatment is associated with a large placebo effect.120 In patients taking high dose ICS-LABA, bronchial thermoplasty was associated with an increase in asthma exacerbations during the 3 month treatment period, and a subsequent decrease in exacerbations, but no beneficial effect on lung function or asthma symptoms compared with sham-controlled patients.120 Extended follow up of some treated patients reported a sustained reduction in exacerbations compared with pre-treatment.322 However, longer-term follow up of larger cohorts comparing effectiveness and safety, including^jgnung function, in both active and sham-treated patients is needed.
Advice
• For adult patients whose asthma remains uncontrolled despite optimization of asthma therapy and referral to a severe asthma specialty center, bronchial thermoplasty is a potential treatment option at Step 5 in some countries (Evidence B).
• Caution should be used in selecting patients for this procedure. The number of studies is small, people with chronic sinus disease, frequent chest infections or FEVi <60% predicted were excluded from the pivotal sham-controlled study, and patients did not have their asthma treatment optimized before bronchial thermoplasty was performed.
• Bronchial thermoplasty should be performed in adults with severe asthma only in the context of an independent Institutional Review Board-approved systematic registry or a clinical study, so that further evidence about effectiveness and safety of the procedure can be accumulated.144
Vitamin D
Several cross-sectional studies have shown that low serum levels of Vitamin D are linked to impaired lung function, higher exacerbation frequency and reduced corticosteroid response.323 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.324 In a meta-analysis, benefit for worsening asthma was seen in some studies, but to date, there is
76
3. Treating to control symptoms and minimize future risk
no good-quality evidence that Vitamin D supplementation leads to improvement in asthma control or reduction in exacerbations.325 327 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 smoking and ETS	• At every visit, strongly encourage people with asthma who smoke to quit. Provide access to counseling and smoking cessation programs (if available).	A
exposure	• Advise parents/carers of children with asthma not to smoke and not to allow smoking in rooms or cars that their children use.	A
	• Strongly encourage people with asthma to avoid environmental smoke exposure.	B
	• Assess smokers/ex-smokers for COPD or overlapping features of asthma and COPD (asthma-COPD overlap, ACO, Chapter 5, p.135), as additional treatment strategies may be required.	D
Physical activity	• Encourage people with asthma to engage in regulaf£pnysical activity for its general health benefits.	A
	• Provide advice about prevention of exercise-induced bronchoconstriction with regular ICS.	A
	• Provide advice about prevention of breakthrough exercise-induced bronchoconstriction with o   warm-up before exercise o    SABA before exercise o    low dose ICS-formotero>l9^fore exercise.	A A B
	• Regular physical activity improves cardiopulmonary fitness, and can have a small benefit for asthma control and lung function, including with swimming in young people with asthma.	B
	• There is little evide^ra'to recommend one form of physical activity over another.	D
Avoidance of occupational exposures	• Ask all patients with adult-onset asthma about their work history and other exposures.	D
	• In manaasfiieYit of occupational asthma, identify and eliminate occupational sensitizers as soon as possible, and remove sensitized patients from any further exposure to these agents.	A
	• Patients with suspected or confirmed occupational asthma should be referred for expert assessment and advice, if available.	A
Avoidance of medications that may make asthma worse	• Always ask about asthma before prescribing NSAIDs, and advise patients to stop using them if asthma worsens.	D
	• Always ask people with asthma about concomitant medications.	D
	• Aspirin and NSAIDs (non-steroidal anti-inflammatory drugs) are not generally contraindicated unless there is a history of previous reactions to these agents (see p.99).	A
	• Decide about prescription of oral or ophthalmic beta-blockers on a case-by-case basis. Initiate treatment under close medical supervision by a specialist.	D
	• If cardioselective beta-blockers are indicated for acute coronary events, asthma is not an absolute contra-indication, but the relative risks/benefits should be considered.	D
Healthy diet	• Encourage patients with asthma to consume a diet high in fruit and vegetables for its general health benefits.	A
3. Treating to control symptoms and minimize future risk
77
Box 3-9 (continued)    Non-pharmacological interventions - Summary
Intervention	Advice/recommendation	Evidence
Avoidance of indoor allergens	• Allergen avoidance is not recommended as a general strategy in asthma.	A
	• For sensitized patients, there is limited evidence of clinical benefit for asthma in most circumstances with single-strategy indoor allergen avoidance.	A
	• Remediation of dampness or mold in homes reduces asthma symptoms and medication use in adults.	A
	• For patients sensitized to house dust mite and/or pets, there is limited evidence of clinical benefit for asthma with avoidance strategies (only in children).	B
	• Allergen avoidance strategies are often complicated and expensive, and there are no validated methods for identifying those who are likely to benefit.	D
Weight reduction	• Include weight reduction in the treatment plan for obese patients with asthma.	B
	• For obese adults with asthma a weight reduction program plus twice-weekly aerobic and strength exercises is more effective for symptom control than weight reduction atáffě^	B
Breathing exercises	• Breathing exercises may be a useful supplement to asthma pharmacotherapy for symptoms and quality of life, but they do not reduce exacerbation risk or have consistent effects on lung function.	A
Avoidance of indoor air pollution	• Encourage people with asthma to use non-polluting heating and cooking sources, and for sources of pollutants to be vented outdoors where possible.	B
Avoidance of outdoor allergens	• For sensitized patients, when pollen and mold counts are highest, closing windows and doors, remaining indoors, and using air conditioning may reduce exposure to outdoor allergens.	D
Dealing with emotional stress	• Encourage patients to identify goals and strategies to deal with emotional stress if it makes their asthma worse.	D
	• There is insufficient evidence to^roport one stress-reduction strategy over another, but relaxation strategies and breathing exercises may be helpful.	B
	• Arrange a mental health>af^essment for patients with symptoms of anxiety or depression.	D
Avoidance of outdoor air pollutants/weather conditions	• During unfavorable environmental conditions (very cold weather or high air pollution) it may be helpful to stay indoors in a climate-controlled environment, and to avoid strenuous outdoor physical activity; and to avoid polluted environments during viral infections, if feasible.	D
Avoidance of foods and food	• Food avoidance should not be recommended unless an allergy or food chemical sensitivity has been clearly demonstrated, usually by carefully supervised oral challenges.	D
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 sensitivity often decreases when asthma control improves.	D
NSAID: non-steroidal anti-inflammatory drugs; SABA: short-acting beta2-agonist. Interventions with highest level evidence are shown first.
78
3. Treating to control symptoms and minimize future risk
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, chronic obstructive pulmonary disease (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.328 After smoking cessation, lung function improves and airway inflammation decreases.329 Reduction of passive smoke exposure improves asthma control and reduces hospital admissions in adults and children.330
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).
• Strongly encourage people with asthma to avoid environmental smoke exposure {Science B).
• Advise parents/carers of children with asthma not to smoke and not to allow saving in rooms or cars that their children use (Evidence A).
• Assess patients with a >10 pack-year smoking history for COPD or asthma^COPD overlap, as additional treatment strategies may be required (see Chapter 5, p.135).
A
<?
Physical activity
For people with asthma, as in the general population, regular moderate physical activity has important health benefits including reduced cardiovascular risk and improved quality sttafe. There is some evidence that aerobic exercise training can have a small beneficial effect on asthma symptom control and lung function, although not airway inflammation.331 Improved cardiopulmonary fitness may reduce the risk of dyspnea unrelated to airflow limitation being mistakenly attributed to asthma. In one study of non-obese patients with asthma, high intensity interval training together with a diet with high protein and low glycemic index improved asthma symptom control, although no benefit on lung function was seen.332 In young people with asthma, swimmmg training is well tolerated and leads to increased lung function and cardio-pulmonary fitness;333 however, there are some concerns about exposure to chlorine and trichloramine with indoor pools.43
Exercise is an important cause of^Nnma symptoms for many asthma patients, but EIB can usually be reduced with maintenance ICS.43 Breakthrough exercise-related symptoms can be managed with warm-up before exercise,43 and/or by taking SABA43 or low dose ICS-formoterol195 before or during exercise.
Advice
• Encourage people with asthma to engage in regular physical activity because of its general health benefits (Evidence A). However, regular physical activity confers no specific benefit on lung function or asthma symptoms perse, 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.334 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.40. Cost-effective minimization of latex sensitization can be achieved by using non-powdered low-allergen gloves instead of powdered latex gloves.40
3. Treating to control symptoms and minimize future risk
79
Advice
• Ask all patients with adult-onset asthma about their work history and other exposures (Evidence D).
• 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.335 Beta-blocker drugs, including topical ophthalmic preparations, may cause bronchospasm336 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.337
Xv'
Advice
• Always ask people with asthma about concomitant medications, including eyedrops (Evidence D).
• Always ask about asthma and previous reactions before prescribing NSAIDs, and advise patients to stop using these medications if asthma worsens.
• Aspirin and NSAIDs are not generally contraindicated in asthma unless there is a history of previous reactions to these agents (Evidence A). (See 'Aspirin-exacerbated respiratory disease', p.99)
• For people with asthma who may benefit from oral or ophthalmic beta-blocker treatment, a decision to prescribe these medications should be made on a case-by-case basis, and treatment should only be initiated under close medical supervision by a specialist (Evidence D).
• Asthma should not be regarded as an absolute contraindicaWn to use cardioselective beta-blockers when they are indicated for acute coronary events, but the relative risks and benefits should be considered (Evidence D). The prescribing physician and patient should be aware of the risks and benefits of treatment.338
Avoidance of indoor allergens
Because many asthma patients react to multiple factors that are ubiquitous in the environment, avoiding these factors completely is usually impractical and very burdensome for the patient. Medications to maintain good asthma control have an important role because patients are often less affected by environmental factors when their asthma is well-controlled.
There is conflicting evidence about whether measures to reduce exposure to indoor allergens are effective at reducing asthma symptoms.339,340 The majority of single interventions have failed to achieve a sufficient reduction in allergen load to lead to clinical improvem^oT339,341 342 It is likely that no single intervention will achieve sufficient benefits to be cost effective (Box 3-10, p.81). 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.343
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.344 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.345 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.346
Furred pets: complete avoidance of pet allergens is impossible for sensitized patients as these allergens are ubiquitous outside the home347 in schools,348 public transport, and even cat-free buildings, probably transferred on clothes.348
80
3. Treating to control symptoms and minimize future risk
Although removal of such animals from the home of a sensitized patient is encouraged,349 it can be many months before allergen levels decrease,350 and the clinical effectiveness of this and other interventions remains unproven.351
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.352 High level evidence for the effectiveness of removing rodents is lacking, as most integrated pest management interventions also remove other allergen sources;352 one non-sham-controlled study showed comparable clinical improvement with pest reduction education and integrated pest management.353
Box 3-10. Effectiveness of avoidance measures for indoor allergens
Measure	Evidence of effect on allergen levels	Evidence of clinical benefit
House dust mites		
Encase bedding in impermeable covers	Some (A)	/ Adults - none (A) Children - some (A)
Wash bedding on hot cycle (55-60°C)	Some (C)	None(D)
Replace carpets with hard flooring	Some (B)	None(D)
Acaricides and/or tannic acid	Weak (C)	None(D)
Minimize objects that accumulate dust	None(D)	None(D)
Vacuum cleaners with integral HEPA filter and double-thickness bags	............._______________________________________________________ Weak (C)	None(D)
Remove, hot wash, or freeze soft toys	None(D)	None
Pets		
Remove cat/dog from the home	Weak (C)	None(D)
Keep pet from the main living areas/bedroojn<§~	Weak (C)	None(D)
HEPA-filter air cleaners	Some (B)	None (A)
Wash pet	Weak (C)	None(D)
Replace carpets with hard flooring	None(D)	None(D)
Vacuum cleaners with integral HEPA filter and double-thickness bags	None(D)	None(D)
Cockroaches		
Bait plus professional extermination of cockroaches	Minimal (D)	None(D)
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 al:
3. Treating to control symptoms and minimize future risk
81
Cockroaches: avoidance measures for cockroaches are only partially effective in removing residual allergens355 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.356 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.357
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 whp^e likely to benefit (Evidence D).
Healthy diet
In the general population, a diet high in fresh fruit and vegetables has many health benefits, including prevention of many chronic diseases and forms of cancer. Many epidemiological studies report that a high fruit and vegetable diet is associated with a lower risk of asthma and lung function decline. There is some evidence that increasing fruit and vegetable intake leads to an improvement in asthma control and a reduced risk of exacerbations.358
. o
Advice
• Encourage patients with asthma to consume a diet high in fruit and vegetables for its general health benefits (Evidence A).
✓
Weight reduction for obese patients
Asthma can be more difficult to control in obese patients,359 361 the risk of exacerbations is greater,92,93 and response to ICS may be reduced.362 There is limited evidence about the effect of weight loss on asthma control. Studies have ranged from dietary restriction to multifactociiWnterventions with exercise training and cognitive behavioral therapy, but populations have generally been small, and interventions and results have been heterogeneous.363 In some studies, weight loss has improved asthma control, lung function and health status, and reduced medication needs in obese patients with asthma.364,365 The moj-^jstriking results have been observed after bariatric surgery,366,367 but even 5-10% weight loss with diet, with or witlmit exercise, can lead to improved asthma control and quality of life.368
Advice
• 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 with no consistent effect on lung function and no reduction in risk of exacerbations.369
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.370 This suggests that perceived improvement with breathing exercises may be largely due to factors such
82
3. Treating to control symptoms and minimize future risk
as relaxation, voluntary reduction in use of rescue medication, or engagement of the patient in their care. The cost of some commercial programs may be a potential limitation.
Breathing exercises used in some of these studies are available at www.breathestudy.co.uk371 and www.woolcock.orq.au/moreinfo.370
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 health include nitric oxide, nitrogen oxides, carbon monoxide, carbon dioxide, sulfur dioxide, formaldehyde, and biologicals (endotoxin).372,373 Sources include cooking and heating devices, particularly if they are not externally flued (vented). Installation of non-polluting, more effective heating (heat pump, wood pellet burner, flued gas) in the homes of children with asthma does not significantly improve lung function but significantly reduces symptoms of asthma, days off school, healthcare utilization, and pharmacist visits.374
Advice
• Encourage people with asthma to use non-polluting heating and cooking sources, and for sources of pollutants to be vented outdoors where possible (Evidence B).
Strategies for dealing with emotional stress
Emotional stress may lead to asthma exacerbations in children^and adults. Hyperventilation associated with laughing, crying, anger, or fear can cause airway narrowing.376,377 Panic attacks have a similar effect.378,379 However, it is important to note that asthma is not primarily a psychosomatic disorder. During stressful times, medication adherence may also decrease.
Advice
• Encourage patients to identify goals and strategies to deal with emotional stress if it makes their asthma worse (Evidence D).
• There is insufficient evidence to support one strategy over another, but relaxation strategies and breathing exercises may be helpful in reducing asthma symptoms (Evidence B).
• Arrange a mental health asse^Sjment for patients with symptoms of anxiety or depression (Evidence D).
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.98 Proximity to main roads at home and school is associated with greater asthma morbidity.380 Certain weather and atmospheric conditions like thunderstorms381,382 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
3. Treating to control symptoms and minimize future risk
83
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.383
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, where possible, 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.94
Food chemicals, either naturally occurring or added during processing, may also trigger asthma symptoms especially when asthma is poorly controlled. Sulfites (common food and drug preservatives found uraiich foods as processed potatoes, shrimp, dried fruits, beer, and wine) have often been implicated in causing severe asthma exacerbations.384 However, the likelihood of a reaction is dependent on the nature of the food, the lecar^and form of residual sulfite, the sensitivity of the patient, and the mechanism of the sulfite-induced reaction.384 TiQ>ře is little evidence to support any general role for other dietary substances including benzoate, the yellow dye, tartrazine, and monosodium glutamate in worsening asthma.
Advice
• Ask people with asthma about symptoms associated with any specific foods (Evidence D).
• Food avoidance should not be recommended unless an allera^or food chemical sensitivity has been clearly demonstrated (Evidence D), usually by carefully supervised oral challenges.94
• If food allergy is confirmed, food allergen avoidance can reduce asthma exacerbations (Evidence D).
• If food chemical sensitivity is confirmed, complete avoidance is not usually necessary, and sensitivity often decreases when overall asthma control improves (Evidence D).
84
3. Treating to control symptoms and minimize future risk
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 foi^reatment
Suspected occupational asthma
• Refer for confirmatory testing and identification of sensitizing or irritant ageaKspecific advice about eliminating exposure and pharmacological treatment. See specific guidelines40 for deratfe.
Persistent or severely uncontrolled asthma or frequent exacerbations
• Patient's symptoms remain uncontrolled, or patient has ongoing exacerbations or low lung function despite correct inhaler technique and good adherence with Step 4 treatment (medium dose ICS-LABA, Box 3-5, p.59). Before referral, depending on the clinical context, identify and treai^modifiable risk factors (Box 2-2, p.36; Box 3-8, p.74) and comorbidities (p.92).
• Patient has frequent asthma-related health care utilization (e.g. multiple ED visits or urgent primary care visits).
• See Section 3E (p.101) on difficult to treat and severe asthma, including a decision tree.
Any risk factors for asthma-related death (see Box 4-1, p.119)
• Near-fatal asthma attack (ICU admission, or mechanical ventilation for asthma) at any time in the past
• Anaphylaxis or confirmed food allergy in a patient with asthma
Evidence of, or risk of, significant treatment side-effects
_N. X_
• Patients with significant sid&^rfects from treatment
• Need for long-term oral corticosteroid use
• Frequent courses of oral corticosteroids (e.g. two or more courses a year) Symptoms suggesting complications or sub-types of asthma
• e.g. aspirin-exacerbated respiratory disease (p.99); 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.6_D 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.152.
3. Treating to control symptoms and minimize future risk
85
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.
In developing, customizing and evaluating self-management interventions for different cuMwes, sociocultural factors should be taken into account.385
SKILLS TRAINING FOR EFFECTIVE USE OF INHALER DEVICES
Delivery of respiratory medications by inhalation achieves a high concentratjessfn the airways, more rapid onset of action, and fewer systemic adverse effects than systemic delivery. However,, using an inhaler is a skill that must be learnt and maintained in order for the medication to be delivered effectively.
Poor inhaler technique leads to poor asthma control, increased risk of exacerbations and increased adverse effects.91 Most patients (up to 70-80%) are unable to use their inhaler correctly. Unfortunately, many health care providers are unable to correctly demonstrate how to use the inhalers the^otescribe.386 Most people with incorrect technique are unaware that they have a problem. There is no 'perfect' inhaler - patients can have problems using any inhaler device.
Strategies for ensuring effective use of inhaler device^Tre summarized in Box 3-12, p.87.387
These principles apply to all types of inhaler devils. For patients prescribed pressurized metered dose inhalers (pMDIs), use of a spacer improves delivery and (for ICS) reduces the potential for local side-effects such as dysphonia and oral candidiasis.388 With ICS, the risk of candidiasis can also be reduced by rinsing and spitting out after use.
Checking and correcting inhaler techrw&ue using a standardized checklist takes only 2-3 minutes and leads to improved asthma control in adults389,390 and older children387 (Evidence A). A physical demonstration is essential to improve inhaler technique.391 This is easiest if the health care provider has placebo inhalers and a spacer. After training, inhaler technique falls off with time, so checking and re-training must be repeated regularly. This is particularly important for patients with poor symptom control or a history of exacerbations. Attaching a pictogram392 or a list of inhaler technique steps393 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.387,394 396
Some inhaler devices and techniques for their use are illustrated on the GINA website (www.ginasthma.org) and the ADMIT website (www.inhalers4u.org).
86
3. Treating to control symptoms and minimize future risk
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.59), 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.
Ask the patient to show you how they use their inhaler (don't just ask if they knowlft>w to use it). Identify any errors using a device-specific checklist._^ ?_
CORRECT
Show the patient how to use the device correctly with a physical demonstration, e.g. using a placebo inhaler. Check technique again, paying attention to problematic steps. You may need to repeat this process 2-3 times.389 Only consider an alternative device if the patient cannot use Ufe)inhaler correctly after several repeats of training. Re-check inhaler technique frequently. After initial training, errors often recur within 4-6 weeks.397
CONFIRM
Clinicians should be able to demonstrate correct technique for each of the inhalers they prescribe. Pharmacists and nurses can provide highly effective inhaler skills training.394'395_
ADHERENCE WITH MEDICATIONS AND OTHER ADVICE
Identifying poor adherence
Poor adherence is defined as tbg^ailure of treatment to be taken as agreed upon by the patient and the health care provider. There is increasing awareness of the importance of poor adherence in chronic diseases, and of the potential to develop interventions to improve adherence.398 Approximately 50% of adults and children on long-term therapy for asthma fail to take medications as directed at least part of the time.399
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.88 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;400 and drug assay such as for prednisolone.401
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.88. They include both intentional and unintentional factors. Issues such as ethnicity,402 health literacy,403,404 and numeracy159 are often overlooked. Patients' concerns about side-effects may be either real or perceived.291,405
3. Treating to control symptoms and minimize future risk
87
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.150,153
• Inhaler reminders, either proactively or for missed doses, improved adherence and reduced exacerbations and oral corticosteroid use.406 408
• 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.409
• 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.410
• 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.411
• In one study, directly observed controller medication administration at school, combined with telemedicine oversight, was associated with more symptom-free days and fewer urgent visits than usual care.412
Improving adherence to controller medications may not necessarily translate to improved clinical outcomes.413 Further studies are needed of adherence strategies that are feasible for implementation in primary care.
AT
Box 3-13. Poor medication adherence in asthma Factors contributing to poor adherence
Medication/regimen factors
Difficulties using inhaler device (e.g. arthritis) Burdensome regimen (e.g. multiple times per day) Multiple different inhalers Unintentional poor adherence
Misunderstanding about instructions Forgetfulness Absence of a daily routine Cost
Intentional poor adherence .
Perception that treatment is not necessary Denial or anger about asthma or its treatment Inappropriate expectations Concerns about side-effects (real or perceived) Dissatisfaction with health care providers Stigmatization Cultural or religious issues Cost
Examples of successful adherence interventions
Shared decision-making for medication/dose choice150,153 Inhaler reminders, either proactively or for missed doses406 408 Prescribing low dose ICS once-daily versus twice-daily416 Home visits for a comprehensive asthma program by an asthma nurse409
How to identify poor adherence in clinical practice
Ask a^empathic question
^^Acknowledge the likelihood of incomplete adherence and encourage an open non-judgmental discussion. Examples are:
o   '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, 2, 3 or more days a week?'4U
o   'Do you find it easier to remember your inhaler in the morning or the evening?'
Check medication usage
• Check the date of the last controller prescription
• Check the date and dose counter on the inhaler
• In some health systems, prescribing and dispensing frequency can be monitored electronically by clinicians and/or pharmacists
• See review articles for more detail.149,415
88
3. Treating to control symptoms and minimize future risk
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.417 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.418
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.419 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 pictorial420,421 information about asthma and its treatment. The GINA website (www.ginasthma.org) contains patient educational materials as well as links to several asthma websites. Patients and their families should be encouraged to make a note of any questions that arise from reading this information or as a result of the consultation, and should be given time to addres^these during the next consultation.
Asthma education and training, for both adults and children, can be delivered effectively by a range of health care providers including pharmacists and nurses394'395'422,423 (Evidence A). Trained lay health workers (also known as community health workers) can deliver discrete areas of respiratory care such as asthma self-management education. Asthma education by trained lay health workers has been found to improve patient outcomes and healthcare utilization compared with usual care,396 424 and to a similar extent as nurse^ed education in primary care425 (Evidence B). These findings suggest the need for additional studies to assess applicability in other settings and populations.
Goal: To provide the person with asthma, their family and other carers with suitable information and training to manage their asthma in partnership with their health care providers
Box 3-14. Asthma information
Approach
Content
Focus on the development q£Hje partnership.
Asthma diagnosis
Accept that this is a conijmTtng process.
Rationale for treatment, and differences between 'relievers' and 'controllers'
Share information.
Adapt the approach to the patient's level of health literacy (Box 3-1, p.45).
Potential side-effects of medications
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
3. Treating to control symptoms and minimize future risk
89
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:151
• 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 adults151,396,426 (Evidence A) and children152 426 (Evidence A). Benefits include reduction of one-third to two-thirds in asthma-related hospitalizations, emergency department visits and unscheduled doctor or gM visits, missed work/school days, and nocturnal wakening.151 It has been estimated that the implementation of a self-management program in 20 patients prevents one hospitalization, and successful completion of such a program by 8 patients prevents one emergency department visit.151 427 Less intensive interventions that involve self-management education but not a written action plan are less effective,428 and information alone is ineffective^9 A systematic meta-review of 270 RCTs on supported self-management for asthma confirmed that it reduces unscheduled healthcare use, improves asthma control, is applicable to a wide range of target groups and clinical settings, and does not increase health care costs (Evidence A).426
Self-monitoring of symptoms and/or peak flow
Patients should be trained to keep track of their symptomsiwtwi or without a diary), and notice and take action if necessary when symptoms start to worsen. Peak expiratory flow (PEF) monitoring may sometimes be useful:
• Short-term monitoring
o Following an exacerbation, to monitor recovery
o Following a change in treatment, to help in assessing whether the patient has responded
o If symptoms appear excessive (for objective evidence of degree of lung function impairment)
o To assist in identification of occupational or domestic triggers for worsening asthma control
• Long-term monitoring
o For earlier detection of exacerbations, mainly in patients with poor perception of airflow limitation132
o For patients with a hjslpry of sudden severe exacerbations
o For patients who have d iff icu lt-to-co ntro I or severe asthma
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.143 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 asthma429 (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.430431
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 PEF431 (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 doctor428 (Evidence A).
90
3. Treating to control symptoms and minimize future risk
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.orq.uk; Asthma Society of Canada, www.asthma.ca; Family Physician Airways Group of Canada, www.fpaqc.com; National Asthma Council Australia, www.nationalasthma.orq.au') and in research publications.432,433 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.123).
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 the following:
• Ask the patient if they have any questions and concerns.
Discuss issues, and provide additional educational messages as necessary; if available, refer the patient to someone trained in asthma education.
• Assess asthma control.
Review the patient's level of symptom control and risk factors (Box 2-2, p.36).
Ask about flare-ups to identify contributory factors and whether the patient's response was appropriate (e.g. was an action plan used?).
Review the patient's symptom or PEF diary, if they keep one. Assess comorbidities.
• Assess treatment issues.
Watch the patient use their inhaler, and correct and re-check technique if necessary (Box 3-12 p.87). Assess medication adherence and ask about adherence barriers (Box 3-13, p.88). Ask about adherence with other interventions (e.g. smoking cessation).
Review the asthma action plan and update it if level of asthma control or treatment have changed.434
A single page prompt to clinicians has been shown to improve the provision of preventive care to children with asthma during office visits.435 Follow-up by tele-healthcare is unlikely to benefit in mild asthma but may be of benefit in those with severe disease at risk of hospital admission.429
School-based programs for children
A systematic review found that school-based studies (most conducted in the US and Canada) that included self-management skills for children aged 5-18 years was associated with a 30% decrease in emergency department visits, and a significant decrease in hospitalizations and in days of reduced activity.436
3. Treating to control symptoms and minimize future risk
91
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.
Refer patients with difficult-to-treat or severe asthma to a specialist or severe asthma service, after addressing common problems such as incorrect diagnosis, incorrect inhaler technique, ongoing environmental exposures, and poor adherence (see Section 3E, p.101).
__._izz:__
MANAGING COMORBIDITIES
Several comorbidities are commonly present in patients with asthma, particularly those with difficult-to-treat or severe asthma.93 Active management of comorbidities is recommended because they may contribute to symptom burden, impair quality of life, and lead to medication interactions. Some comorbidities also contribute to poor asthma control.437
Obesity
Clinical features
Being overweight or obese is a risk factor for childhood asthma and wheeze, particularly in girls.438 Asthma is more difficult to control in obese patients.359 362 This may be due to a different type of airway inflammation, contributory comorbidities such as obstructive sleep apnea and gastroesophageal reflux disease (GERD), mechanical factors, or other as yet undefined factors. In addition, lack of fitness and reduction in lung volume due to abdominal fat may contribute to dyspnea.
Diagnosis
Document body mass index (BMI) for all patients with asthma. Because of other potential contributors to dyspnea and wheeze in obese patients, it is important to confirm the diagnosis of asthma with objective measurement of variable expiratory airflow limitation (Box 1-2, p.23). Asthma is more common in obese than non-obese patients,53 but both over-and under-diagnosis of asthma occur in obesity.33,54
Management
As for other patients with asthma, ICS are the mainstay of treatment in obese patients (Evidence B), although their response may be reduced.362 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).368 Weight loss can improve asthma control, lung function, health status and reduces medication needs in obese patients,364,365 but the studies have generally been small, quality of some studies is poor, and the interventions and results have been variable.363 The most striking results have been observed after bariatric surgery,366,367,439 but even 5-10% weight loss can lead to improved asthma control and quality of life.368 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.440
92
3. Treating to control symptoms and minimize future risk
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,437 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.437
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 24-hour pH monitoring or endoscopy may be considered.
Management
A review of proton pump inhibitors in patients with confirmed asthma, most of whom had a diagnosis of GERD, showed a significant but small benefit for morning PEF, but no significant benefit fotjpjwer asthma outcomes.441 In a study of adult patients with symptomatic asthma but without symptoms of GERD ©jatment with high dose proton pump inhibitors did not reduce asthma symptoms or exacerbations.442 In general, benefits of proton pump inhibitors in asthma appear to be limited to patients with both symptomatic reflux and night-time respiratory symptoms.443 Other treatment options include motility agents, lifestyle changes and fundoplicsrfStpn. In summary, symptomatic reflux should be treated, but patients with poorly controlled asthma should not be treated with anti-reflux therapy unless they also have symptomatic reflux (Evidence A). Few data are available tgj children with asthma symptoms and symptoms of GERD.444,445
Anxiety and depression
Clinical features
Psychiatric disorders, particularly depressive and anxiety disorders, are more prevalent among people with asthma.446 Psychiatric comorbidity is also associated with worse asthma symptom control and medication adherence, and worse asthma-related quality of life.447 AflNibus and depressive symptoms have been associated with increased asthma-related exacerbations and emergency visits.448 Panic attacks may be mistaken for asthma.
Diagnosis
Although several tools are available for screening for anxious and depressive symptomatology in primary care, the 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.449 Results for anxiety were conflicting, and none of the studies found significant treatment differences for depression. Drug treatments and cognitive behavior therapy450 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.
3. Treating to control symptoms and minimize future risk
93
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.94 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.451 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.452
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.453 Refer patients with suspected food allergy or intolerance for specialist allergy assessment. This may include appropriate allergy testing such as skin prick testing and/or blood testing for specific IgE. On occasion, carefully supervised food challenges may be needed.
Management
Patients who have a confirmed food allergy that puts them at risk for anaphylaxis must have an epinephrine auto-injector available at all times, and be trained how to use it. They, and their family, must be educated in appropriate food avoidance strategies, and in the medical notes, they should be flagged as being at high risk. It is especially important to 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.
Rhinitis, sinusitis and nasal polyps
Clinical features
Evidence clearly supports a link between diseases of the upper and lower airways.454 Most patients with asthma, either allergic or non-allergic, have concurrent rhinitis, and 10-40% of patients with allergic rhinitis have asthma.455 Depending on sensitization and exposure, allergic rhinitis may be seasonal (e.g. ragweed or grass pollen), perennial (e.g. mite allergens), or intermittent (e.g. furred pets).456 ^
Rhinitis is defined as irritation and inflammation of the mucous membranes of the nose. Allergic rhinitis may be accompanied by ocular symptoms (corrfynctivitis). Rhinosinusitis is defined as inflammation of the nose and paranasal sinuses characterized by more thai\($o symptoms including nasal blockage/obstruction and/or nasal discharge (anterior/posterior nasal drip).457 Other symptoms may include facial pain/pressure and/or a reduction or loss of smell. Sinusitis rarely occurs in the absence of rhinitis.
Rhinosinusitis is defined as acute when symptoms last <12 weeks with complete resolution, and chronic when 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.458 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.459
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)454 recommend intranasal corticosteroids for treatment of allergic rhinitis. In a case-control study, treatment of rhinitis with intranasal corticosteroids was associated with less need
94
3. Treating to control symptoms and minimize future risk
for asthma-related hospitalization and emergency department visits,460 but a meta-analysis found improvement in asthma outcomes only in patients not also receiving ICS.461 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.462
In patients with nasal polyposis, omalizumab,463 mepolizumab464,465 and dupilumab466 improved subjective and objective assessments including nasal symptoms and polyp size, compared with placebo. In patients with chronic sinusitis with nasal polyposis and comorbid asthma, asthma symptom control and lung function were also improved with dupilumab.466
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
Communities with limited resources are found not only in low and middle income countries, but also in affluent nations. In these settings, in general, the GINA strategy may be followed for asthma management at the individual level (Box 3-3), as it offers options for low cost diagnostic procedures, and therapeutic interventions which have been shown to be effective and reduce costs among the underserved.467,468 In dealing with asthma control at the population level (Box 3-3), it is critical to prioritize the most cost-effective approach to asthma treatment in primary health care, which includes the use of ICS and SABA;469 these are listed as essential medications by the World Health Organization (WHO). Budesonide-formoterol is also listed as an essential medication by the WHO, but at present access is limited. For diagnosis of asthma and monitoring of treatment response, WHO also lists PEF meters as essential tools in the Package of Essential Non-communicable Diseases Interventions,56 with pulse oximeters also recommended when resources permit, for assessment of severitvKtfacute asthma. It is possible to build capacity of primary health care teams, including nurses and other health professionals, for the development of an integrated approach to the most common diseases and symptoms, including asthma.470
Adolescents
Clinical features
Care of teenagers with asthma should take into account the rapid physical, emotional, cognitive and social changes that occur during adolescence. Asthma control may improve or worsen, although remission of asthma is seen more commonly in males than females.471 Exploratory and risk-taking behaviors such as smoking occur at a higher rate in adolescents with chronic diseases than in healthy adolescents.
In a large meta-analysis of adherence with ICS by adolescents and young adults,399 overall adherence was 28%, and slightly higher in those <18 years (36%). However, pharmacy refill data provided lower estimates of adherence than self-report measures. Predictors of adherence included personality, illness perceptions, and treatment beliefs.
Management
General principles for managing chronic disease in adolescents have been published by WHO.472 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
3. Treating to control symptoms and minimize future risk
95
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.38,43
Management
Regular controller treatment with ICS significantly reduces EIB43 (Evidence A). Training and sufficient warm-up reduce the incidence and severity of EIB43 (Evidence A). Taking SABAs, LABAs or chromones prior to exercise prevents EIB (Evidence A), but tolerance to the protective effects of SABAs and LABAs againsK^JB develops with regular (more than once-daily) use (Evidence A).43 However, in a 6-week study in patients with mild^rathma, low dose budesonide-formoterol, taken as needed for relief of symptoms and before exercise, was non-inferior for reducing EIB to regular daily ICS with as-needed SABA.195 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).
Breakthrough EIB often indicates poorly controlled asthma, and stepping up controller treatment (after checking inhaler technique and adherence) generally results in the reduction of exercise-related symptoms.
Athletes
Clinical features
Athletes, particularly those competing at a hig^level, have an increased prevalence of various respiratory conditions compared to non-athletes. They experience a higher prevalence of asthma, EIB, allergic or non-allergic rhinitis, chronic cough, inducible laryngeal obstruction, and recurrent respiratory infections. Airway hyperresponsiveness is common in elite athletes, often without reportecUjyhiptoms. Asthma in elite athletes is commonly characterized by less correlation between symptoms and pulmonary function; higher lung volumes and expiratory flows; less eosinophilic airway inflammation; more difficulty in controlling symptoms; and some improvement in airway dysfunction after cessation of training.
Management
Preventative measures to avoid high exposure to air pollutants, allergens (if sensitized) and chlorine levels in pools, particularly during training periods, should be discussed with the athlete. They should avoid training in extreme cold or pollution (Evidence C), and the effects of any therapeutic trials of asthma medications should be documented. Adequate anti-inflammatory therapy, especially ICS, is advised; minimization of use of beta2-agonists will help to avoid the development of tolerance.43 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)LEN473 and the World Anti-Doping Agency website (www.wada-ama.org).
96
3. Treating to control symptoms and minimize future risk
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.474 Exacerbations are common in pregnancy, particularly in the second trimester.95 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,475 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).95 If asthma is well controlled throughout pregnancy there is little or no increased risk of adverse maternal or fetal complications.45
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 medications45
(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.476
Importantly, ICS reduce the risk of exacerbations of asthma during pregnancy45'477,478 (Evidence A), and cessation of ICS during pregnancy is a significant risk factor for exacerbations95 (Evidence A). A study using administrative data reported that uncontrolled maternal asthma increased the risk of early-onset asthma in the offspring.479 One study reported that a treatment algorithm in non-smoking pregnant worrfefi based on monthly FeNO and ACQ was associated with significantly fewer exacerbations and better fetal outcomes than an algorithm based only on ACQ.480 However, the ACQ-only algorithm did not reflect current clinical recommefisations, as LABA was introduced only after ICS had been increased to medium dose, and ICS could be stopped; 58% of women in the ACQ-only group were being treated without 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 children of women in the FeNO group and in children of women receiving ICS in the ACQ group, compared with women in the clinical group who did not receive ICS.481 Use of ICS in early pregnancy (before randomization at weeks 12-20) also appeared to be protective for asthma in the child.481
On balance, given the evidence in pregifoncy and infancy for adverse outcomes from exacerbations during pregnancy45 (Evidence A), including due to lack of ICS or poor adherence,95 and evidence for safety of usual doses of ICS and LABA476 (Evidence A), a low priority should be placed on stepping down treatment (however guided) until after delivery (Evidence D), and ICS^stiould not be stopped in preparation for pregnancy or during pregnancy
(Evidence C).
Despite lack of evidence for adverse effects of asthma treatment in pregnancy, many women and doctors remain concerned.482 Pregnant patients with asthma should be advised that poorly controlled asthma, and exacerbations, provide a much greater risk to their baby than do current asthma treatments. Educational resources about asthma management during pregnancy may provide additional reassurance.483 During pregnancy, monthly monitoring of asthma is recommended.483 It is feasible for this to be achieved by pharmacist-clinician collaboration, with monthly telephone monitoring of asthma symptom control.484 One observational study found that pregnant women whose asthma was well-controlled without controller therapy and who have no history of previous exacerbations were at low risk for exacerbations during pregnancy.485 However, they should still be closely monitored.
Respiratory infections should be monitored and managed appropriately during pregnancy.475 During acute asthma exacerbations, pregnant women may be less likely to be treated appropriately than non-pregnant patients.95 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
3. Treating to control symptoms and minimize future risk
97
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.486
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.487
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.488
Management
In addition to the usual strategies for management of asthma, oral contraceptives and/or leukotriene receptor antagonists may be helpful488 (Evidence D). Further research is needed.
_
Clinical features
In the occupational setting, rhinitis often precedes the development of asthma (see p.28 regarding diagnosis of occupational asthma). Once a patient has become sensitized to an occupational allergen, the level of exposure necessary to induce symptoms may be extremely low; resulting exacerbations become increasingly severe, and with continued exposure, persistent symptoms and irreversible am&w limitation may result.40
Management
Detailed information is available in evidence-based guidelines about management of occupational asthma.40 All patients with adult-onset asthma should be asked about their work history and other exposures (Evidence A). The early identification and elimination of occupational sensitizers and the removal of sensitized patients from any further exposure are important aspects of the management of occupational asthma (Evidence A). Attempts to reduce occupational exposure have been successful, especially in industrial settings.40 Cost-effective minimization of latex sensitization can be achieved by usJljgmon-powdered low-allergen gloves instead of powdered latex gloves.40 Patients with suspected or confirmed occupational asthma should be referred for expert assessment and advice, if this is available, because of the economic and legal implications of the diagnosis (Evidence A).
The elderly
Clinical features
Lung function generally decreases with longer duration of asthma and increasing age, due to stiffness of the chest wall, reduced respiratory muscle function, loss of elastic recoil and airway wall remodeling. Older patients may not report asthma symptoms, and may attribute breathlessness to normal aging or comorbidities such as cardiovascular disease and obesity.489 491 Comorbid arthritis may contribute to reduced exercise capacity and lack of fitness, and make inhaler device use difficult. Asthma costs may be higher amongst older patients, because of higher hospitalization rates and medication costs.490
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.489,490 Data on efficacy of asthma medications in the elderly are limited because these patients are
98
3. Treating to control symptoms and minimize future risk
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.489 Clearance of theophylline is also reduced.489 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,490,492 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.135.
Surgery and asthma
Clinical features
There is no evidence of increased peri-operative risk for the general asthma populationWrlowever, there is an increased risk for patients with COPD,493 and this may also apply to asthma patients with reduced FEW The incidence of severe peri-operative bronchospasm in people with asthma is low, but it may be life threatening.494
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 astfjma, uncontrolled symptoms, exacerbation history, or persistent airflow limitation494 (Evidence B). For patients requiring emergency surgery, the risks of proceeding without first achieving good asthma control should be weighed against the need for immediate surgery. Patients taking long-term high dose ICS or who have received OCS for more than 2 weeks during the previous 6 months should receive hydrocortisone peri-operatively as they are at risk of adre(Q)l crisis in the context of surgery495 (Evidence B). More immediate intra-operative issues relating to asthma management are reviewed in detail elsewhere.494 For all patients, maintaining regular controller therapy throughout the peri-operative period is important.
Aspirin-exacerbated respiratory disease
Clinical features
The clinical picture and course of aspirin-exacerbated respiratory disease (AERD, previously called aspirin-induced asthma) are well established.335 It starts with nasal congestion and anosmia, and progresses to chronic rhinosinusitis with nasal polyps that re-grow rapidly after surgery. Asthma and hypersensitivity to aspirin and non-steroidal antiinflammatory drugs (NSAIDafaevelop subsequently. Following ingestion of aspirin or NSAIDs, an acute asthma attack develops within minutes>i<Q-2 hours. It is usually accompanied by rhinorrhea, nasal obstruction, conjunctival irritation, and scarlet flush of the head and neck, and may sometimes progress to severe bronchospasm, shock, loss of consciousness, and respiratory arrest.496,497 AERD is more likely to be associated with low lung function and severe asthma,498,499 and with increased need for emergency care.499 The prevalence of AERD is 7% in general adult asthma populations, and 15% in severe asthma.499,500
Diagnosis
A history of exacerbation following ingestion of aspirin or other NSAIDs is highly suggestive of AERD. Aspirin challenge (oral, bronchial or nasal) is the gold standard for diagnosis501,502 as there are no reliable in vitro tests, but oral aspirin challenge tests must only be conducted in a specialized center with cardiopulmonary resuscitation capabilities because of the high risk of severe reactions.501,502 Bronchial (inhalational) and nasal challenges with lysine aspirin are safer than oral challenges and may be safely performed in allergy centers.502,503
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
3. Treating to control symptoms and minimize future risk
99
medical conditions, a COX-2 inhibitor (e.g. celocoxib.or etoricoxib), or paracetamol (acetaminophen), may be considered504,505 with appropriate health care provider supervision and observation for at least 2 hours after administration506 (Evidence B). ICS are the mainstay of asthma therapy in AERD, but OCS are sometimes required; LTRA may also be useful497,506 (Evidence B), but note the recent FDA warning about adverse effects with montelukast.215. See Chapter 3E (p.101) fortreatment options for patients with severe asthma. An additional option is aspirin desensitization, which may be conducted under specialist care in a clinic or hospital.507 Desensitization to aspirin followed by daily aspirin treatment can significantly improve upper respiratory symptoms and overall quality of life, decrease recurrence of nasal polyps, reduce the need for OCS and sinus surgery, and improve nasal and asthma scores, but few double-blind studies have examined asthma outcomes.502'508,509 Aspirin desensitization is associated with a significantly increased risk of adverse effects such as gastritis and gastrointestinal bleeding.509
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 ips^r 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.510 Sensitization to fungal allergens, without the full picture of ABPA, is often found in asthma, particular in severe asthma, where it is sometimes called 'severe asthma with fungal sensitization'.
Management
Current first-line therapy is with oral corticosteroids (e.flN4 month tapering course), with itraconazole reserved for those with exacerbations or requiring long-term OCS.510,511 One open-label study comparing itraconazole and OCS found that patients treated with itraconazole had a slightly lower response rate at 6 weeks but similar long-term response rates, with substantially fewer side-effects than with OCS.512 A randomized double-blind placebo-controlled study in patients with severe asthma and ABPA found signifjppntly fewer exacerbations with omalizumab (anti-lgE) than placebo.513 In ABPA patients with bronchiectasis, regular physiotherapy and daily drainage are recommended.
DifficuIt-to-treat and severe asthma are covered in the next section, Chapter 3 Part E.
100
3. Treating to control symptoms and minimize future risk
PART E. DIFFICULT-TO-TREAT AND SEVERE ASTHMA IN ADULTS AND ADOLESCENTS KEY POINTS
What are difficult to treat and severe asthma?
• DifficuIt-to-treat asthma is asthma that is uncontrolled despite prescribing of medium or high dose ICS-LABA treatment or that requires high dose ICS-LABA 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 optimized high dose ICS-LABA 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 factors that may be contributing to symptoms, poor quality of life, or exacerbations.
• Refer for expert advice at any stage, or if asthma does not improve in response to optimizing treatment.
• For patients with persistent symptoms and/or exacerbations despite high dose ICS, the clinical or inflammatory phenotype should be assessed, as this may guide the selection of add-on treatment.
Management of severe asthma
• Add-on treatments for severe asthma include LAMA, LTRA      dose azithromycin (adults), and biologic agents for severe allergic or severe Type 2 asthma. Maintenance OCS should be avoided if other options are available, because of its serious side-effects.
• Assess the response to any add-on treatment, stop^effective treatments, and consider other options.
• Utilize specialist multidisciplinary team care for severe asthma, if available.
• For patients with severe asthma, continue to optimize patient care in collaboration with the primary care clinician, and taking into account the patient's social and emotional needs.
• Invite patients with severe asthma to enroll in a registry or clinical trial, if available and relevant, to help fill evidence gaps.
__
Although the majority of patiejus*can achieve the goal of well controlled asthma, some patients' asthma will not be well controlled even with optimal therapy. The material that follows is from the GINA Pocket Guide for health professionals on Diagnosis and Management of Difficult-to-Treat and Severe Asthma in Adolescent and Adult Patients v2.1, published in April 2021. A copy of the Pocket Guide can be downloaded from the GINA website (www.ginasthma.org).
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
3. Treating to control symptoms and minimize future risk
101
Difficult-to-treat asthmaU4 is asthma that is uncontrolled despite prescribing of medium or high dose inhaled corticosteroids (ICS) with a second controller (usually LABA) or with maintenance OCS, or that requires high dose 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 asthmaU4 is a subset of difficult-to-treat asthma (Box 3-15). It means asthma that is uncontrolled despite adherence with maximal optimized high dose ICS-LABA treatment and management of contributory factors, or that worsens when high dose treatment is decreased.144 At present, therefore, 'severe asthma' is a retrospective label. It is sometimes called 'severe refractory asthma'144 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.144
PREVALENCE: HOW MANY PEOPLE HAVE SEVERE ASTHMA?
A study in the Netherlands estimated that around 3.7% of asthma patients have sevewLirethma, based on the number of patients prescribed high dose ICS-LABA, or medium or high dose ICS-LABA plus long-term OCS, who had poor symptom control (by Asthma Control Questionnaire) and had good adherence and inhaler technique (Box 3-15).514
Box 3-15. What proportion of adults have difficult-to-treat or severe asthma?
:::::::::: ^° :::::::::: <p
••••••••••
:::::::::: <r
••••••••••
••••••••••     ••••• •••••
24%
High intensity treatment
= high dose ICS-LABA or medium dose ICS-LABA + OCS)
17%
difficult-to-treat asthma
= high intensity treatment + poor symptom control
3.7%
9 severe asthma
= high intensity treatment + poor symptom control + good adherence and inhaler technique
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,281 which in the past were a mainstay of treatment for severe asthma. Adverse effects of long-term OCS include obesity, diabetes, osteoporosis, cataracts,
102
3. Treating to control symptoms and minimize future risk
hypertension and adrenal suppression; psychological side-effects such as depression and anxiety are particularly concerning for patients.515 Even short- term use of OCS is associated with sleep disturbance, and increased risk of infection, fracture and thromboembolism.516 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.515
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. Severe asthma may improve over 3 years in approximately 30% of male and female adolescents, with the only predictor being higher baseline blood eosinophils.517 Studies with longer follow-up time are needed.
Healthcare utilization and costs
Severe asthma has very high healthcare costs due to medications, physicianraSFts, 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.518 In a Canadian study, severe uncontrolled asthma was estimated to acceirm for more than 60% of asthma costs.519
Patients with severe asthma and their families also bear a significant financial burden, not only for medical care and medications, but also through lost earnings and career choicesx
ASSESSMENT AND MANAGEMENT OF DIFFICULT-TO-TREAT AND SEVERE ASTHMA
The clinical decision tree starting on page 104, provides brief information about what should be considered in each phase of diagnosis and management of difficult-to-treat and severe asthma. The decision tree is divided into three broad areas:
• Sections 1 -4 (green) are for use in primary care and/or specialist care.
• Sections 5-7 (blue) are mainly relevant to respiratory specialists.
• Section 8 (brown) is about maintaining ongoing collaborative care between the patient, GP, specialist and other health professionals.
Development of the Pocket Guide and decision tree included extensive collaboration with experts in human-centered 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 principles.
Further information follows the decision tree.
3. Treating to control symptoms and minimize future risk
103
Box 3-16A. Decision tree - investigate and manage adult and adolescent patients with difficult-to-treat asthma
GP OR SPECIALIST CARE
Investigate and manage adult and adolescent patients with difficult-to-treat asthma
Consider referring to specialist or severe asthma clinic at any stage
Confirm the diagnosis
(asthma/differential
diagnoses)
For adolescents and adults with symptoms andtor exacerbations despite medium or highdoselCS-L4BA; or -.a-dng
maintenance OCS
Key
intervent on, treatment
diagnosis, co-ti "nation
Look for factors
contributing to symptoms, exacerbations and poor quality of life
• Incorrect inhaler technique
• Suboptimal adherence
• Comorbidities including obesity, GERD, chronic rhinosinusitis, OSA
■ Modifiable risk factors and triggers at home or work, including smoking, environmental exposures, allergen exposure (if sensitized on skin prick testing or specific IgE); medications such as beta-blockers and NSAIDs
■ Overuse of SABA relievers
■ Medication side effects
■ Anxiety, depression and social difficulties
Optimize management.
including:
• Asthma education
• Optimize treatment (e.g. check and correct inhaler technique and adherence; switch to ICS-formoterol maintenance and reliever therapy, if available)
■ Treat comorbidities
and modifiable risk factors
■ Consider non-biologic add-on therapy
(e.g. I_ABA, LAMA, LIWLTRA, if not used)
■ Consider non-pharmacological interventions (e.g. smoking cessation, exercise, weight loss, mucus clearance, influenza vaccination)
■ Consider trial of high dose ICS-LABA. if not used
-X
Consider referring to specialist or severe asthma clinic at any stage
)
Review response " after ~3-6 months
fe asthma still uncontrolled?
yes
If not done by now, refer to a specialist, if possible.
Restore previous dose
Consider stepping down treatment, OCS first (if used.)
Does asthma become uncontrolled when treatment is stepped down?
yes_
Continue optimizing management
104
3. Treating to control symptoms and minimize future risk
Box 3-16B. Decision tree - assess and treat severe asthma phenotypes
SPECIALIST CARE; SEVERE ASTHMA CLINIC IF AVAILABLE
Assess and treat severe asthma phenotypes
Continue to optimize management as in section 3 (including inhaler technique, adherence, comorbidities)
Assess the severe asthma pheriotype
and factors contributing to symptoms, quality of life and exacerbations
Assess the severe asthma phenotype during high dose ICS treatment (or lowest possible dose of OGS)
->6a
Type 2 inflammation	
Could patient have Type 2 airway inflammation ? Note: these are not the criteria foiradcf-on biologic tberupy {see 6bj	■ Blood eosinophils S1507ul and/or ■ FeNO i20 ppb and/or ■ Sputum eosinophils a2%, and/or ■ Asthma is clinically allergen-driver and/or ■ Need for maintenance OCS (Repeat blood eosinophils and FeNO up to 3x. on lowest possible OCS dose)
Investigate for comorbldities/dlfferential diagnoses
and treat/refer as appropriate
- Consider: CBC, CRP, IgG, IgA, IgM. IgE, fungal precipitins; CXR and/or HRCT chest; DLCO
- Skin prick testing or specific IgE for relevant allergens, if not already done
- Other directed testing (e.g. ANCA, CT sinuses, BNP, echocardiogram) based on clinical suspicion
Consider need for social/psychological support
involve nuiltidisciplinary team care (if available)
invite patient to enroll in registry (if available) or clinical trial (if appropriate)
Consider non-biologic treatments*
Considei" adherence tests
Consider increasing the ICS dose for 3-6 months
Consider AERD, ABPA, chronic rtiinosinusitis, nasal polyposis, atopic dermatitis (clinical Type 2 phenotypes with specific add-on treatment)
yes
Is add-on Type 2 biologic therapy available/ affordable?
If add-on Type 2 biologic therapy is NOT available/affordable
■ Consider higher dose ICS, if not used
■ Consider non-biologic add-on therapy
(eg LABA, LAMA. LM/LTRA. azithromycin)
■ Consider add-on low dose OCS, but implement strategies to minimize side-effects
■ Stop ineffective add-on therapies
If no evidence of Type 2 inflammation:
• Review the basics: differential diagnosis, inhaler technique, adherence, comorbidities, side-effects
■ Avoid exposures (tobacco smoke, allergens, irritants)
■ Consider investigations (if available and not done)
- Sputum induction
- High resolution chest CT
- Bronchoscopy for alternative/additional diagnoses
• Consider add-on treatments
- Trial of LAMA or azithromycin (if not already tried)
- Consider add<m low dose OCS, but implement strategies to minimize side-effects
- Stop ineffective add-on therapies
• Consider bronchial thermoplasty (+ registry)
Wot currently eligible for biologies
3. Treating to control symptoms and minimize future risk
105
Box 3-16C. Decision tree - consider add-on biologic Type 2 targeted treatments
SPECIALIST CARE; SEVERE ASTHMA CLINIC IF AVAILABLE
Assess and treat severe asthma phenotypes
Continue to optimize management as in section 3 (including inhaler technique, adherence, comorbidities)
6b
Consider add-on biologic Type 2 1
targeted treatments
■ Consider add-on Type 2-targeted biologic for patients with exacerbations or poor symptom control on high dose ICS-LABA, whoO
- have eosinophilic or allergic biomarkers, or
- need maintenance OCS
■ Consider local payer eligibility criteria, © comorbidities and predictors of response when choosing between available therapies
Also consider cost, dosing frequency, route (SC or IV), patient preference
Which biologic is appropriate to start First?
Anti-lgE			What factors may predict good asthma response to anti-lgE? • Blood eosinophils i2607ul ++ ■ FeNO^20ppb + • Allergen-driven symptoms + ■ Childhood-onset asthma +
Is the patient eligible For anti-lgE for severe allergic asthma? • Sensitization on skin prick testing or specific IgE© ■ Total serum IgE and weight within dosage range © ■ Exacerbations in last year O			
.■?o _\	f t	no	
Anti-IL5/Anti-IL5R			What factors may predict good asthma response to anti-IL5/5R? • Higher blood eosinophils+++ ■ More exacerbations in previous year +++ ■ Adult-onset of asthma ++
Is the patient eligible For anti-IL51anti-ILbR for severe eosinophilic asthma? • Exacerbations in last year © - Blood eosinophils,0eg S150/ulorS300/ul			
no	t t	' Nasal polyposis++ no	
Anti-IL4R			What factors may predict good asthma response to anti-IL4R? • Higher blood eosinophils +++ ■ Higher FeNO +++
Is the patient eligible For anti-tL4R ... for severe eosinophilic/Type 2 asthma? ■ Exacerbations in last year© ■ Blood eosinophils S150/ul° or FeNO S25 ppb° ... or because of need for maintenance OCS© ?			
Check local eligibility criteria for speciFic biologic therapies as these may vary from those listed
Eligible for none? Return to section 6&
Choose one if eligible; trial for at least 4 months and assess response
Extend trial to 6-12 months
unclear
yes
Good asthma response?  Good response ©        to T2-tar<|eted therapy
Consider switching to a different Type 2-targeted therapy, if eligible
Little/no response to T2-targeted therapy
106
3. Treating to control symptoms and minimize future risk
Box 3-16D. Decision tree - monitor and manage severe asthma treatment
SPECIALIST.AND PRIMARY CARE IN COLLABORATION
Monitor / Manage severe asthma treatment
Continue to optimize management
yes
Review response
* Asthma: symptom control, exacerbations, lung function
* Type 2 comorbidities
e.g. nasal polyposis, atopic dermatitis
* Medications: treatment intensity, side-effects, affordability
* Patient satisfaction
If good response to Type 2-targeted therapy
* Re-evaluate the patient every 3-6 months**
* For oral treatments: consider decreasing/stopping OCS first, then stopping other add-on medication
* For inhaled treatments: consider decreasing after 3-6 months; continue at least moderate dose ICS
* Re-evaluate need for ongoing biologic therapy
* Order of reduction of treatments based on observed benefit, potential side-effects, cost and patient preference
^ O Continue to optimize management
as in section 3, including:
■ Inhaler technique
■ Adherence
■ Comorbidity management
■ Patients' social/emotional needs
■ Two-way communication with GP for ongoing care
Notes:
If no good response to Type 2-targeted therapy
* Stop the biologic therapy
* Review the basics: differential diagnosis, inhaler technique, adherence, comorbidities, side-effects, emotional support
* Consider high resolution chest CT (if not done)
* Reassess phenotype and treatment options
- Induced sputum (if available)
- Consider add-on azithromycin
- Consider add-on low dose OCS. but implement strategies to minimize side-effects
- Consider bronchoscopy for alternative/additional diagnoses
- Consider bronchial thermoplasty (+ registry)
* Stop ineffective add-on therapies
* Do not stop ICS
3. Treating to control symptoms and minimize future risk
107
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 medium or high dose ICS with another controller such as LABA, or maintenance OCS, or requires high dose ICS-LABA treatment to maintain good symptom control and prevent exacerbations. 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
<s
Food allergy or anaphylaxis, as this increases the risk of death
Symptoms are suggestive of infective or cardiac cause
Symptoms are suggestive of complications such as bronchiectasis
Presence of multiple comorbidities
Are the symptoms due to asthma?
Perform a careful history and physical examination to identify whethe(£/ymptoms are typical of asthma, or are more likely due to an alternative diagnosis or comorbidity. Investigate aecfcrding to clinical suspicion.
• Dyspnea: COPD, obesity, cardiac disease, deconditioning
• Cough: inducible laryngeal obstruction (also called vocal cord dysfunction, VCD), upper airway cough syndrome (also called post-nasal drip), gastro-esophageal reflux disease (GERD), bronchiectasis, ACE inhibitors
• Wheeze: obesity, COPD, tracheobronchom$acia, VCD
How can the diagnosis of asthma be confirmed?
Confirmation of the diagnosis is important, because in 12-50% of people assumed to have severe asthma, asthma is not found to be the correct diagnosis.525^<efform spirometry, before and after bronchodilator, to assess baseline lung function and seek objective evidence of variable expiratory airflow limitation. If initial reversibility testing is negative (<200 mL or <12% increase in FE^r), consider repeating when symptomatic. Check full flow-volume curve to assess for upper airway obstruction. If spirometry is normal or is not available, provide the patient with a peak flow diary for 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)23. Strategies for 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.
108
3. Treating to control symptoms and minimize future risk
• 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.88). 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.
• Regular or over-use of SABAs: this causes beta-receptor down-regulaKqlsand reduction in response,521 leading in turn to greater use. Overuse may also be habitual. Dispensijwof >3 SABA canisters per year (corresponding to average use more than daily) is associated with increased risk of emergency department visit or hospitalization independent of severity,89,123 and dispensing of >12 canisters per year (one a month) is associated with substantially increased risk of death.88,89 Risks are higher with nebulized SABA.522
• Anxiety, depression and social and economic problems: these are very common in asthma, particularly in difficult asthma515 and contribute to symptoms, impairesNquality of life, and poor adherence.
• Medication side-effects: systemic effects, particularly with frequent or continuous OCS, or long-term high dose ICS may contribute to poor quality of life and incase the likelihood of poor adherence. Local side-effects of dysphonia or thrush may occur with high do$e or potent ICS especially if inhaler technique is poor. Consider drug interactions including risk of adrenakjkjsppression with use of P450 inhibitors such as itraconazole.
3. REVIEW AND OPTIMIZE MANAGEMENT
Review and optimize treatment for asthl^i, and for comorbidities and risk factors identified in Section 2. For more details, see Chapter 3D, p.92.
• Provide asthma self-management education, and confirm that patient has (and knows how to use) a personalized written or electronic asthma action plan. Refer to an asthma educator if available.
• Optimize inhaled ©ntroller medications: confirm that the inhaler is suitable for the patient; check and correct inhaler technique-with a physical demonstration and teach-back method, check inhaler technique again at each visit.523 Address suboptimal adherence, both intentional and unintentional.413 Switch to ICS-formoterol maintenance and reliever regimen if available, to reduce the risk of exacerbations.173
• 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.93). Avoid medications that make asthma worse (beta-blockers including eye-drops; aspirin and other NSAIDs in patients with aspirin-exacerbated respiratory disease, p.99). 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.77.
• Consider trial of non-biologic medication added to medium/high dose ICS, e.g. LABA, LAMA, leukotriene modifier if not already tried.
3. Treating to control symptoms and minimize future risk
109
• Consider trial of high dose ICS-LABA 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?
YES: if asthma is still uncontrolled, the diagnosis of severe asthma has been confirmed. If not done by now, refer the patient to a specialist or severe asthma clinic if possible.
NO: if asthma is now well-controlled, consider stepping down treatment. Start by decreasing/ceasing OCS first (if used), then remove other add-on therapy, then decrease ICS dose (do not stop ICS). See Box 3-7 (p.73) for how to gradually down-titrate treatment intensity.
Does asthma become uncontrolled when treatment is stepped down?
YES: if asthma symptoms become uncontrolled or an exacerbation occurs when high dose treatment is stepped down, the diagnosis of severe asthma has been confirmed. Restore the patient's previous dose to regain good asthma control, and refer to a specialist or severe asthma clinic if possible, if not done already.
NO: if symptoms and exacerbations remain well-controlled despite treatment being stepped down, the patient does not have severe asthma. Continue optimizing management.
ASSESS AND TREAT SEVERE ASTHMA PHENOTYPES
5. ASSESS THE SEVERE ASTHMA PHENOTYPE AND OTHER CONTRIBUTORS
Further assessment and management should be by a specialist, preferably in a multidisciplinary severe asthma clinic if available. The team may include a certified asthma educator and health professionals from fields such as speech pathology, ENT, social work and mental health.
Assessment includes:
• 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 support515
• 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 the majority 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
110
3. Treating to control symptoms and minimize future risk
eosinophilia or increased FeNO, and may be accompanied by atopy, whereas non-Type 2 inflammation is often characterized by increased neutrophils.524 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 effects281282 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/ul, 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 suppresagirby OCS. If possible, therefore, these tests should be performed before starting OCS (a short course, or maintenance treatment), or on the lowest possible OCS dose.
The above criteria are suggested for initial assessment; those for blood eosinophils and FeNO are based on lowest levels associated with response to some biologies. They are not the criteria for eligibility for Type 2-targeted biologic therapy, which may differ - see section 6b and local criteria. ConsidOrepeating blood eosinophils and FeNO up to 3 times (e.g. when asthma worsens, before giving OCS), before assuming asthma is non-Type 2. One study of patients with uncontrolled asthma taking medium-high dose ICS-LABj^lound that 65% had a shift in their blood eosinophil category over 48-56 weeks.525
Why is the inflammatory phenotype assessed on high dose ICS?
• Most RCT evidence about Type 2 targeted biologies is in such patients.
• Currently, the high cost of biologic therapies generally precludes their widespread clinical use in patients whose symptoms or exacerbations and Type 2 biomarkers are found to respond to ICS when it is taken correctly.
• Modifiable ICS treatment problems such as poor adherence and incorrect inhaler technique are common causes of uncontrolled Type 2 inflammation.
What other tests may be considered at the specialist level?
Additional investigations rp$ be appropriate for identifying less-common comorbidities and differential diagnoses contributing to symptoms and/or exacerbations. Tests should be based on clinical suspicion, and may include:
• Blood tests: CBC, CRP, IgG, IgA, IgM, IgE, fungal precipitins including Aspergillus
• Allergy testing for clinically relevant allergens: skin prick test or specific IgE, if not already done
• Other pulmonary investigations: DLCO; CXR or high resolution chest CT
• Other directed testing, e.g. ANCA, CT sinuses, BNP, echocardiogram
• 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.515 Consider the need for psychological or psychiatric referral, including for patients with anxiety and/or depression.
3. Treating to control symptoms and minimize future risk
111
Involve multidisciplinary team care (if available)
Multidisciplinary assessment and treatment of patients with severe asthma increases the identification of comorbidities, and improves outcomes.526
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.263
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.
• Consider additional diagnostic investigations (if available and not already done): sputum induction to confirm inflammatory phenotype, high resolution chest CT, bronchoscopy to exclude unusual comorbidities or alternative diagnoses such as tracheobronchomalacia or sub-glottic stenosis; functional laryngoscopy for inducible laryngeal obstruction.
• Consider a trial of non-biologic add-on treatment if not already tried, e.g. LAMA, leukotriene modifier, low dose azithromycin (adults),266,527 but with azithromycin cori|)der potential for antibiotic resistance. Consider add-on low dose OCS, but implement strategies such as alternate-day treatment to minimize side-effects. Stop ineffective add-on therapies.
• Consider bronchial thermoplasty, with regj&nv"enrollment. However, the evidence for efficacy and long-term safety is limited.120,322
No biologic options are currently available for non-Type 2 severe asthma.
6a Non-biologic options if there IS evidence of Type 2 inflammation
For patients with elevated Type 2 biomarkers despite high dose ICS (see section 5), consider non-biologic options first, given the current high cost of biologic therapy:
• Assess adherence objectively by monitoring of prescribing or dispensing records, blood prednisone levels,528 or electronic inhaler monitoring.400 In one study, suppression of high FeNO after 5 days of directly observed therapy was an indicator of past poor adherence.529
• Consider clinical Type 2 phenotypes for which specific add-on treatment is available (see Chapter 3D, p.92). For example, for aspirin-exacerbated respiratory disease (AERD), consider add-on leukotriene modifier and possibly aspirin desensitization (p.99). For allergic bronchopulmonary aspergillosis (ABPA), consider add-on OCS ± anti-fungal agent (p.100). For chronic rhinosinusitis and/or nasal polyposis, consider intensive intranasal corticosteroids; surgical advice may be needed (p.94). 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.
112
3. Treating to control symptoms and minimize future risk
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-lgE, anti-IL5/5R oranti-IL4R. When choosing between available therapies, consider the following:
Does the patient satisfy local payer eligibility criteria?
Predictors of asthma response (see below)
Type 2 comorbidities such as atopic dermatitis, nasal polyposis
Cost
Dosing frequency
Delivery route (IV or SC; potential for self-administration) Patient preference
Local payer eligibility criteria for biologic therapy may vary substantially ©r 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.
There is an urgent need for head-to-head comparisons of different biologies in patients eligible for more than one biologic.
Add-on anti-lgE for severe allergic asthma
Currently approved: omalizumab for ages >6 years, given by SC injection every 2-4 weeks, with dose based on weight and serum IgE. May also be indicated for nasal polyposis and chronic idiopathic urticaria. Self- administration may be an option.
Mechanism: binds to Fc part of free IgE, preventing binding of IgE to Fc8R1 receptors, reducing free IgE and down-regulating receptor expression.
Eligibility criteria vary betweejvpa"yers, but usually include:
• Sensitization to inhaled allergen(s) on skin prick testing or specific IgE, and
• Total serum IgE and body weight within local dosing range, and
• More than a specified number of exacerbations within the last year
Benefits: RCTs in severe asthma: 34% decrease in severe exacerbations,530 but no significant difference in symptoms or quality of life.268 In open-label studies in patients with severe allergic asthma and >1 severe exacerbation in last 12 months, there was a 50-65% reduction in exacerbation rate,531,532 a significant improvement in quality of life,531 and 40-50% reduction in OCS dose.531,532 In patients with nasal polyposis, omalizumab improved subjective and objective outcomes.463
Potential predictors of good asthma response to omalizumab:
• Baseline IgE level does not predict likelihood of response531
• In one observational study, a greater decrease in exacerbations was observed (cf. placebo) with blood eosinophils >260/ul533'534 or FeNO >20 ppb533 (these criteria representing their median value in that study) but in
3. Treating to control symptoms and minimize future risk
113
two large observational studies, exacerbations were reduced with both low or high blood eosinophils532,535,536 or with both low or high FeNO.536
• Childhood-onset asthma
• Clinical history suggesting allergen-driven symptoms Adverse effects: injection site reactions; anaphylaxis in -0.2% patients268 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, or benralizumab (anti-IL5 receptor a), 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 6-11 years, mepolizumab (anti-IL5), 40mg by SC injection every 4 weeks. Mepolizumab may also be indicated for eosinophilic granulomatosis with polyangiitis (EGPA) and hypereosinophilic syndrome. Self-administration may be an option.
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 ye^yand
• Blood eosinophils above locally specified level (e.g. >150 or >300/ul). There is sometimes a different eosinophil cut-point for patients taking OCS.
Outcomes: RCTs in severe asthma patients with exacerbations in the last year, with varying eosinophil criteria: anti-IL5 and anti-IL5R led to -55% reduction in severe exacerbations-aKa improved quality of life, lung function and symptom control.274 All reduced blood eosinophils; almost completely with benralizumab.274 In patients taking OCS, median OCS dose was able to be reduced by -50% with mepolizumab537 or benralizumab273 compared with placebo. Efficacy data for mepolizumab in children are limited to one very smaJJs^rTcontrolled open label study.275 In patients with nasal polyposis, mepolizumab improved subjective and objective outcomes and reduced the need for surgery.464,465
Potential predictors of good asthma response to anti-IL5 or anti-IL5R:
• Higher blood eosinophils (strongly predictive)538
• Higher number of severe exas^KBations in previous year (strongly predictive)538
• Adult-onset asthma539
• Nasal polyposis540
• Maintenance OCS at baseline540
• Low lung function (FEVi <65% predicted in one study)541
Adverse effects: injection site reactions; anaphylaxis is rare; adverse events generally similar between active and placebo groups
Suggested initial trial: at least 4 months
Add-on anti-IL4R for severe eosinophilic/Type 2 asthma or patients requiring maintenance OCS
Currently approved: For ages >12 years: dupilumab (anti-IL4 receptor a), 200mg or 300mg by SC injection every 2 weeks for severe eosinophilic/Type 2 asthma; 300mg by SC injection every 2 weeks for OCS-dependent severe asthma or if there is concomitant moderate/severe atopic dermatitis. May also be indicated for treatment of moderate-severe atopic dermatitis and for chronic rhinosinusitis with nasal polyposis (CRSwNP). Self-administration may be an option.
Mechanism: binds to interleukin-4 (IL-4) receptor alpha, blocking both IL-4 and IL-13 signaling
114
3. Treating to control symptoms and minimize future risk
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/ul or FeNO >25 ppb); OR
• Requirement for maintenance OCS
Outcomes: RCTs in patients with uncontrolled severe asthma (ACQ-5 >1.5) and 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.276,278 In patients with OCS-dependent severe asthma, without minimum requirements for blood eosinophil count or FeNO, treatment with anti-IL4R reduced mean OCS dose by -30% versus placebo.542 Dupilumab is also indicated for treatment of moderate-severe atopic dermatitis.543 In patients with chronic rhinosinusitis with nasal polyposis, dupilumab reduced the size of nasal polyps, improved nasal symptoms and reduced the need for OCS or sinus surgery.466,544
Potential predictors of good asthma response to dupilumab:
• Higher blood eosinophils (strongly predictive)276
• Higher FeNO276
Adverse effects: injection-site reactions; transient blood eosinophilia; rare cases of eosinophilic granulomatosis with polyangiitis (EGPA). Patients with blood eosinophils >1,500 cells/uL at baseline were excluded from Phase III trials.
Suggested initial trial: at least 4 months
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 tlrectrial 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;532,545 review response as above
MANAGE AND MONITOR SEVERE ASTHMA TREATMENT
7. REVIEW RESPONSE AND IMPLICATIONS FOR TREATMENT
Review response to add-on biologic therapy after 3-4 months, and every 3-6 months for ongoing care, including:
• Asthma: symptom control, e.g. Asthma Control Test, Asthma Control Questionnaire; frequency and severity of exacerbations (e.a-^s/ere OCS needed), lung function
• Type 2 comorbidities, e.g. nasal polyposis, atopic dermatitis
• Medications: treatment intensity, including dose of OCS, side-effects, affordability
• Patient satisfaction
If the patient has had a good response to Type 2 targeted therapy:
Re-evaluate the need for each asthma medication every 3-6 months, but do not completely stop inhaled therapy. Base the order of reduction or cessation of add-on treatments on the observed benefit when they were started, patient risk factors, medication side-effects, cost, and patient satisfaction.
For oral treatments, consider gradually decreasing or stopping OCS first, because of their significant adverse effects. Tapering in severe asthma may be supported by internet-based monitoring of symptom control and FeNO.546 Monitor patients for risk of adrenal suppression, and provide patient and GP with advice about the need for extra corticosteroid doses during injury, illness or surgery for up to 6 months after cessation of long-term OCS. Continue to assess for presence of osteoporosis, and review need for preventative strategies including bisphosphonates.283
3. Treating to control symptoms and minimize future risk
115
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,547,548 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, socioeconomic and mental health issues.
Consider additional investigations (if not already done): high resolution chest CT; indwed 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 az4TjrVomycin (adults),266 but consider potential for antibiotic resistance; consider add-on low dose maintenance OC^cbut implement strategies such as alternate- day therapy and add-on bisphosphonates283 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 invelves a collaboration between the patient, the GP, specialist(s), and other health professionals, to optimi^Ewflinical outcomes and patient satisfaction.
Continue to review the patient every 3-6 months including:
• Clinical asthma measures (symptom control; exacerbations; lung function)
• Comorbidities
• The patient's risk factors for exacerbations
• Treatments (check inhaleidechnique and adherence; review need for add- on treatments; assess side-effects including of OCS; optiirtze comorbidity management and non-pharmacologic strategies)
• The patient's socialQjjTcl emotional needs
The optimal frequency and location of review (GP or specialist) will depend on the patient's asthma control, risk factors and comorbidities, and their confidence in self-management, and may depend on local payer requirements and availability of specialist physicians.
Communicate regularly about:
• Outcome of review visits (as above)
• Patient concerns
• Action plan for worsening asthma or other risks
• Changes to medications (asthma and non-asthma); potential side-effects
• Indications and contact details for expedited review
116
3. Treating to control symptoms and minimize future risk
SECTION 1. ADULTS, ADOLESCENTS AND CHILDREN 6 YEARS AND OLDER
Chapter 4.
Management of worsening asthma and exacerbations
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.
Written asthma action plans
• 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.
• On the action plan, state when and how to change reliever and controller medications^rse oral corticosteroids, and access medical care if symptoms fail to respond to treatment.
• Base the action plan on changes in symptoms or (only in adults) peak expiratory flow. Management of exacerbations in a primary care or acute care facility
• Assess exacerbation severity from the degree of dyspnea, respiKaJory rate, pulse rate, oxygen saturation and lung function, while starting short-acting beta2-agonist (SABA) aneNixygen therapy. Infection control procedures should be followed.
• Arrange immediate transfer to an acute care facility if there are signs of severe exacerbation, or to intensive care if the patient is drowsy, confused, or has a silent che$t. During transfer, give inhaled SABA and ipratropium bromide, controlled oxygen and systemic corticosteroids.
• Start treatment with repeated administration of SABA (in most patients, by pressurized metered dose inhaler and spacer), early introduction of oral corticosteroids, and controlled flow oxygen if available. Review response of symptoms, oxygen saturation and lung function after 1 hour. Give ipratropium bromide only for severe exacerbations. Consider intravenous magnesium sulfate for patients with severe exacerbations not responding to initial treatment.
• Do not routinely request a chest X-ray, and do not routinely prescribe antibiotics for asthma exacerbations.
• Decide about hospitalization based on the patient's clinical status, lung function, response to treatment, recent and past history of exacerbations, and ability to manage at home.
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. At follow-up: o   Review the patient's symptom control and risk factors for further exacerbations.
o   Prescribe ICS-containing controller therapy to reduce the risk of further exacerbations. If already taking
controller therapy, continue increased doses for 2-4 weeks, o   Provide a written asthma action plan and, where relevant, advice about avoiding exacerbation triggers
• Check inhaler technique and adherence.
For management of asthma exacerbations in children 5 years and younger, see Chapter 6, p.162. 118 4. Management of worsening asthma and exacerbations
• Advise patients who have a history of rapid deterioration to go to an acute can immediately their asthma starts to worsen.
ility or see their doctor
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.20 Exacerbations may occur in patients with a preexisting 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.549,550 Severe exacerbations can occur in patients with mild or well-controlled asthma symptoms.14,200 Box2-2B (p.36) lists factors that increase a patient's risk of exacerbations, independent of their level of symptom control.
Common exacerbation triggers include:
• Viral respiratory infections551
• Allergen exposure e.g. grass pollen,552 soy bean dust,553 fungal sa&es
• Food allergy94
• Outdoor air pollution99,549
• Seasonal changes and/or returning to school in fall (autumn)554
• Poor adherence with ICS555
• Epidemics of severe asthma exacerbations may occur suddenly, putting high pressure on local health system responses. Such epidemics have been reported in association with springtime thunderstorms and either rye grass pollen or fungal spores,556 and with environmental exposure to soy bean dust.553
Identifying patients at risk of asthma-related death
In addition to factors known to increase the risk of asthma exacerbations (Box 2-2, p.36), some features are specifically associated with an increase in the risk of asthma-related death (Box 4-1). The presence of one or more of these risk factors should be quickly identifiable/roThe clinical notes, and these patients should be encouraged to seek urgent medical care early in the course of an exacerbation.
Box 4-1. Factors that increase the risk of asthma-related death
A history of near-fatal asthma requiring intubation and mechanical ventilation557 Hospitalization557,558 or emergency care visit for asthma in the past year
Currently using or having recently stopped using oral corticosteroids (a marker of event severity)557 Not currently using inhaled corticosteroids90,557
Over-use of SABAs, especially use of more than one canister of salbutamol (or equivalent) monthly89,107,559
Poor adherence with ICS-containing medications and/or poor adherence with (or lack of) a written asthma action plan100
A history of psychiatric disease or psychosocial problems100 Food allergy in a patient with asthma452,560
Several comorbidities including pneumonia, diabetes and arrhythmias were independently associated with an increased risk of death after hospitalization for an asthma exacerbation.[558
4. Management of worsening asthma and exacerbations
119
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.561,562 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.561,562 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.20 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),563 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 frequency of symptoms may, however, be a more sensitive measure of the onset of an exacerbation than PEF.564
A minority of patients perceive airflow limitation poorly and can experience a significant decline in lung function without a change in symptoms.132,133,141 This especially affects patients with a history of near-fatal asthma and also appears to be more common in males.
Severe exacerbations are potentially life threatening and their treatment requires careful assessment and close monitoring. Patients with severe exacerbations should be advised to see their health care provider promptly or, depending on the organization of local health services, to proceed to the nearest facility that provides emergency access for patients with acute asthma.
SELF-MANAGEMENT OF EXACERBATIONS WITH A WRITTEN ASTHMA ACTION PLAN
All patients with asthma should be provided with guided self-management education as described in Chapter 3 (p.86), including monitoring of symptoms and/or lung function, a written asthma action plan, and regular review by a health professional.426 (For children 5 years and younger, see Chapter 6, p.145) A sample written asthma action plan template is included in the GINA toolbox, available from the GINA website at www.ginasthma.org/gina-implementation-guide/.
Treatment options for written asthma action plans
A written asthma action plan helps patients to recognize and respond appropriately to worsening asthma. It should include specific instructions for theWxrtient about changes to reliever and controller medications, how to use oral corticosteroids (OCS) if needed (Box 4-2) and when and how to access medical care.
The criteria for initiating an (Qprease in controller medication will vary from patient to patient. For patients taking 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.431
Inhaled reliever medication
For patients with mild asthma prescribed as-needed combination low dose ICS-formoterol (see Box 3-5A, p.59), 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,168 and is non-inferior for progression to severe exacerbation compared with daily ICS plus as-needed SABA.168,169 After a day of even small increased doses of ICS-formoterol, the risk of severe exacerbation in the following 3 weeks is reduced compared with the same doses of SABA alone.192 Based on product information, the maximum recommended dose of ICS-formoterol in a single day is a total of 48 meg formoterol for beclometasone-formoterol (36 meg delivered dose), and 72 meg formoterol for budesonide-formoterol (54 meg delivered dose).
120
4. Management of worsening asthma and exacerbations
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 with173 or without168,169 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,172 and it reduces exacerbations requiring OCS, and hospitalizations173,224-227 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 budesonide-formoterol is 72 meg (delivered dose 54 meg) and with beclometasone-formoterol is 48 meg (delivered dose 36 meg). The benefit of this regimen in preventing exacerbations appears to be due to intervention at a very early stage of worsening asthma.289,290 This regimen was also effective in reducing exacerbations in children aged 4-11 years,245 (Evidence B). This approach should not be attempted with other combination ICS-LABA controller therapies with a slower-onset LABA, or that lack evidence of efficacy and safety with a maiofenance and reliever regimen.
Other ICS and ICS-LABA maintenance controller regimens
In a systematic review of self-management studies, action plans in which the ICS dose was at least doubled were associated with improved asthma outcomes and reduced health care utilization431 (Evidence A). In placebo-controlled trials, temporarily doubling the dose of ICS was not effective565 (Evidence A); however, the delay before increasing the ICS dose (mean 5-7 days566,567) may have contributed. Some studies in adults568 and young children569 have reported that higher ICS doses might help prevent worsening asthma progressing to a severe exacerbation. In a randomized controlled trial in primary care with patients agedi^j5"years, those who quadrupled their ICS dose (to average of 2000 meg/day BDP equivalent) after their PEF fell were significantly less likely to require OCS.570 In an open-label primary care randomized controlled trial of adult and adolescent patients using ICS with or without LABA, early quadrupling of ICS dose (to average 3200 meg/day BDP equivalent) was associated with a modest reduction in prescribing of OCS.571 However, a double-blind placebo-controlled study in children 5-11 years with high adherence to low dose ICS found no difference in the rate of severe exacerbations requiring OCS if maintenance ICS was quintupled (to 1600 meg BDP equivalent) versus continuing maintenance low dose therapy.572 Given the shape of the ICS dose-response curve, the effect of increasing maintenance ICS when asthma worsens may be greater when background adherence is lower. In adult patients with an acute deterioration, high dose ICS for 7-14 days (500-1600 meg BDP-HFA equivalent) had an equivalent benefit to a short course of OCS568 (Evidence A).
For adults taking combination ICS-LABA as a maintenance controller medication, the ICS dose may be increased by adding a separate ICS inhaler568,571 (Evidence D). More research is needed to standardize this strategy.
Leukotriene receptor antagonists
For patients with mild asthma 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,568 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 FEVi <60% of their personal best or predicted value
• Have a history of sudden severe exacerbations.
4. Management of worsening asthma and exacerbations
121
For children 6-11 years, the recommended dose of prednisone 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.573 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, but preferably before ceasing oral corticosteroids if prescribed), for assessment of symptom control and additional risk factors for exacerbations (Box 2-2, p.36), and to identify the potential cause of the exacerbation.
This visit provides an opportunity for additional asthma education by a trained asthma edtt^jHor 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 reduced to 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 technique and adherence have been checked, a step up in treatment may be indicated (Box 3-5, p.59).
Adult and adolescent patients with more than 1-2 exacerbations per year despite Step 4-5 therapy should be referred to a specialist center for assessment (see decision tree in Chapter 3E, p.101).
122
4. Management of worsening asthma and exacerbations
Box 4-2. Self-management of worsening asthma in adults and adolescents with a written asthma action plan
Effective asthma self-management education requires:
* Self-monitoring of symptoms and/or lung function
* Written asthma action plan
* Regular medical review
////.
All patients
Increase reliever
Early increase in controller as below
Review response
-
If PEF or
<60% best, or not improving after 48 hours
Continue relieve
Continue controls
Add prednisolone 40-50 mg/day
Contact doctc
EARLY OR MILD
LATE OR SEVERE
Evidence Medication                   Short-term change (1-2 weeks) for worsening asthma \qmq\		
Increase usual reliever: Low dose ICS-formoterol t	Increase frequency of as-needed ICS-formoterol t	A
Short-acting beta2-agonist (SABA)	Increase frequency of SABA use ForpMDI, add spacerT	A A
Increase usual controller: Maintenance and reliever ICS-formoterol t	Continue maintenance ICS-formoterol and increase reliever ICS-formoterol as needed, t	A
Maintenance ICS with SABA as reliever	In adulfc§(amd adolescents, quadruple ICS dose. In children with hjgiredherence, 5x increase in ICS dose is not effective.	B
Maintenance ICS-formoterol with SABA as relievert	Quadruple maintenance ICS-formoterol. t	B
Maintenance ICS plus o<Ber LABA with SABA as reliever	Step up to higher dose formulation of ICS plus other LABA In adults, consider adding a separate ICS inhaler to quadruple ICS dose.	B D
Add oral corticosteroids (OC. OCS (prednisone or prednisolone)	5) and contact doctor; review before ceasing Add OCS for severe exacerbations (e.g. PEF or FEVi <60% 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 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.	A D B
BDP: beclometasone dipropionate; FEVi: 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.
■f 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 48 meg formoterol for beclometasone-formoterol (36 meg delivered dose), and 72 meg formoterol for budesonide-formoterol (54 meg delivered dose).
4. Management of worsening asthma and exacerbations
123
MANAGEMENT OF ASTHMA EXACERBATIONS IN PRIMARY CARE (ADULTS, ADOLESCENTS, CHLDREN 6-11 YEARS)
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
• Any risk factors for asthma-related death (Box 4-1, p.119)
• All current reliever and controller medications, including doses and devices ^scribed, adherence pattern, any recent dose changes, and response to current therapy.
Physical examination
The physical examination should assess:
• Signs of exacerbation severity (Box 4-3, p. 125) and vital sig^(e.g. level of consciousness, temperature, pulse rate, respiratory rate, blood pressure, ability to complete sentences, use of accessory muscles, wheeze).
• Complicating factors (e.g. anaphylaxis, pneumonia, pneumothorax)
• Signs of alternative conditions that could explain acute breathlessness (e.g. cardiac failure, inducible laryngeal obstruction, inhaled foreign body or pulmonary embolism).
Objective measurements
• Pulse oximetry. Saturation levels <90% in children or adults signal the need for aggressive therapy. PEF in patients older than 5 years (Box 4-3, p. 125)
Treating exacerbations in primary care
The main initial therapies include repetitive administration of short-acting inhaled bronchodilators, early introduction of systemic corticosteroids, and controlled flow oxygen supplementation.563 The aim is to rapidly relieve airflow obstruction and hypoxemia, address th([>jnderlying inflammatory pathophysiology, and prevent relapse. Infection control procedures should be followed.
Inhaled short-acting beta2-agonists
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 limitation574 (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 nebulizer574,575 (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,576 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.
124
4. Management of worsening asthma and exacerbations
Box 4-3. Management of asthma exacerbations in primary care (adults, adolescents, children 6-11 years)
r			
L	PRIMARY CARE	Patient presents with acute or sub-acute asthma exacerbation	J
			
r			
		Is it asthma?	
	ASSESS the PATIENT	Factors for asthma-related death?	
■		Severity of exacerbation? (consider worst feature)	
L			
MILD or MODERATE
Talks in phrases, prefers sitting to lying, not agitated Respiratory rate increased Accessory muscles not used Pulse rate 100-120 bpm 02 saturation (on air) 90-95% PEF >50% predicted or best
SEVERE
Talks in words, sits bunched forwards, agitated Respiratory rate >307min Accessory muscles in use Pulse rate >120 bpm Oj saturation (on air) <90% PEF i50% predicted or best
LIFE-THREATENING
Drowsy, confused sr si srt ciss:
f
WORSENING
START TREATMENT
SABA 4-10 puffs by pMDI + spacer, repeat every 20 minutes for 1 hour Prednisolone: adults 40-SD mg, children 1-2 rng/kg, max. 40 mg Controlled oxygen (if available): target saturation 93-95% (children: 94-93%)
CONTINUE TREATMENT with SABA as needed ASSESS RESPONSE AT 1 HOUR (or earlier)
—N I
URGENT
1 +
TRANSFER TO ACUTE CARE FACILITY
While waiting: give SABA,
ipratropium bromide, O:, systemic corticosteroid
millll
4mÉÉ
WORSENING
7
IMPROVING
T
	ASSESS FOR DISCHARGE	ARRANGE at DISCHARGE
	Symptoms improved, not needing SABA	Reliever: continue as needed
	PEF improving, and >6Q-80% of personal	: Controller: start, or step up.
	best or predicted	Check inhaler technique, adherence
	Oxygen saturation >94% room air	. Prednisolone: continue, usually for 5-7 days
	Resources at home adequate	[3-5 day s for chil dren)
		Follow up: within 2-7 days 0-2 days for children)
I
FOLLOW UP
Review symptoms and signs: Is the exacerbation resolving? Should prednisone be continued? Reliever: reduce to as-needed. Controller: continue higher dose for short term (1-2 weeks) or long (3 months), depending on background to exacerbation
Risk factors: check and correct modifiable risk factors that may have contributed to exacerbation, including inhaler technique and adherence. Refer if >1-2 exacerbations in a year.
Action plan: Is it understood? Was it used appropriately? Does it need modification?
Q2: oxygen; PEF: peak expiratory flow; SABA: short-acting beta2-agonist (doses are forsalbutamol).
4. Management of worsening asthma and exacerbations
125
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 therapy577 580 (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.577 580 If supplemental oxygen is administered, oxygen saturation should be maintained no higher than 96% in adults.581
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 of prednisolone for adults is 1 mg/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 adults582,583 and 3-5 days in children584 (Evidence B). Patients should be advised about common side-effects, including sleep disturbance, increased appetite, reflux and mood changes.573
Controller medication
Patients already prescribed controller medication should be provided with advicaQ^bout increasing the dose for the next 2-4 weeks, as summarized in Box 4-2 (p.123). Patients not currently taking controller medication should be commenced on regular ICS-containing therapy, as SABA-only treatment of asthma is no longer recommended. An exacerbation requiring medical care indicates that the patient is at increased risk of future exacerbations (Box 2-2, p.36).
Antibiotics (not recommended)
Evidence does not support routine use of antibiotics in the treatment of acute asthma exacerbations unless there is strong evidence of lung infection (e.g. fever and purulent srwhtti or radiographic evidence of pneumonia).585
Reviewing response
During treatment, patients should be closely monitored, and treatment titrated according to their response. Patients who present with signs of a severe or life-threatening exacerbation (Box 4-3, p.125), who fail to respond to treatment, or who continue to deteriorate should be transferred immediately to an acute care facility. Patients with little or slow response to SABA treatment should be closely monitored.
For many patients, lung function can be monitored after SABA therapy is initiated. Additional treatment should continue until PEF or FEVi reaches a plateau or (ideally) returns to the patient's previous best. A decision can then be made whether to send the patient home or transfer them to an acute care facility.
Follow up
Discharge medications should include as-needed reliever medication (low dose ICS-formoterol or SABA), 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.59) may be indicated.
126
4. Management of worsening asthma and exacerbations
MANAGEMENT OF ASTHMA EXACERBATIONS IN THE EMERGENCY DEPARTMENT (ADULTS, ADOLESCENTS, CHILDREN 6-11 YEARS)
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). Infection control procedures should be followed. Management of asthma in the intensive care unit is beyond the scope of this report and readers are referred to a comprehensive review.586
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.119)
All current reliever and controller medications, including doses and devices prescribed, adherence pattern, any recent dose changes, and response to current therapy.
Physical examination
The physical examination should assess:
• Signs of exacerbation severity (Box 4-4), including vital signs (e.g. level of consciousness, temperature, pulse rate, respiratory rate, blood pressure, ability to complete sentences, use of accessory muscles)
• Complicating factors (e.g. anaphylaxis, pneumonia, atelectasis, pneumothorax or pneumomediastinum)
• Signs of alternative conditions that could explain acute breathlessness (e.g. cardiac failure, inducible laryngeal obstruction, inhaled foreign body or pulmonary embolism).
Objective assessments
Objective assessments are also needed as the physical examination alone may not indicate the severity of the exacerbation.587,588 However, patients, and i^&Ptheir laboratory values, should be the focus of treatment.
• Measurement of lung function: this is strongly recommended. If possible, and without unduly delaying treatment, PEF or FEVi should be recorded before treatment is initiated, although spirometry may not be possible in children with acute asthma. Lung function should be monitored at one hour and at intervals until a clear response to treatment has occurred or a plateau is reached.
• Oxygen saturationcTjms should be closely monitored, preferably by pulse oximetry. This is especially useful in children if they are unable to perform PEF. In children, oxygen saturation is normally >95%, and saturation <92% is a predictor of the need for hospitalization589 (Evidence C). Saturation levels <90% in children or adults signal the 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:590 They should be considered for patients with PEF or FEVi <50% predicted,591 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 PaC02 is often below normal (<40 mmHg). Fatigue and somnolence suggest that pC02 may be increasing and airway intervention may be needed. PaO2<60 mmHg (8 kPa) and normal or increased PaC02 (especially >45 mmHg, 6 kPa) indicate respiratoryfailure.
• 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.592 Similarly, in children, routine CXR is not recommended unless there are physical signs suggestive of pneumothorax, parenchymal
4. Management of worsening asthma and exacerbations
127
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.593
Treatment in acute care settings such as the emergency department
The following treatments are usually administered concurrently to achieve rapid improvement.594 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 therapy577-579 (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.
Ay
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 spacer574,576 (Evidence A). Evidence is less robust in severe and near-fatal asthma. Systematic reviews of intermittent versus continuous SABA in acute asthma, which mostly used nebulized SABA, provide conflicting results. Use of nebulizers can disseminate aerosols and potentially contribute to spread of respiratory viral infections.595
Current evidence does not support the routine use of intravenous beta2-agonists in patients with severe asthma exacerbations596 (Evidence A).
Epinephrine (for anaphylaxis)
Intramuscular epinephrine (adrenaline) is indicated in addition to standard therapy for acute asthma associated with anaphylaxis and angioedema. It is not routinely indicated for other asthma exacerbations.
Systemic corticosteroids
Systemic corticosteroids speed resolution of exacerbations and prevent relapse, and in acute care settings should be utilized in all but the mildest exacerbations^ aoults, adolescents and children 6-11 years.597 599 (Evidence A). Where possible, systemic corticosteroids should be administered to the patient within 1 hour of presentation.598,600 Use of systemic corticosteroids is particularly important in the emergency department if:
• Initial SABA treatment fails to achieve lasting improvement in symptoms
• The exacerbation developed while the patient was taking OCS
• The patient has a history of previous exacerbations requiring OCS.
Route of delivery: oral administration is as effective as intravenous. The oral route is preferred because it is quicker, less invasive and less expensive.601,602 For children, a liquid formulation is preferred to tablets. OCS require at least 4 hours to produce a clinical improvement. Intravenous corticosteroids can be administered when patients are too dyspneicto 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,603 especially if there are concerns about adherence with oral therapy.604 However, current evidence does not demonstrate a benefit of intramuscular over oral corticosteroids.599
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.605
Duration: 5- and 7-day courses in adults have been found to be as effective as 10- and 14-day courses respectively582,583 (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
128
4. Management of worsening asthma and exacerbations
Box 4-4. Management of asthma exacerbations in acute care facility, e.g. emergency department
INITIAL ASSESSMENT
A: airway B: breathing C: circulation
Are any of the following} present?
Drowsiness. Confusion, Silent chest
_
NO
Further TRIAGE BY CLINICAL STATUS
according to worst feature
MILD or MODERATE
Talks in phrases Prefers sitting to lying Not agitated
Respiratory rate increased Accessory muscles not jsed Pulse rate 100-120 bpm 02 saturation (on air) 90-95% PEF >&[>% predicted or best
Short-acting beta,-agonists Consider ipratropium bromide Controlled Oa to maintain saturation 93-95% (children 94-98%] Oral corticosteroids
-1
YES
7 ^ Consult ICU, start SABA and 02. and prepare patient for intubation
SEVERE
Talks in words
Sits hunched forwards
Agitated
Respiratory rate >30/min Accessory muscles being jsed Pulse rate > 120 bpm O, saturation (on air) < 90% PEF £50% predicted or best
Short-acting betaE-agonists Ipratropium bromide Controlled 0; to maintain saturation 93-95% (children 94-98%) Oral or IV corticosteroids Consider IV magnesium Consider high dose ICS
If continuing deterioration, treat as severe and re-assess for ICU
ASSESS CLINICAL PROGRESS FREQUENTLY
MEASURE LUNG FUNCTION in all patients one hour after initial treatment
FEV, or PEF 60-60% of predicted or personal best and symptoms improved MODERATE Consider for discharge planning _
FEV, or PEF «60% of predicted or personal best,or lack of clinical response
SEVERE Continue treatment as above and reassess frequently
ICS: inhaled corticosteroids; ICU: intensive care unit; IV: intravenous; 02: oxygen; PEF: peak expiratory flow; FEVi: forced expiratory volume in 1 sec
4. Management of worsening asthma and exacerbations
129
relapse rate was similar to that with prednisolone for 3-5 days, with a lower risk of vomiting.606 608. Oral dexamethasone should not be continued beyond 2 days because of concerns about metabolic side-effects. If there is a failure of 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 term609 or over several weeks610 (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 corticosteroids600 (Evidence A). When given in addition to systemic corticosteroids, evidence is conflicting in adults.611 In children, administration of ICS in addition to systemic corticosteroids within the first hours of attendance to the emergency department might reduce the risk of hospital admission611 Evidence B). Overall, ICS are well tolerated; however, cost may be 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 ongoing ICS-containing treatment since the occurrence of a severe exacerbation is a risk factor for future exacerbations (Evidence B) (Box 2-2, p.36), and ICS-containing medications significantly reduce the risk of asthma-related death or hospitalization202 (Evidence AJNSABA-only treatment of asthma is no longer recommended. For short-term outcomes such as relapse requiring admission, symptoms, and quality of life, a systematic review found no significant differences when ICS were added to systemic corticosteroids after discharge.612 There was some evidence, however, that post-discharge ICS were as effectQi as systemic corticosteroids for milder exacerbations, but the confidence limits were wide.612 (Evidence B). Cost may be a significant factor for patients in the use of high dose ICS, and further studies are required to establish their role.612
Other treatments
Ipratropium bromide
For adults and children with moderate-severe exacerbations, treatment in the emergency department with both SABA and ipratropium, a short-acting anticholinergic, was associated with fewer hospitalizations (Evidence A for adults613/adolescents; Evidence B for children614) rafTgreater improvement in PEF and FEVi compared with SABA alone.613615 (Evidence A, adults/adolescents) For children hospitalized for acute asthma, no benefits were seen from adding ipratropium to SABA, including no red^tion in length of stay,614 but the risk of nausea and tremor was reduced.614
Aminophylline and theophylline (not reeftmmended)
Intravenous aminophylline and tifl|sphylline should not be used in the management of asthma exacerbations, in view of their poor efficacy and safety/profile, and the greater effectiveness and relative safety of SABA.616 Nausea and/or vomiting are more common with aminophylline.614,616 The use of intravenous aminophylline is associated with severe and potentially fatal side-effects, particularly in patients already treated with sustained-release theophylline. In adults with severe asthma exacerbations, add-on treatment with aminophylline does not improve outcomes compared with SABA alone.616
Magnesium
Intravenous magnesium sulfate is not recommended for routine use in asthma exacerbations; however, when administered as a single 2 g infusion over 20 minutes, it reduces hospital admissions in some patients, including adults with FEVi <25-30% predicted at presentation; adults and children who fail to respond to initial treatment and have persistent hypoxemia; and children whose FEVi fails to reach 60% predicted after 1 hour of care617619 (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 adolescents620 622 or children.621,623 (Evidence B).
130
4. Management of worsening asthma and exacerbations
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.624
Leukotriene receptor antagonists (LTRAs)
There is limited evidence to support a role for oral or intravenous LTRAs in acute asthma. Small studies have demonstrated improvement in lung function625,626 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,627 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.628^
Antibiotics (not recommended)
Evidence does not support the routine use of antibiotics in the treatment of acut^rsisthma exacerbations unless there is strong evidence of lung infection (e.g. fever or purulent sputum or radiographic evidence of pneumonia).585
Sedatives (must be avoided)
Sedation should be strictly avoided during exacerbations of asthma because of the respiratory depressant effect of anxiolytic and hypnotic drugs. An association between the use of (h^Se drugs and avoidable asthma deaths has been reported.629,630
Non-invasive ventilation (NIV)
The evidence regarding the role of NIV in asthma is weaY. A systematic review identified five studies involving 206 participants with acute severe asthma treated with NIV or placebo.631 Two studies found no difference in need for endotracheal intubation but one study identified^wer admissions in the NIV group. No deaths were reported in either study. Given the small size of the studies, no/recommendation is offered. If NIV is tried, the patient should be monitored closely (Evidence D). It should not be attempted in agitated patients, and patients should not be sedated in order to receive NIV (Evidence D).
Reviewing response
Clinical status and oxygen saturation should be re-assessed frequently, with further treatment titrated according to the patient's response (Box 4<3iVl29). Lung function should be measured after one hour, i.e. after the first three bronchodilator treatments, and patients who deteriorate despite intensive bronchodilator and corticosteroid treatment should be re-evaluated for transfer to the intensive care unit.
Criteria for hospitalization versus discharge from the emergency department
From retrospective analyses, clinical status (including the ability to lie flat) and lung function 1 hour after commencement of treatment are more reliable predictors of the need for hospitalization than the patient's status on arrival.632,633
Spirometric criteria proposed for consideration for admission or discharge from the emergency department include:634
• If pre-treatment FEVi or PEF is <25% predicted or personal best, or post-treatment FEVi 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. 119) 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.
4. Management of worsening asthma and exacerbations
131
Other factors associated with increased likelihood of need for admission include:635 637
• 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 (1-2 days for children), and strategies to improve asthma management including medications, inhaler skills and written asthma action plan, should be addressed (Box4-5).287
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 transport and telephone reminders improve primary care follow up but hatfe»shown no effect on long-term outcomes.287
Patients discharged following an emergency department presentation or hospitalization for asthma should be especially targeted for an asthma education program, if one is available. Paiiehts who were hospitalized may be particularly receptive to information and advice about their illness. Health csr^s providers should take the opportunity to review:
• The patient's understanding of the cause of their astKJpa exacerbation
• Modifiable risk factors for exacerbations (including, where relevant, smoking) (Box 3-8, p.74)
• The patient's understanding of the purposes and correct uses of medications
• The actions the patient needs to take to respond to worsening symptoms or peak flows.
After emergency department presentation, comprehensive intervention programs that include optimal controller management, inhaler technique, and elempglts of self-management education (self-monitoring, written action plan and regular review151) are cost effective and^ave shown significant improvement in asthma outcomes287 (Evidence B).
Referral for expert advice should be considered for patients who have been hospitalized for asthma, or who repeatedly present to an acute care setting despite having a primary care provider. No recent studies are available, but earlier studies suggest that follow-up by a specialist is associated with fewer subsequent emergency department visits or hospitalizations and better asthma control.287
132
4. Management of worsening asthma and exacerbations
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.53- p.57). Patients currently prescribed ICS-containing medication should generally have their treatment stepped up for 2-4 weeks (Box 4-2, p.123) 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)612and 3-5 days for children (1-2 mg/kg/day to a maximum of 40 mg/day)638 (Evidence A). Review progress before ceasing OCS. If the OCS is dexamethasone, treatment is only for total 1-2 days,606 but if there is failure of resolution, or relapse of symptoms, consideration should be given to switching to prednisolone. For patients considered at risk of poor adherence, intramuscular corticosteroids may be considered599 (Evidence B).
Reliever medication - as-needed rather than regular
Transfer patients back to as-needed rather than regular reliever medication use, based on symptomatic and objective improvement. If ipratropium bromide was used in the emergency department or hospital, it may be quickly discontinued, as it is unlikely to provide ongoing benefit.
Risk factors and triggers that contributed to the exacerbation
Identify factors that may have contributed to the exacerbation arirfimplement strategies to reduce modifiable risk factors (Box 3-8, p.74). An exacerbation severe enough to require hospitalization may follow irritant or allergen exposure, viral respiratory infections, inadequate long-term treatment, problems with adherence, and/or lack of a written asthma action plan. Handwashing, masks and social/physical distancing is associated with a reduced risk of acquiring viral respiratory infections, including influenza.
Self-management skills and written asthma action plan
• Review inhalertechnique (Box 3-12, p.87).
• Review technique with PEF meter if used.
• Provide a written asthma action plan (Box 4-2, p.123) or review the patient's existing plan, either at discharge or as soon as possible afterwards. Patients discharged from the emergency department with an action plan and PEF meter have better outcomesGjran patients discharged without these resources.639
• 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.639,640
• 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 (1-2 days for children) 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
4. Management of worsening asthma and exacerbations
133
Al
. v>>.
Chapter 5.
Diagnosis and initial treatment of adults with features of asthma, COPD
or both ('asthma-COPD overlap')
KEY POINTS
Asthma and chronic obstructive pulmonary disease (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 identify adult patients who, for safety, should not be treated with long-acting bronchodilators alone.
• In COPD, high dose ICS should not be used because of the risk of pneumonia.
•  Distinguishing asthma from COPD can be difficult, particularly in smokers and older adults, and some patients may
have features of both asthma and COPD. •  The terms 'asthma-COPD overlap' (ACO) or 'asthma+COPD' are Blwsple descriptors for patients who have features
• These terms do not refer to a single disease entity. They include patients with several clinical phenotypes that are likely caused by a range of different underlying mechanisms.
• More research is needed to better define these phenotypes and mechanisms, but in the meantime, safety of pharmacologic treatment is a high priority.
• Diagnosis in patients with chronic respiratory symptoms involves a stepwise approach, first recognizing that the patient is likely to have chronic airwayO)isease, then syndromic categorization as characteristic asthma, characteristic COPD, with features of both or having other conditions such as bronchiectasis.
• Spirometry is essential for conf^Qjrhg persistent airflow limitation, but variable airflow obstruction can be detected with serial peak flow measurements and/or measurements before and after bronchodilator.
Initial treatment for safety and clinical efficacy
• For asthma: 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 long-acting muscarinic antagonist (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 202150 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/u.l.
• 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.
Many patients have features of both asthma and COPD
of both asthma and COPD.
Diagnosis
136
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 comrapn to both asthma and COPD.641
The most easily recognized phenotypes of asthma and COPD such as allergic asthma in children/young adults and emphysema in older smokers are clearly distinguishable. Regulatory studies of pharmacotherapy in asthma and COPD are largely restricted to patients with very clearly defined asthma or COPD. However, in the community, the features of asthma and COPD may overlap, especially in older adults.
There are extremely important differences in treatment recommendations for asthma and COPD. In particular, treatment with long-acting bronchodilators alone (i.e. without ICSVr9-recommended for initial treatment in COPD642 but is contraindicated in asthma due to the risk of severe exacerbations and death. 121,210,643,644 several studies have also shown that patients with diagnoses of both asthma and COPD are at increased risk of hospitalization or death if they are treated with LABA compared with ICS-LABA.645 647
Challenges in clinical diagnosis of asthma and COPD
Although asthma is characterized by variable exf^rtory airflow limitation, at least initially (Box 1-2, p.23), and COPD is characterized by persistent airflow limitation^\we definitions of asthma and COPD are not mutually exclusive (Box 5-1, p.138). This means that clinical features are also important in making a diagnosis.
In children and young adults with chro<$ror recurrent respiratory symptoms, the differential diagnosis is different from that in older adults. Once infectious disease and nonpulmonary conditions (e.g. congenital heart disease, inducible laryngeal obstruction) have been excluded, the most likely chronic airway disease in children and young adults is asthma.
However, in adults with a-rHStory of long-standing asthma,648,649 persistent airflow limitation may be found 650 654 Distinguishing these from patients with COPD is problematic, especially if they are smokers or have other risk factors for COPD.655 658 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.52,659
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
137
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;653,660 662 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.659'663,664
There is broad agreement that patients with features of both asthma and COPD have a greater burden of symptoms,665 experience frequent exacerbations,52'651,665 have poor quality of life,526S06e5 a more rapid decline in lung function,665 higher mortality,651'659 and greater use of healthcare resources52,666 compared with patients with asthma or COPD alone.
ASSESSMENT AND MANAGEMENT OF PATIENTS WITH CHRONIC RESPIRATORY SYMPTOMS
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 inflamfff^non. 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. [GINA 2021]
COPD
Chronic obstructive pulmonary disease (COPD) is a common, preventable and treatable disease that is characterized by persistent respiratory symptoms and airflow limitation that is due to airway and/or alveolar abnormalities usually caused by significant exposure to noxious particles or gases and influenced by host factors including abnormal lung development. [GOLD 2021 ]50
Asthma-COPD overlap, also called asthma+COPD ^
Asthma-COPD overlap' and 'asthma +COPD' are terms used to collectively describe patients who have persistent airflow limitation together with clinical features that are consistent with both asthma and COPD.
This is not a definition of a single disease entity, but a descriptive term for clinical use that includes several different clinical phenotypes reflecting different underlying mechanisms.
#1: History and clinical assessment to establish the following:
• The nature and pattepfQf 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.12 Physical examination may provide supportive information.
138
5. Diagnosis and initial treatment of asthma, COPD and asthma-COPD overlap
Box 5-2. Approach to initial treatment in patients with asthma and/or COPD
CLINICAL PHENOTYPE - ADULTS WITH CHRONIC RESPIRATORY SYMPTOMS (dyspnea, cough, chest tightness, wheeze)
HIGHLY LIKELY TO BE ASTHMA
if several of the following features TREAT AS ASTHMA
HISTORY
■ Symptoms vary over time and in intensity
- Triggers may include laughter, exercise, allergens, seasonal
- Onset before age 40 years
- Symptoms improve spontaneously or with bronchodilators (minutes) or ICS (days to weeks)
• Current asthma diagnosis, or asthma diagnosis in childhood
LUNG FUNCTION
• Variable expiratory airflow limitation
■ Persistent airflow limitation may be present
FEATURES OF BOTH ASTHMA + COPD TREAT AS ASTHMA
LIKELY TO BE COPD
if several of the following features TREAT AS COPD
HISTORY
■ Symptoms intermittent or episodic - May have started before or after age 40
■ May have a history of smoking and/or other toxic exposures, or history of low birth weight or respiratory illness such as tuberculosis
■ Any of asthma features at left (e.g. common triggers: symptoms improve spontaneously or with bronchodilators or ICS: current asthma diagnosis or asthma diagnosis in childhood)
LUNG FUNCTION
■ Persistent expiratory airflow limitation
■ With or without bronchodilator reversibility
_
_
HISTORY
• Dyspnea persistent (most days)
- Onset after age 40 years
- Limitation of physical activity
- May have been preceded by cough/sputum
- Bronchodilator provides only limited relief
• History of smoking and/or other toxic exposure, or history of low birth weight or respiratory illness such as tuberculosis
• No past or current diagnosis of asthma LUNG FUNCTION
• Persistent expiratory airflow limitation
• With or without bronchodilator reversibility
INITIAL PHARMACOLOGICAL TREATMENT (as well as treating comorbidities and risk factors. See Box 3-5A)
ICS-CONTAINING TREATMENT IS ESSENTIAL to reduce risk of severe exacerbations and death. See Box 3-5A
- As-needed low dose ICS-formoterol may be used as reliever. See Box 3-5A
DO NOT GIVE LABA and/or LAMA without ICS
Avoid maintenance OCS
ICS-CONTAINING TREATMENT IS ESSENTIAL
to reduce risk of severe exacerbations and death. See Box 3-5A
Add-on LABA and/or LAMA usually also needed
Additional COPD treatments as per GOLD
DO NOT GIVE LABA and/or LAMA without ICS
Avoid maintenance OCS
TREAT AS COPD (see GOLD report)
- Initially LAMA and/or LABA
- Add ICS as per GOLD for patients with hospitalizations, >2 exacerbations/year requiring OCS, or blood eosinophils >300/ul
Avoid high dose ICS, avoid maintenance OCS
Reliever containing ICS is not recommended
REVIEW PATIENT AFTER 2-3 MONTHS. REFER FOR EXPERT ADVICE IF DIAGNOSTIC UNCERTAINTY OR INADEQUATE RESPONSE
GOLD: Global Initiative for Obstructive Lung Disease; ICS: inhaled corticosteroid; LABA: long-acting p2-agonist; LAMA: long-acting muscarinic antagonist
5. Diagnosis and initial treatment of asthma, COPD and asthma-COPD overlap
139
#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.139, Box 5-3, p.140).
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.
Box 5-3. Spirometrie measures in asthma and COPD
Spirometrie variable                  Asthma                           COPD Asthma+COPD			
Normal FEVi/FVC pre- or post BD	Compatible with asthma	Not compatibles^ COPD	Not compatible
Reduced post-BD FEWFVC (< lower limit of normal, or <0.7 (GOLD))	Indicates airflow limitation but may improve spontaneously or on treatment	Required®rdiagnosis of COPD C	Required for diagnosis of asthma+COPD
Post-BD FEVi >80% predicted	Compatible with diagnosis o^ asthma (good asthma control or interval between symptoms)	Compatible with mild persistent airflow limitation if post-BD FEWFVC is reduced	Compatible with mild persistent airflow limitation if post-BD FEWFVC is reduced
Post-BD FEVi <80% predicted	Compatible with diagnosis of asthma. Risk factor for asthma exacerbations	An indicator of severity of airflow limitation and risk of future events (e.g. mortality and COPD exacerbations)	As for COPD and asthma
Post-BD increase in FEVi >12% and 200 mL from baseline (reversible airflow < limitation).	UsujjjKat some time in course of asthma, but may not be present when well-controlled or on controller therapy	Common and more likely when FEVi is low	Common and more likely when FEVi is low
Post-BD increase in FEVi >12% and 400 mL from baseline (marked reversibility)	High probability of asthma	Unusual in COPD	Compatible with asthma+COPD
BD: bronchodilator; FEV<: forced expiratory volume in 1 second; FVC: forced vital capacity; GOLD: Global Initiative for Obstructive Lung Disease.
140
5. Diagnosis and initial treatment of asthma, COPD and asthma-COPD overlap
#3: Selecting initial treatment (See Box 5-2, p.139) For asthma
Commence treatment as described in Chapter 3 (Box 3-4.A-D, p.53 - p.57). 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.59). Inhaled therapy should be optimized to minimize the need for oral corticosteroids (OCS).
For COPD
Commence treatment as in the current GOLD strategy report.50 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/uL, but is not used alone as monotherapy without LABA and/or LAMA. Inhaled therapy should be optimized to reduce the need for OCS. In patients with features of COPD, high dose ICS should be avoided because of the risk of pneumonia.667,668
For patients with features of asthma and COPD
Start treatment as for asthma (Box 3-4.A-D, p.53 - p.57) until further investigations have been performed.
ICS play a pivotal role in preventing morbidity and even death in patients with uncontrolled asthma symptoms, for whom even seemingly 'mild' symptoms (compared to those of moderate oj»-severe COPD) might indicate significant risk of a life-threatening attack.669 For patients with asthma+COPD, ICS should be used initially in a low or medium dose (see Box 3-6, p.61J, depending on level of symptoms and risk of adverse effects, including pneumonia.
Patients with features or diagnosis of both asthma and COPD will usually also require add-on treatment with LABA and/or LAMA to provide adequate symptom control.
Patients with any features of asthma should not be treated with LABA and/or LAMA alone, without ICS. A large case-control study in community patients with HtnvTy diagnosed COPD found that those who also had a diagnosis of asthma had a lower risk of COPD hospitalizations and death if treated with combination ICS-LABA than with LABA alone.645 In another large retrospective longitudinal population cohort study of patients aged >66 years, those recorded as having asthma with COPD had lower morbidity and hospitalizations if they received ICS treatment; a similar benefit was seen in those with COPD plus concurrent asthma.647
All patients with chronic airflow limitation
Provide advice, as described in the GINA and GOLD reports, about:
• Treatment of modifiable risk factors including advice about smoking cessation
• 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.
5. Diagnosis and initial treatment of asthma, COPD and asthma-COPD overlap
141
#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-COPD overlap, as outlined in the GINA and GOLD strategy reports.
Box 5-4 (p.142) summarizes specialized investigations that are sometimes used to distinguish asthma and COPD. Box 5-4. Specialized investigations sometimes used in distinguishing asthma and COPD
	Asthma	COPD
Lung function tests		
DLCO	Normal (or slightly elevated)	Often reduced
Arterial blood gases	Normal between exacerbattsris	May be chronically abnormal between exacerbations in more severe forms of COPD
Airway hyperresponsiveness (AHR)	Not useful ojrtfe'own in distinguishing asthma from COPD, but higher levels of AHR favor asthma	
Imaging		
High resolution CT Scan	Usually normal but air trapping and increased bronchial wall thickness may be observed.	Low attenuation areas denoting either air trapping or emphysematous change can be quantitated; bronchial wall thickening and features of pulmonary hypertension may be seen.
Inflammatory biomarkers		
A positive test for atopy (specific IgE and/or skin prick test to aeroallergens)	Increases probability of allergic asthma; not essential for diagnosis of asthma	Conforms to background prevalence; does not rule out COPD
FeNO	A high level (>50 ppb) in non-smokers is moderately associated with eosinophilic airway inflammation.	Usually normal Low in current smokers
Blood eosinophilia	Supports diagnosis of eosinophilic airway inflammation	May be present in COPD including during exacerbations
Sputum inflammatory cell analysis	Role in differential diagnosis is not established in large populations.	
DLCO: diffusing capacity of the lungs for carbon monoxide; FeNO: fractional concentration of exhaled nitric oxide; IgE: immunoglobulin E
142 5. Diagnosis and initial treatment of asthma, COPD and asthma-COPD overlap
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.
5. Diagnosis and initial treatment of asthma, COPD and asthma-COPD overlap
143
Al
. v>>.
SECTION 2. CHILDREN 5 YEARS AND YOUNGER
Chapter 6.
Diagnosis and management of asthma in children 5 years and younger
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 relatives
o   Clinical improvement during 2-3 months of controller treatment, and worsening after cessation.
ASTHMA AND WHEEZING IN YOUNG CHILDREN
Asthma is the most common chronic disease of childhood and the leading cauke of childhood morbidity from chronic disease as measured by school absences, emergency department visits and hospitalizations.670 Asthma often begins in early childhood; in up to half of people with asthma, symptoms comrrrenee during childhood.671 Onset of asthma is earlier in males than females.672-674
No intervention has yet been shown to prevent the development of asthma or modify its long-term natural course. Atopy is present in the majority of children with asthma who are o<^r3 years old, and allergen-specific sensitization (and particularly multiple early-life sensitizations) is one of the most important risk factors for the development of asthma.675
Viral-induced wheezing
Recurrent wheezing occurs in a large proportion of children aged 5 years or younger. It is typically associated with upper respiratory tract infections (URTI), which aeS^ir in this age group around 6-8 times per year.676 Some viral infections (respiratory syncytial virus and rhinovirus) are associated with recurrent wheeze throughout childhood. Wheezing in this age group is a highly heterogeneous condition, and not all wheezing indicates asthma. A large proportion of wheezing episodes in young children is virally induced whether the child has asthma or not. Therefore, deciding when wheezing with a respiratory infection is truly an isolated event or represents a recurrent clinical presentation of childhood asthma may be difficult.674,677 In chiWrWi aged under 1 year, bronchiolitis may present with wheeze. It is usually accompanied by other chest signs such as crackles on auscultation.
Wheezing phenotypes
In the past, two main classifications of wheezing (called 'wheezing phenotypes') were proposed:
• Symptom-based classification:678 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.674 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.679,680
146
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. For example, one study conducted in a research setting with high medication adherence found that daily ICS treatment reduced exacerbations in pre-school children characterized as 'sensitization with indoor pet exposure' or 'multiple sensitization with eczema', but not among those characterized as 'minimal sensitization' or 'sensitization with tobacco smoke exposure'.681
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,682,683 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,684 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
SYMPTOM PATTERN
(may change over time)
Symptoms (cough, wheeze, heavy breathing) for <10 days during upper respiratory tract infections
2-3 episodes per year
No symptoms between episodes
Symptoms (cough, wheeze, heavy breathing) for >10 days during upper respiratory tract infections
>3 episodes per year, or severe episodes and/or night worsening
Between episodes child may have occasional cough, wheeze or heavy breathing
Symptoms {cough, wheeze, heavy breathing) for >10 days during upper respiratory tract infections
>3 episodes per year, or severe episodes and/or night worsening
Between episodes child has cough, wheeze or heavy breathing during play or when laughing
Allergic sensitization, atopic dermatitis, food allergy, or family history of asthma
Few have asthma
Some have asthma
Most have asthma
Symptoms suggestive of asthma in children 5 years and younger
As shown in Box 6-1 and Box6-2/2A 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.
6. Diagnosis and Management of asthma in children 5 years and younger
147
Box 6-1 is a schematic figure showing the estimated probability of an asthma diagnosis685,686 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 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 overtime 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.675
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 accompanied by wheezing and breathing difficulties • Cough occurring with exercise, laughing, crying or exposure to tobacco smoke, particularly in trrejarosence of an apparent respiratory infection
Wheezing	•  Recurrent wheezing, including during sleep or with triggers such as activity, laughing, crying-erexposure to tobacco smoke or air pollution
Difficult or heavy breathing or shortness of breath	•  Occurring with exercise, laughing, or crying
Reduced activity	•  Not running, playing or laughing at the same intensity as other children; tujfs earlier during walks (wants to be carried)
Past or family history	✓^Other allergic disease (atopic dermatitis or allergic rhinitis, food allergy). Asthma in first-degree relative(s)
Therapeutic trial with low dose ICS (Box 6-5, p.159), and as-needed SABA	•  Clinical improvement during 2-3 months of controller treatment and worsening when treatment is stopped
ICS: inhaled corticosteroid; SABA: short-acting beta2-agonist
148
6. Diagnosis and management of asthma in children 5 years and younger
Box 6-2A. Questions that can be used to elicit features suggestive of asthma
• 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,687 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 othei^fisease with breathing problems?
Wheeze
Wheeze is the most common and specific symptom associated with asthma if^fchildren 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'.688 Some cultures do not have a<gprd for wheeze.
, o
Wheezing may be interpreted differently based on:
• Who observes it (e.g. parent/carer versus the health dSjte 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 importa|jce of certain symptoms can differ between cultures, as can the diagnosis and treatment of respiratory tract diseases in general).
Cough
Cough due to asthma is generally non-productive, recurrent and/or persistent, and is usually accompanied by wheezing episodes and breathing difficulties. Allergic rhinitis may be associated with cough in the absence of asthma. A nocturnal cough (when the child is asleepXsba cough that occurs with exercise, laughing or crying, in the absence of an apparent respiratory infection, support&l^Kjiagnosis of asthma. The common cold and other respiratory illnesses are also associated with coughing. Prolonged cough in infancy, and cough without cold symptoms, are associated with later parent-reported physician-diagnosed asthma, independent of infant wheeze. Characteristics of cough in infancy may be early markers of asthma susceptibility, particularly among children with maternal asthma.689
Breathlessness
Parents may also use terms such as 'difficult breathing', 'heavy breathing', or 'shortness of breath'. Breathlessness that occurs during exercise and is recurrent increases the likelihood of the diagnosis of asthma. In infants and toddlers, crying and laughing are equivalent to exercise in older children.
Activity and social behavior
Physical activity is an important trigger of asthma symptoms in young children. Young children with poorly controlled asthma often abstain from strenuous play or exercise to avoid symptoms, but many parents are unaware of such changes in their children's lifestyle. Engaging in play is important for a child's normal social and physical development. For this reason, careful review of the child's daily activities, including their willingness to walk and play, is important when assessing a potential asthma diagnosis in a young child. Parents may report irritability, tiredness and mood changes in their child as the main problems when asthma is not well controlled.
6. Diagnosis and Management of asthma in children 5 years and younger
149
TESTS TO ASSIST IN DIAGNOSIS
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.690
cT
Chest X-ray
Radiographs are rarely indicated; however, if there is doubt about the ofj^gnosis of asthma in a wheezing or coughing child, a plain chest X-ray may help to exclude structural abnormalitjesVe.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
Due to the inability of most children 5 years and younger to perform reproducible expiratory maneuvers, lung function testing, bronchial provocation testing, and otherjmy^iological tests do not have a major role in the diagnosis of asthma 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 visuaM^entives.
Exhaled nitric oxide
Measurement of fractional concentration of exhaled nitric oxide (FeNO) is not widely available for most children in this age group and currently remains primarily a research tool. FeNO can be measured in young children with tidal breathing, and normal reference values have been published for children aged 1-5 years.691 In pre-school children with recurrent coughing and wheezing, an elevated FeNO recorded 4 weeks from any URTI predicted physician-diagnosed asthma at school age,692 and increased the odds for wheezing, asthma and ICS use by school age, independent of clinical history and presence of specific IgE.693
Risk profiles
A number of risk profile tools aimed at identifying which wheezing children aged 5 years and younger are at high risk of developing persistent asthma symptoms have been evaluated for use in clinical practice. However, these tools have shown limited performance for clinical practice. Only three prediction tools have been externally validated (Asthma Predictive Index694 from Tucson, USA, PIAMA index675 from the Netherlands, and Leicester tool695 from the UK), and a recent systematic review has shown that these tools have poor predictive accuracy, with variation in sensitivity and positive predictive value.696 Larger predictive studies using more advanced statistical methods, and with objective measurements for asthma diagnosis, are probably needed to propose a practical tool in clinical care to predict persistent asthma in recurrent wheezers in infancy and pre-school age. The role of these tools is to help identify children at greater
150
6. Diagnosis and management of asthma in children 5 years and younger
risk of developing persistent asthma symptoms, not as criteria for the diagnosis of asthma in young children. Each tool demonstrates different performance characteristics with varying criteria used to identify risk.697
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).682
Box 6-3. Common differential diagnoses of asthma in children 5 years and younger
Condition	Typical features
Recurrent viral respiratory tract infections	Mainly cough, runny congested nose for <10 days; no symptoms between infections
Gastroesophageal reflux	Cough when feeding; recurrent chest infections; vomits easily especially after large feeds; poor response to asthma medications
Foreign body aspiration	Episode of abrupt, severe cough and/or stridor during eating or play; recurrent chest infections and cough; focal lung signs
Persistent bacterial bronchitis	Persistent wet cough; poor response to asthma medications
Tracheomalacia	Noisy breathing when crying ^Sating, or during upper airway infections (noisy inspiration if extrathoracic or expiratjpAJf intrathoracic); harsh cough; inspiratory or expiratory retraction; symptoms often present since birth; poor response to asthma medications
Tuberculosis	Persistent noisy respirations and cough; fever unresponsive to normal antibiotics; enlarged lymph nodes; poor response to bronchodilators or inhaled corticosteroids; contact with someone who has tuberculosis
Congenital heart disease	Cardiac murmur; cyanosis when eating; failure to thrive; tachycardia; tachypnea or hepatomegaly; poor response to asthma medications
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 dysplasia	Infant born prematurely; very low birth weight; needed prolonged mechanical ventilation or supplemental oxygen; difficulty with breathing present from birth
Immune deficiency	Recurrent fever and infections (including non-respiratory); failure to thrive
6. Diagnosis and Management of asthma in children 5 years and younger
151
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.
152
6. Diagnosis and management of asthma in children 5 years and younger
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 (SABA), regardless of whether the diagnosis of asthma has been made. However, for initial episodes of wheeze in children <1 year in the setting of infectious bronchiolitis, SABAs are generally ineffective.
• Atrial 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.
• The choice of inhaler device should be based on the child's age and capability. Tl^preferred device is a pressurized metered dose inhaler and spacer, with face mask for <3 years and mouthpiece for most 3-5 year-olds. Children should be switched from a face mask to mouthpiece as soon as th^are able to demonstrate good technique.
«  Review the need for asthma treatment frequently, as asthma-like symfaibms remit in many young children._
GOALS OF ASTHMA MANAGEMENT
As with other age groups, the goals of asthma management in young children are:
• To achieve good control of symptoms and maintain normal activity levels
• To minimize future risk; that is to reduce the risk of flare-ups, maintain lung function and lung development as close to normal as possible, and minimize medication side-effects.
Maintaining normal activity levels is particularly important in young children because engaging in play is important for their normal social and physical developmer|ťSť1s important to also elicit the goals of the parent/carer, as these may differ from conventional medical goals.
The goals of asthma management are achieved through a partnership between the parent/carer and the health professional team, with a cycle of:
• Assess (diagnosis, symptom control, risk factors, inhaler technique, adherence, parent preference)
• Adjust treatment (medications, non-pharmacological strategies, and treatment of modifiable risk factors)
• Review response including medication effectiveness and side-effects. This is carried out in combination with:
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.20,62 It has two components (Box 6-4, p.154): 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.38.
6. Diagnosis and management of asthma in children 5 years and younger
153
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 can be used for children aged 4-11 years.79 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.83
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
A. Symptom control	Level of asthma symptom control
In the past 4 weeks, has the child had:	Well          Partly      „      .   „ . Uncontrolled controlled controlled
Daytime asthma symptoms for more than a few minutes,   YesD Nod	
more than once a week?	
Any activity limitation due to asthma? (Runs/plays less      YesD Nod than other children, tires easily during walks/playing?) Reliever medication needed* more than once a week?      YesQ NoD	None            1-2 3-4 of these       of these        of these
Any night waking or night coughing due to asthma?         (JesD Nod	
B. Future risk for poor asthma outcomes	
Risk factors for asthma exacerbations within the next few months	
•   Uncontrolled asthma symptoms	
•   One or more severe exacerbations (ED attendance, hospitalization, or course of OCS) in previous year	
•   The start of the child's usual 'flare-up' season (especially if autumn/fall)	
•   Exposures: tobacco smoke; indoor or outdoor air pollution; indoor allergens (e.g. house dust mite, cockroach,	
pets, mold), especially in combination with viral infection698	
•   Major psychological or socio-economic problems for child or family	
•   Poor adherence with controller medication, or incorrect inhaler technique	
•   Outdoor pollution (NO2 and particles)99	
Risk factors for persistent airflow limitation	
•   Severe asthma with several hospitalizations	
•   History of bronchiolitis	
Risk factors for medication side-effects	
•   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.
154
6. Diagnosis and management of asthma in children 5 years and younger
Assessing future risk of adverse outcomes
The relationship between symptom control and future risk of adverse outcomes, such as exacerbations (Box 6-4, 0.154), 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.699
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,118 and poorly controlled asthma can affect growth.117 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.
If ICS is delivered through a face-mask or nebulizer, the skin on the nose and around the mouth should be cleaned shortly after inhalation in order to avoid local side-effects such as steroid rash (redQhžprng and atrophy).
MEDICATIONS FOR SYMPTOM CONTROL AND RISK REDUCTION
Choosing medications for children 5 years and younger
Good control of asthma can be achieved in the overwhelming majority of young children with a pharmacological intervention strategy.700 This should be developed in a partnership between the family/carer and the health care provider. As with older children and adults, medications comprise only one component of asthma management in young children; other key components include education, skills training for inhaler devices and adherence, non-pharmacological strategies including environmental control where appropriate, regular monitoring, and clinical review (see later sections in this chapter).
When recommending treatment for a young child, both general and individual questions apply (Box 3-3, p.48).
• What is the 'preferred' medication option at each treatment step to control asthma symptoms and minimize future risk? These decisions are based an wata for efficacy, effectiveness and safety from clinical trials, and on observational data. Recent studies suggest that consideration of factors such as allergic sensitization and/or peripheral blood count may help to better identify which children are more likely to have a short-term response to ICS.701 However, further studies are needed to assess the applicability of these findings in a wider range of settings, particularly in areas where blood eosinophilia may reflect helminth infection rather than asthma or atopy.
• How does this particular child differ from other children with asthma, in terms of: 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.159), 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.161).
6. Diagnosis and management of asthma in children 5 years and younger
155
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.162). 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.148; Box 6-2A, p.149) and respiratory symptoms are uncontrolled (Box 6-4, p.154) 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.159) 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 whether the symptoms are due to asthma (Evidence D). Referral for specialist opinion should also be considered at this stage.
It is important to discuss the decision to prescribe controller treatment and the choice of treatment with the child's parents or carers. They should be aware of both the relative benefits and risks of the treatments, and the importance of maintaining normal activity levels for their child's normal physical and social development. Although effects of ICS on growth velocity are seen in pre-pubertal children in the first 1-2 years of treatment, this is not progressive or cumulative, and the one study that examined long-term outcomes showed a difference of only 0.7% in adult height. 118702 Poorly controlled asthma itself adversely affects adult height.117 For more detail see Appendix Chapter 5B.
Treatment steps to control asthma symptoms and minimize future risk for children 5 years and younger
Asthma treatment in young children follows a stepwise approach (Box 6-5), with medication adjusted up or down to achieve good symptom control and minimize future risk of exacerbations and medication side-effects. The need for controller treatment should be re-assessed reguLar/ty? More details about asthma medications for children 0-5 years are provided in Appendix Chapter 5, Part C.
Before considering a step-up of controller treatment
If symptom control is poor and/or exacerbations persist despite 3 months of adequate controller therapy, check the following before any step up in treqi&ient is considered.
• Confirm that the symptoms are due to asthma rather than a concomitant or alternative condition (Box 6-3, p.105). Refer for expert assessment if the diagnosis is in doubt.
• 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.154).
156 6. Diagnosis and management of asthma in children 5 years and younger
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.161) 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. Initial episodes of wheeze in children <1 year often occur in the setting of infectious bronchiolitis, and this should be managed according to local bronchiolitis guidelines. SABAs are generally ineffective for bronchiolitis.703
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).
For children with intermittent viral-induced wheeze and no interval symptoms, particularly those with underlying atopy (positive mAPI) in whom inhaled SABA medication is not sufficient, intermittent>ffl]gn dose ICS may be considered569'704,705 (see Management of worsening asthma and exacerbation p.162), but because of the risk of side-effects, this should only be considered if the physician is confident that the treatment will be used appropriately.
STEP 2: Initial controller treatment plus as-needed SABA
Preferred option: regular daily low dose ICS plus as-needed SABA
Regular daily, low dose ICS (Box 6-6, p.160) is recommended as the preferred initial treatment to control asthma in children 5 years and younger (Evidence A).699'706-708 This initial treatment should be given for at least 3 months to establish its effectiveness in achieving good asthma control.
Other options
In young children with persistent asthma, regular treatment with a leukotriene receptor antagonist (LTRA) modestly reduces symptoms and need for oral corticosteroids compared with placebo.709 However, for young children with recurrent viral- induced wheezing, afferent review concluded that neither regular nor intermittent LTRA reduces OCS-requiring exacerbations (Evidence A).710 A further systematic review found that in pre-schoolers with asthma or recurrent wheezing, daily ICS was more effective in improving symptom control and reducing exacerbations than regular LTRA monotherapy.711 Parents should be counselled about the potential adverse effects of montelukast on sleep and behavior, and health professionals should consider the benefits and risks of side effects before prescribing; the FDA has required a boxed warning about these problems.215
For pre-school children with asthma characterized by frequent viral-induced wheezing and interval asthma symptoms, as-needed (prn)712 or episodic ICS713 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.708 See also Initial home management of asthma exacerbations, p.163.
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.
6. Diagnosis and management of asthma in children 5 years and younger
157
• Confirm that the symptoms are due to asthma rather than a concomitant or alternative condition (Box 6-3, p.152).
• 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.154). 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.215
Not recommended
There are insufficient data about the efficacy and safety of ICS-LABA in children^Fyears old to recommend their use. A short-term (8 week) placebo-controlled study did not show any significant difference in symptoms between combination fluticasone propionate-salmeterol vs fluticasone propionate alone; no additional safety signals were noted in the group receiving LABA.714
STEP 4: Continue controller treatment and refer for expert assessment
Preferred option: refer the child for expert advice and further investigation (Evidence D).
If doubling the initial dose of ICS fails to achieve and maintain good asthma control, carefully reassess inhaler technique and medication adherence as these are common problems in this age group. In addition, reassess and address control of environmental factors where relevant, and rececrorderthe asthma diagnosis.
Other options
The best treatment for this population has not been established. If the diagnosis of asthma has been confirmed, options to consider, with specialist advice, are-V
• Further increase the dose of ICS for a few weeks until the control of the child's asthma improves (Evidence D). Monitor for side-effects_<
• Add LTRA (data base^dJon studies in older children, Evidence D). Benefits, and risks of side effects, should be considered, as described previously.215
• Add long acting beta agonist (LABA) in combination with ICS; data based on studies in children >4 years of age
• 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.
158
6. Diagnosis and management of asthma in children 5 years and younger
Box 6-5. Personalized management of asthma in children 5 years and younger
Children 5 years and younger
Personalized asthma management:
Assess, Adjust, Review response
Asthma medication options:
Adjust treatment up and down for individual child's needs
PREFERRED
CONTROLLER
CHOICE
Other
controller options RELIEVER
CONSIDER THIS STEP FOR CHILDREN WITH:
STEP 1
Symptoms Exacerbations Side-effects Parent satisfaction
Exclude alternative diagnoses Symptom control & modifiable risk factors Comorbidities
Inhaler technique & adherence Parent preferences and goals
'reat modifiable risk factors and comorbidities Non-pharmacological strategies Asthma medications Education & skills training
STEP 2
Daily low dose inhaled corticosteroid (ICS) (see table of ICS dose ranges for pre-school children)
	Daily leukotriene receptor antagonist (LTRA), or intermittent short courses of ICS at onset of respiratory illness	Low dose ICS + LTRA Consider specialist referral	Add LTRA, or increase ICS frequency, or add intermittent ICS
As-needed short-acting ß2-agonist			
			
Infrequent viral       Symptom pattern not consistent with asthma but wheezing wheezing and no    episodes requiring SABA occur frequently, e.g. >3 per year, or few interval        Give diagnostic trial for 3 months. Consider specialist referral, symptoms Symptom pattern consistent with asthma, and asthma
symptoms not well-controlled or >3 exacerbations per year.
Asthma diagnosis, and asthma not well-controlled on low dose ICS
Asthma not well-controlled on double ICS
Before stepping up, check for alternative diagnosis, check inhaler skills, review adherence and exposures
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.159), 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 (meg) Inhaled corticosteroid                        .              ...    .      .     ' .     j „a'.          . . x (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)
Budesonide nebulized	500 (ages 1 year and older)
Fluticasone propionate (pMDI, standard particle, HFA)	50 (ages 4 years and older)
Fluticasone furoate (DPI)	Not sufficiently studied in children 5 years and younger)
Mometasone furoate (pMDI, standard particle, HFA)	100 (ages 5 years and older)
Ciclesonide (pMDI, extrafine particle, HFA)	Not sufficiently studied in children 5 years and younger
BDP: beclometasone dipropionate; DPI: dry powder inhaler; HFA: hydrofluoroalkane propellant; ICS: inhaled corticosteroid; pMDI: pressurized metered dose inhaler (non-chlorofluorocarbon formulations); in children, pMDI should always be used with a spacer
REVIEWING RESPONSE AND ADJUSTING TREATMENT^
Assessment at every visit should include asthma sympUjm' control and risk factors (Box 6-4, p.154), and side-effects. The child's height should be measured every year, o^wore often. Asthma-like symptoms remit in a substantial proportion of children of 5 years or younger,715717 so the need for continued controller treatment should be regularly assessed (e.g. every 3-6 months) (Evidence D). If therapy is stepped-down or discontinued, schedule a follow-up visit 3-6 weeks later to check whether symptoms have recurred, as therapy may need to be stepped-up or reinstituted (Evidence D).
Marked seasonal variations may be seen in symptoms and exacerbations in this age-group. For children with seasonal symptoms whose daily long-term cqifijoller treatment is to be discontinued (e.g. 4 weeks after their season ends), the parent/carer should be provided WHgra written asthma action plan detailing specific signs of worsening asthma, the medications that should be initiated to treat it, and when and how to contact medical care.
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 system718 (Box 6-7, p.161) (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.
160
6. Diagnosis and management of asthma in children 5 years and younger
• 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 cannot be taught effective use of a spacer device. If a nebulizer is used for delivery of ICS, it should be used with a mouthpiece to avoid the medication reaching the eyes.
Box 6-7. Choosing an inhaler device for children 5 years and younger
t ^ Age                      Preferred device                                           Alternate device		
0-3 years	Pressurized metered dose inhaler plus dedicated spacer with face mask	Neh(0Jizer with face mask
4-5 years	Pressurized metered dose inhaler plus dedicated spacer with mouthpiece	Pressurized metered dose inhaler plus dedicated spacer with face mask or nebulizer with mouthpiece or face mask
ASTHMA SELF-MANAGEMENT EDUCATION FOR CARERS OF YOUNG CHILDREN
Asthma self-management education should b«y6rovided to family members and carers of wheezy children 5 years and younger when wheeze is suspected to be caused by asthma. An educational program should contain:
• A basic explanation about asthra^nd the factors that influence it
• Training about correct inhalation technique
• Information on the importaj{c!fe of the child's adherence to the prescribed medication regimen
• A written asthma action plan.
Crucial to a successful asthma education program are a partnership between patient/carer and health care providers, with a high level of agreement regarding the goals of treatment for the child, and intensive follow-up (Evidence D).21
Written asthma action plans
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,719 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.162.
6. Diagnosis and management of asthma in children 5 years and younger
161
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.
• Parents/carers should seek urgent medical care if the child is acutely distressed, leth^fgtc, fails to respond to initial bronchodilator therapy, or is worsening, especially in children <1 year of age.
• Medical attention should be sought on the same day if inhaled SABA is needed more often than 3-hourly or for more than 24 hours.
• There is no compelling evidence to support parent-initiated oral corticosteroids. Management of exacerbations in primary care or acute care facility
• Assess severity of the exacerbation while initiating treatment with SABA (2-6 puffs every 20 minutes for first hour) and oxygen (to maintain saturation 94-98%).
• Recommend immediate transferto hospital if there is no response to inhaled SABA within 1-2 hours; if the child is unable to speak or drink, has a respiratory rate >40/minute or is cyanosed, if resources are lacking in the home, or if oxygen saturation is <92% on room air.
• Consider oral prednisone/prednisolone 1-2 mg/kg/day for up to 5 days for children attending an Emergency 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 dexamethasone 0.6 mg/kg/day for 2 days. If there is failure of resolution, or relapse of symptoms with dexamethasone, consideration should be given to switching to prednisolone.
Arrange early follow-up after an exacerbation
• Children who have experienced^ asthma exacerbation are at risk of further exacerbations. Arrange follow-up within 1-2 days of an exacerbation and again 1-2 months later to plan ongoing asthma management.
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.
162
6. Diagnosis and management of asthma in children 5 years and younger
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.720
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.701
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 medications and dosages and when and how to access medical care.
Need for urgent medical attention
Parents/carers should be advised to seek medical attention immediately if:
• The child is acutely distressed
• The child's symptoms are not relieved promptly by inhaled bronchodilator
• The period of relief after doses of SABA becomes progressively shorter
• A child younger than 1 year requires repeated inhaled SABA over several hours.
Initial treatment at home
Inhaled SABA via a mask or spacer, and review response^
The parent/carer should initiate treatment with twsyjuffs of inhaled SABA (200 meg salbutamol or equivalent), given one puff at a time via a spacer device with or without a facemask (Evidence D). This may be repeated a further two times at 20-minute intervals, if needed. The child should be observed by the family/carer and, if improving, maintained in a restful and reassuring atmosphere for an hour or more. Medical attention should be sought urgently if any of the features listed above apply; or on the same day if rpd^than 6 puffs of inhaled SABA are required for symptom relief within the first 2 hours, or if the child has not recoye^a after 24 hours.
Family/carer-initiated corticosteroids
Although practiced in some parts of the world, the evidence to support the initiation of oral corticosteroid (OCS) treatment by family/carers in the home management of asthma exacerbations in children is weak.721725 Preemptive episodic high dose nebulized ICS may reduce exacerbations in children with intermittent viral triggered wheezing.708 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.166).
Leukotriene receptor antagonists
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.726 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.727 Parents should be counseled about the FDA warning about risk of adverse effects on sleep and behavior with montelukast.215
6. Diagnosis and management of asthma in children 5 years and younger
163
Box 6-8. Management of acute asthma or wheezing in children 5 years and younger
PRIMARY CARE
Chile presents wlh acutEor sub-aojlE asthrr.aesacerfcaton cr acute v^eezing epiinde
ASSESS the CHILD
Consider olher d agncses "^isk facici'sfor hosprta izaiic" Severity of exacerbation?
MILD or MODERATE
Brealhless, ag taled
Pulse rates"13Dbpm (0-3 yrs) oriTfO bpmr^-nyrs) Osygen saiuraticn ld2%
START TREATMENT
Salbutamol 10C meg '.wo puffs sy pN'CI - spaceror 2£mg by nebulizer
Repeat ewry 20 min for the Frs1 hour if needed Controlled oxygen (if needed and available): target satiation 94-B8%
Cons-ider add ng iprasrop in 1-2 puffs
MONITOR CLOSELY for 1-2 hours
Transfer to !n igh level [are f any of:
■ Lack of response ,o salburarrDl overJ -2 hrs
■ Any 5 gns cf -severe exacerbation
■ Increasing n=sp rabory raie
■ Decreas-"g oxyge" saruration
IMPROVING
T
CONTINUE TREATMENT IF NEEDED
Monitor cfcseJy as abnwB If symptoms recur wilnin 3r4 hrs
■ Give extra salbutanrol 2-3 pun's per hour
■ Give prednisolone 2mgJtg (max. 2Cmg tor<2 yrs:
: srj y
SEVERE OR LIFE THREATENING
any of:
Unable bo speak or drink Central cyanosis Confusion or drowsiness Respiatory rate HOfrnin Dicygen sa1ura1ion <fl2% Silent chesl -on aus-cuItalian
Pulse rate >1:■! bpnn (D-S yrs) or >'M I;: i yrs)
T
URGENT
Worsening, or —   latk of —| improvefne-nr
Worsening, or failure to res-pond to
10 puffs salbutamol over 3-i hrs
TRANSFER TO HIGH LEVEL CARE [e.g. ICU}
While waiting give:
Ealbulamol 1 DO mog 6 pufs by prV D kspaoer (or 2.5ng nebulizer"!. Repeat every 2D rnin as needed.
Oxygen (rf available) la keep saturation W-BffX, PredmBc/one 2mgrkg (max. 20 mg tot <2 yrs; nax. 3D mg for2-5 yrs? as a starting dose
Cons :er ' -2 dese-s- :F neb_ :z==: ipratrDp /' bromide 2aCncg
w
IMPROVING T
DISCHARGE/FOLLOW-UP PLANNING
Ensure that resources at hone are adequate. Reliever: continue-as needed
Controller: consider need For. or adjustment of, regular controller Check inhaler technic ue and adherence Follow up: within 1-2 working day*; precnisone for 23-5 days Provide and: explain act-on plan
FOLLOW UP VISITS
Review symptoms and signs: Is the exacerbation resohrng? Should prednisone be continued? Reliever: Reduce to as-^eedec
Controller Continue or adjust depending on cause of exace^bartson, and duration of need for extra sa butarrol
Risk factors: Check and correct rr-odrlable risk factors that may have contributed :o exacerbation, including in-aler technique and adherence
Action plan: Is it undersiaoc? Was fused appropriately? Does it need nodirltaticci? Schedule next follow up visit
^jj^^.......
164
6. Diagnosis and management of asthma in children 5 years and younger
PRIMARY CARE OR HOSPITAL MANAGEMENT OF ACUTE ASTHMA EXACERBATIONS IN CHILDREN 5 YEARS OR YOUNGER
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.589 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.728
Box 6-9. Initial assessment of acute asthma exacerbations in children 5 years and younger
Symptoms	Mild	Severe*
Altered consciousness	No	Agitated, confused or drowsy
Oximetry on presentation (Sa02)**	>95%	<92%
Speech1'	Sentences	Words
Pulse rate	<100 beats/minute	>180 beats/minute (0-3 years) >150 beats/minute (4-5 years)
Respiratory rate	<40/minute	>40/minute
Central cyanosis	Absent	Likely to be present
Wheeze intensity	Variable	Chest may be quiet
*Any of these features indicates a severe asthma exacerbation. "Oximetry before treatment with oxygen or bronchodilator. f The normal developmental capability of the child must be taken into account.
Indications for immediate transfer to hospital
Children with features of a severe exacerbation that fail to resolve within 1-2 hours despite repeated dosing with inhaled SABA must be referred to hospital for observation and further treatment (Evidence D). Other indications are respiratory arrest or impending arrest; lack of supervision in the home or doctor's office; and recurrence of signs of a severe 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.166).
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.
6. Diagnosis and management of asthma in children 5 years and younger
165
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
• Social environment that limits delivery of acute treatment, or parent/carer unable to manage acute asthma at home
During transfer to hospital, continue to give inhaled SABA, oxygen (if available) to maintain saturation 94-98%, and give systemic corticosteroids (see Box 6-8, p. 164)
'Normal respiratory rates: <60 breaths/minute in children 0-2 months; <50 breaths/minute in chil*B5"2-12 months; <40 breaths/minute in children 1-5 years.
Bronchodilator therapy
The initial dose of SABA may be given by a pMDI with spacer and mask or mouthpiece or an air-driven nebulizer; or, if oxygen saturation is low, by an oxygen-driven nebulizer (as^ielBcribed above). For most children, pMDI plus spacer is favored as it is more efficient than a nebulizer for bronchodilator delivery729 (Evidence A), and nebulizers can spread infectious particles. The initial dose of SABA is two puf^Of salbutamol (100 meg per puff) or equivalent, except in acute, severe asthma when six puffs should be given. When a nebulizer is used, a dose of 2.5 mg salbutamol solution is recommended, and infection control procedures should be followed. The frequency of dosing depends on the response observed over 1-2 hours (see below).
For children with moderate-severe exacerbations and a poor response to initial SABA, nebulized ipratropium bromide may be added every 20 minutes for 1_"b^Njr only.729
Magnesium sulfate
The role of magnesium sulfate is not established for children 5 years and younger, because there are few studies in this age group. Nebulized isotonic magnesium sulfate may be considered as an adjuvant to standard treatment with 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.165), particularly those with symptoms lasting <6 hours.730 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.731
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. Consider adding 1-2 puffs of ipratropium. Failure to respond at 1 hour, or earlier deterioration, should prompt urgent admission to hospital, addition of nebulized ipratropium, and a short-course of oral corticosteroids (Evidence D).
166
6. Diagnosis and management of asthma in children 5 years and younger
• 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 immediately 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 and/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 oxygVt saturation 94-98%
Short-acting beta2-agonist (SABA)	2-6 puffs of salbutamol by spacer, or 2.5 mg of salbutamol by nebulizer, every 20 minutes for first hour*, then reassess severity. If symptoms persist or recur, give an additional 2-3 puffs per hour. Admit to hospital if >10 puffs reoMftea in 3-4 hours.
Systemic corticosteroids	Give initial dose of oral prednisolone (1-2 mg/kg up to a maximum 20 mg for children <2 years old; 30 mg for children 2-5 years) OR, intravenous methylprednisolonQI mg/kg 6-hourly on day 1
Additional options in the first hour of treatment	
Ipratropium bromide	Consider adding 1-2 puffs of ipratropium bromide by pMDI and spacer For children with mo^gpate-severe exacerbations with a poor response to initial SABA, give nebulized ipratropium bromide 250 meg every 20 minutes for 1 hour only
Magnesium sulfate	Consider naj&iized isotonic magnesium sulfate (150 mg) 3 doses in the first hour of treatment for children aged >2 years with severe exacerbation (Box 6-9, p.165)
*lf inhalation is not possible an intravendBMJolus of terbutaline 2 mcg/kg may be given over 5 minutes, followed by continuous infusion of 5 mcg/kg/hour732 (Evidence C). The cbjjarshould be closely monitored, and the dose should be adjusted according to clinical improvement and side-effects. See below for additional and ongoing treatment, including controller therapy. If a nebulizer is used, follow infection control procedures.
Additional treatment
When treatment in addition to SABA is required for an exacerbation, the options available for children in this age group include ICS; a short course of oral corticosteroid; and/or LTRA (see p.163). 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.160) may be given and continued for a few weeks or months (Evidence D). Some studies have used high dose ICS (1600 meg/day, preferably divided into four doses over the day and given for 5-10 days) as this may reduce the need for
6. Diagnosis and management of asthma in children 5 years and younger
167
OQS.569,704,705,733,734 Addition of ICS to standard care (including OCS) does not reduce risk of hospitalization but reduces length of stay and acute asthma scores in children in the emergency department.735 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,736 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),737 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).721-724'738'739 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.740 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 cortico^jeroid may be an alternative to a course of OCS for preventing relapse.599 There is insufficient evidence to recommend intramuscular over oral corticosteroids.599
Regardless of treatment, the severity of the child's symptoms must be carefully monitored. The sooner therapy is started in relation to the onset of symptoms, the more likely it is that the impending exacerbation may be clinically attenuated or prevented.
Discharge and follow up after an exacerbation
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 without problems).
Children who have recently had an asthma exacerbation are at risk of further exacerbations and require follow up. The purpose is to ensure complete recovery, tp^ptablish the cause of the exacerbation, and, when necessary, to establish appropriate maintenance treatment and/^&herence (Evidence D).
Prior to discharge from the emergeRWdepartment or hospital, family/carers should receive the following advice and information (all are Evidence D)»^
• Instruction on recognition of signs of recurrence and worsening of asthma. The factors that precipitated the exacerbation should be identified, and strategies for future avoidance of these factors implemented.
• A written, individualized action plan, including details of accessible emergency services
• Careful review of inhaler technique
• Further treatment advice explaining that:
o   SABAs should be used on an as-needed basis, but the daily requirement should be recorded to ensure it is
being decreased overtime to pre-exacerbation levels, o   ICS has been initiated where appropriate (at twice the low initial dose in Box 6-6 (p. 160) 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
168
6. Diagnosis and management of asthma in children 5 years and younger
SECTION 2. CHILDREN 5 YEARS AND YOUNGER
Chapter 7.
Primary prevention of asthma
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.
FACTORS CONTRIBUTING TO THE DEVELOPMENT OF ASTHMA IN CHILDREN
Asthma is generally believed to be a heterogeneous disease whose inception^nbrpersistence is driven by gene-environment interactions. The most important of these interactions may occur in early life and even in utero. There is consensus that a 'window of opportunity' exists during pregnancy and early in life when environmental factors may influence asthma development. Multiple environmental factors, both biological and sociological, may be important in the development of asthma. Data supporting the role of environmental risk factors for the development of asthma include a focus on: nutrition, allergens (both inhaled and ingested), pollutants (particularly environmental tobacco smoke), microbes, and psychosocial factors. Additional information about factors contributing to the development of asthma, including occupational asthma, is found in Appendix Chapter 2.
'Primary prevention' refers to preventing the onset of disease. This chapter focuses on primary prevention in children. See p.98 and review articles40 for strategies for pr^/pnting occupational asthma.
FACTORS ASSOCIATED WITH INCREASED OR DECREASED RISK OF ASTHMA IN CHILDREN
Nutrition of mother and baby Maternal diet
For some time, the mother's diet during pregnancy has been a focus of concern relating to the development of allergy and asthma in the child. There is no firm evidence that ingestion of any specific foods during pregnancy increases the risk for asthma. However, a recent study of a pre-birth cohort observed that maternal intake of foods commonly considered allergenic (peanut and milk) was associated with a decrease in allergy and asthma in the offspring.741 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.742,743 Epidemiological studies and randomized controlled trials on maternal dietary intake offish or long-chain polyunsaturated fatty acids during pregnancy showed no consistent effects on the risk of wheeze, asthma or atopy in the child.744 747 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-analysis748 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.
170
7. Primary prevention of asthma
However, no recommendations can be made at present, as unguided weight loss in pregnancy should not be encouraged.
Breastfeeding
Despite the existence of many studies reporting a beneficial effect of breastfeeding on asthma prevention, results are conflicting,749 and caution should be taken in advising families that breastfeeding will prevent asthma.750 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).751 In the case of peanuts,>early introduction may prevent peanut allergy in high risk infants.751
Dietary supplements for mothers and/or babies Vitamin D
Intake of vitamin D may be through diet, dietary supplementation or sunli(JT)r. A systematic review of cohort, case control and cross-sectional studies concluded that maternal dietary intake of vitamin D, and of vitamin E, was associated with lower risk of wheezing illnesses in children.752 This was not confirm© in two randomized controlled trials of vitamin D supplementation in pregnancy comparing standard dose with high dose vitamin D, although a significant effect was not ruled out.753,754 When the results from these two trials were combined, there was a 25% reduction of risk of asthma/recurrent wheeze at ages 0-3 years.755 The effect was greatest among women who maintained 25(OH)vitamin D levels of at least 30 ng/ml from the time of study entry through delivery, suggesting that sufficient levels of Vitamin D during early pregnancy may be important in decreasing risk for early life wheezing episodes,755 although in both trials, no effects of vitamin D supplementation on the dfl&fcelopment of asthma and recurrent wheeze were evident at the age of 6 years.756
Fish oil and long-chain polyunsaturated fatty acids
Systematic reviews of cohort studies about maternal dietary intake of fish or seafood during pregnancy744,757 and of randomized controlled trials on rrpjsfrial dietary intake offish or long-chained polyunsaturated fatty acids during pregnancy744 showed no consistent effects on the risk of wheeze, asthma or atopy in the child. One recent study demonstrated decreased wheeze/asthma in pre-school children at high risk for asthma when mothers were given a high dose fish oil supplement in the third trimester;758 however 'fish oil' is not well defined, and the optimal dosing regimen has not been establishes
Probiotics
A meta-analysis provided insufficient evidence to recommend probiotics for the prevention of allergic disease (asthma, rhinitis, eczema or food allergy).759
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,760,761 the relationship for animal allergen appears to be more complex.749 Some studies have found that exposure to pet allergens is associated with increased risk of sensitization to these allergens,762,763 and of asthma and wheezing.764,765 By contrast, other studies have demonstrated a decreased risk of developing allergy with exposure to pets.766,767 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.768 For children at risk of
7. Primary prevention of asthma
171
asthma, dampness, visible mold and mold odor in the home environment are associated with increased risk of developing asthma.769 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.
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,770 the Canadian Asthma Primary Prevention Study,771 and the Prevention of Asthma in Children study772 were associated with lower risk of asthma diagnosis in children younger than 5 years.773 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.770,774 The Isle of Wight study has shown a continuing positive benefit for early-life intervention through to 18 years of age;775 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.776 Additional studies are needed.
Pollutants
Maternal smoking during pregnancy is the most direct route of pre-natal environmental tobacco smoke exposure.777 A meta-analysis concluded that pre-natal smoking had its strongest effect on young children, whereas post-natal maternal smoking seemed relevant only to asthma development in older children-^v3 Exposure to outdoor pollutants, such as living near a main road, is associated with increased risk of asthma.779,780 A recent study suggested that up to 4 million new pediatric asthma cases (13% of the global incidence) may be attributable to exposure to traffic-related air pollution (TRAP).781 Prenatal NO2, SO2, and PM10 exposures are associated with an increased risk of asthma in childhood,782 but it is difficult to separate pre- and post-natal exposure.
Microbial effects
The 'hygiene hypothesis', and the more recently coined 'microflora hypothesis' and 'biodiversity hypothesis',783 suggest that human interaction with microbiota may be beneficial in preventing asthma. For example, there is a lower risk of asthma among children raised on farms with exposure to stables and consumption of raw farm milk than among children of non-farmers.784 The risk of asthma is4|j6o reduced in children whose bedrooms have high levels of bacterial-derived lipopolysaccharide endotoxin.785,786 Similarly, children in homes with >2 dogs or cats are less likely to be allergic than those in homes without dogs or cats.767 Exposure of an infant to the mother's vaginal microflora through vaginal delivery may also be beneficial; the prevalence of asthma is higher in children born by cesarean section than those born vaginally.787,788 This may relate to differences in the infant gut microbiota according to their mode of delivery.789
Respiratory syncytial virus infection is associated with subsequent recurrent wheeze, and preventative treatment of premature infants with monthly injections of the monoclonal antibody, palivizumab, (prescribed for prophylaxis of respiratory syncytial virus) is associated with a reduction in recurrent wheezing in the first year of life.790 However, there 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.791 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 792,793 although not all studies have shown this association.794 Intake of the analgesic, paracetamol (acetaminophen), may be associated with asthma in both children and adults,795 although exposure during infancy may be confounded by use of paracetamol for respiratory tract infections.795 Frequent use of paracetamol by pregnant women has been associated with asthma in their children.796 There is no evidence that vaccinations increase the risk of a child developing asthma.
172
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 pregnancy797 or during the child's early years798 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.438 In adults, there is evidence suggesting that obesity affects the risk of asthma, but that asthma does not affect the risk of obesity.799,800
ADVICE ABOUT PRIMARY PREVENTION OF ASTHMA
Based on the results of cohort and observational studies,801 and a GRADE-based analysis for the Allergic Rhinitis and its Impact on Asthma (ARIA) guidelines,749 parents enquiring about how to reduce the risk of their children developing asthma can be provided with the advice summarized in Box 7-1.
Possibly the most important factor is the need to provide a positive, supportive ep^ehment for discussion that decreases stress, and which encourages families to make choices with which tKgy feel comfortable.
Box 7-1. Advice about primary prevention of asthma in children 5 years and younger
Parents enquiring about how to reduce the risk of their child de^eWping asthma can be provided with the following advice:
• Children should not be exposed to environmental tobacco smoke during pregnancy or after birth.
• Identification and correction of Vitamin D insufficiency in women with asthma who are pregnant, or planning pregnancy, may reduce the risk of early life wheezing episodes.
• Vaginal delivery should be encouraged where possible.
• Breastfeeding is advised, for reasons other than prevention of allergy and asthma.
• The use of broad-spectrum antibiotics during the first year of life should be discouraged.
7. Primary prevention of asthma
173
. v>>.
SECTION 3. TRANSLATION INTO CLINICAL PRACTICE
Chapter 8.
Implementing asthma management strategies into health systems
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.
INTRODUCTION
Due to the exponential increase in medical research publications, practical syntheses are needed to guide policy makers and health care professionals in delivering evidence-based care. When asthma-care is consistent with evidence-based recommendations, outcomes improve.162'802,803 The Global Strategy for Asthma Management and Prevention is a resource document for health care professionals to establish the main goals of asthma treatment and the actions required to ensure their fulfilment, as well as to facilitate the achievement of standards for quality asthma care.
The recent adoption of rigorous methodologies such as GRADE2 for the development of clinical practice recommendations, and the ADAPTE804 and similar approaches for assisting the adaptation of recommendations for local country and regional conditions, has assisted in reducing biased opinion as the basis for asthma programs worldwide. Adaptation of clinical practice recommendations to local conditions using the GRADE method is costly and often requires expertise that is not available locally; in addition, regular revision is required to remain abreast of developments, including drug availability and new evidence, and this is not easily achieved.805 Further, there is generally very limited high quality evidence addressing the many decision nodes in comprehensive clinical practice guidelines, particularly in developing countries.
ADAPTING AND IMPLEMENTING ASTHMA CLINICAL PRACTICE GUIDELINES
Implementation of asthma management strategies may be carried out at a national, regional or local level.806 Ideally, implementation should be a multidisciplinary effort involving many stakeholders, and using cost-effective methods of knowledge translation.806 808 Each implementation initiative needs to consider the nature of the local health system and 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.
176
8. Implementing asthma management strategies in health systems
Box 8-1. Approach to implementation of the Global Strategy for Asthma Management and Prevention
		Update on asthma diagnosis and management r
GLOBAL		
		Production of Global Strategy for Asthma Management and Prevention and tools
		
		Assess local needs
		Adapt guideline recommendations to local context
LOCAL	:	Develop implementation framework and step-by-step plan r Assess uptake, effectiveness and sustainability
Box 8-2. Essential elements required to implement a health-related strategy Steps in implementing an asthma strategy into a health system
1. Develop a multidisciplinary working group.
2. Assess the current status of asthma care delivery, care gaps and current needs.
3. Select the material to be-lQ>plemented, agree on main goals, identify key recommendations for diagnosis and treatment, and adapt them to the local context or environment.
4. Identify barriers to, and facilitators of, implementation.
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
177
BARRIERS AND FACILITATORS
Many barriers to, and facilitators of, implementation procedures have been described.808-811 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
Resistance to change	Lack of agreement with recommendations
External barriers (organizational, health policies,	Cultural and economic barriers
financial constraints)	Peer influence
Lack of time and resources	Attitudes, beliefs, preferences, fears and
Medico-legal issues	misconcesmsns
EXAMPLES OF HIGH IMPACT IMPLEMENTATION INTERVENTIONS
Ideally, interventions should be applied at the level of both the patient and the health care provider and, where relevant, the health system. Studies of the most effective means of medical education show that it may be difficult to induce changes in clinical practice. Examples of highly effective interventions are shown in Box 8-4.
Box 8-4. Examples of high-impact interventions in asthma management
• Free ICS for patients with a recent hospital admission and/or severe asthma812
• Early treatment with ICS, guideri&elf-management, reduction in exposure to tobacco smoke, improved access to asthma education162
• Self-inking stamp prompting assessment of asthma control and treatment strategies813
• Use of individualized written asthma action plans as part of self-management education431
• An evidence-based care process model for acute and chronic pediatric asthma management, implemented at multiple hospitals814
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.815
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.
178
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.qinasthma.org').
8. Implementing asthma management strategies in health systems
179
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:
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).
Reddel HK. Reply: About the recommendation of the GINA strategy report on asthma step 1. Eur Respir J 2021 ;57: 2004226 (doi: 10.1183/13993003.04226-2020).
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;318:L998-L1000 (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 2020; 4:3-6 (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 FW, Krishnan JA, Levy ML, Lin J, Pedersen SE, Sheikh A, Yorgancioglu A, BouleW^p. 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 (open access: doi: 10.<Do3/13993003.01046-2019)
Boulet LP, Reddel HK, Bateman ED, Pedersen S, FitzGerald JM and O'Byrne PM. The Global Initiative for Asthma (GINA): 25 years later. Eur Respir J 2019;54:1900598 (doi: 10.1183/13993003.00598-2019).
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).
Reddel HK, Bateman ED, Becker A, Boulet LP, Cruz AA, Drazen JM, Haahtela T, Hurd SS, Inoue H, de Jongste JC, Lemanske RF Jr, Levy ML, O'Byrne PM, Paggiaro P, Pedersen SE, Pizzichini E, Soto-Quiroz M, Szefler SJ, Wong GW, FitzGerald JM. A summary of the new GINA strategy: a roadmap to asthma control. Eur Respir J 2015;46:622-39 (open access; doi 10.1183/13993003.00853-2015).
Reddel HK, Hurd SS, FitzGerald JM. World Asthma Day. GINA 2014: a global asthma strategy for a global problem. Int J Tuberc Lung Dis 2014;18:505-6 (open access: doi.org/10.5588/ijtld.14.0246).
Boulet LP, FitzGerald JM, Reddel HK. The revised 2014 GINA strategy report: opportunities for change. Curr Opin Pulm Med 2015;21:1-7.
Reddel HK, Levy ML. The GINA astfjjna strategy report: what's new for primary care? NPJ Prim Care Respir Med 2015;25:15050 (open access: doi 10.1038/npjpcrm.2015.50).
Bateman ED, Hurd SS, Barnes PJ, Bousquet J, Drazen JM, FitzGerald JM, Gibson P, et al. Global strategy for asthma management and prevention: GINA executive summary. Eur Respir J. 2008;31:143-78.
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.
180
Peer-reviewed publications
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, 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, 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. Williamson EJ, Walker AJ, Bhaskaran K, et al. Factors associated with COVID-19-related death using OpenSAFELY. Nature 2020;584:430-6.
6. Liu S, Cao Y, Du T, Zhi Y. Prevalence of comorbid asthma and related outcomes in COVID-19: a systematic review and meta-analysis. J Allergy Clin Immunol Pract 2021;9:693-701.
7. Bloom CI, Drake TM, Docherty AB, et al. Risk of adverse outcomes in patients with underlying respiratory conditions admitted to hospital with COVID-19: a national, multicentre prospective cohort study using the ISARIC WHO Clinical Characterisation Protocol UK. Lancet Respir Med 2021.
8. Bel EH. Clinical phenotypes of asthma. Curr Opin Pulm Med 2004;10:44-50.
9. Moore WC, Meyers DA, Wenzel SE, et al. Identification of asthm^phenotypes using cluster analysis in the Severe Asthma Research Program. Am J Respir Crit Care Med 2010;181:315-23.
10. Wenzel SE. Asthma phenotypes: the evolution from clinical to molecular approaches. Nature Medicine 2012;18:716-25.
11. Westerhof GA, Coumou H, de Nijs SB, Weersink EJ, Bel EH. Clinical predictors of remission and persistence of adult-onset asthma. J Allergy Clin Immunol 2018;141:10^.e3.
12. Levy ML, Fletcher M, Price DB, Hausen T, Haibert 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.
13. Quanjer PH, Stanojevic S, Cole TJ, et al/OT&ilti-ethnic reference values for spirometry for the 3-95-yr age range: the global lung function 2012 equations. Eur^£$pir J 2012;40:1324-43.
14. Reddel H, Ware S, Marks G, Salome C, Jenkins C, Woolcock A. Differences between asthma exacerbations and poor asthma control [erratum in Lancet 1999;353:758]. Lancet 1999;353:364-9.
15. Aaron SD, Vandemheen KLg-RtzGerald JM, et al. Reevaluation of diagnosis in adults with physician-diagnosed asthma. JAMA 2017;317:269-79^
16. Graham BL, Steenbruggen I, Miller MR, et al. Standardization of spirometry 2019 update. An official American Thoracic Society and European Respiratory Society technical statement. Am J Respir Crit Care Med 2019;200:e70-e88.
17. Miller MR, Hankinson J, Brusasco V, et al. Standardisation of spirometry. Eur Respir J 2005;26:319-38.
18. Pellegrino R, Viegi G, Brusasco V, et al. Interpretative strategies for lung function tests. Eur Respir J 2005;26:948-68.
19. Tan WC, Vollmer WM, Lamprecht B, et al. Worldwide patterns of bronchodilator responsiveness: results from the Burden of Obstructive Lung Disease study. Thorax 2012;67:718-26.
20. Reddel HK, Taylor DR, Bateman ED, 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.
21. Brouwer AF, Brand PL. Asthma education and monitoring: what has been shown to work. Paediatr Respir Rev 2008;9:193-9.
22. Coates AL, Wanger J, Cockcroft DW, et al. ERS technical standard on bronchial challenge testing: general considerations and performance of methacholine challenge tests. Eur Respir J 2017;49.
23. Hallstrand TS, Leuppi JD, Joos G, et al. ERS technical standard on bronchial challenge testing: pathophysiology and methodology of indirect airway challenge testing. Eur Respir J 2018;52.
References
181
24. Ramsdale EH, Morris MM, Roberts RS, Hargreave FE. Asymptomatic bronchial hyperresponsiveness in rhinitis. J Allergy Clin Immunol 1985;75:573-7.
25. 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.
26. 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.el.
27. 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.
28. 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.
29. Korevaar DA, Westerhof GA, Wang J, et al. Diagnostic accuracy of minimally invasive markers for detection of airway eosinophilia in asthma: a systematic review and meta-analysis. Lancet Respir Med 2015;3:290-300.
30. Fahy JV. Type 2 inflammation in asthma-present in most, absent in many. Nature Reviews Immunology 2015;15:57-65.
31. American Thoracic Society, European Respiratory Society. ATS/ERS Recomnjjärtaations for Standardized Procedures for the Online and Offline Measurement of Exhaled Lower Respirator^Kitric Oxide and Nasal Nitric Oxide, 2005. Am J Respir Crit Care Med 2005;171:912-30.
32. Haccuria A, Michils A, Michiels S, Van Muylem A. Exhaled nitric oxjd^: a biomarker integrating both lung function and airway inflammation changes. J Allergy Clin Immunol 2014;134:554-9.
33. Aaron SD, Vandemheen KL, Boulet LP, et al. Overdiagnosis of asthma in obese and nonobese adults. CMAJ 2008;179:1121-31.
34. Lucas AE, Smeenk FW, Smeele IJ, van Schayck CP. Overtreatment with inhaled corticosteroids and diagnostic problems in primary care patients, an exploratory study. Fam Pract 2008;25:86-91.
35. Marklund B, Tunsater A, Bengtsson C. How oftenyjslhe diagnosis bronchial asthma correct? Fam Pract 1999;16:112-6.
36. Montnemery P, Hansson L, Lanke J, et al. Accuracy of a first diagnosis of asthma in primary health care. Fam Pract 2002;19:365-8.
37. Gibson PG, Chang AB, Glasgow NJ, et al. CICADA: Cough in Children and Adults: Diagnosis and Assessment. Australian cough guidelines summary stajfeeörent. Med J Aust 2010;192:265-71.
38. Halvorsen T, Walsted ES, Bucca^Oet al. Inducible laryngeal obstruction: an official joint European Respiratory Society and European Laryngological Society statement. Eur Respir J 2017;50.
39. Desai D, Brightling C. CotfgTrdue to asthma, cough-variant asthma and non-asthmatic eosinophilic bronchitis. Otolaryngol Clin North Am 2010;43:123-30.
40. Baur X, Sigsgaard T, Aasen TB, 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.
41. Henneberger PK, Patel JR, de Groene GJ, et al. Workplace interventions for treatment of occupational asthma. Cochrane Database Syst Rev 2019;10:CD006308.
42. Levy ML, Nicholson PJ. Occupational asthma case finding: a role for primary care. Br J Gen Pract 2004;54:731-3.
43. Parsons JP, Hallstrand TS, Mastronarde JG, et al. An official American Thoracic Society clinical practice guideline: exercise-induced bronchoconstriction. Am J Respir Crit Care Med 2013;187:1016-27.
44. Carlsen KH, Anderson SD, Bjermer L, 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.
45. Murphy VE, Gibson PG. Asthma in pregnancy. Clin Chest Med 2011;32:93-110, ix.
46. Adams RJ, Wilson DH, Appleton S, et al. Underdiagnosed asthma in South Australia. Thorax 2003;58:846-50.
182
References
47. 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.
48. Parshall MB, Schwartzstein RM, Adams L, 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.
49. Januzzi JL, Jr., Camargo CA, Anwaruddin S, et al. The N-terminal Pro-BNP investigation of dyspnea in the emergency department (PRIDE) study. Am J Cardiol 2005;95:948-54.
50. Global Initiative for Chronic Obstructive Lung Disease (GOLD). Global Strategy for Diagnosis, Management and Prevention of COPD. 2021 Report. Fontana, Wl, USA: GOLD; 2021.
51. Hanania NA, Celli BR, Donohue JF, Martin UJ. Bronchodilator reversibility in COPD. Chest 2011;140:1055-63.
52. 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.
53. Boulet LP. Asthma and obesity. Clin Exp Allergy 2013;43:8-21.
54. van Huisstede A, Castro Cabezas M, van de Geijn GJ, et al. Underdiagnosis and overdiagnosis of asthma in the morbidly obese. Respir Med 2013;107:1356-64.
55. English RG, Bachmann MO, Bateman ED, et al. Diagnostic accuracy of an integrated respiratory guideline in identifying patients with respiratory symptoms requiring screening for pulmonary tuberculosis: a cross-sectional study. BMC Pulm Med 2006;6:22.
56. Package of essential noncommunicable (PEN) disease interventions for primary health care in low-resource settings. WHO, 2010. at www.who.int/cardiovascular diseases/publications/pen2010/en/.)
57. Ait-Khaled N, Enarson DA, Chiang C-Y, Marks G, K B. Management of asthma: a guide to the essentials of good clinical practice. Paris, France: International Union Against Tuberculosis and Lung Disease; 2008.
58. Barreto ML, Ribeiro-Silva Rde C, Malta DC, Oliveira-Campos M, Andreazzi MA, Cruz AA. Prevalence of asthma symptoms among adolescents in Brazil: National Adolescent School-based Health Survey (PeNSE 2012). Revista Brasileira de Epidemiológia 2014;17 Suppl 1:106-15.
59. To T, Stanojevic S, Moores G, et al. Global asthma prevalence in adults: findings from the cross-sectional world health survey. BMC Public Health 2012;12:204.
60. Jose BP, Camargos PA, Cruz Filho AA, Correa Rde A. Diagnostic accuracy of respiratory diseases in primary health units. Rev Assoc Med Bras 2014;60:599-612.
61. Burney P, Jithoo A, Kato B, et al. Chronic obstructive pulmonary disease mortality and prevalence: the associations with smoking and poverty-a BOLD analysis. Thorax 2014;69:465-73.
62. Taylor DR, Bateman ED, Boulet LP, et al. A new perspective on concepts of asthma severity and control. Eur Respir J 2008;32:545-54.
63. Aroni R, Goeman D, Stewart K, et al. Enhancing validity: what counts as an asthma attack? J Asthma 2004;41:729-37.
64. McCoy K, Shade DM, Irvin CG, et al. Predicting episodes of poor asthma control in treated patients with asthma. J Allergy Clin Immunol 2006;118:1226-33.
65. Meitzer EO, Busse WW, Wenzel SE, et al. Use of the Asthma Control Questionnaire to predict future risk of asthma exacerbation. J Allergy Clin Immunol 2011;127:167-72.
66. Schatz M, Zeiger RS, Yang SJ, et al. The relationship of asthma impairment determined by psychometric tools to future asthma exacerbations. Chest 2012;141:66-72.
67. O'Byrne PM, Reddel HK, Eriksson G, et al. Measuring asthma control: a comparison of three classification systems. Eur Respir J 2010;36:269-76.
68. Thomas M, Kay S, Pike J, et al. 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.
69. 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.
70. 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.
References
183
71. Pinnock H, Burton C, Campbell S, 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.
72. Yawn BP, Wollan PC, Rank MA, Bertram SL, Juhn Y, Pace W. Use of Asthma APGAR Tools in primary care practices: a cluster-randomized controlled trial. Ann Fam Med 2018;16:100-10.
73. 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.
74. 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.
75. Juniper EF, Bousquet J, Abetz L, Bateman ED. Identifying 'well-controlled' and 'not well-controlled' asthma using the Asthma Control Questionnaire. Respir Med 2006;100:616-21.
76. Juniper EF, Bousquet J, Abetz L, Bateman ED, The GOAL Committee. Identifying 'well-controlled' and 'not well-controlled' asthma using the Asthma Control Questionnaire. Respir Med 2006;100:616-21.
77. Nathan RA, Sorkness CA, Kosinski M, et al. Development of the asthma control test: a survey for assessing asthma control. J Allergy Clin Immunol 2004;113:59-65.
78. Schatz M, Kosinski M, Yarlas AS, Hanlon J, Watson ME, Jhingran P. The minimally J09j>ortant difference of the Asthma Control Test. J Allergy Clin Immunol 2009;124:719-23 el.
79. Liu AH, Zeiger R, Sorkness C, et al. Development and cross-sectional validation of the Childhood Asthma Control Test. J Allergy Clin Immunol 2007;119:817-25.
80. Juniper EF, Gruffydd-Jones K, Ward S, Svensson K. Asthma Control Questionnaire in children: validation, measurement properties, interpretation. Eur Respir J 2010;36:1410-6.
81. Nguyen JM, Holbrook JT, Wei CY, et al. Validation and psychometric properties of the Asthma Control Questionnaire among children. J Allergy Clin Immunol 2014;133:91-7.e4?-6.
82. Chipps B, Zeiger RS, Murphy K, et al. Longitudinal validation of the Test for Respiratory and Asthma Control in Kids in pediatric practices. Pediatrics 2011;127:e737-47.
83. Murphy KR, Zeiger RS, Kosinski M, et al. Test for respiratory and asthma control in kids (TRACK): a caregiver-completed questionnaire for preschool-aged children. J AJIe'rgy Clin Immunol 2009;123:833-9 e9.
84. Zeiger RS, Mellon M, Chipps B, et al. Test for Respiratory and Asthma Control in Kids (TRACK): clinically meaningful changes in score. J Allergy Clin Immunol 2011;128:983-8.
85. Wildfire JJ, Gergen PJ, Sorkness CA, et al. Development and validation of the Composite Asthma Severity Index-an outcome measure for use in children and adolescents. J Allergy Clin Immunol 2012;129:694-701.
86. Haselkorn T, Fish JE, Zeiger RS, et><SCConsistently 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.el-4.
87. Patel M, Pilcher J, ReeW^I HK, et al. Metrics of salbutamol use as predictors of future adverse outcomes in asthma. Clin Exp Allergy 2013;43:1144-51.
88. Suissa S, Ernst P, Boivin JF, 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.
89. Nwaru Bl, Ekstrom M, Hasvold P, Wiklund F, Teig G, Janson C. Overuse of short-acting beta2-agonists in asthma is associated with increased risk of exacerbation and mortality: a nationwide cohort study of the global SABINA programme. Eur Respir J 2020;55:1901872.
90. Ernst P, Spitzer WO, Suissa S, et al. Risk of fatal and near-fatal asthma in relation to inhaled corticosteroid use. JAMA 1992;268:3462-4.
91. Melani AS, Bonavia M, Cilenti V, et al. Inhaler mishandling remains common in real life and is associated with reduced disease control. Respir Med 2011;105:930-8.
92. Fitzpatrick S, Joks R, Silverberg Jl. 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.
93. Denlinger LC, Phillips BR, Ramratnam S, et al. Inflammatory and comorbid features of patients with severe asthma and frequent exacerbations. Am J Respir Crit Care Med 2017;195:302-13.
184
References
94. Burks AW, Tang M, Sicherer S, et al. ICON: food allergy. J Allergy Clin Immunol 2012;129:906-20.
95. Murphy VE, Clifton VL, Gibson PG. Asthma exacerbations during pregnancy: incidence and association with adverse pregnancy outcomes. Thorax 2006;61:169-76.
96. Osborne ML, Pedula KL, O'Hollaren M, et al. Assessing future need for acute care in adult asthmatics: the Profile of Asthma Risk Study: a prospective health maintenance organization-based study. Chest 2007;132:1151-61.
97. Lim H, Kwon HJ, Lim JA, et al. Short-term effect of fine particulate matter on children's hospital admissions and emergency department visits for asthma: A systematic review and meta-analysis. J Prev Med Public Health 2016;49:205-19.
98. Zheng XY, Ding H, Jiang LN, et al. Association between air pollutants and asthma emergency room visits and hospital admissions in time series studies: A systematic review and meta-analysis. PLoS One 2015;10:e0138146.
99. Mazenq J, Dubus JC, Gaudart J, Charpin D, Viudes G, Noel G. City housing atmospheric pollutant impact on emergency visit for asthma: A classification and regression tree approach. Respir Med 2017;132:1-8.
100. Sturdy PM, Victor CR, Anderson HR, et al. Psychological, social and health behaviour risk factors for deaths certified as asthma: a national case-control study. Thorax 2002;57:1034-9.
101. Fuhlbrigge AL, Kitch BT, Paltiel AD, et al. FEV1 is associated with risk of asthma attacks in a pediatric population. J Allergy Clin Immunol 2001;107:61-7.
102. Ulrik CS. Peripheral eosinophil counts as a marker of disease activity in intrinsic and extrinsic asthma. Clin Exp Allergy 1995;25:820-7.
103. Pongracic JA, Krause RZ, Babineau DC, et al. Distinguishing characteristics of difficult-to-control asthma in inner-city children and adolescents. J Allergy Clin Immunol 2016;138:1030-4l4v
104. Belda J, Giner J, Casan P, Sanchis J. Mild exacerbations and eosinophilic inflammation in patients with stable, well-controlled asthma after 1 year of follow-up. Chest 2001;119:1011-7.
105. Ulrik CS, Frederiksen J. Mortality and markers of risk of asthma death among 1,075 outpatients with asthma. Chest 1995;108:10-5.
106. Zeiger RS, Schatz M, Zhang F, et al. Elevated exha^a nitric oxide is a clinical indicator of future uncontrolled asthma in asthmatic patients on inhaled corticosteroid^'j Allergy Clin Immunol 2011;128:412-4.
107. Turner MO, Noertjojo K, Vedal S, Bai T, CrWrcp S, FitzGerald JM. Risk factors for near-fatal asthma. A case-control study in hospitalized patients with asthma. Arrv^espir Crit Care Med 1998;157:1804-9.
108. Miller MK, Lee JH, Miller DP, Wenzel SE. Recent asthma exacerbations: a key predictor of future exacerbations. Respir Med 2007;101:481-9.
109. Buelo A, McLean S, Julious S, erah At-risk children with asthma (ARC): a systematic review. Thorax 2018;73:813-24.
110. den Dekker HT, Sonnenschein-van der Voort AMM, de Jongste JC, et al. Early growth characteristics and the risk of reduced lung function and^swima: A meta-analysis of 25,000 children. J Allergy Clin Immunol 2016;137:1026-35.
111. Lange P, Parner J,/Nre«tbo 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.
112. Ulrik CS. Outcome of asthma: longitudinal changes in lung function. Eur Respir J 1999;13:904-18.
113. 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.
114. Raissy HH, Kelly HW, Harkins M, Szefler SJ. Inhaled corticosteroids in lung diseases. Am J Respir Crit Care Med 2013;187:798-803.
115. Foster JM, Aucott L, van der Werf RH, et al. 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.
116. 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.
117. Pedersen S. Do inhaled corticosteroids inhibit growth in children? Am J Respir Crit Care Med 2001;164:521-35.
118. 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.
References
185
119. Wechsler ME, Kelley JM, Boyd 10, et al. Active albuterol or placebo, sham acupuncture, or no intervention in asthma. N Engl J Med 2011;365:119-26.
120. Castro M, Rubin AS, Laviolette M, et al. Effectiveness and safety of bronchial thermoplasty in the treatment of severe asthma: a multicenter, randomized, double-blind, sham-controlled clinical trial. Am J Respir Crit Care Med 2010;181:116-24.
121. Lazarus SC, Boushey HA, Fahy JV, et al. Long-acting beta2-agonist monotherapy vs continued therapy with inhaled corticosteroids in patients with persistent asthma: a randomized controlled trial. JAMA 2001;285:2583-93.
122. Loymans RJ, Honkoop PJ, Termeer EH, et al. Identifying patients at risk for severe exacerbations of asthma: development and external validation of a multivariable prediction model. Thorax 2016;71:838-46.
123. Stanford RH, Shah MB, D'Souza AO, Dhamane AD, Schatz M. Short-acting ß-agonist use and its ability to predict future asthma-related outcomes. Annals of Allergy, Asthma & Immunology 2012;109:403-7.
124. Kohansal R, Martinez-Camblor P, Agusti A, Buist AS, Mannino DM, Soriano JB. The natural history of chronic airflow obstruction revisited: an analysis of the Framingham offspring cohort. Am J Respir Crit Care Med 2009;180:3-10.
125. McGeachie MJ, Yates KP, Zhou X, et al. Patterns of growth and decline in lung function in persistent childhood asthma. N Engl J Med 2016;374:1842-52.
126. Kerstjens HA, Brand PL, de Jong PM, Koeter GH, Postma DS. Influence of treatrnsrt °n peak expiratory flow and its relation to airway hyperresponsiveness and symptoms. The Dutch CNSLD Study Group. Thorax 1994;49:1109-15.
127. Brand PL, Duiverman EJ, Waalkens HJ, van Essen-Zandvliet EE, Kerrebijn K^Peak flow variation in childhood asthma: correlation with symptoms, airways obstruction, and hyperresponsiveness during long-term treatment with inhaled corticosteroids. Dutch CNSLD Study Group. Thorax 1999;54:103-7>4
128. Bateman ED, Boushey HA, Bousquet J, et al. Can guideline-definejSasthma control be achieved? The Gaining Optimal Asthma ControL study. Am J Respir Crit Care Med 2004; 170^8^0-44.
129. 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.
130. 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;151:647-5^/
131. Kitch BT, Paltiel AD, Kuntz KM, et al. A single measure of FEV1 is associated with risk of asthma attacks in long-term follow-up. Chest 2004;126:1875-82.
132. 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. <
133. Rosi E, Stendardi L, Binazzi B, Scano G. Perception of airway obstruction and airway inflammation in asthma: a review. Lung 2006;184:251-8.
134. Reddel HK, Jenkins CR, Marks GB, et al. Optimal asthma control, starting with high doses of inhaled budesonide. Eur Respir J 2000;16:226-35.
135. Szefler SJ, Martin RJ,xfcg TS, et al. Significant variability in response to inhaled corticosteroids for persistent asthma. J Allergy Clin lmmunol2002;109:410-8.
136. Santanello NC, Zhang J, Seidenberg B, Reiss TF, Barber BL. What are minimal important changes for asthma measures in a clinical trial? Eur Respir J 1999;14:23-7.
137. Reddel HK, Marks GB, Jenkins CR. When can personal best peak flow be determined for asthma action plans? Thorax 2004;59:922-4.
138. Frey U, Brodbeck T, Majumdar A, et al. Risk of severe asthma episodes predicted from fluctuation analysis of airway function. Nature 2005;438:667-70.
139. 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.
140. Kikuchi Y, Okabe S, Tamura G, et al. Chemosensitivity and perception of dyspnea in patients with a history of near-fatal asthma. N Engl J Med 1994;330:1329-34.
141. 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.
186
References
142. Nuijsink M, Hop WC, Jongste JC, Sterk PJ, Duiverman AE, Cato Study G. Perception of bronchoconstriction: a complementary disease marker in children with asthma. J Asthma 2013;50:560-4.
143. Jansen J, McCaffery KJ, Hayen A, Ma D, Reddel HK. Impact of graphic format on perception of change in biological data: implications for health monitoring in conditions such as asthma. Prim Care Respir J 2012;21:94-100.
144. Chung KF, Wenzel SE, Brozek JL, et al. International ERS/ATS Guidelines on Definition, Evaluation and Treatment of Severe Asthma. Eur Respir J 2014;43:343-73.
145. Reddel HK, Busse WW, Pedersen S, et al. Should recommendations about starting inhaled corticosteroid treatment for mild asthma be based on symptom frequency: a post-hoc efficacy analysis of the START study. Lancet 2017;389:157-66.
146. Reddel HK, FitzGerald JM, Bateman ED, 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.
147. FitzGerald JM, Barnes PJ, Chipps BE, et al. The burden of exacerbations in mild asthma: a systematic review. ERJ Open Res 2020;6.
148. Bousquet J, Mantzouranis E, Cruz AA, et al. Uniform definition of asthma severity, control, and exacerbations: document presented for the World Health Organization Consultation on Severe Asthma. J Allergy Clin Immunol 2010;126:926-38.
149. Boulet L-P, Vervloet D, Magar Y, Foster JM. Adherence: the goal to control asthma. Clin Chest Med 2012;33:405-17.
150. Taylor YJ, Tapp H, Shade LE, Liu TL, Mowrer JL, Dulin MF. Impact of shared decision making on asthma quality of life and asthma control among children. J Asthma 2018;55:675-83. |
151. Gibson PG, Powell H, Coughlan J, et al. Self-management education and regular practitioner review for adults with asthma. Cochrane Database Syst Rev 2003:CD001117.
152. Guevara JP, Wolf FM, Grum CM, Clark NM. Effects pteducational interventions for self management of asthma in children and adolescents: systematic review and metaanalysis. BMJ 2003;326:1308-9.
153. Wilson SR, Strub P, Buist AS, et al. Shared treatment decision making improves adherence and outcomes in poorly controlled asthma. Am J Respir Crit Care Mb^OIO; 181:566-77.
154. Cabana MD, Slish KK, Evans D, et al. Impact of physician asthma care education on patient outcomes. Pediatrics 2006;117:2149-57.
155. Partridge MR, Hill SR. Enhancing care for people with asthma: the role of communication, education, training and self-management. 1998 World Asthma Meeting Education and Delivery of Care Working Group. Eur Respir J 2000;16:333-48.
156. Maguire P, Pitceathly C. Key communication skills and how to acquire them. BMJ 2002;325:697-700.
157. Clark NM, Cabana MD, Nan B, et al. The clinician-patient partnership paradigm: outcomes associated with physician communication behavior. Clin Pediatr (Phila) 2008;47:49-57.
158. Rosas-Salazar C, Apter AJ, Canino G, Celedon JC. Health literacy and asthma. J Allergy Clin Immunol 2012;129:935-42.
159. Rosas-Salazar C, Ramratnam SK, Brehm JM, et al. Parental numeracy and asthma exacerbations in Puerto Rican children. Chest 2013;144:92-8.
160. Apter AJ, Wan F, Reisine S, et al. The association of health literacy with adherence and outcomes in moderate-severe asthma. J Allergy Clin Immunol 2013;132:321-7.
161. Poureslami I, Nimmon L, Doyle-Waters M, et al. Effectiveness of educational interventions on asthma self-management in Punjabi and Chinese asthma patients: a randomized controlled trial. J Asthma 2012;49:542-51.
162. Haahtela T, Tuomisto LE, Pietinalho A, et al. A 10 year asthma programme in Finland: major change for the better. Thorax 2006;61:663-70.
163. Ait-Khaled N, Enarson DA, Bencharif N, et al. Implementation of asthma guidelines in health centres of several developing countries. Int J Tuberc Lung Dis 2006;10:104-9.
References
187
164. Plaza V, Cobos A, Ignacio-Garcia JM, et al. [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 (Bare) 2005;124:201-6.
165. Haldar P, Pavord ID, Shaw DE, et al. Cluster analysis and clinical asthma phenotypes. Am J Respir Crit Care Med 2008;178:218-24.
166. 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.
167. 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.
168. O'Byrne PM, FitzGerald JM, Bateman ED, et al. Inhaled combined budesonide-formoterol as needed in mild asthma. N Engl J Med 2018;378:1865-76.
169. Bateman ED, Reddel HK, O'Byrne PM, et al. As-needed budesonide-formoterol versus maintenance budesonide in mild asthma. N Engl J Med 2018;378:1877-87.
170. Beasley R, Holliday M, Reddel HK, et al. Controlled trial of budesonide-formoterol as^x^eded for mild asthma. N Engl J Med 2019;380:2020-30.
171. Hardy J, Baggott C, Fingleton J, et al. Budesonide-formoterol reliever therapy versus maintenance budesonide plus terbutaline reliever therapy in adults with mild to moderate asthma (PRACTICAuNa 52-week, open-label, multicentre, superiority, randomised controlled trial. The Lancet 2019;394:919-28.
172. Bateman ED, Reddel HK, Eriksson G, et al. Overall asthma control: the relationship between current control and future risk. J Allergy Clin Immunol 2010;125:600-8.
173. Sobieraj DM, Weeda ER, Nguyen E, et al. Association of inhaled corticosteroids and long-acting beta-agonists as controller and quick relief therapy with exacerbations and symptom control in persistent asthma: A systematic review and meta-analysis. JAMA 2018;319:1485-96.
174. Petsky HL, Li A, Chang AB. Tailored interventions based on sputum eosinophils versus clinical symptoms for asthma in children and adults. Cochrane Database Syst Rev 2Qir7;8:Cd005603.
175. Gibson PG. Using fractional exhaled nitric oxide to guide asthma therapy: design and methodological issues for ASthma TReatment ALgorithm studies. Clin Exp Allergy 2009;39:478-90.
176. Dweik RA, Boggs PB, Erzurum SC, et al. An^mrcial ATS clinical practice guideline: interpretation of exhaled nitric oxide levels (FENO) for clinical applications. Am^espir Crit Care Med 2011;184:602-15.
177. Petsky HL, Kew KM, Chang AB. Exhaled nitric oxide levels to guide treatment for children with asthma. Cochrane Database Syst Rev 2016;ll:Cd011439.
178. Petsky HL, Kew KM, Turner C, Chang AB. Exhaled nitric oxide levels to guide treatment for adults with asthma. Cochrane Database Syst Rev 2016;9:Cd011440.
179. Heaney LG, Busby J, Hanratty CE, et al. Composite type-2 biomarker strategy versus a symptom-risk-based algorithm to adjust corticosteroid dose in patients with severe asthma: a multicentre, single-blind, parallel group, randomised controlled trial. Lancet Respir Med 2021;9:57-68.
180. Roche N, Reddel HK, Agusti A, et al. Integrating real-life studies in the global therapeutic research framework. Lancet Respir Med 2013;l:e29-e30.
181. Chung KF. New treatments for severe treatment-resistant asthma: targeting the right patient. Lancet Respir Med 2013;1:639-52.
182. Drazen JM. Asthma: the paradox of heterogeneity. J Allergy Clin Immunol 2012;129:1200-1.
183. Busse WW, Pedersen S, Pauwels RA, et al. The Inhaled Steroid Treatment As Regular Therapy in Early Asthma (START) study 5-year follow-up: effectiveness of early intervention with budesonide in mild persistent asthma. J Allergy Clin Immunol 2008;121:1167-74.
184. Selroos O, Pietinalho A, Lofroos AB, Riska H. Effect of early vs late intervention with inhaled corticosteroids in asthma. Chest 1995;108:1228-34.
185. Selroos O. Effect of disease duration on dose-response of inhaled budesonide in asthma. Respir Med 2008;102:1065-72.
188
References
186. Price DB, Buhl R, Chan A, 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.
187. Wechsler ME, Szefler SJ, Ortega VE, et al. Step-up therapy in black children and adults with poorly controlled asthma. N Engl J Med 2019;381:1227-39.
188. Kerstjens HAM, Maspero J, Chapman KR, et al. Once-daily, single-inhaler mometasone-indacaterol-glycopyrronium versus mometasone-indacaterol or twice-daily fluticasone-salmeterol in patients with inadequately controlled asthma (IRIDIUM): a randomised, double-blind, controlled phase 3 study. Lancet Respir Med 2020;8:1000-12.
189. El Baou C, Di Santostefano RL, Alfonso-Cristancho R, et al. 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.
190. O'Byrne PM, Barnes PJ, Rodriguez-Roisin R, et al. Low dose inhaled budesonide and formoterol in mild persistent asthma: the OPTIMA randomized trial. Am J Respir Crit Care Med 2001;164(8 Pt l):1392-7.
191. Dusser D, Montani D, Chanez P, et al. Mild asthma: an expert review on epidemiology, clinical characteristics and treatment recommendations. Allergy 2007;62:591-604.
192. O'Byrne PM, FitzGerald JM, Bateman ED, et al. Effect of a single day of increasejuas-needed budesonide-formoterol use on short-term risk of severe exacerbations in patients with mild asthma: a post-hoc analysis of the SYGMA 1 study. Lancet Respir Med 2021;9:149-58.
193. Barnes CB, Ulrik CS. Asthma and adherence to inhaled corticosteroids^juYrent status and future perspectives. Respir Care 2015;60.
194. Hancox RJ. Concluding remarks: can we explain the association^beta-agonists with asthma mortality? A hypothesis. Clin Rev Allergy Immunol 2006;31:279-88.
195. Lazarinis N, J0rgensen L, Ekström T, et al. Combination of budesonide/formoterol on demand improves asthma control by reducing exercise-induced bronchoconstriction. Thorax 2014;69:130-6.
196. Papi A, Canonica GW, Maestrelli P, et al. Rescue use of beclomethasone and albuterol in a single inhaler for mild asthma. N Engl J Med 2007;356:2040-52.
197. Martinez FD, Chinchilli VM, Morgan WJ, et al. Use of beclomethasone dipropionate as rescue treatment for children with mild persistent asthma (TREXA): a rariHBrnised, double-blind, placebo-controlled trial. Lancet 2011;377:650-7.
198. Calhoun WJ, Ameredes BT, King TS, et al. Comparison of physician-, biomarker-, and symptom-based strategies for adjustment of inhaled corticosteroid therapy in adults with asthma: the BASALT randomized controlled trial. JAMA 2012;308:987-97.
199. Sumino K, Bacharier LB, TayMr\l, et al. A pragmatic trial of symptom-based inhaled corticosteroid use in African-American children with mild asthma. The journal of allergy and clinical immunology In practice 2019.
200. Pauwels RA, Pedersen S, Busse WW, et al. Early intervention with budesonide in mild persistent asthma: a randomised, double-blind trial. Lancet 2003;361:1071-6.
201. Crompton G. A brief history of inhaled asthma therapy over the last fifty years. Prim Care Respir J 2006;15:326-31.
202. 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.
203. 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.
204. 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.
205. Haahtela T, Jarvinen M, Kava T, et al. Comparison of a £>2-agonist, terbutaline, with an inhaled corticosteroid, budesonide, in newly detected asthma. N Engl J Med 1991;325:388-92.
206. 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.
References
189
207. Tattersfield AE, Lofdahl CG, Postma DS, et al. Comparison of formoterol and terbutaline for as-needed treatment of asthma: a randomised trial. Lancet 2001;357:257-61.
208. Pauwels RA, Sears MR, Campbell M, et al. Formoterol as relief medication in asthma: a worldwide safety and effectiveness trial. Eur Respir J 2003;22:787-94.
209. 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.
210. Rodrigo GJ, Castro-Rodriguez JA. Safety of long-acting beta agonists for the treatment of asthma: clearing the air. Thorax 2012;67:342-9.
211. Adams NP, Bestall JB, Malouf R, Lasserson TJ, Jones PW. Inhaled beclomethasone versus placebo for chronic asthma. Cochrane Database Syst Rev 2005:CD002738.
212. Adams NP, Bestall JC, Lasserson TJ, Jones P, Cates Ci. Fluticasone versus placebo for chronic asthma in adults and children. Cochrane Database Syst Rev 2008:CD003135.
213. Sumino K, Bacharier LB, Taylor J, 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.
214. Chauhan BF, Ducharme FM. Anti-leukotriene agents compared to inhaled corticosteroids in the management of recurrent and/or chronic asthma in adults and children. Cochrane Database Syst Rev 2012;5:CD002314.
215. FDA requires Boxed Warning about serious mental health side effects for asttma and allergy drug montelukast (Singulair); advises restricting use for allergic rhinitis. FDA, 2020. (Accessed 04 Ma^h 2020, 2020, at https://www.fda.gov/drugs/drug-safety-and-availabilitv/fda-requires-boxed-warning-about-serious-mental-health-side-effects-asthma-and-allergv-drug.)
216. Ni Chroinin M, Greenstone I, Lasserson TJ, Ducharme FM. Addition of inhaled long-acting beta2-agonists to inhaled steroids as first line therapy for persistent asthma in steroicjzpart/e adults and children. Cochrane Database Syst Rev 2009:CD005307.
217. Dahl R, Larsen BB, Venge P. Effect of long-term treatment with inhaled budesonide or theophylline on lung function, airway reactivity and asthma symptoms. Respir Med 2002;96:432-8.
218. Rivington RN, Boulet LP, Cote J, et al. Efficacy of Uniphyl, salbutamol, and their combination in asthmatic patients on high-dose inhaled steroids. Am J Respir Crit Care Med 1995;151:325-32.
219. American Lung Association Asthma Clinical Research Centers. Clinical trial of low-dose theophylline and montelukast in patients with poorly controlled asthma. Am J Respir Crit Care Med 2007;175:235-42.
220. Tsiu SJ, Self TH, Burns R. Theophylline toxicity: update. Ann Allergy 1990;64:241-57.
221. Guevara JP, Ducharme FM, Kererxft/Nihtianova S, Zorc J. Inhaled corticosteroids versus sodium cromoglycate in children and adults with asthma. Cochrane Database Syst Rev 2006:CD003558.
222. Sridhar AV, McKean M. Nedocromil sodium for chronic asthma in children. Cochrane Database Syst Rev 2006:CD004108.
223. 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.
224. 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 Rev2013;4:CD007313.
225. 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.
226. Papi A, Corradi M, Pigeon-Francisco C, 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.
227. Patel M, Pilcher J, Pritchard A, et al. Efficacy and safety of maintenance and reliever combination budesonide/formoterol inhaler in patients with asthma at risk of severe exacerbations: a randomised controlled trial. Lancet Respir Med 2013;1:32-42.
228. Bateman ED, Harrison TW, Quirce S, et al. Overall asthma control achieved with budesonide/formoterol maintenance and reliever therapy for patients on different treatment steps. Respir Res 2011;12:38.
190
References
229. Jorup C, Lythgoe D, Bisgaard H. Budesonide/formoterol maintenance and reliever therapy in adolescent patients with asthma. Eur Respir J 2018;51.
230. Demoly P, Louis R, S0es-Petersen U, et al. Budesonide/formoterol maintenance and reliever therapy versus conventional best practice. Respir Med 2009;103:1623-32.
231. Cates Ci, 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.
232. Busse WW, Bateman ED, Caplan AL, et al. Combined analysis of asthma safety trials of long-acting beta2-agonists. N Engl J Med 2018;378:2497-505.
233. Peters SP, Bleecker ER, Canonica GW, et al. Serious asthma events with budesonide plus formoterol vs. budesonide alone. N Engl J Med 2016;375:850-60.
234. Stempel DA, Raphiou IH, Krai KM, et al. Serious asthma events with fluticasone plus salmeterol versus fluticasone alone. N Engl J Med 2016;374:1822-30.
235. Woodcock A, Vestbo J, Bakerly ND, 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.
236. Svedsater H, Jones R, Bosanquet N, 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.
237. Virchow JC, Backer V, Kuna P, et al. Efficacy of a house dust mite sublingtjahallergen immunotherapy tablet in adults with allergic asthma: a randomized clinical trial. JAMA 2016;315:1715-2^sr'
238. Mosbech H, Deckelmann R, de Blay F, et al. Standardized quality (SQ) house dust mite sublingual immunotherapy tablet (ALK) reduces inhaled corticosteroid use while maintaining asthma control: a randomized, double-blind, placebo-controlled trial. J Allergy Clin Immunol 2014;134:568-75.e7.
239. Ducharme FM, Ni Chroinin M, Greenstone I, Lasserson TL Addition of long-acting beta2-agonists to inhaled steroids versus higher dose inhaled steroids in adults and children with persistent asthma. Cochrane Database Syst Rev 2010:CD005533.
240. Powell H, Gibson PG. Inhaled corticosteroid doses in asthma: an evidence-based approach. Med J Aust 2003;178:223-5.
241. Chauhan BF, Ducharme FM. Addition to inhaled corticosteroids of long-acting beta2-agonists versus anti-leukotrienes for chronic asthma. Cochrane Database Syst Rev 2014;1:CD003137.
242. Evans DJ, Taylor DA, Zetterstrom O.S^Ong KF, O'Connor BJ, Barnes PJ. A comparison of low-dose inhaled budesonide plus theophylline and high- dose inhaled budesonide for moderate asthma. N Engl J Med 1997;337:1412-8.
243. 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.
244. Vaessen-Verberne AA, van den Berg NJ, van Nierop JC, et al. Combination therapy salmeterol/fluticasone versus doubling dose of fluticasone in children with asthma. Am J Respir Crit Care Med 2010;182:1221-7.
245. 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.
246. Stempel DA, Szefler SJ, Pedersen S, et al. Safety of adding salmeterol to fluticasone propionate in children with asthma. N Engl J Med 2016;375:840-9.
247. 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.
248. Sobieraj DM, Baker WL, Nguyen E, et al. Association of inhaled corticosteroids and long-acting muscarinic antagonists with asthma control in patients with uncontrolled, persistent asthma: a systematic review and metaanalysis. JAMA 2018;319:1473-84.
249. Virchow JC, Kuna P, Paggiaro P, et al. Single inhaler extrafine triple therapy in uncontrolled asthma (TRIMARAN and TRIGGER): two double-blind, parallel-group, randomised, controlled phase 3 trials. Lancet 2019;394:1737-49.
250. Lee LA, Bailes Z, Barnes N, et al. Efficacy and safety of once-daily single-inhaler triple therapy (FF/UMEC/VI) versus FF/VI in patients with inadequately controlled asthma (CAPTAIN): a double-blind, randomised, phase 3A trial. Lancet Respir Med 2021;9:69-84.
References
191
251. Gessner C, Kornmann O, Maspero J, et al. Fixed-dose combination of indacaterol/glycopyrronium/mometasone furoate once-daily versus salmeterol/fluticasone twice-daily plus tiotropium once-daily in patients with uncontrolled asthma: A randomised, Phase 1Mb, non-inferiority study (ARGON). Respir Med 2020;170:106021.
252. 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.
253. Casale TB, Aalbers R, Bleecker ER, et al. Tiotropium Respimat(R) add-on therapy to inhaled corticosteroids in patients with symptomatic asthma improves clinical outcomes regardless of baseline characteristics. Respir Med 2019;158:97-109.
254. 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.
255. 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.
256. Lofdahl CG, Reiss TF, Leff JA, et al. Randomised, placebo controlled trial of effect     Leukotriene receptor antagonist, montelukast, on tapering inhaled corticosteroids in asthmatic patients. BMJ 1999;319:87-90.
257. Price DB, Hernandez D, Magyar P, et al. Randomised controlled trial of montelukast plus inhaled budesonide versus double dose inhaled budesonide in adult patients with asthma. Thorax 2003;58:211-6.
258. Vaquerizo MJ, Casan P, Castillo J, et al. Effect of montelukast added to inhaled budesonide on control of mild to moderate asthma. Thorax 2003;58:204-10.
259. Virchow JC, Prasse A, Naya I, Summerton L, Harris A. Zafirlukast(flyproves asthma control in patients receiving high-dose inhaled corticosteroids. Am J Respir Crit Care Med 2000;lJ2s378-85.
260. Tamaoki J, Kondo M, Sakai N, et al. Leukotriene antagonist prevents exacerbation of asthma during reduction of high-dose inhaled corticosteroid. The Tokyo Joshi-ldai Asthma Research Group. Am J Respir Crit Care Med 1997;155:1235-40.
261. Szefler SJ, Vogelberg C, Bernstein JA, et al. Tiotropium Is Efficacious in 6- to 17-Year-Olds with Asthma, Independent of T2 Phenotype. J Allergy Clin ImmunoUgjSct 2019;7:2286-95 e4.
262. Travers J, Marsh S, Williams M, et al. External validity of randomised controlled trials in asthma: to whom do the results of the trials apply? Thorax 2007;62:219-23.
263. Brown T, Jones T, Gove K, et al. Randomised controlled trials in severe asthma: selection by phenotype or stereotype. Eur Respir J 2018;52.
264. Broersen LH, Pereira AM, Jorgensen JO, Dekkers OM. Adrenal insufficiency in corticosteroids use: Systematic review and meta-analysis. J Clin Endocrinol Metab 2015;100:2171-80.
265. Taylor SL, Leong LEX, Mobegi FM, et al. Long-term azithromycin reduces Haemophilus influenzae and increases antibiotic resistance in severe asthma. Am J Respir Crit Care Med 2019;200:309-17.
266. Gibson PG, Yang IA, Upham JW, et al. Effect of azithromycin on asthma exacerbations and quality of life in adults with persistent uncontrolled asthma (AMAZES): a randomised, double-blind, placebo-controlled trial. Lancet 2017;390:659-68.
267. Hiles SA, McDonald VM, Guilhermino M, Brusselle GG, Gibson PG. Does maintenance azithromycin reduce asthma exacerbations? An individual participant data meta-analysis. Eur Respir J 2019;54.
268. Normansell R, Walker S, Milan SJ, Walters EH, Nair P. Omalizumab for asthma in adults and children. Cochrane Database Syst Rev 2014;1:CD003559.
269. 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.
270. Haldar P, Brightling CE, Hargadon B, et al. Mepolizumab and exacerbations of refractory eosinophilic asthma. N Engl J Med 2009;360:973-84.
271. Pavord ID, Korn S, Howarth P, et al. Mepolizumab for severe eosinophilic asthma (DREAM): a multicentre, double-blind, placebo-controlled trial. Lancet 2012;380:651-9.
192
References
272. Castro M, Zangrilli J, Wechsler ME, 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.
273. Nair P, Wenzel S, Rabe KF, et al. Oral glucocorticoid-sparing effect of benralizumab in severe asthma. N Engl J Med 2017;376:2448-58.
274. Farne HA, Wilson A, Powell C, Bax L, Milan SJ. Anti-IL5 therapies for asthma. Cochrane Database Syst Rev 2017;9:Cd010834.
275. Gupta A, Ikeda M, Geng B, 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.
276. Castro M, Corren J, Pavord ID, et al. Dupilumab efficacy and safety in moderate-to-severe uncontrolled asthma. The New England journal of medicine 2018;378:2486-96.
277. Wenzel S, Castro M, Corren J, 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.
278. Zayed Y, Kheiri B, Banifadel M, et al. Dupilumab safety and efficacy in uncontrolled asthma: a systematic review and meta-analysis of randomized clinical trials. J Asthma 2018:1-10.
279. Chupp G, Laviolette M, Cohn L, et al. Long-term outcomes of bronchial thermoplasty in subjects with severe asthma: a comparison of 3-year follow-up results from two prospective multir^itre studies. Eur Respir J 2017;50.
280. Walsh U, Wong CA, Oborne J, et al. Adverse effects of oral corticosteroids in relation to dose in patients with lung disease. Thorax 2001;56:279-84.
281. Lefebvre P, Duh MS, Lafeuille M-H, et al. Acute and chronic systemic corticosteroid-related complications in patients with severe asthma. J Allergy Clin Immunol 2015;136:1488-95.
282. Price DB, Trudo F, Voorham J, et al. Adverse outcomes from initiation of systemic corticosteroids for asthma: long-term observational study. J Asthma Allergy 2018;11:193^04.
283. Grossman JM, Gordon R, Ranganath VK, et al. American College of Rheumatology 2010 recommendations for the prevention and treatment of glucocorticoid-induced osteoporosis. Arthritis Care Res 2010;62:1515-26.
284. Bateman ED, Bousquet J, Keech ML, Busse WW, ClarkTJ, Pedersen SE. The correlation between asthma control and health status: the GOAL study. Eur Respir J 2007;29:56-62.
285. Sont JK. How do we monitor asthma^ntrol? Allergy 1999;54 Suppl 49:68-73.
286. Mintz M, Gilsenan AW, Bui CL, et^TXssessment of asthma control in primary care. Curr Med Res Opin 2009;25:2523-31.
287. Schatz M, Rachelefsky G, KwMrhan JA. Follow-up after acute asthma episodes: what improves future outcomes? Proc Am Thorac Soc 2009;6:386-93.
288. Thomas A, Lemanske RF, Jr., Jackson DJ. Approaches to stepping up and stepping down care in asthmatic patients. J Allergy Clin Immunol 2011;128:915-24.
289. Bousquet J, Boulet LP, Peters MJ, et al. Budesonide/formoterol for maintenance and relief in uncontrolled asthma vs. high-dose salmeterol/fluticasone. Respir Med 2007;101:2437-46.
290. Buhl R, Kuna P, Peters MJ, et al. The effect of budesonide/formoterol maintenance and reliever therapy on the risk of severe asthma exacerbations following episodes of high reliever use: an exploratory analysis of two randomised, controlled studies with comparisons to standard therapy. Respir Res 2012;13:59.
291. Boulet LP. Perception of the role and potential side effects of inhaled corticosteroids among asthmatic patients. Chest 1998;113:587-92.
292. Usmani OS, Kemppinen A, Gardener E, et al. A randomized pragmatic trial of changing to and stepping down fluticasone/formoterol in asthma. J Allergy Clin Immunol Pract 2017;5:1378-87.e5.
293. DiMango E, Rogers L, Reibman J, 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.
294. Leuppi JD, Salome CM, Jenkins CR, et al. Predictive markers of asthma exacerbation during stepwise dose reduction of inhaled corticosteroids. Am J Respir Crit Care Med 2001;163:406-12.
References
193
295. Rogers L, Sugar EA, Blake K, 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.el.
296. 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.
297. Bose S, Bime C, Henderson RJ, et al. Biomarkers of Type 2 airway inflammation as predictors of loss of Aathma control during step-down therapy for well-controlled disease: the Long-Acting Beta-Agonist Step-Down Study (LASST). J Allergy Clin Immunol Pract 2020;8:3474-81.
298. Wang K, Verbakel JY, Oke J, et al. Using fractional exhaled nitric oxide to guide step-down treatment decisions in patients with asthma: a systematic review and individual patient data meta-analysis. Eur Respir J 2020;55.
299. Rank MA, Hagan JB, Park MA, 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.
300. Hagan JB, Samant SA, Volcheck GW, et al. The risk of asthma exacerbation after reducing inhaled corticosteroids: a systematic review and meta-analysis of randomized controlled trials. Allergy 2014;69:510-6.
301. 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.
302. Rank MA, Gionfriddo MR, Pongdee T, 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.
303. Masoli M, Weatherall M, Holt S, Beasley R. Budesonide once versus twice-daily administration: meta-analysis. Respirology 2004;9:528-34.
304. Boulet LP, Drollmann A, Magyar P, et al. Comparative efficacy of once-daily ciclesonide and budesonide in the treatment of persistent asthma. Respir Med 2006;100:785-94.
305. Rice JL, Diette GB, Suarez-Cuervo C, et al. Allergen-specific immunotherapy in the treatment of pediatric asthma: A systematic review. Pediatrics 2018;141.
306. Lin SY, Erekosima N, Kim JM, et al. Sublingual immunotherapy for the treatment of allergic rhinoconjunctivitis and asthma: a systematic review. JAMA 2013;309:1278-88.
307. Di Bona D, Frisenda F, Albanesi M, Di Lorenzo G, Caiaffa MF, Macchia L. Efficacy and safety of allergen immunotherapy in patients with allergy to molds: A systematic review. Clin Exp Allergy 2018;48:1391-401.
308. Abramson MJ, Puy RM, Weiner JM. Injection allergen immunotherapy for asthma. Cochrane Database Syst Rev 2010:CD001186.
309. Klimek L, Fox GC, Thum-Oltmer S. SCIT with a high-dose house dust mite allergoid is well tolerated: safety data from pooled clinical trials and more than 10 years of daily practice analyzed in different subgroups. Allergo journal international 2018;27:131-9.
310. Xu K, Deng Z, Li D, et al. Efficacy of add-on sublingual immunotherapy for adults with asthma: A meta-analysis and systematic review. Ann Allergy Asthma Immunol 2018;121:186-94.
311. Calamita Z, Saconato H, Pela AB, Atallah AN. Efficacy of sublingual immunotherapy in asthma: systematic review of randomized-clinical trials using the Cochrane Collaboration method. Allergy 2006;61:1162-72.
312. Normansell R, Kew KM, Bridgman A. Sublingual immunotherapy for asthma. Cochrane Database Syst Rev 2015.
313. Fortescue R, Kew KM, Leung MST. Sublingual immunotherapy for asthma. Cochrane Database Syst Rev 2020;9:CD011293.
314. Marogna M, Spadolini I, Massolo A, et al. Long-term comparison of sublingual immunotherapy vs inhaled budesonide in patients with mild persistent asthma due to grass pollen. Ann Allergy Asthma Immunol 2009;102:69-75.
315. Baena-Cagnani CE, Larenas-Linnemann D, Teijeiro A, Canonica GW, Passalacqua G. Will sublingual immunotherapy offer benefit for asthma? Curr Allergy Asthma Rep 2013.
316. Burks AW, Calderon MA, Casale T, 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.
194
References
317. 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.
318. Cates Ci, Rowe BH. Vaccines for preventing influenza in people with asthma. Cochrane Database Syst Rev 2013;2:CD000364.
319. Vasileiou E, Sheikh A, Butler C, et al. Effectiveness of Influenza Vaccines in Asthma: A Systematic Review and Meta-Analysis. Clin Infect Dis 2017;65:1388-95.
320. Talbot TR, Hartert TV, Mitchel E, et al. Asthma as a risk factor for invasive pneumococcal disease. N Engl J Med 2005;352:2082-90.
321. Sheikh A, Alves B, Dhami S. Pneumococcal vaccine for asthma. Cochrane Database Syst Rev 2002:CD002165.
322. Wechsler ME, Laviolette M, Rubin AS, et al. Bronchial thermoplasty: Long-term safety and effectiveness in patients with severe persistent asthma. J Allergy Clin Immunol 2013;132:1295-302.e3.
323. Cassim R, Russell MA, Lodge Ci, Lowe AJ, Kopiin JJ, Dharmage SC. The role of circulating 25 hydroxyvitamin D in asthma: a systematic review. Allergy 2015;70:339-54.
324. Jolliffe DA, Greenberg L, Hooper RL, 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.
325. Riverin BD, Maguire JL, Li P. Vitamin D supplementation for childhood asinma: A systematic review and metaanalysis. PLoS One 2015;10:e0136841.
326. Pojsupap S, lliriani K, Sampaio TZ, et al. Efficacy of high-dose vitamin D in pediatric asthma: a systematic review and meta-analysis. J Asthma 2015;52:382-90.
327. Castro M, King TS, Kunselman SJ, et al. Effect of vitamin D3 qnvisthma treatment failures in adults with symptomatic asthma and lower vitamin D levels: the VIDA randomized clinical trial. Jama 2014;311:2083-91.
328. Lazarus SC, Chinchilli VM, Rollings NJ, et al. Smoking alights response to inhaled corticosteroids or leukotriene receptor antagonists in asthma. Am J Respir Crit Care Med 2007;175:783-90.
329. Chaudhuri R, Livingston E, McMahon AD, et al. Effects of smoking cessation on lung function and airway inflammation in smokers with asthma. Am J Respir Crit Care Med 2006;174:127-33.
330. Rayens MK, Burkhart PV, Zhang M, et al. Reduction in asthma-related emergency department visits after implementation of a smoke-free law. J Allergy Clin Immunol 2008;122:537-41.
331. Hansen ESH, Pitzner-Fabricius A, Toennesen LL, et al. Effect of aerobic exercise training on asthma in adults: a systematic review and meta-analysis. Eur Respir J 2020;56.
332. Toennesen LL, Meteran H, Hostrup M, et al. Effects of exercise and diet in nonobese asthma patients-a randomized controlled trial. J Allergy Clin Immunol Pract 2018;6:803-11.
333. Beggs S, Foong YC, Le HC, Noor D, Wood-Baker R, Walters JA. Swimming training for asthma in children and adolescents aged 18 years and under. Cochrane Database Syst Rev 2013;4:CD009607.
334. Kogevinas M, Zock-j® Jarvis D, et al. Exposure to substances in the workplace and new-onset asthma: an international prospective population-based study (ECRHS-II). Lancet 2007;370:336-41.
335. Szczeklik A, Nizankowska E, Duplaga M. Natural history of aspirin-induced asthma. AIANE Investigators. European Network on Aspirin-Induced Asthma. Eur Respir J 2000;16:432-6.
336. Covar RA, Macomber BA, Szefler SJ. Medications as asthma triggers. Immunol Allergy Clin North Am 2005;25:169-90.
337. 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.
338. 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.
339. Gotzsche PC, Johansen HK. House dust mite control measures for asthma. Cochrane Database Syst Rev 2008:CD001187.
340. Leas BF, D'Anci KE, Apter Al, et al. Effectiveness of indoor allergen reduction in asthma management: A systematic review. J Allergy Clin Immunol 2018;141:1854-69.
341. Sheffer AL Allergen avoidance to reduce asthma-related morbidity. N Engl J Med 2004;351:1134-6.
References
195
342. Platts-Mills TA. Allergen avoidance in the treatment of asthma and rhinitis. N Engl J Med 2003;349:207-8.
343. 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.
344. Crocker DD, Kinyota S, Dumitru GG, 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 PrevMed 2011;41:S5-32.
345. Morgan WJ, Crain EF, Gruchalla RS, et al. Results of a home-based environmental intervention among urban children with asthma. N Engl J Med 2004;351:1068-80.
346. 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.
347. Custovic A, Green R, Taggart SC, et al. Domestic allergens in public places. II: Dog (Can fl) 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.
348. 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 lmrri|jju>l 1999;103:1012-7.
349. Shirai T, Matsui T, Suzuki K, Chida K. Effect of pet removal on pet allergic asthma. Chest 2005;127:1565-71.
350. Wood RA, Chapman MD, Adkinson NF, Jr., Eggleston PA. The effect of cat removal on allergen content in household-dust samples. J Allergy Clin Immunol 1989;83:730-4.
351. Erwin EA, Woodfolk JA, Custis N, Platts-Mills TA. Animal danders. Immunol Allergy Clin North Am 2003;23:469-81.
352. Phipatanakul W, Matsui E, Portnoy J, et al. Environmental assessment and exposure reduction of rodents: a practice parameter. Ann Allergy Asthma Immunol 2012;109:375-87.
353. Matsui EC, Perzanowski M, Peng RD, et al. Effect of an integrated pest management intervention on asthma symptoms among mouse-sensitized children and adolescents with asthma: A randomized clinical trial. Jama 2017;317:1027-36.
354. Custovic A, Wijk RG. The effectiveness of measures to change the indoor environment in the treatment of allergic rhinitis and asthma: ARIA update (in collaboration with GA(2)LEN). Allergy 2005;60:1112-5.
355. Eggleston PA, Wood RA, Rand C, Nixon WJ, Chen PH, Lukk P. Removal of cockroach allergen from inner-city homes. J Allergy Clin Immunol 1999;104:842-6. ^
356. Denning DW, O'Driscoll B R, HogaboWrCM, Bowyer P, Niven RM. The link between fungi and severe asthma: a summary of the evidence. Eur Respir J 2006;27:615-26.
357. Hirsch T, Hering M, Burkner K/^Kal. House-dust-mite allergen concentrations (Der f 1) and mold spores in apartment bedrooms before and after installation of insulated windows and central heating systems. Allergy 2000;55:79-83.
358. Wood LG, Garg ML, Sprwt JM, Scott HA, Barker D, Gibson PG. Manipulating antioxidant intake in asthma: a randomized controlled trial. Am J Clin Nutr 2012;96:534-43.
359. Boulet LP, Franssen E. Influence of obesity on response to fluticasone with or without salmeterol in moderate asthma. Respir Med 2007;101:2240-7.
360. Lavoie KL, Bacon SL, Labrecque M, Cartier A, Ditto B. Higher BMI is associated with worse asthma control and quality of life but not asthma severity. Respir Med 2006;100:648-57.
361. Saint-Pierre P, Bourdin A, Chanez P, Daures JP, Godard P. Are overweight asthmatics more difficult to control? Allergy 2006;61:79-84.
362. 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.
363. Okoniewski W, Lu KD, Forno E. Weight Loss for Children and Adults with Obesity and Asthma. A Systematic Review of Randomized Controlled Trials. Ann Am Thorac Soc 2019;16:613-25.
364. Adeniyi FB, Young T. Weight loss interventions for chronic asthma. Cochrane Database Syst Rev 2012;7:CD009339.
196
References
365. Moreira A, Bonini M, Garcia-Larsen V, et al. Weight loss interventions in asthma: EAACI Evidence-Based Clinical Practice Guideline (Part I). Allergy 2013;68:425-39.
366. 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.
367. Dixon AE, Pratley RE, Forgione PM, et al. Effects of obesity and bariatric surgery on airway hyperresponsiveness, asthma control, and inflammation. J Allergy Clin Immunol 2011;128:508-15 el-2.
368. Scott HA, Gibson PG, Garg ML, et al. 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.
369. Santino TA, Chaves GS, Freitas DA, Fregonezi GA, Mendonca KM. Breathing exercises for adults with asthma. Cochrane Database Syst Rev 2020;3:CD001277.
370. Slader CA, Reddel HK, Spencer LM, et al. Double blind randomised controlled trial of two different breathing techniques in the management of asthma. Thorax 2006;61:651-6.
371. Bruton A, Lee A, Yardley L, et al. Physiotherapy breathing retraining for asthma: a randomised controlled trial. Lancet Respir Med 2018;6:19-28.
372. Upham JW, Holt PG. Environment and development of atopy. Curr Opin AllergasOlin Immunol 2005;5:167-72.
373. Belanger K, Holford TR, Gent JF, Hill ME, Kezik JM, Leaderer BP. Household kfflefs of nitrogen dioxide and pediatric asthma severity. Epidemiology 2013;24:320-30.
374. Howden-Chapman P, Pierse N, Nicholls S, et al. Effects of improved home heating on asthma in community dwelling children: randomised controlled trial. BMJ 2008;337:al411.
375. Tibosch MM, Verhaak CM, Merkus PJ. Psychological characteristics associated with the onset and course of asthma in children and adolescents: a systematic review of longitudinal effects. Patient Educ Couns 2011;82:11-9.
376. Rietveld S, van Beest I, Everaerd W. Stress-induced breathlessness in asthma. Psychol Med 1999;29:1359-66.
377. Sandberg S, Paton JY, Ahola S, et al. The role of acute and chronic stress in asthma attacks in children. Lancet 2000;356:982-7.
378. Lehrer PM, Isenberg S, Hochron SM. Asthma and^)notion: a review. J Asthma 1993;30:5-21.
379. Nouwen A, Freeston MH, Labbe R, Boulet LP.psychological factors associated with emergency room visits among asthmatic patients. Behav Modif 1999;23:217-33.^
380. Hauptman M, Gaffin JM, Petty CR, et al. Proximity to major roadways and asthma symptoms in the School Inner-City Asthma Study. J Allergy Clin Immunol 20$>r;145:119-26 e4.
381. Newson R, Strachan D, Archibald^vEmberlin J, Hardaker P, Collier C. Acute asthma epidemics, weather and pollen in England, 1987-1994. Eur Respir J 1998;11:694-701.
382. Thien F, Beggs PJ, Csutoros D, et al. The Melbourne epidemic thunderstorm asthma event 2016: an investigation of environmental triggers, effect on health services, and patient risk factors. The Lancet Planetary Health 2018;2:e255-e63.
383. Li Y, Wang W, Wa»gJ* Zhang X, Lin W, Yang Y. Impact of air pollution control measures and weather conditions on asthma during the 2008 Summer Olympic Games in Beijing. Int J Biometeorol 2011;55:547-54.
384. Taylor SL, Bush RK, Seiner JC, et al. Sensitivity to sulfited foods among sulfite-sensitive subjects with asthma. J Allergy Clin Immunol 1988;81:1159-67.
385. 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.
386. 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.
387. 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.
388. Newman SP. Spacer devices for metered dose inhalers. Clin Pharmacokinet 2004;43:349-60.
389. 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.
References
197
390. Giraud V, Allaert FA, Roche N. Inhaler technique and asthma: feasability and acceptability of training by pharmacists. Respiratory medicine 2011;105:1815-22.
391. 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.
392. 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.
393. 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.
394. Armour CL, Reddel HK, LeMay KS, 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.
395. 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.
396. Federman AD, O'Conor R, Mindlis I, et al. Effect of a self-management support intervention on asthma outcomes in older adults: The SAMBA study randomized clinical trial. JAMA Intern Med 2019.
397. Crompton GK, Barnes PJ, Broeders M, et al. The need to improve inhalation technique in Europe: a report from the Aerosol Drug Management Improvement Team. Respir Med 2006;100:1479-94.
398. Viswanathan M, Golin CE, Jones CD, et al. Interventions to improve adherence to self-administered medications for chronic diseases in the United States: a systematic review. Ann Intern Med 2012;157:785-95.
399. Murphy J, McSharry J, Hynes L, Matthews S, Van Rhoon L, Molloy GJ. Prevalence and predictors of adherence to inhaled corticosteroids in young adults (15-30 years) with asthma: a systematic review and meta-analysis. J Asthma 2020:1-23.
400. Chan AH, Harrison J, Black PN, Mitchell EA, Foster JM. Using electronic monitoring devices to measure inhaler adherence: a practical guide for clinicians. J Allergy Clin Immunol Pract 2015;3:335-49.el-5.
401. Cohen JL, Mann DM, Wisnivesky JP, et al. Assessing the>varidity of self-reported medication adherence among inner-city asthmatic adults: the Medication Adherence Report Scale for Asthma. Ann Allergy Asthma Immunol 2009;103:325-31.
402. Poureslami IM, Rootman I, Balka E, Devarakonda R, Hatch J, FitzGerald JM. A systematic review of asthma and health literacy: a cultural-ethnic perspective in Canada. MedGenMed 2007;9:40.
403. Berkman ND, Sheridan SL, Donahue KE, Halpern DJ, Crotty K. Low health literacy and health outcomes: an updated systematic review. Ann Intern Med 2011;155:97-107.
404. Zeni MB. Systematic review of health literacy in Cochrane database studies on paediatric asthma educational interventions: searching beyond rigorous design. Int J Evid Based Healthc 2012;10:3-8.
405. Partridge MR, Dal Negro RW, Olivieri D. Understanding patients with asthma and COPD: insights from a European study. Prim Care Respir J 2011;20:315-23, 17 p following 23.
406. Foster JM, Usherwood T, Smith L, et al. Inhaler reminders improve adherence with controller treatment in primary care patients with asthma. J Allergy Clin Immunol 2014;134:1260-8.
407. 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.
408. Morton RW, Elphick HE, Rigby AS, et al. 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.
409. Otsuki M, Eakin MN, Rand CS, et al. Adherence feedback to improve asthma outcomes among inner-city children: a randomized trial. Pediatrics 2009;124:1513-21.
410. Williams LK, Peterson EL, Wells K, 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 el-4.
411. Bender BG, Cvietusa PJ, Goodrich GK, 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.
412. Halterman JS, Fagnano M, Tajon RS, 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:el74938.
198
References
413. Normansell R, Kew KM, Stovold E. Interventions to improve adherence to inhaled steroids for asthma. Cochrane Database Syst Rev 2017;4:Cd012226.
414. Foster JM, Smith L, Bosnic-Anticevich SZ, et al. Identifying patient-specific beliefs and behaviours for conversations about adherence in asthma. Intern Med J 2012;42:el36-44.
415. 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.
416. Price D, Robertson A, Bullen K, Rand C, Home 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.
417. Kew KM, Carr R, Crossingham I. Lay-led and peer support interventions for adolescents with asthma. Cochrane Database Syst Rev 2017;4:Cd012331.
418. Clark NM, Shah S, Dodge JA, Thomas U, Andridge RR, Little RJ. An evaluation of asthma interventions for preteen students. J Sch Health 2010;80:80-7.
419. Gibson PG, Powell H, Coughlan J, et al. Limited (information only) patient education programs for adults with asthma. Cochrane Database Syst Rev 2002:CD001005.
420. Houts PS, Bachrach R, Witmer JT, Tringali CA, Bucher JA, Localio RA. Using pictographs to enhance recall of spoken medical instructions. Patient Educ Couns 1998;35:83-8.
421. Meade CD, McKinney WP, Barnas GP. Educating patients with limited literacy skills: the effectiveness of printed and videotaped materials about colon cancer. Am J Public Health 1994;84:119-21.
422. Manfrin A, Tinelli M, Thomas T, Krska J. A cluster randomised control trial to evaluate the effectiveness and cost-effectiveness of the Italian medicines use review (l-MUR) for asthma patients. BMC Health Serv Res 2017;17:300.
423. Gao G, Liao Y, Mo L, Gong Y, Shao X, Li J. A randomized controlled trial of a nurse-led education pathway for asthmatic children from outpatient to home. Int J Nurs Pract 2020;26:el2823.
424. Campbell JD, Brooks M, Hosokawa P, Robinson J, Spog4., Krieger J. Community health worker home visits for medicaid-enrolled children with asthma: Effects on asthma outcomes and costs. Am J Public Health 2015;105:2366-72.
425. Partridge MR, Caress AL, Brown C, et al. Can lay people deliver asthma self-management education as effectively as primary care based practice nurses? Thorax 2008;63:778-83.
426. Pinnock H, Parke HL, Panagioti M, et al. Systematic meta-review of supported self-management for asthma: a healthcare perspective. BMC Med 2017;15:64.
427. Boyd M, Lasserson TJ, McKean MC, Gibson PG, Ducharme FM, Haby M. Interventions for educating children who are at risk of asthma-related emergeruw&epartment attendance. Cochrane Database Syst Rev 2009:CD001290.
428. Powell H, Gibson PG. Optiorixfor self-management education for adults with asthma. Cochrane Database Syst Rev 2003:CD004107.
429. McLean S, Chandler D, Nurmatov U, et al. Telehealthcare for asthma. Cochrane Database Syst Rev 2010:CD007717.
430. 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.
431. Gibson PG, Powell H. Written action plans for asthma: an evidence-based review of the key components. Thorax 2004;59:94-9.
432. 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.
433. 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.
434. Ring N, Malcolm C, Wyke S, et al. Promoting the use of Personal Asthma Action Plans: a systematic review. Prim Care Respir J 2007;16:271-83.
435. Halterman JS, Fisher S, Conn KM, et al. Improved preventive care for asthma: a randomized trial of clinician prompting in pediatric offices. Arch Pediatr Adolesc Med 2006;160:1018-25.
References
199
436. 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 metaanalysis. Thorax 2019;74:432-8.
437. Boulet LP. Influence of comorbid conditions on asthma. Eur Respir J 2009;33:897-906.
438. 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:el2532.
439. 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.
440. Serrano-Pariente J, Plaza V, Soriano JB, et al. Asthma outcomes improve with continuous positive airway pressure for obstructive sleep apnea. Allergy 2017;72:802-12.
441. 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.
442. Mastronarde JG, Anthonisen NR, Castro M, et al. Efficacy of esomeprazole for treatment of poorly controlled asthma. N Engl J Med 2009;360:1487-99.
443. Kiljander TO, Harding SM, Field SK, et al. Effects of esomeprazole 40 mg twice daily on asthma: a randomized placebo-controlled trial. Am J Respir Crit Care Med 2006;173:1091-7.
444. Sopo SM, Radzik D, Calvani M. Does treatment with proton pump inhibitors for gastroesophageal reflux disease (GERD) improve asthma symptoms in children with asthma and GERD? A systematic review. J Investig Allergol Clin Immunol 2009;19:1-5.
445. Holbrook JT, Wise RA, Gold BD, et al. Lansoprazole for children wijMpoorly controlled asthma: a randomized controlled trial. JAMA 2012;307:373-81.
446. Goodwin RD, Jacobi F, Thefeld W. Mental disorders and asthma in the community. Arch Gen Psychiatry 2003;60:1125-30.
447. Lavoie KL, Cartier A, Labrecque M, et al. Are psychiatric disorders associated with worse asthma control and quality of life in asthma patients? Respir Med 2005;99:1249-57.
448. Ahmedani BK, Peterson EL, Wells KE, Williams LKvExaminingthe relationship between depression and asthma exacerbations in a prospective follow-up study. Psychosom Med 2013;75:305-10.
449. Yorke J, Fleming SL, Shuldham C. Psychological interventions for adults with asthma. Cochrane Database Syst Rev 2009.
450. Parry GD, Cooper CL, Moore JM, et al. Cognitive behavioural intervention for adults with anxiety complications of asthma: prospective randomised trial. Respir Med 2012;106:802-10.
451. Bock SA, Munoz-Furlong A, Sampson HA. Further fatalities caused by anaphylactic reactions to food, 2001-2006. J Allergy Clin Immunol 2007;119:10ö£g.
452. Pumphrey RSH, Gowland MH. Further fatal allergic reactions to food in the United Kingdom, 1999-2006. J Allergy Clin Immunol 2007;119:1018r9p
453. Liu AH, Jaramillo R, Sicherer SH, 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.el3.
454. Brozek JL, Bousquet J, Agache I, et al. Allergic Rhinitis and its Impact on Asthma (ARIA) guidelines-2016 revision. J Allergy Clin Immunol 2017;140:950-8.
455. Cruz AA, Popov T, Pawankar R, 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.
456. Bousquet J, Schunemann HJ, Samolinski B, 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.
457. Fokkens WJ, Lund VJ, Mullol J, et al. EPOS 2012: European position paper on rhinosinusitis and nasal polyps 2012. A summary for otorhinolaryngologists. Rhinol 2012;50:1-12.
458. Tan BK, Chandra RK, Pollak J, et al. Incidence and associated premorbid diagnoses of patients with chronic rhinosinusitis. J Allergy Clin Immunol 2013;131:1350-60.
200
References
459. Hamilos DL. Chronic rhinosinusitis: epidemiology and medical management. J Allergy Clin Immunol 2011;128:693-707.
460. 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.
461. Lohia S, Schlosser RJ, Soler ZM. Impact of intranasal corticosteroids on asthma outcomes in allergic rhinitis: a meta-analysis. Allergy 2013;68:569-79.
462. Dixon AE, Castro M, Cohen Rl, 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.
463. Gevaert P, Omachi TA, Corren J, et al. Efficacy and safety of omalizumab in nasal polyposis: 2 randomized phase 3 trials. J Allergy Clin Immunol 2020;146:595-605.
464. Gevaert P, Van Bruaene N, Cattaert T, 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.
465. Bachert C, Sousa AR, Lund VJ, et al. Reduced need for surgery in severe nasal polyposis with mepolizumab: Randomized trial. J Allergy Clin Immunol 2017;140:1024-31.el4.
466. Bachert C, Han JK, Desrosiers M, et al. Efficacy and safety of dupilumab in patients with severe chronic rhinosinusitis with nasal polyps (LIBERTY NP SINUS-24 and LIBERTY NP SINUS-52): results from two multicentre, randomised, double-blind, placebo-controlled, parallel-group phase 3 trials. Lancet 2019;394:1638-50.
467. Souza-Machado C, Souza-Machado A, Franco R, et al. Rapid reduction in hospitalisations after an intervention to manage severe asthma. Eur Respir J 2010;35:515-21.
468. Franco R, Nascimento HF, Cruz AA, et al. The economic impact of severe asthma to low-income families. Allergy 2009;64:478-83.
469. Bahadori K, Quon BS, Doyle-Waters MM, Marra C, Fitzgerald JM. A systematic review of economic evaluations of therapy in asthma. J Asthma Allergy 2010;3:33-42.
470. Fairall L, Bateman E, Cornick R, et al. Innovating to improve primary care in less developed countries: towards a global model. BMJ Innovations 2015.
471. Patton GC, Viner R. Pubertal transitions in hea^tf. Lancet 2007;369:1130-9.
472. Michaud P-A, Suris JC, Viner R. The adolescent with a chronic condition : epidemiology, developmental issues and health care provision. Geneva: WHO; 2007/<x
473. Carlsen KH, Anderson SD, Bjermer L,^"al. Treatment of exercise-induced asthma, respiratory and allergic disorders in sports and the relationship to doping: Part II of the report from the Joint Task Force of European Respiratory Society (ERS) and European AcademyjajrWlergy and Clinical Immunology (EAACI) in cooperation with GA(2)LEN. Allergy 2008;63:492-505.
474. Gluck JC, Gluck PA. The effect of pregnancy on the course of asthma. Immunol Allergy Clin North Am 2006;26:63-80.
475. Murphy VE, PoweWw Wark PA, Gibson PG. A prospective study of respiratory viral infection in pregnant women with and without asthma. Chest 2013;144:420-7.
476. Lim A, Stewart K, Konig K, George J. Systematic review of the safety of regular preventive asthma medications during pregnancy. Ann Pharmacother 2011;45:931-45.
477. Wendel PJ, Ramin SM, Barnett-Hamm C, Rowe TF, Cunningham FG. Asthma treatment in pregnancy: a randomized controlled study. Am J Obstet Gynecol 1996;175:150-4.
478. Schatz M, Leibman C. Inhaled corticosteroid use and outcomes in pregnancy. Annals of Allergy, Asthma & Immunology 2005;95:234-8.
479. 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.
480. Powell H, Murphy VE, Taylor DR, 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.
481. Morten M, Collison A, Murphy VE, et al. Managing Asthma in Pregnancy (MAP) trial: FENO levels and childhood asthma. J Allergy Clin Immunol 2018;142:1765-72.e4.
References
201
482. 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.
483. 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.
484. 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.
485. AN Z, Nilas L, Ulrik CS. Determinants of low risk of asthma exacerbation during pregnancy. Clin Exp Allergy 2018;48:23-8.
486. Nelson-Piercy C. Asthma in pregnancy. Thorax 2001;56:325-8.
487. 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.
488. 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.
489. Reed CE. Asthma in the elderly: diagnosis and management. J Allergy Clin Immunol 2010;126:681-7.
490. Gibson PG, McDonald VM, Marks GB. Asthma in older adults. Lancet 2010;376:803-13.
491. Slavin RG, Haselkorn T, Lee JH, et al. Asthma in older adults: observations from the epidemiology and natural history of asthma: outcomes and treatment regimens (TENOR) study. Ann Allergy0ST.hma Immunol 2006;96:406-14.
492. Vincken W, Dekhuijzen PR, Barnes P, on behalf of the ADMIT Working-woup. 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.
493. Smetana GW, Lawrence VA, Cornell JE. Preoperative pulmonary risk stratification for noncardiothoracic surgery: systematic review for the American College of Physicians. Ann Intern Med 2006;144:581-95.
494. Woods BD, Sladen RN. Perioperative considerations for the patient with asthma and bronchospasm. Br J Anaesth 2009;103 Suppl l:i57-65.
495. Wakim JH, Sledge KC. Anesthetic implications for paij^nts receiving exogenous corticosteroids. AANA Journal 2006;74:133-9.
496. Stevenson DD. Diagnosis, prevention, and treamient of adverse reactions to aspirin and nonsteroidal antiinflammatory drugs. J Allergy Clin Immunol 1984;^*£l7-22.
497. Szczeklik A, Sanak M, Nizankowska-MoaJfTtcka E, Kielbasa B. Aspirin intolerance and the cyclooxygenase-leukotriene pathways. CurrOpin Pulm Med 2Q04;10:51-6.
498. Mascia K, Haselkorn T, Deniz YM/<&eT. Aspirin sensitivity and severity of asthma: evidence for irreversible airway obstruction in patients with severe or difficult-to-treat asthma. J Allergy Clin Immunol 2005;116:970-5.
499. Morales DR, Guthrie B, LipwmrEn BJ, Jackson C, Donnan PT, Santiago VH. NSAID-exacerbated respiratory disease: a meta-analysis evaluating prevalence, mean provocative dose of aspirin and increased asthma morbidity. Allergy 2015;70:828-35.
500. Rajan JP, Wineinger NE, Stevenson DD, White AA. Prevalence of aspirin-exacerbated respiratory disease among asthmatic patients: A meta-analysis of the literature. J Allergy Clin Immunol 2015;135:676-81.el.
501. Nizankowska E, Bestynska-Krypel A, Cmiel A, Szczeklik A. Oral and bronchial provocation tests with aspirin for diagnosis of aspirin-induced asthma. Eur Respir J 2000;15:863-9.
502. Szczeklik A, Stevenson DD. Aspirin-induced asthma: advances in pathogenesis and management. J Allergy Clin Immunol 1999;104:5-13.
503. 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.
504. 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.
505. 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.
202
References
506. Dahlen SE, Malmstrom K, Nizankowska E, 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.
507. 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.
508. Swierczynska-Krepa M, Sanak M, Bochenek G, 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.
509. Chu DK, Lee DJ, Lee KM, Schunemann HJ, Szczeklik W, Lee JM. Benefits and harms of aspirin desensitization for aspirin-exacerbated respiratory disease: a systematic review and meta-analysis. Int Forum Allergy Rhinol 2019;9:1409-19.
510. Agarwal R, Chakrabarti A, Shah A, et al. Allergic bronchopulmonary aspergillosis: review of literature and proposal of new diagnostic and classification criteria. Clin Exp Allergy 2013;43:850-73.
511. 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.
512. Agarwal R, Dhooria S, Singh Sehgal I, et al. A Randomized Trial of Itraconazole vs Prednisolone in Acute-Stage Allergic Bronchopulmonary Aspergillosis Complicating Asthma. Chest 2018;153:656-64.
513. Voskamp AL, Gillman A, Symons K, et al. Clinical efficacy and immunologic effects of omalizumab in allergic bronchopulmonary aspergillosis. J Allergy Clin Immunol Pract 2015;3:192-9.
514. Hekking PP, Wener RR, Amelink M, Zwinderman AH, Bouvy ML, Bel EH. The prevalence of severe refractory asthma. J Allergy Clin Immunol 2015;135:896-902.
515. Foster JM, McDonald VM, Guo M, Reddel Helen K. "I have lost in every facet of my life": the hidden burden of severe asthma. Eur Respir J 2017;50:1700765.
516. Waljee AK, Rogers MA, Lin P, et al. Short term use of oral corticosteroids and related harms among adults in the United States: population based cohort study. BMJ 2017;357:jl415.
517. Ross KR, Gupta R, DeBoer MD, et al. Severe asthrt^l during childhood and adolescence: A longitudinal study. J Allergy Clin Immunol 2020;145:140-6 e9.
518. O'Neill S, Sweeney J, Patterson CC, et al. The cost of treating severe refractory asthma in the UK: an economic analysis from the British Thoracic Society Difficult Asthma Registry. Thorax 2015;70:376-8.
519. Sadatsafavi M, Lynd L, Marra C, et aktotrect health care costs associated with asthma in British Columbia. Can Respir J 2010;17:74-80.
520. Hashimoto S, Bel EH. Current treatment of severe asthma. Clin Exp Allergy 2012;42:693-705.
521. Hancox RJ, Cowan JO, Flanp&cy EM, Herbison GP, McLachlan CR, Taylor DR. Bronchodilator tolerance and rebound bronchoconstriction during regular inhaled beta-agonist treatment. Respir Med 2000;94:767-71.
522. Paris J, Peterson EL, Wells K, et al. Relationship between recent short-acting beta-agonist use and subsequent asthma exacerbations. Arrnvwlergy Asthma Immunol 2008;101:482-7.
523. Basheti IA, Armour CL, Bosnic-Anticevich SZ, Reddel HK. Evaluation of a novel educational strategy, including inhaler-based reminder labels, to improve asthma inhaler technique Patient Educ Couns 2008;72:26-33.
524. Israel E, Reddel HK. Severe and difficult-to-treat asthma in adults. N Engl J Med 2017;377:965-76.
525. Lugogo NL, Kreindler JL, Martin UJ, Cook B, Hirsch I, Trudo FJ. Blood eosinophil count group shifts and kinetics in severe eosinophilic asthma. Ann Allergy Asthma Immunol 2020;125:171-6.
526. 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.
527. Brusselle GG, Vanderstichele C, Jordens P, et al. Azithromycin for prevention of exacerbations in severe asthma (AZISAST): a multicentre randomised double-blind placebo-controlled trial. Thorax 2013;68:322-9.
528. 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.
529. 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.
References
203
530. Hanania NA, Alpan O, Hamilos DL, et al. Omalizumab in severe allergic asthma inadequately controlled with standard therapy: a randomized trial. Ann Intern Med 2011;154:573-82.
531. Brusselle G, Michils A, Louis R, et al. "Real-life" effectiveness of omalizumab in patients with severe persistent allergic asthma: The PERSIST study. Respir Med 2009;103:1633-42.
532. 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.
533. Hanania NA, Wenzel S, Rosen K, 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.
534. Casale TB, Chipps BE, Rosen K, et al. Response to omalizumab using patient enrichment criteria from trials of novel biologies in asthma. Allergy 2018;73:490-7.
535. Busse WW. Are peripheral blood eosinophil counts a guideline for omalizumab treatment? STELLAIR says no! Eur Respir J 2018;51:1800730.
536. Casale TB, Luskin AT, Busse W, et al. Omalizumab effectiveness by biomarker status in patients with asthma: evidence from PROSPERO, a prospective real-world study. J Allergy Clin Immunol Pract 2019;7:156-64 el.
537. Bel EH, Wenzel SE, Thompson PJ, et al. Oral glucocorticoid-sparing effect of mepolizumab in eosinophilic asthma. N Engl J Med 2014;371:1189-97.
538. Albers FC, Licskai C, Chanez P, et al. Baseline blood eosinophil count as a predictor of treatment response to the licensed dose of mepolizumab in severe eosinophilic asthma. Respir Med 2019;159:105806.
539. Brusselle G, Germinaro M, Weiss S, Zangrilli J. Reslizumab in patients with inadequately controlled late-onset asthma and elevated blood eosinophils. Pulm Pharmacol Ther 2017;43:39-45.
540. FitzGerald JM, Bleecker ER, Menzies-Gow A, et al. Predictors of enhanced response with benralizumab for patients with severe asthma: pooled analysis of the SIROCCO and CALhMA studies. Lancet Respir Med 2018;6:51-64.
541. Bleecker ER, Wechsler ME, FitzGerald JM, et al. Baseline patient factors impact on the clinical efficacy of benralizumab for severe asthma. Eur Respir J 2018;52.
542. Rabe KF, Nair P, Brusselle G, et al. Efficacy and safety of dupilumab in glucocorticoid-dependent severe asthma. N Engl J Med 2018;378:2475-85.
543. Simpson EL, Akinlade B, Ardeleanu M. Two Phase 3 trials of dupilumab versus placebo in atopic dermatitis. N Engl J Med 2017;376:1090-1.
544. Bachert C, Mannent L, Naclerio RM, et al. Effect of subcutaneous dupilumab on nasal polyp burden in patients with chronic sinusitis and nasal polyposis: A^raomized clinical trial. Jama 2016;315:469-79.
545. Chipps BE, Newbold P, Hirsch I, Tfoflo F, Goldman M. Benralizumab efficacy by atopy status and serum immunoglobulin E for patients with severe, uncontrolled asthma. Ann Allergy Asthma Immunol 2018;120:504-11.e4.
546. Hashimoto S, Brinke AT, Roldaan AC, et al. Internet-based tapering of oral corticosteroids in severe asthma: a pragmatic randomised controlled trial. Thorax 2011;66:514-20.
547. Haldar P, Brightling CE, Singapuri A, et al. Outcomes after cessation of mepolizumab therapy in severe eosinophilic asthma: a 12-month follow-up analysis. J Allergy Clin Immunol 2014;133:921-3.
548. Ledford D, Busse W, Trzaskoma B, et al. A randomized multicenter study evaluating Xolair persistence of response after long-term therapy. J Allergy Clin Immunol 2017;140:162-9.e2.
549. Orellano P, Quaranta N, Reynoso J, Balbi B, Vasquez J. Effect of outdoor air pollution on asthma exacerbations in children and adults: Systematic review and multilevel meta-analysis. PLoS One 2017;12:e0174050.
550. 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.
551. Jackson DJ, Johnston SL. The role of viruses in acute exacerbations of asthma. J Allergy Clin Immunol 2010;125:1178-87.
552. Erbas B, Jazayeri M, Lambert KA, 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.
553. Anto JM, Sunyer J, Reed CE, et al. Preventing asthma epidemics due to soybeans by dust-control measures. N Engl J Med 1993;329:1760-3.
204
References
554. Pike KC, Akhbari M, Kneale D, Harris KM. Interventions for autumn exacerbations of asthma in children. Cochrane Database Syst Rev 2018;3:Cd012393.
555. Williams LK, Peterson EL, Wells K, et al. Quantifying the proportion of severe asthma exacerbations attributable to inhaled corticosteroid nonadherence. J Allergy Clin Immunol 2011;128:1185-91.e2.
556. Andrew E, Nehme Z, Bernard S, et al. Stormy weather: a retrospective analysis of demand for emergency medical services during epidemic thunderstorm asthma. BMJ 2017;359:j5636.
557. 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.
558. Chang YL, Ko HK, Lu MS, et al. Independent risk factors for death in patients admitted for asthma exacerbation in Taiwan. NPJ Prim Care Respir Med 2020;30:7.
559. 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.
560. 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.
561. Blaiss MS, Nathan RA, Stoloff SW, Meitzer 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.
562. 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.
563. FitzGerald JM, Grunfeld A. Status asthmaticus. In: Lichtenstein yty/Fauci AS, eds. Current therapy in allergy, immunology, and rheumatology. 5th edition. St. Louis, MO: Mosby; 1996:p. 63-7.
564. Chan-Yeung M, Chang JH, Manfreda J, Ferguson A, Becker A. Changes in peak flow, symptom score, and the use of medications during acute exacerbations of asthma. Am J Re4g)r Crit Care Med 1996;154:889-93.
565. Kew KM, Quinn M, Quon BS, Ducharme FM. Increa&ecFversus stable doses of inhaled corticosteroids for exacerbations of chronic asthma in adults and children. G^jtnrane Database Syst Rev 2016:Cd007524.
566. FitzGerald JM, Becker A, Sears MR, et al. Doubling the dose of budesonide versus maintenance treatment in asthma exacerbations. Thorax 2004;59:550-6.
567. Harrison TW, Oborne J, Newton S, Tatl^reweld AE. Doubling the dose of inhaled corticosteroid to prevent asthma exacerbations: randomised controlled trial, leitet 2004;363:271-5.
568. Reddel HK, Barnes DJ. Pharmacological strategies for self-management of asthma exacerbations. Eur Respir J 2006;28:182-99.
569. Ducharme FM, Lemire C, Noya FJ, et al. Preemptive use of high-dose fluticasone for virus-induced wheezing in young children. N Engl J Med 200^60:339-53.
570. Oborne J, Mortimer K, Hubbard RB, Tattersfield AE, Harrison TW. Quadrupling the dose of inhaled corticosteroid to prevent asthma exacerbations: a randomized, double-blind, placebo-controlled, parallel-group clinical trial. American journal of respiratory and critical care medicine 2009;180:598-602.
571. McKeever T, Mortimer K, Wilson A, et al. Quadrupling inhaled glucocorticoid dose to abort asthma exacerbations. N Engl J Med 2018;378:902-10.
572. Jackson DJ, Bacharier LB, Mauger DT, et al. Quintupling inhaled glucocorticoids to prevent childhood asthma exacerbations. N Engl J Med 2018;378:891-901.
573. Richards RN. Side effects of short-term oral corticosteroids. J Cutan Med Surg 2008;12:77-81.
574. Cates CJ, Welsh EJ, Rowe BH. Holding chambers (spacers) versus nebulisers for beta-agonist treatment of acute asthma. Cochrane Database Syst Rev 2013.
575. Selroos O. Dry-powder inhalers in acute asthma. Therapeutic Delivery 2014;5:69-81.
576. 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.
577. Chien JW, Ciufo R, Novak R, et al. Uncontrolled oxygen administration and respiratory failure in acute asthma. Chest 2000;117:728-33.
References
205
578. Rodrigo GJ, Rodriquez Verde M, Peregalli V, Rodrigo C. Effects of short-term 28% and 100% oxygen on PaC02 and peak expiratory flow rate in acute asthma: a randomized trial. Chest 2003;124:1312-7.
579. Perrin K, Wijesinghe M, Healy B, et al. Randomised controlled trial of high concentration versus titrated oxygen therapy in severe exacerbations of asthma. Thorax 2011;66:937-41.
580. 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.
581. Siemieniuk RAC, Chu DK, Kim LH, et al. Oxygen therapy for acutely ill medical patients: a clinical practice guideline. BMJ 2018;363:k4169.
582. Hasegawa T, Ishihara K, Takakura S, et al. Duration of systemic corticosteroids in the treatment of asthma exacerbation; a randomized study. Intern Med 2000;39:794-7.
583. Jones AM, Munavvar M, Vail A, et al. Prospective, placebo-controlled trial of 5 vs 10 days of oral prednisolone in acute adult asthma. Respir Med 2002;96:950-4.
584. Chang AB, Clark R, Sloots TP, et al. A 5- versus 3-day course of oral corticosteroids for children with asthma exacerbations who are not hospitalised: a randomised controlled trial. Med J Aust 2008;189<^6-10.
585. Normansell R, Sayer B, Waterson S, Dennett EJ, Del Forno M, Dunleavy A. Antibiotics for exacerbations of asthma. Cochrane Database Syst Rev 2018;6:Cd002741.
586. Leatherman J. Mechanical ventilation for severe asthma. Chest 2015; 147:KeC^-80.
587. Shim CS, Williams MH, Jr. Evaluation of the severity of asthma: patients versus physicians. Am J Med 1980;68:11-3.
588. Atta JA, Nunes MP, Fonseca-Guedes CH, et al. Patient and physiciaMfivaluation of the severity of acute asthma exacerbations. Braz J Med Biol Res 2004;37:1321-30.
589. Geelhoed GC, Landau LI, Le Souef PN. Evaluation of Sa02 as^ 'pj'edictor of outcome in 280 children presenting with acute asthma. Ann Emerg Med 1994;23:1236-41.
590. Nowak RM, Tomlanovich MC, Sarkar DD, Kvale PA, Anderson JA. Arterial blood gases and pulmonary function testing in acute bronchial asthma. Predicting patient outcomes. JAMA 1983;249:2043-6.
591. Carruthers DM, Harrison BD. Arterial blood gas analysis or oxygen saturation in the assessment of acute asthma? Thorax 1995;50:186-8.
592. White CS, Cole RP, Lubetsky HW, Austin JH. Acute asthma. Admission chest radiography in hospitalized adult patients. Chest 1991;100:14-6.
593. Roback MG, Dreitlein DA. Chest radiograph in the evaluation of first time wheezing episodes: review of current clinical practice and efficacy. Pediatr Emerg Care 1998;14:181-4.
594. Cates C, FitzGerald JM, O'Byrne PM. Asthma. Clin Evidence 2000;3:686-700.
595. Hui DS, Chow BK, Chu LC, et al. Exhaled air and aerosolized droplet dispersion during application of a jet nebulizer. Chest 2009;135:648-54.
596. Travers AH, Milan SJ,*J8«es 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.
597. Manser R, Reid D, Abramson M. Corticosteroids for acute severe asthma in hospitalised patients. Cochrane Database Syst Rev 2000;2.
598. 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.
599. 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.
600. 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.
601. Ratto D, Alfaro C, Sipsey J, Glovsky MM, Sharma OP. Are intravenous corticosteroids required in status asthmaticus? JAMA 1988;260:527-9.
206
References
602. Harrison BD, Stokes TC, Hart GJ, Vaughan DA, AN 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.
603. 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.
604. Krishnan JA, Riekert KA, McCoy JV, et al. Corticosteroid use after hospital discharge among high-risk adults with asthma. Am J Respir Crit Care Med 2004;170:1281-5.
605. 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.
606. Keeney GE, Gray MP, Morrison AK, et al. Dexamethasone for acute asthma exacerbations in children: a metaanalysis. Pediatrics 2014;133:493-9.
607. 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.
608. Cronin JJ, McCoy S, Kennedy U, et al. A randomized trial of single-dose oral dexamethasone versus multidose prednisolone for acute exacerbations of asthma in children who attend the emergencv£qjEpartment. Ann Emerg Med 2016;67:593-601.e3.
609. O'Driscoll BR, Kalra S, Wilson M, Pickering CA, Carroll KB, Woodcock AA.<Khjble-blind trial of steroid tapering in acute asthma. Lancet 1993;341:324-7.
610. Lederle FA, Pluhar RE, Joseph AM, Niewoehner DE. Tapering of copwsSsteroid therapy following exacerbation of asthma. A randomized, double-blind, placebo-controlled trial. Arch Intern Med 1987;147:2201-3.
611. Kearns N, Maijers I, Harper J, Beasley R, Weatherall M. Inhaled corticosteroids in acute asthma: a systemic review and meta-analysis. J Allergy Clin Immunol Pract 2020;8:60£%# e6.
612. Edmonds ML, Milan SJ, Brenner BE, Camargo CA, Jr., Rowe BH. Inhaled steroids for acute asthma following emergency department discharge. Cochrane Database Syst Rev 2012;12:CD002316.
613. Kirkland SW, Vandenberghe C, Voaklander B, Nikel T, Campbell S, Rowe BH. Combined inhaled beta-agonist and anticholinergic agents for emergency management in^cfults with asthma. Cochrane Database Syst Rev 2017;l:Cd001284.
614. Craig SS, Dalziel SR, Powell CV, Graudins A, Babl FE, Lunny C. Interventions for escalation of therapy for acute exacerbations of asthma in children: an overview of Cochrane Reviews. Cochrane Database Syst Rev 2020;8:CD012977.
615. Rodrigo GJ, Castro-Rodriguez JA.>«mcholinergics in the treatment of children and adults with acute asthma: a systematic review with meta-analysis. Thorax 2005;60:740-6.
616. Nair P, Milan SJ, Rowe BH. Addition of intravenous aminophylline to inhaled beta(2)-agonists in adults with acute asthma. Cochrane Database Sysdfev 2012;12:CD002742.
617. Rowe BH, Bretzlaff JA, Bourdon C, Bota GW, Camargo CA, Jr. Magnesium sulfate for treating exacerbations of acute asthma in the emergency department. Cochrane Database Syst Rev 2000;2.
618. FitzGerald JM. Magnesium sulfate is effective for severe acute asthma treated in the emergency department. West J Med 2000;172:96.
619. 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.
620. 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.
621. Griffiths B, Kew KM. Intravenous magnesium sulfate for treating children with acute asthma in the emergency department. Cochrane Database Syst Rev 2016;4:Cd011050.
622. Knightly R, Milan SJ, Hughes R, et al. Inhaled magnesium sulfate in the treatment of acute asthma. Cochrane Database Syst Rev 2017;ll:Cd003898.
623. 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.
References
207
624. 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.
625. 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.
626. 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.
627. 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.
628. Peters Jl, 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.
629. 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.
630. FitzGerald JM, Macklem P. Fatal asthma. Annu Rev Med 1996;47:161-8.
631. Lim WJ, Mohammed Akram R, Carson KV, et al. Non-invasive positive pressure ventilation for treatment of respiratory failure due to severe acute exacerbations of asthma. Cochrane Database Syst Rev 2012;12:CD004360.
632. Kelly A-M, Kerr D, Powell C. Is severity assessment after one hour of treatmentffsrtter for predicting the need for admission in acute asthma? Respir Med 2004;98:777-81.
633. Wilson MM, Irwin RS, Connolly AE, Linden C, Manno MM. A prospective evaluation of the 1-hour decision point for admission versus discharge in acute asthma. J Intensive Care Med 2003;18:275-85.
634. Grunfeld A, FitzGerald J. Discharge considerations for adult asthmatic patients treated in emergency departments. Can Respir J 1996;3:322 - 7.
635. Pollack CV, Jr., Pollack ES, Baren JM, et al. A prospective multicenter study of patient factors associated with hospital admission from the emergency department among childr£^ with acute asthma. Arch Pediatr Adolesc Med 2002;156:934-40.
636. Rowe BH, Villa-Roel C, Abu-Laban RB, et al. Admissions to Canadian hospitals for acute asthma: a prospective, multicentre study. Can Respir J 2010;17:25-30.
637. Weber EJ, Silverman RA, Callaham ML, et al. A prospective multicenter study of factors associated with hospital admission among adults with acute asthma. Am J Med 2002;113:371-8.
638. Kirkland SW, Vandermeer B, Campbell S, et al. Evaluating the effectiveness of systemic corticosteroids to mitigate relapse in children assessed and tre«teo for acute asthma: A network meta-analysis. J Asthma 2018:1-12.
639. Cowie RL, Revitt SG, Underwood MF, Field SK. The effect of a peak flow-based action plan in the prevention of exacerbations of asthma. Chest 1997;112:1534-8.
640. Ducharme FM, Zemek RL, CrtsHit D, et al. Written action plan in pediatric emergency room improves asthma prescribing, adherence, and control. Am J Respir Crit Care Med 2011;183:195-203.
641. Postma DS, Rabe KF.^Q Asthma-COPD Overlap Syndrome. N Engl J Med 2015;373:1241-9.
642. Global Initiative for Chronic Obstructive Lung Disease (GOLD). Global Strategy for Diagnosis, Management and Prevention of COPD Fontana, Wl, USA 2020.
643. 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.
644. 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:ell47-54.
645. Gershon AS, Campitelli MA, Croxford R, et al. Combination long-acting P-agonists and inhaled corticosteroids compared with long-acting P-agonists alone in older adults with chronic obstructive pulmonary disease. JAMA 2014;312:1114-21.
646. Suissa S, Ernst P. Observational studies of inhaled corticosteroid effective ness in COPD: Lessons learned. Chest 2018;154:257-65.
647. Kendzerska T, Aaron SD, To T, 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.
208
References
648. 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.
649. Lange P, Celli B, Agusti A, et al. Lung-function trajectories leading to chronic obstructive pulmonary disease. N Engl J Med 2015;373:111-22.
650. 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.
651. 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.
652. 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 2000;160:1683-9.
653. Marsh SE, Travers J, Weatherall M, et al. Proportional classifications of COPD phenotypes. Thorax 2008;63:761-7.
654. Shirtcliffe P, Marsh S, Travers J, Weatherall M, Beasley R. Childhood asthma and GOLD-defined chronic obstructive pulmonary disease. Internal medicine journal 2012;42:83-8.
655. Guerra S, Sherrill DL, Kurzius-Spencer M, et al. The course of persistent airflaasnimitation in subjects with and without asthma. Respir Med 2008;102:1473-82.
656. Silva GE, Sherrill DL, Guerra S, Barbee RA. Asthma as a risk factor for COPD in a longitudinal study. Chest 2004;126:59-65.
657. van Schayck CP, Levy ML, Chen JC, Isonaka S, Haibert RJ. Coordinated diagnostic approach for adult obstructive lung disease in primary care. Prim Care Respir J 2004;13:218-21.
658. Zeki AA, Schivo M, Chan A, Albertson TE, Louie S. The asthma-COPD overlap syndrome: a common clinical problem in the elderly. J Allergy 2011;2011:861926.
659. Kendzerska T, Sadatsafavi M, Aaron SD, et al. Concurrent physician-diagnosed asthma and chronic obstructive pulmonary disease: A population study of prevalence, incidence and mortality. PLoS One 2017;12:e0173830.
660. Kauppi P, Kupiainen H, Lindqvist A, et al. Overlap syndrome of asthma and COPD predicts low quality of life. J Asthma 2011;48:279-85.
661. Weatherall M, Travers J, Shirtcliffe PM, et al. Distinct clinical phenotypes of airways disease defined by cluster analysis. Eur Respir J 2009;34:812-8.
662. Inoue H, Nagase T, Morita S, Yoshida A, Jinnai T, Ichinose M. Prevalence and characteristics of asthma-COPD overlap syndrome identified by a stepwise approach. Int J Chron Obstruct Pulmon Dis 2017;12:1803-10.
663. Uchida A, Sakaue K, Inoue H. Epidemiology of asthma-chronic obstructive pulmonary disease overlap (ACO). Allergol Int 2018;67:165-71.
664. Krishnan JA, Nibber A, Chisholm A, et al. Prevalence and characteristics of Asthma-Chronic Obstructive Pulmonary Disease OverlaeVH routine primary care practices. Annals of the American Thoracic Society 2019;16:1143-50.
665. Barrecheguren M, Pinto L, Mostafavi-Pour-Manshadi SM, et al. Identification and definition of asthma-COPD overlap: The CanCOLD study. Respirology 2020;25:836-49.
666. 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.
667. Kew KM, Seniukovich A. Inhaled steroids and risk of pneumonia for chronic obstructive pulmonary disease. Cochrane Database Syst Rev 2014;3:CD010115.
668. Suissa S, Patenaude V, Lapi F, Ernst P. Inhaled corticosteroids in COPD and the risk of serious pneumonia. Thorax 2013;68:1029-36.
669. Louie S, Zeki AA, Schivo M, et al. The asthma-chronic obstructive pulmonary disease overlap syndrome: pharmacotherapeutic considerations. Expert Rev Clin Pharmacol 2013;6:197-219.
670. 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.
671. 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.
References
209
672. Bisgaard H, Szefler S. Prevalence of asthma-like symptoms in young children. Pediatr Pulmonol 2007;42:723-8.
673. 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.
674. 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.
675. Sly PD, Boner AL, Björksten B, et al. Early identification of atopy in the prediction of persistent asthma in children. Lancet 2008;372:1100-6.
676. Heikkinen T, Jarvinen A. The common cold. Lancet 2003;361:51-9.
677. Caudri D, Wijga A, CM AS, et al. Predicting the long-term prognosis of children with symptoms suggestive of asthma at preschool age. J Allergy Clin Immunol 2009;124:903-10 el-7.
678. Brand PL, Baraldi E, Bisgaard H, et al. Definition, assessment and treatment of wheezing disorders in preschool children: an evidence-based approach. Eur Respir J 2008;32:1096-110.
679. Beigrave DCM, Simpson A, Semic-Jusufagic A, et al. Joint modeling of parentally reported and physician-confirmed wheeze identifies children with persistent troublesome wheezing. J Allergy Clin Immunol 2013;132:575-83.el2.
680. Savenije OE, Kerkhof M, Koppelman GH, Postma DS. Predicting who will have asthma at school age among preschool children. J Allergy Clin Immunol 2012;130:325-31.
681. Fitzpatrick AM, Bacharier LB, Guilbert TW, et al. Phenotypes of recurrent wheezing in preschool children: identification by latent class analysis and utility in prediction of future exacerbation. J Allergy Clin Immunol Pract 2019;7:915-24 e7.
682. Doherty G, Bush A. Diagnosing respiratory problems in young children. Practitioner 2007;251:20, 2-5.
683. Pedersen S. Preschool asthma-not so easy to diagnose. Prim Care Respir J 2007;16:4-6.
684. Brand PL, Caudri D, Eber E, et al. Classification and pharmacological treatment of preschool wheezing: changes since 2008. Eur Respir J 2014;43:1172-7.
685. Cano Garcinuno A, Mora Gandarillas I, Group SS. Early patterns of wheezing in asthmatic and nonasthmatic children. Eur Respir J 2013;42:1020-8.
686. Just J, Saint-Pierre P, Gouvis-Echraghi R, et al. Wheeze phenotypes in young children have different courses during the preschool period. Ann Allergy Asthma Immunol 2013;111:256-61.el.
687. Saglani S, McKenzie SA, Bush A, Payne Rfi^A video questionnaire identifies upper airway abnormalities in preschool children with reported wheeze. Arch Dis Child 2005;90:961-4.
688. Mellis C. Respiratory noises: how useful are they clinically? Pediatr Clin North Am 2009;56:1-17, ix.
689. Oren E, Rothers J, Stern DA, Morgan WJ, Halonen M, Wright AL. Cough during infancy and subsequent childhood asthma. Clin Exp Allergy 2015;45:1439-46.
690. Azad MB, Chan-Yeung M, Chan ES, et al. Wheezing patterns in early childhood and the risk of respiratory and allergic disease in adolescenceÜAMA pediatrics 2016;170:393-5.
691. 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.
692. Singer F, Luchsinger I, Inci D, et al. Exhaled nitric oxide in symptomatic children at preschool age predicts later asthma. Allergy 2013;68:531-8.
693. Caudri D, Wijga AH, Hoekstra MO, et al. Prediction of asthma in symptomatic preschool children using exhaled nitric oxide, Rint and specific IgE. Thorax 2010;65:801-7.
694. Castro-Rodrfguez 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.
695. Pescatore AM, Dogaru CM, Duembgen L, et al. A simple asthma prediction tool for preschool children with wheeze or cough. J Allergy Clin Immunol 2014;133:111-8.el-13.
696. Colicino S, Munblit D, Minelli C, Custovic A, Cullinan P. Validation of childhood asthma predictive tools: A systematic review. Clin Exp Allergy 2019;49:410-8.
697. Bacharier LB. The recurrently wheezing preschool child-benign or asthma in the making? Ann Allergy Asthma Immunol 2015;115:463-70.
210
References
698. Murray CS, Poletti G, Kebadze T, et al. 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.
699. Guilbert TW, Morgan WJ, Zeiger RS, et al. Long-term inhaled corticosteroids in preschool children at high risk for asthma. N Engl J Med 2006;354:1985-97.
700. 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.
701. Fitzpatrick AM, Jackson DJ, Mauger DT, et al. Individualized therapy for persistent asthma in young children. J Allergy Clin Immunol 2016;138:1608-18.el2.
702. Kelly HW, Sternberg AL, Lescher R, et al. Effect of inhaled glucocorticoids in childhood on adult height. N Engl J Med 2012;367:904-12.
703. Gadomski AM, Scribani MB. Bronchodilators for bronchiolitis. Cochrane Database Syst Rev 2014;6:CD001266.
704. Bisgaard H, Hermansen MN, Loland L, Halkjaer LB, Buchvald F. Intermittent inhaled corticosteroids in infants with episodic wheezing. N Engl J Med 2006;354:1998-2005.
705. Wilson NM, Silverman M. Treatment of acute, episodic asthma in preschool children using intermittent high dose inhaled steroids at home. Arch Dis Child 1990;65:407-10.
706. Nielsen KG, Bisgaard H. The effect of inhaled budesonide on symptoms, lung function, and cold air and methacholine responsiveness in 2- to 5-year-old asthmatic children. Am J Respir Crit Care Med 2000;162:1500-6.
707. Szefler SJ, Baker JW, Uryniak T, Goldman M, Silkoff PE. Comparative study of budesonide inhalation suspension and montelukast in young children with mild persistent asthma. J Allergy Clin Immunol 2007;120:1043-50.
708. Kaiser SV, Huynh T, Bacharier LB, et al. Preventing exacerbatior^jn preschoolers with recurrent wheeze: a metaanalysis. Pediatrics 2016;137.
709. Knorr B, Franchi LM, Bisgaard H, et al. Montelukast, a leukotriene receptor antagonist, for the treatment of persistent asthma in children aged 2 to 5 years. Pediatrics 2001;108:E48.
710. Brodlie M, Gupta A, Rodriguez-Martinez CE, Castro-Rodriguez JA, Ducharme FM, McKean MC. Leukotriene receptor antagonists as maintenance and intermittent therapy for episodic viral wheeze in children. Cochrane Database Syst Rev2015:Cd008202.
711. Castro-Rodriguez JA, Rodriguez-Martinez CE, Ducharme FM. Daily inhaled corticosteroids or montelukast for preschoolers with asthma or recurrent wheezing: A systematic review. Pediatr Pulmonol 2018;53:1670-7.
712. Papi A, Nicolini G, Baraldi E, et al. Regular vs prn nebulized treatment in wheeze preschool children. Allergy 2009;64:1463-71.
713. Zeiger RS, Mauger D, Bacharier LB, et al. Daily or intermittent budesonide in preschool children with recurrent wheezing. N Engl J Med 2011;365:1990-2001.
714. Yoshihara S, Tsubaki T, Ikeda M, et al. The efficacy and safety of fluticasone/salmeterol compared to fluticasone in children younger than four years of age. Pediatr Allergy Immunol 2019;30:195-203.
715. 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.
716. Wennergren G, Hansson S, Engstrom I, et al. Characteristics and prognosis of hospital-treated obstructive bronchitis in children aged less than two years. Acta Paediatr 1992;81:40-5.
717. Goksor E, Amark M, Aim B, Gustafsson PM, Wennergren G. Asthma symptoms in early childhood-what happens then? Acta Paediatr 2006;95:471-8.
718. 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.
719. 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.
720. Swern AS, Tozzi CA, Knorr B, Bisgaard H. Predicting an asthma exacerbation in children 2 to 5 years of age. Ann Allergy Asthma Immunol 2008;101:626-30.
721. 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.
References
211
722. 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.
723. 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.
724. 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.
725. Vuillermin P, South M, Robertson C. Parent-initiated oral corticosteroid therapy for intermittent wheezing illnesses in children. Cochrane Database Syst Rev 2006:CD005311.
726. Robertson CF, Price D, Henry R, et al. Short-course montelukast for intermittent asthma in children: a randomized controlled trial. Am J Respir Crit Care Med 2007;175:323-9.
727. Bacharier LB, Phillips BR, Zeiger RS, et al. Episodic use of an inhaled corticosteroid or leukotriene receptor antagonist in preschool children with moderate-to-severe intermittent wheezing. J Allergy Clin Immunol 2008;122:1127-35 e8.
728. Gouin S, Robidas I, Gravel J, Guimont C, Chalut D, Amre D. Prospective evaluation of two clinical scores for acute asthma in children 18 months to 7 years of age. Acad Emerg Med 2010;17:598-603.
729. Pollock M, Sinha IP, Hartling L, Rowe BH, Schreiber S, Fernandes RM. Inhaled short-acting bronchodilators for managing emergency childhood asthma: an overview of reviews. Allergy 2017;72:183-200.
730. Powell C, Kolamunnage-Dona R, Lowe J, et al. Magnesium sulphate in acute severe asthma in children (MAGNETIC): a randomised, placebo-controlled trial. Lancet Respir Med 2013;1:301-8.
731. Pruikkonen H, Tapiainen T, Kallio M, et al. Intravenous magnesium sulfate for acute wheezing in young children: a randomised double-blind trial. Eur Respir J 2018;51.
732. Fuglsang G, Pedersen S, Borgstrom L. Dose-response relationships of intravenously administered terbutaline in children with asthma. J Pediatr 1989;114:315-20.
733. Connett G, Lenney W. Prevention of viral induced asthma attacks using inhaled budesonide. Arch Dis Child 1993;68:85-7.
734. Svedmyr J, Nyberg E, Thunqvist P, Asbrink-Nilsson E, Hedlin G. Prophylactic intermittent treatment with inhaled corticosteroids of asthma exacerbations due to airway infections in toddlers. Acta Paediatr 1999;88:42-7.
735. Cai KJ, Su SQ, Wang YG, Zeng YM. Dexamethasone versus prednisone or prednisolone for acute pediatric asthma exacerbations in the emergency department: a meta-analysis. Pediatr Emerg Care 2020.
736. Garrett J, Williams S, Wong C, Holdaway D. Treatment of acute asthmatic exacerbations with an increased dose of inhaled steroid. Arch Dis Child 1998;79:12-7.
737. Rowe BH, Spooner C, Ducharme FM, Bretzlaff JA, Bota GW. Early emergency department treatment of acute asthma with systemic corticosteroietefcochrane Database Syst Rev 2001:CD002178.
738. Panickar J, Lakhanpaul M, Lambert PC, et al. Oral prednisolone for preschool children with acute virus-induced wheezing. N Engl J Med 2009;360:329-38.
739. Webb MS, Henry RL, Milner AD. Oral corticosteroids for wheezing attacks under 18 months. Arch Dis Child 1986;61:15-9.
740. 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.
741. Bunyavanich S, Rifas-Shiman SL, Platts-Mills TA, et al. Peanut, milk, and wheat intake during pregnancy is associated with reduced allergy and asthma in children. J Allergy Clin Immunol 2014;133:1373-82.
742. Maslova E, Granstrom C, Hansen S, et al. 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.
743. Maslova E, Strom M, Oken E, et al. 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.
744. 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.
212
References
745. Best KP, Sullivan T, Palmer D, et al. Prenatal fish oil supplementation and allergy: 6-year follow-up of a randomized controlled trial. Pediatrics 2016;137.
746. Hansen S, Strom M, Maslova E, et al. Fish oil supplementation during pregnancy and allergic respiratory disease in the adult offspring. J Allergy Clin Immunol 2017;139:104-11.e4.
747. Best KP, Sullivan TR, Palmer DJ, et al. 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.
748. Forno E, Young OM, Kumar R, Simhan H, Celedon JC. Maternal obesity in pregnancy, gestational weight gain, and risk of childhood asthma. Pediatrics 2014;134:e535-46.
749. Brozek JL, Bousquet J, Baena-Cagnani CE, et al. Allergic Rhinitis and its Impact on Asthma (ARIA) guidelines: 2010 revision. J Allergy Clin Immunol 2010;126:466-76.
750. Chan-Yeung M, Becker A. Primary prevention of childhood asthma and allergic disorders. Curr Opin Allergy Clin Immunol 2006;6:146-51.
751. Greer FR, Sicherer SH, Burks AW. The effects of early nutritional interventions on the development of atopic disease in infants and children: The role of maternal dietary restriction, breastfeeding, hydrolyzed formulas, and timing of introduction of allergenic complementary foods. Pediatrics 2019;143.
752. Nurmatov U, Devereux G, Sheikh A. Nutrients and foods for the primary prevention of asthma and allergy: systematic review and meta-analysis. J Allergy Clin Immunol 2011;127:724-33^v-30.
753. Chawes BL, Bonnelykke K, Stokholm J, et al. Effect of vitamin D3 supplementation during pregnancy on risk of persistent wheeze in the offspring: a randomized clinical trial. JAMA 2016;315:353-61.
754. Litonjua AA, Carey VJ, Laranjo N, et al. Effect of Prenatal Supplementation With Vitamin D on Asthma or Recurrent Wheezing in Offspring by Age 3 Years: The VDAART Randomized Clinical Trial. JAMA 2016;315:362-70.
755. Wolsk HM, Harshfield BJ, Laranjo N, et al. Vitamin D supplementation in pregnancy, prenatal 25(OH)D levels, race, and subsequent asthma or recurrent wheeze in offspring: Secondary analyses from the Vitamin D Antenatal Asthma Reduction Trial. J Allergy Clin Immunol 2017;140:1423-9.e5.
756. Litonjua AA, Carey VJ, Laranjo N, et al. Six-year follow-up of a trial of antenatal vitamin D for asthma reduction. N Engl J Med 2020;382:525-33.
757. Stratakis N, Roumeliotaki T, Oken E, et al. Fish and seafood consumption during pregnancy and the risk of asthma and allergic rhinitis in childhood: a pooled analysis of 18 European and US birth cohorts. Int J Epidemiol 2017;46:1465-77.
758. Bisgaard H, Stokholm J, Chawes BL, et al. Fish oil-derived fatty acids in pregnancy and wheeze and asthma in offspring. N Engl J Med 2016;375:2530-9.
759. Azad MB, Coneys JG, Kozyrskyj AL, et al. Probiotic supplementation during pregnancy or infancy for the prevention of asthma and wheeze: systematic review and meta-analysis. BMJ 2013;347:f6471.
760. Celedon JC, Milton DK, Ramsey CD, et al. Exposure to dust mite allergen and endotoxin in early life and asthma and atopy in childhood. J Allergy Clin Immunol 2007;120:144-9.
761. Lodge CJ, Lowe AJ, Gurrin LC, et al. House dust mite sensitization in toddlers predicts current wheeze at age 12 years. J Allergy Clin Immunol 2011;128:782-8.e9.
762. 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.
763. Perzanowski MS, Chew GL, Divjan A, 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.
764. 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.
765. 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.
766. Bufford JD, Gern JE. Early exposure to pets: good or bad? Current Allergy & Asthma Reports 2007;7:375-82.
References
213
767. 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.
768. Lodrup Carlsen KC, Roll S, Carlsen KH, 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.
769. 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.
770. 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.
771. Becker A, Watson W, Ferguson A, Dimich-Ward H, Chan-Yeung M. The Canadian asthma primary prevention study: outcomes at 2 years of age. J Allergy Clin Immunol 2004;113:650-6.
772. Schönberger HJAM, Dompeling E, Knottnerus JA, et al. The PREVASC study: the clinical effect of a multifaceted educational intervention to prevent childhood asthma. Eur Respir J 2005;25:660-70.
773. van Schayck OCP, Maas T, Kaper J, Knottnerus AJA, Sheikh A. Is there any role for allergen avoidance in the primary prevention of childhood asthma? J Allergy Clin Immunol 2007;119:1323-8.
774. Chan-Yeung M, Ferguson A, Watson W, et al. The Canadian Childhood Asthma Primary Prevention Study: outcomes at 7 years of age. J Allergy Clin Immunol 2005;116:49-55.
775. Scott M, Roberts G, Kurukulaaratchy RJ, Matthews S, Nove A, Arshad SH. Mjwfaceted allergen avoidance during infancy reduces asthma during childhood with the effect persisting until age 18 years. Thorax 2012;67:1046-51.
776. Valovirta E, Petersen TH, Piotrowska T, et al. Results from the 5-year SCsgrass sublingual immunotherapy tablet asthma prevention (GAP) trial in children with grass pollen allergy. J Allergy Clin Immunol 2018;141:529-38.el3.
777. Wongtrakool C, Wang N, Hyde DM, Roman J, Spindel ER. Prenatal nicotine exposure alters lung function and airway geometry through 7 nicotinic receptors. Am J Respir Cell Mol Biol 2012;46:695-702.
778. Burke H, Leonardi-Bee J, Hashim A, et al. Prenatal and passive smoke exposure and incidence of asthma and wheeze: systematic review and meta-analysis. Pediatrics 2012;129:735-44.
779. Bowatte G, Lodge C, Lowe AI, et al. The influence of childhood traffic-related air pollution exposure on asthma, allergy and sensitization: a systematic review and a meta-analysis of birth cohort studies. Allergy 2015;70:245-56.
780. Khreis H, Kelly C, Tate J, Parslow R, Lucas K, WgXwenhuijsen 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.
781. Achakulwisut P, Brauer M, Hystad P, Anenberg SC. Global, national, and urban burdens of paediatric asthma incidence attributable to ambient N02 pollution: estimates from global datasets. Lancet Planet Health 2019;3:el66-e78.
782. Hehua Z, Qing C, Shanyan G, Qijiuqw, Yuhong Z. The impact of prenatal exposure to air pollution on childhood wheezing and asthma: A systematic review. Environ Res 2017;159:519-30.
783. Haahtela T, Holgate S, Pawankar R, et al. The biodiversity hypothesis and allergic disease: world allergy organization position statement. World Allergy Org J 2013;6:3.
784. Riedler J, Braun-Fahrlander C, Eder W, et al. Exposure to farming in early life and development of asthma and allergy: a cross-sectional survey. Lancet 2001;358:1129-33.
785. Braun-Fahrlander C, Riedler J, Herz U, et al. Environmental exposure to endotoxin and its relation to asthma in school-age children. N Engl J Med 2002;347:869-77.
786. Karvonen AM, Hyvarinen A, Gehring U, 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.
787. 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.
788. 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:el002494.
789. Azad MB, Konya T, Maughan H, et al. Gut microbiota of healthy Canadian infants: profiles by mode of delivery and infant diet at 4 months. CMAJ 2013;185:385-94.
790. Blanken MO, Rovers MM, Molenaar JM, et al. Respiratory syncytial virus and recurrent wheeze in healthy preterm infants. N Engl J Med 2013;368:1791-9.
214
References
791. Scheltema NM, Nibbelke EE, Pouw J, et al. Respiratory syncytial virus prevention and asthma in healthy preterm infants: a randomised controlled trial. Lancet Respir Med 2018;6:257-64.
792. Marra F, Marra CA, Richardson K, et al. Antibiotic use in children is associated with increased risk of asthma. Pediatrics 2009;123:1003-10.
793. Stensballe LG, Simonsen J, Jensen SM, Bonnelykke K, Bisgaard H. Use of antibiotics during pregnancy increases the risk of asthma in early childhood. J Pediatr 2013;162:832-8.e3.
794. 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.
795. Cheelo M, Lodge CJ, Dharmage SC, et al. Paracetamol exposure in pregnancy and early childhood and development of childhood asthma: a systematic review and meta-analysis. Arch Dis Child 2015;100:81-9.
796. Eyers S, Weatherall M, Jefferies S, Beasley R. Paracetamol in pregnancy and the risk of wheezing in offspring: a systematic review and meta-analysis. Clin Exp Allergy 2011;41:482-9.
797. Flanigan C, Sheikh A, DunnGalvin A, Brew BK, Almqvist C, Nwaru Bl. Prenatal maternal psychosocial stress and offspring's asthma and allergic disease: A systematic review and meta-analysis. Clin Exp AJfepgy 2018;48:403-14.
798. Kozyrskyj AL, Mai XM, McGrath P, Hayglass KT, Becker AB, Macneil B. Continued exposure to maternal distress in early life is associated with an increased risk of childhood asthma. Am J Respir Crit Care Med 2008;177:142-7.
799. Xu S, Gilliland FD, Conti DV. Elucidation of causal direction between asthcapand obesity: a bi-directional Mendelian randomization study. Int J Epidemiol 2019.
800. Sun YQ, Brumpton BM, Langhammer A, Chen Y, Kvaloy K, Mai XM. Adiposity and asthma in adults: a bidirectional Mendelian randomisation analysis of The HUNT Study. Thorax 2020;75:202-8.
801. Beasley R, Semprini A, Mitchell EA. Risk factors for asthma: is prevention possible? Lancet 2015;386:1075-85.
802. Burgers J, Eccles M. Clinical guidelines as a tool for implementing change in patient care. Oxford: Butterworth-Heinemann; 2005.
803. Woolf SH, Grol R, Hutchinson A, Eccles M, GrimshaJAuTclinical guidelines: potential benefits, limitations, and harms of clinical guidelines. BMJ 1999;318:527-30.
804. ADAPTE Framework. Available from http://www.adapte.org. 2012.
805. Brouwers MC, Kho ME, Browman GP, et aK^GREE II: advancing guideline development, reporting and evaluation in health care. CMAJ 2010;182:E839-42.
806. Boulet LP, FitzGerald JM, Levy ML, et al. A guide to the translation of the Global Initiative for Asthma (GINA) strategy into improved care. Eur Respir J2012;39:1220-9.
807. Davis DA, Taylor-Vaisey A. Translating guidelines into practice. A systematic review of theoretic concepts, practical experience and research e^joence in the adoption of clinical practice guidelines. CMAJ 1997;157:408-16.
808. 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.
809. Partridge MR. Translating research into practice: how are guidelines implemented? Eur Respir J Suppl 2003;39:23s-9s.
810. 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.
811. Boulet LP, Becker A, Bowie D, 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.
812. Franco R, Santos AC, do Nascimento HF, et al. Cost-effectiveness analysis of a state funded programme for control of severe asthma. BMC Public Health 2007;7:82.
813. 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.
814. Nkoy F, Fassl B, Stone B, et al. Improving pediatric asthma care and outcomes across multiple hospitals. Pediatrics 2015;136:el602-10.
815. Cochrane Effective Practice and Organisation of Care Group (EPOC). Available at http://epoc.cochrane.org. 2013.
References
215
Visit the GINA website at www.ginasthma.org © 2021 Global Initiative for Asthma