COPDX Plan 2023

The COPD-X Plan:
Australian and New Zealand Guidelines

for the management of
Chronic Obstructive Pulmonary Disease
2023
Current COPD Guidelines Committee
Professor Ian Yang, MBBS(Hons), PhD, FRACP, Grad Dip Clin Epid, FAPSR, FThorSoc, FERS
Thoracic Physician, The Prince Charles Hospital and The University of Queensland, Brisbane, QLD (Co-Chair)
Associate Professor Eli Dabscheck, MBBS, M Clin Epi, FRACP, Staff Specialist, Department of
Respiratory Medicine, The Alfred Hospital, Melbourne, VIC (Co-Chair)
Associate Professor Johnson George, BPharm, MPharm, PhD, Grad Cert Higher Education,
Associate Professor, Faculty of Pharmacy and Pharmaceutical Sciences, Monash University, Melbourne, VIC
Dr Renae McNamara, BAppSc(Phty), PhD, Clinical Specialist Physiotherapist, Prince of Wales Hospital,
Sydney, NSW and Clinical Research Fellow, The University of Sydney and Woolcock Institute of Medical
Research
Professor Christine McDonald, AM, FAHMS, MBBS(Hons), PhD, FRACP, FThorSoc, Director,
Department of Respiratory and Sleep Medicine, The Austin Hospital, Melbourne, VIC
Professor Vanessa McDonald DipHlthScien (Nurs), BNurs, PhD, FThorSoc, Professor of Chronic
Disease and Academic Clinical Nurse Consultant, The University of Newcastle and John Hunter Hospital,
Newcastle, NSW
Professor Brian Smith, MBBS, Dip Clin Ep & Biostats, PhD, FRACP, Staff Specialist, Bendigo Hospital
VIC
Professor Nick Zwar, MBBS, MPH, PhD, FRACGP, Executive Dean, Faculty of Health Sciences and
Medicine, Bond University QLD
Lung Foundation Australia Staff

Ms Alicia Goodwin, BPH, Senior Program Manager – COPD, Lung Foundation Australia, Sydney
Ms Robyn Ordman, MRes, BA(Psych), COPD-X Guidelines Manager, Lung Foundation Australia, Sydney
Ms Kelcie Herrmann BSpPath General Manager Clinical Programs Research and Innovation, Lung
Foundation Australia, Melbourne
Literature Searches: Literature search strategy provided by Megan Neumann, Client Services Librarian
at The Prince Charles Hospital, Brisbane undertaken by the Lung Foundation Australia Guidelines
Coordinator. Search strategy reviewed in May 2023 by Jana Waldmann, Acting Manager, Library Services
at The Prince Charles Hospital, Brisbane.
These guidelines have been developed and revised by Lung Foundation Australia and the Thoracic Society
of Australia and New Zealand as part of a national COPD program.
Correspondence: Lung Foundation Australia, PO Box 1949, Milton QLD 4064 copdx@lungfoundation.com.au
The COPD-X Plan – Version 2 71 (July 2023)
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Past Committee Members
Past Chairpersons
Professor Michael Abramson, MBBS, BMedSc(Hons), PhD, FRACP, FAFPHM, Deputy Head, School of
Public Health and Preventive Medicine, Monash University, Melbourne, VIC (Principal Author) (Chair: 2004-
2014)
Professor Alan J Crockett, PSM, MPH, PhD, FANZSRS Professor of Clinical Respiratory Physiology,
Division of Health Sciences, University of South Australia; Emeritus Fellow, Discipline of General Practice,
School of Population Health, University of Adelaide, Adelaide, SA (Chair: 2003-2004)
Past Committee Members

Professor Michael Abramson, MBBS, BMedSc(Hons), PhD, FRACP, FAFPHM, Deputy Head, School of
Public Health and Preventive Medicine, Monash University, Melbourne, VIC (Principal Author) (Chair: 2004-
2014)
Professor Alan J Crockett, PSM, MPH, PhD, FANZSRS Professor of Clinical Respiratory Physiology,
Division of Health Sciences, University of South Australia; Emeritus Fellow, Discipline of General Practice,
School of Population Health, University of Adelaide, Adelaide, SA (Chair: 2003-2004)
Associate Professor David K McKenzie, PhD, FRACP, Director of Cardiac and Respiratory Services,
South East Sydney Local Health District and Head of Department, Respiratory and Sleep Medicine, Prince of
Wales Hospital, Randwick, NSW (Principal author)
Professor Peter A Frith, MBBS, FRACP, Professor in Respiratory Medicine, Flinders University and
Repatriation General Hospital, Daw Park, SA
Professor Norbert Berend, MD, FRACP, Director, Woolcock Institute of Medical Research, Royal Prince
Alfred Hospital, Sydney, NSW
Ms Jenny Bergin, BPharm, MPS, Pharmacist Consultant, Pharmacy Guild of Australia
Dr Jonathan G W Burdon, MD, FRACP, Respiratory Physician, Department of Respiratory Medicine, St
Vincent’s Hospital, Melbourne, VIC
Associate Professor Stephen Cala, PhD, FRACP, Respiratory Physician, and Head, Respiratory
Investigation Unit, Gosford Hospital and University of Newcastle, NSW
Professor Peter Gibson, MBBS, FRACP, Respiratory Specialist, John Hunter Hospital, Newcastle, NSW
Professor Nicholas Glasgow, MBChB, MD, FRNZGP, FRACGP, FAChPM, Dean, Medicine and Health
Sciences, College of Medicine, Biology and Environment, the Australian National University, Canberra, ACT
Professor Christine Jenkins, AM, MD, FRACP, Thoracic Physician, Concord Hospital, Sydney, NSW
Mr Ross Lisle, Consumer Representative, Toowoomba, QLD
Professor Guy Marks, Australian Centre for Asthma Management, Sydney, NSW
Dr Jitendra Parikh, MD, MPM, Royal Australian College of General Practitioners
Professor Harold H Rea, MD, FRACP, Academic Head of Medicine, South Auckland Clinical School,
University of Auckland, New Zealand
Mrs Marilyn Robinson, RN, Respiratory/Asthma Educator, Townsville Community Health Service,
Townsville Health Services District, QLD
Professor Julian A Smith, MS, FRACS, Professor, and Head, Department of Surgery, Monash University,
and Head, Cardiothoracic Surgery Unit, Monash Medical Centre, Clayton, VIC
Associate Professor Greg. Snell, MBBS, FRACP, Respiratory and Lung Transplant Physician, Department
of Respiratory Medicine, Alfred Hospital, Melbourne, VIC
Associate Professor Robin D Taylor, MD, FRCPC, Department of Respiratory Medicine, Dunedin School
of Medicine, University of Otago, Dunedin, NZ
Professor G Ian Town, DM, FRACP, Dean, Christchurch School of Medicine and Health Sciences, New
Zealand
Mr Marcus Weidinger, Pharmaceutical Society of Australia
Dr Richard Wood-Baker, MBBS, DM, FRACGP, FRCP, MRCP[I], MEd, Director of Cardiorespiratory
Medicine, Royal Hobart Hospital; Honorary Fellow, Menzies Research Institute, Hobart, TAS
Associate Professor Sue Jenkins, OAM, GradDipPhys, PhD, Physiotherapy Department, Sir
Charles Gairdner Hospital; School of Physiotherapy and Exercise Science, Curtin University; Institute
for Respiratory Health, Perth, WA
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Other contributors - Past and Present
Associate Professor Jenny Alison, Physiotherapist
Dr Guy Bannink, Staff Specialist Palliative Medicine
Ms Kate Baumwol, Senior Speech Pathologist
Mr Paul Cafarella, Psychologist
Associate Professor Donald Campbell, Respiratory Physician
Ms Nola Cecins, Physiotherapist
Dr Belinda Cochrane, Staff Specialist Respiratory and Sleep Physician
Dr Karen Detering, Respiratory Physician
Dr Tanja Effing, Respiratory Scientist/ Epidemiologist
Dr Michael Epton, Respiratory Physician
Dr Nichola Gale, Senior Lecturer: Physiotherapy/ Researcher
Professor Charles Gilks, International Public Health Specialist
Dr David Hart, Respiratory Physician
Associate Professor Peter Holmes, Respiratory Physician
Associate Professor Kylie Hill, Physiotherapist
Dr Alice YM Jones, Physiotherapist; Honorary Professor; Adjunct Professor
Ms Kim Jones, Research Assistant
Dr Kirk Kee, Respiratory Physician
Dr Jun (JK) Khoo, Specialist Respiratory and Sleep Disorders Physician
Ms Leona Knapman, Exercise Physiologist
Associate Professor John Kolbe, Respiratory Physician
Ms Zoe Kopsaftis, Research Officer
Dr Tom Kotsimbos, Respiratory Physician
Dr Nicole Livermore, Senior Clinical Psychologist
Ms Maria Loder, Respiratory Nurse
Dr James Markos, Respiratory Physician
Dr R Doug McEvoy, Respiratory and Sleep Physician
Dr Ruth McKenzie, General Practitioner
Associate Professor Lucy Morgan, Respiratory Physician
Dr Shirley PC Ngai, Physiotherapist; Assistant Professor
Dr Cristino C Oliveira, Physiotherapist
Dr Matthew Peters, Respiratory Physician
Professor Philippa Poole, Senior Lecturer
Professor Robert Pierce, Respiratory Physician (deceased)
Associate Professor Robyn Richmond, Researcher
Dr Jonathan Rutland, Respiratory Physician
Professor Paul Seale, Respiratory Physician
Associate Professor Natasha Smallwood, Respiratory Physician
Ms Laura Smith, PhD Student
Ms Sheree Smith, Respiratory Nurse
Professor Greg Snell, Lung Transplant Physician
Ms Gillian Syres, Research Fellow
Mr Pieter Walker, Psychologist
Conjoint Professor Peter Wark, Senior Staff Specialist
Professor Trevor Williams, Respiratory & Sleep Medicine Physician
Mr Jamie Wood, Senior Physiotherapist – Cystic Fibrosis
Prof Lisa Wood, Nutritional Biochemist
Associate Professor Iven Young, Respiratory Physician
Ms Juliet L Brown, BA(Hons), MLib, Former COPD Project and Guidelines Manager, Lung Foundation
Australia, Brisbane
Ms Mearon O’Brien, BPubH, Former Guidelines Manager, Lung Foundation Australia, Brisbane; Honorary
Adjunct Fellow, The University of Queensland, Brisbane
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Table of Contents
Current COPD Guidelines Committee ......................................................................................... 1
Lung Foundation Australia Staff ................................................................................................ 1
Past Committee Members ........................................................................................................ 2
Past Chairpersons ................................................................................................................ 2
Past Committee Members ..................................................................................................... 2
Other contributors - Past and Present ..................................................................................... 3
Table of Contents ................................................................................................................... 4
Foreword .............................................................................................................................. 8
The origins of the COPD-X guidelines..................................................................................... 10
COPD-X Methodology .......................................................................................................... 11
Levels of evidence ................................................................................................................. 12
Key Recommendations of the COPD-X Guidelines ....................................................................... 13
C: Case finding and confirm diagnosis ...................................................................................... 17
C1. Aetiology and natural history .......................................................................................... 19

C1.1 Natural history ......................................................................................................... 23
C2. Diagnosis..................................................................................................................... 24
C2.1 History ................................................................................................................... 24
C2.2 Physical examination ................................................................................................ 25
C2.3 Spirometry .............................................................................................................. 26
C2.4 Flow volume tests .................................................................................................... 28
C2.5 COPD case finding .................................................................................................... 28
C3. Assessing the severity of COPD ....................................................................................... 30
C4. Assessing acute response to bronchodilators ..................................................................... 31

C4.1 Confirm or exclude asthma ........................................................................................ 32
C5. Specialist referral .......................................................................................................... 32

C5.1 Complex lung function tests ....................................................................................... 33
C5.2 Exercise testing........................................................................................................ 33
C5.3 Sleep studies ........................................................................................................... 33
C5.4 Chest x-rays ............................................................................................................ 34
C5.5 High resolution computed tomography ........................................................................ 34
C5.6 Ventilation and perfusion scans .................................................................................. 34
C5.7 Transcutaneous oxygen saturation .............................................................................. 34
C5.8 Arterial blood gas measurement ................................................................................. 34
C5.9 Sputum examination ................................................................................................. 34
C5.10 Haematology and biochemistry ................................................................................. 35
C5.11 Electrocardiography and echocardiography ................................................................. 35
C5.12 Trials of Therapy .................................................................................................... 36
O: Optimise function.............................................................................................................. 37
O1. Inhaled bronchodilators ................................................................................................. 38
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O1.1 Short-acting bronchodilators ...................................................................................... 38
O1.2 Long-acting bronchodilators ....................................................................................... 39
O1.3 Assessment of response and continuation of bronchodilator therapy ................................ 44
O2. Oral bronchodilators ...................................................................................................... 44

O2.1 Methylxanthines ....................................................................................................... 44
O2.2 Phosphodiesterase type-4 inhibitors ............................................................................ 44
O3. Corticosteroids ............................................................................................................. 45

O3.1 Oral corticosteroids .................................................................................................. 45
O3.2 Inhaled corticosteroids (ICS) ..................................................................................... 45
O3.3 Inhaled corticosteroids (ICS) versus long-acting beta2-agonists (LABA) ............................ 47
O4. Combination therapies and biologic therapies ................................................................... 47

O4.1 Inhaled corticosteroids and long-acting beta2-agonists in combination (ICS/LABA) ............. 47
O4.2 Inhaled corticosteroids and long-acting beta2-agonists and long-acting antimuscarinics in
combination (ICS/LABA/LAMA) .......................................................................................... 50
O4.3 Biologic therapies ..................................................................................................... 56
O5. Inhaler technique and adherence .................................................................................... 57

O5.1 Inhaler technique ..................................................................................................... 57
O5.2 Inhaler adherence .................................................................................................... 60
O6. Non-pharmacological interventions .................................................................................. 60

O6.1 Pulmonary rehabilitation ........................................................................................... 61
O6.2 Exercise training ...................................................................................................... 65
O6.3 Inspiratory Muscle Training ........................................................................................ 66
O6.4 Neuromuscular electrical stimulation ........................................................................... 66
O6.5 Physical activity and sedentary behaviour .................................................................... 67
O6.6 Education and self-management................................................................................. 68
O6.7 Breathing exercises .................................................................................................. 69
O6.8 Chest physiotherapy (Airway clearance techniques) ...................................................... 70
O6.9 Smoking cessation ................................................................................................... 71
O6.10 Nutrition ............................................................................................................... 71
O6.11 Complementary therapies ........................................................................................ 75
O7. Comorbidities ............................................................................................................... 75

O7.1 Increased risks from comorbidities in the presence of COPD ........................................... 76
O7.2 Cardiac disease ........................................................................................................ 76
O7.3 Osteoporosis ........................................................................................................... 82
O7.4 Frailty in COPD ........................................................................................................ 82
O7.5 Falls in COPD ........................................................................................................... 84
O7.6 Sleep-related breathing disorders ............................................................................... 85
O7.7 Aspiration ............................................................................................................... 85
O7.8 Gastro-oesophageal reflux disease (GORD) .................................................................. 86
O7.9 Lung cancer ............................................................................................................ 87
O7.10 Bronchiectasis ........................................................................................................ 88
O7.11 Combined pulmonary fibrosis and eEmphysema .......................................................... 88
O7.12 Alcohol and sedatives .............................................................................................. 88
O7.13 Testosterone deficiencies and supplementation ........................................................... 89
O7.14 Cognitive impairment .............................................................................................. 89
O7.15 Anaemia ............................................................................................................... 89
O8. Hypoxaemia and pulmonary hypertension ........................................................................ 91

O8.1 Treatment of hypoxaemia and pulmonary hypertension ................................................. 92
O9. Surgery ....................................................................................................................... 93

O9.1 Bullectomy .............................................................................................................. 93
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O9.2 Lung volume reduction surgery and bronchoscopic interventions ..................................... 93
O9.3 Lung Transplantation ................................................................................................ 94
O9.4 Pre-operative work-up for surgery .............................................................................. 95
O10. Palliative and supportive care ....................................................................................... 96
P: Prevent deterioration ....................................................................................................... 101
P1. Risk factor reduction .................................................................................................... 101

P1.1 Smoking cessation .................................................................................................. 101
P1.2 Treatment of nicotine dependence............................................................................. 102
P1.3 Prevent smoking relapse .......................................................................................... 107
P2. Immunisations ............................................................................................................ 107

P2.1 Influenza immunisation ........................................................................................... 108
P2.2 Pneumococcal immunisation ..................................................................................... 108
P2.3 Haemophilus influenzae immunisation ....................................................................... 108
P3. Immunomodulatory agents ........................................................................................... 110
P4. Macrolides.................................................................................................................. 110
P5. Long-acting bronchodilators .......................................................................................... 110

P5.1 Antimuscarinics ...................................................................................................... 110
P5.2 Comparison of inhaled medications ........................................................................... 111
P6. Corticosteroids............................................................................................................ 111
P7. Mucolytic agents ......................................................................................................... 111
P8. Humidification and nasal high flow (NHF) therapy ............................................................ 113
P9. Regular review ........................................................................................................... 113
P10. Oxygen therapy ........................................................................................................... 114

P10.1 Fitness to fly ........................................................................................................ 117
P11 Long-term home non-invasive ventilation ...................................................................... 117
P12 Alpha1-antitrypsin deficiency ....................................................................................... 118
D: Develop a plan of care ..................................................................................................... 119
D1. Support team ............................................................................................................... 119

D1.1 General Practitioner ................................................................................................ 120
D1.2 Other specialist physicians ....................................................................................... 121
D1.3 GP practice nurse/ nurse practitioner/ respiratory educator/ respiratory nurse ................ 121
D1.4 Physiotherapist ...................................................................................................... 122
D1.5 Occupational therapist ............................................................................................ 122
D1.6 Social worker......................................................................................................... 122
D1.7 Clinical psychologist/psychiatrist .............................................................................. 122
D1.8 Speech pathologist/therapist.................................................................................... 123
D1.9 Pharmacist ............................................................................................................ 123
D1.10 Dietitian/Nutritionist ............................................................................................. 124
D1.11 Exercise physiologist ............................................................................................. 124
D1.12 Non-medical care agencies .................................................................................... 124
D2. Multidisciplinary care plans........................................................................................... 124
D3. Chronic Disease Self-management ................................................................................ 126

D3.1 Maintenance therapy .............................................................................................. 131
D3.2 Exacerbation prevention .......................................................................................... 131
D4. Telehealth ................................................................................................................. 132
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D5. Treat anxiety and depression........................................................................................ 134
D6. Referral to a support group .......................................................................................... 136
X: Manage eXacerbations ..................................................................................................... 136
X1. Home management ..................................................................................................... 143
X2. COPD exacerbation management .................................................................................. 143

X2.1 Confirm exacerbation and categorise severity ............................................................. 143
X2.2 Optimise treatment................................................................................................. 144
X3. Refer appropriately to prevent further deterioration (‘P’) ................................................... 149

X3.1 Controlled oxygen delivery ....................................................................................... 149
X3.2 Non-invasive ventilation .......................................................................................... 150
X3.3 Invasive ventilation (intubation) ............................................................................... 152
X3.4 Clearance of secretions ........................................................................................... 152
X3.5 Develop post-discharge plan and follow-up................................................................. 153
X3.6 Pulmonary rehabilitation .......................................................................................... 154
X3.7 Discharge planning ................................................................................................. 155
X3.8 Support after discharge ........................................................................................... 158
X3.9 Clinical review and follow-up .................................................................................... 158
X4. Uptake and impact of guidelines for exacerbations ........................................................... 159
Appendices ........................................................................................................................ 160

Appendix 1. Use and doses of long-term inhaled bronchodilator and corticosteroids determined in
response trials .............................................................................................................. 160
Appendix 2. Explanation of inhaler devices ........................................................................ 161
Appendix 3. Long term oxygen therapy (McDonald 2016a) .................................................. 164
Appendix 4. Strategies that may assist in reminding people to reduce sedentary time ............. 166
Appendix 5. Table of Minimum Clinically Important Differences (MCID) for COPD (Cazzola 2015b)
................................................................................................................................... 167
Appendix 6: Table of Systematic Reviews Evaluating the Effect of Self Management in COPD .... 169
List of Figures ..................................................................................................................... 173
List of Boxes....................................................................................................................... 173
Glossary of Terms ............................................................................................................... 174
References A-G ................................................................................................................... 176
References H-R ................................................................................................................... 201
References S-Z ................................................................................................................... 225
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Foreword
Chronic Obstructive Pulmonary Disease (COPD) places an enormous burden on people living with this
lung condition and on the Australian healthcare system. The prevalence of COPD in Australians over
the age of 40 is estimated to be 7.5% (Toelle 2013). COPD was the 5th leading cause of death in
Australia in 2017 (AIHW 2021). In 2015–16, COPD cost the Australian health system an estimated
$977 million (AIHW 2020). The Australian Institute of Health and Welfare estimates that COPD is the
foremost cause of preventable hospitalisations amongst chronic health conditions (AIHW 2019).
Furthermore, COPD was the third leading specific cause of total disease burden in Australia in 2015
(AIHW & NIAA 2020).
There is a great deal of work to be done to better understand the prevalence and outcomes of COPD
in First Nations people. The prevalence of COPD among First Nations people is estimated to be 2.3
times as high as in non-Indigenous Australians (AIHW 2020). The mortality rate of COPD among First
Nations people was 2.7 times as high as the non-Indigenous Australians rate (AIHW 2020). The
ultimate aim of these guidelines is to improve health outcomes for all Australians with COPD by
translating the latest evidence-based recommendations into everyday clinical practice.
In 2001 a multidisciplinary steering committee was convened by the Thoracic Society of Australia and
New Zealand (TSANZ) and Lung Foundation Australia (LFA) to write guidelines for the management of
COPD, specific for the Australasian context. The guidelines were launched as ‘COPD-X’ and first
published as a supplement to The Medical Journal of Australia in 2003. The guidelines strive to provide
clear recommendations relevant for Australian healthcare workers, accompanied by a discussion of
the evidence.
COPD-X provides guidance for Case finding and confirming diagnosis, Optimising function, Prevention
of deterioration, Development of care plans and management of eXacerbations. COPD-X highlights
the critical role of reducing risk factors (particularly through smoking avoidance and cessation),
optimising function with multidisciplinary care, improving treatment of comorbidities and referring
symptomatic patients to pulmonary rehabilitation. The guidelines promote the concept of ‘stepwise
management’; beginning with one pharmacological intervention and evaluating response before
adding another agent. The guidelines also emphasise the importance of non-pharmacological therapy
for COPD. The recommendations made in the guidelines are applicable across multiple care settings.
The guidelines recognise that a patient-centred approach involving a team of healthcare workers is
required for optimal outcomes.
The COPD-X Guidelines Committee is a multidisciplinary group of clinicians convened by LFA, that
meets quarterly to review the current COPD literature and update the guidelines. With such frequent
updates and literature reviews, COPD-X should be seen as an early example of ‘Living Guidelines’.
This approach allows the guidelines to constantly evolve in order to meet the needs of people with
COPD.
All changes and updates to the guidelines are made by consensus and quarterly digital updates are
published online. TSANZ endorses the quarterly updates and the Guidelines have received
endorsement from The Royal Australian College of General Practitioners. Across the entire spectrum
of COPD care, the Guidelines aim to provide a detailed discussion of the evidence followed by a
summary of recommendations. The Guidelines are freely accessible via the LFA website in an easily
searchable web-based format and offered as a pdf.
To accompany the comprehensive Guidelines, LFA has launched a complementary suite of resources
to assist Australian health care practitioners caring for individuals with COPD. In 2014, the ‘COPD-X
Concise Guide for Primary Care’ was published with the aim of providing a practical point-of-care guide
for primary care physicians. In 2020, this was relaunched as the ‘Concise Guide’ acknowledging that
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the guidelines provide a wide range of clinicians with succinct, evidence-based recommendations.
‘Stepwise Management of COPD’ is a graphical, single page summary of the pharmacological and
non-pharmacological therapies across the severity continuum of COPD that encapsulates the
management principles outlined in COPD-X.
Our greatest challenge lies in guideline implementation. Our key goal is to translate the evidence-
based recommendations in COPD-X into everyday practice across Australia. For this knowledge
translation to occur, a multi-faceted approach across platforms will be required. Strategies will need
to include digital integration, such as software for clinical decision support systems and prompts in
electronic health records that aid with management decisions accompanied by professional education
delivered by traditional and innovative techniques. Dimensions of impact of uptake of the guidelines
should be measured, to enhance reach and impact of key recommendations, and maintenance of
knowledge translation.
It is our hope that these Guidelines will advance clinical practice and standardise COPD care. The
ultimate aim of these Guidelines is to improve health outcomes and optimise quality of life for people
with COPD.
Professor Ian Yang and Associate Professor Eli Dabscheck

Co-Chairs, COPD Guidelines Committee
June 2021
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The origins of the COPD-X guidelines
THESE GUIDELINES are the outcome of a joint project of the Thoracic Society of Australia and New Zealand
and Lung Foundation Australia. The guidelines aim to:
● effect changes in clinical practice based on sound evidence; and

● shift the emphasis from a predominant reliance on pharmacological treatment of COPD to a
range of interventions which include patient education, self-management of exacerbations and
pulmonary rehabilitation.
These guidelines deal mainly with the management of established disease and exacerbations.
However, this is only one element of the COPD Strategy of Lung Foundation Australia, which has the
long-term goals of:
● primary prevention of smoking;

● improving rates of smoking cessation;
● early detection of airflow limitation in smokers before disablement; and
● improved management of stable disease and prevention of exacerbations.
In May 2001 a multidisciplinary steering committee was convened by the Thoracic Society of Australia
and New Zealand (TSANZ) and The Australian Lung Foundation in accordance with the National Health
and Medical Research Council recommendations for guideline development (National Health and
Medical Research Council 1998). The Committee agreed to use the Global Initiative for Chronic
Obstructive Lung Disease (GOLD) Workshop Report (NHLBI/WHO Workshop Report April 2001) as the
prime evidence base, together with systematic reviews and meta-analyses from the Cochrane
Database. The GOLD Report, released in April 2001, was produced by an international panel of experts
in collaboration with the United States National Heart, Lung, and Blood Institute (NHLBI) and the World
Health Organization (WHO). The levels of evidence in the current guidelines were assigned according
to the system developed by the NHLBI (Box 1). Any changes to the guidelines have been based on
subsequent versions of the GOLD report and on the results of systematic reviews or consistent
evidence from well conducted randomised controlled trials.
The Guidelines Steering Committee supervised the development of specific items such as the COPDX
Plan and a management handbook for primary care clinicians. Drafts of these documents were widely
circulated to key stakeholder groups and professional organisations. In addition, the draft guidelines
were published on the Internet http://www.lungnet.com.au (now www.lungfoundation.com.au) and
access to them was advertised in a national newspaper. The draft guidelines were circulated to all
members of the TSANZ and Australian Divisions of General Practice. All comments received were
reviewed by the Steering Committee. The Guidelines were then published as a supplement to The
Medical Journal of Australia in March 2003.
The Steering Committee then resolved to establish a COPD Guidelines Implementation Committee
and a Guidelines Evaluation Committee. The terms of reference of the Evaluation Committee included
scientific assessment of the impact of the guidelines on clinical practice and rigorous examination of
the relevant medical literature to ensure the guidelines remain up to date. Any suggested
modifications were circulated to members of the COPD Coordinating Committee and other key
stakeholders prior to ratification. Following this, the Guidelines were submitted to the COPD Special
Interest Group of the Thoracic Society of Australia and New Zealand for endorsement.
Associate Professor David K McKenzie and Professor Peter Frith.

Principal authors and members of the COPD Implementation Committee.
July 2005
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COPD-X Methodology
COPD-X is produced by Lung Foundation Australia’s COPD Guidelines Committee, which meets to
evaluate the current literature and undertake quarterly updates of the Guidelines. The Committee is
comprised of a multidisciplinary group of national COPD opinion leaders with expertise in evidence-based
medicine, as well as Lung Foundation Australia staff who represent consumer priorities and lived
experience perspectives in relevant discussions as the national peak consumer organisation.
A PubMed systematic literature search is performed quarterly by the Guidelines Coordinator for new
papers in COPD, emphysema and chronic bronchitis, encompassing systematic reviews, clinical trials,
and cohort and case-control studies. Guidelines committee members also propose studies for inclusion
in the screening and subsequent review process, noting their awareness of key evidence being published
in their respective areas of expertise. The Guidelines co-chairs screen all abstracts for inclusion. Relevant
papers are critically appraised by a committee member with expertise in that area.
At the full Committee meeting, a decision about whether to cite a paper is made by consensus, and
wording for incorporation is discussed. When making changes to Guideline recommendations, the
Committee preferences randomised controlled trials and meta-analyses. The healthcare setting and
patient population are also considered for relevance. Study methodology, bias, consistency of results,
applicability to local practice and magnitude of benefit are all considered. Potential harms and side effects
are also discussed and reported. The Committee discusses all potential Guideline changes and always
reaches a group consensus. Guideline updates are focused on changes that are likely to modify or
influence practice. Any disagreement is resolved with discussion.
All recommendations are linked to the key evidence used in making the recommendation and this
evidence is routinely reviewed and updated. Evidence summaries and tables are provided in the
Guidelines. Economic evaluation and funding implications are beyond the scope of the Guidelines in their
current format. Although current resources do not allow routine audit and analysis with respect to the
impact of and adherence to the Guidelines, independent researchers frequently use the Guidelines to
audit local practice.
The Guidelines are endorsed by the Thoracic Society of Australia New Zealand (TSANZ). The TSANZ
Clinical Care and Resources Sub-committee provides biannual external review and considers key findings
and updates, and the strength of recommendations. The reviewers provide written feedback that is
addressed by the co-Chairs and expert members as applicable. Furthermore, within the Lung Foundation
Australia, key stakeholders such as general practitioners are also invited to provide regular feedback.
Following the external approval process, the updated Guidelines including a summary of changes ., are
uploaded quarterly to the COPD-X website (https://copdx.org.au/).
Ongoing administrative, technical, logistical and financial support for the development of the COPD-X
Guidelines is provided by Lung Foundation Australia as part of its national COPD program. This program
receives sponsorship funding from a number of industry partners. Industry partners of Lung Foundation
Australia have no direct or indirect influence over the content of the COPD-X Guidelines. Lung Foundation
Australia has complete editorial and design control over the content of the COPD-X Guidelines as well
as all other resources, promotions and educational programs. All members of the Guidelines committee
serve as volunteers. No funding body has any influence on content or recommendations. Where
applicable, Lung Foundation Australia funds members’ travel and accommodation for in-person
Guidelines meetings. Committee members’ conflicts of interest are declared on an annual basis and can
be viewed at: https://copdx.org.au/copd-x-plan/copd-guidelines-committee-past-and-
present/conflicts-of-interest/. Any relevant potential conflict is addressed during the quarterly meetings.
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Levels of evidence
THE KEY RECOMMENDATIONS and levels of evidence incorporated in the COPD-X Guidelines were originally
based largely on the Global Initiative for Chronic Obstructive Lung Disease (GOLD), which used the
evidence ranking system of the US National Heart, Lung and Blood Institute (NHLBI) (NHLBI/WHO
Workshop Report April 2001). The NHLBI scheme is shown in Box 1. For comparison, the National
Health and Medical Research Council (NHMRC) (National Health and Medical Research Council 1998)
levels of evidence are also shown, along with the equivalent NHLBI categories.
For this update, the COPD-X Guidelines Committee reclassified NHLBI level A as NHMRC level I and
NHLBI level B as NHMRC level II evidence. All citations to NHLBI level C were individually reviewed
and reclassified as NHMRC level II, III-2, III-3 or IV evidence. On closer examination, some references
originally classified as level C were actually considered level D. As NHLBI level D is not recognised in
the NHMRC classification, these levels were removed whilst the bibliographic citations were retained.
Box 1: Levels of evidence

a) National Heart, Lung, and Blood Institute (NHLBI) categories
NHLBI
Sources of evidence Definition
category
A Randomised controlled Evidence is from endpoints of well-designed RCTs that provide a consistent
trials (RCTs) extensive pattern of findings in the population for which the recommendation is made.
body of data Category A requires substantial numbers of studies involving substantial
numbers of participants.
B Randomised controlled Evidence is from endpoints of intervention studies that include only a limited
trials (RCTs) limited body number of patients, post-hoc or subgroup analysis of RCTs, or meta-analysis
of data of RCTs. In general, category B pertains when few randomised 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 Non-randomised trials, Evidence is from outcomes of uncontrolled or non-randomised trials or from
observational studies observational studies.
D Panel consensus, The panel consensus is based on clinical experience or knowledge that does
judgement not meet the above criteria.
12
b) National Health and Medical Research Council (NHMRC) Evidence Hierarchy: designations of
‘levels of evidence’ according to type of research question
Level Intervention Diagnostic accuracy Prognosis Aetiology Screening intervention

I4 A systematic review of level II A systematic review of level II A systematic review of level II A systematic review of level II A systematic review of level II
studies studies studies studies studies
II A randomised controlled trial A study of test accuracy with: A prospective cohort study A prospective cohort study A randomised controlled trial
an independent, blinded
comparison with a valid
reference standard, among
consecutive persons with a
defined clinical presentation
III-1 A pseudorandomised controlled A study of test accuracy with: All or none of the people with All or none of the people with A pseudorandomised
trial (i.e. alternate allocation or an independent, blinded the risk factor(s) experience the risk factor(s) experience controlled trial (i.e. alternate
some other method) comparison with a valid the outcome; and the data the outcome; and the data allocation or some other
reference standard, among arises from an unselected or arises from an unselected or method)
non-consecutive persons with representative case series representative case series
a defined clinical presentation which provides an unbiased which provides an unbiased
representation of the representation of the
prognostic effect prognostic effect
III-2 A comparative study with A comparison with reference Analysis of prognostic factors A retrospective cohort study A comparative study with
concurrent controls: standard that does not meet amongst persons in a single concurrent controls:
• Non-randomised, the criteria required for Level arm of a randomised • Non-randomised,
experimental trial II and III-1 evidence controlled trial experimental trial
• Cohort study • Cohort study
• Case-control study • Case-control study
• Interrupted timer series
with a control group
III-3 A comparative study without Diagnostic case-control A retrospective cohort study A case-control study A comparative study without
concurrent controls: study concurrent controls:
• Historical control study • Historical control study
• Two or more single arm • Two or more single arm
study study
• Interrupted time series
without a parallel control
group
IV Case series with either post- Study of diagnostic yield (no Case series, or cohort study of A cross-sectional study or Case series
test or pre-test/post-test reference standard) persons at different stages of case series
outcomes disease
The COPD-X Plan – Version 2 71 (July 2023) 13

Key Recommendations of the COPD-X Guidelines
C: Case finding and confirm diagnosis

NHMRC Strength of
level of recommendation*
evidence
Smoking is the most important risk factor in COPD I Strong
development.
Smoking cessation reduces mortality. I Strong
A thorough history and examination is the first step in III-2 Strong

COPD diagnosis.
COPD is confirmed by the presence of persistent airflow III-2 Strong

limitation (post-bronchodilator FEV1/FVC <0.7).
Diagnosis of COPD should be accompanied by regular III-2 Strong

assessment of severity.
If FEV1 increases >400 mL following bronchodilator, III-2 Strong

consider asthma, or coexisting asthma and COPD.
Further investigations may help a) confirm or exclude III-2 Strong

other conditions (either coexisting or with similar
symptoms to COPD) and b) assess the severity of COPD.
Referral to specialist respiratory services may be III-2 Strong

required.
O: Optimise Function
Assessment is the first step to optimising function. III-2 Strong
Optimise pharmacotherapy using a stepwise approach. I Strong
Adherence and inhaler technique need to be checked on I Strong

a regular basis.
Non-pharmacological strategies (such as pulmonary I Strong

rehabilitation and regular exercise) should be provided
to all patients with COPD.
Comorbid conditions are common in patients with COPD. III-2 Strong
Palliative care - ideally from a multidisciplinary team II Weak

which includes the primary care team - should be
considered early, and should include symptom control
and addressing psychosocial issues
Pulmonary rehabilitation improves quality of life and I Strong

exercise capacity and reduces COPD exacerbations
14
Lung volume reduction (surgical and endobronchial) I Weak
improves lung function, exercise capacity and quality of
life.
Long term macrolide antibiotics may reduce I Weak

exacerbations in people with moderate to severe COPD
and frequent exacerbations.
Long term non-invasive ventilation should be considered I Weak

in people with stable COPD and hypercapnia to reduce
mortality.
P: Prevent deterioration
Smoking cessation is the most important intervention to II Strong

prevent worsening of COPD.
Preventing exacerbations has a key role in preventing III-2 Strong

deterioration.
Vaccination reduces the risks associated with influenza I Strong

and pneumococcal infection.
Mucolytics may benefit certain patients with COPD. I Strong
Long-term oxygen therapy has survival benefits for I Strong

COPD patients with hypoxaemia.
D: Develop a plan of care
Good chronic disease care anticipates the wide range of I Strong

needs in patients with COPD.
Clinical support teams working with the primary III-2 Weak

healthcare team can help enhance quality of life and
reduce disability for patients with COPD.
Patients may benefit from self-management support. I Strong
Patients may benefit from support groups and other III-2 Weak
community services.
COPD exacerbation action plans reduce emergency I Strong

department visits and hospital admissions.
X: Manage eXacerbations
A COPD exacerbation is characterised by a change in the III-2 Strong

patient’s baseline dyspnoea, cough, and/or sputum that
is beyond normal day-to-day variations, is acute in
onset, and may warrant a change in regular medication
or hospital admission.
15
Early diagnosis and treatment of exacerbations may III-2 Strong
prevent hospital admission and delay COPD progression.
Multidisciplinary care may assist home management of I Weak

some patients with an exacerbation.
Inhaled bronchodilators are effective for initial treatment I Strong

of exacerbations.
Systemic corticosteroids reduce the severity of, and I Strong

shorten recovery from exacerbations.
Exacerbations with clinical features of infection I Strong

(increased volume and change in colour of sputum
and/or fever) benefit from antibiotic therapy.
Controlled oxygen delivery (0.5-2.0 L/min) is indicated II Strong

for hypoxaemia in patients with exacerbations.
When using supplemental oxygen for hypoxia in COPD II Strong

exacerbations, target SpO2 88–92% improves survival.
Non-invasive ventilation (NIV) is effective for patients I Strong

with rising PaCO2 levels.
Non-invasive ventilation improves survival for people I Strong

with COPD and acute hypercapnic respiratory failure
Consider pulmonary rehabilitation at any time, including I Strong

during the recovery phase following an exacerbation.
Patients with COPD discharged from hospital following an I Strong

exacerbation should receive comprehensive follow-up
led by the primary healthcare team.
*The GRADE system was used to grade the strength of recommendations (Andrews 2013, Guyatt
2008)
16
C: Case finding and confirm diagnosis
CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) is a preventable and treatable disease with
some significant extrapulmonary effects that may contribute to the severity in individual patients. Its
pulmonary component is characterised by airflow limitation which is not fully reversible. The airflow
limitation is usually progressive and associated with an abnormal inflammatory response of the lung
to noxious particles or gases (Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2023). In
clinical practice, diagnosis is usually based on:
● Symptoms of exertional breathlessness, cough and sputum

● A history of smoking, or exposure to other noxious agents
● FEV1/FVC<0.7 post-bronchodilator
Small-airway narrowing (with or without chronic bronchitis) and emphysema caused by smoking are
the common conditions resulting in COPD. Chronic bronchitis is daily sputum production for at least
three months of two or more consecutive years. Emphysema is a pathological diagnosis and consists
of alveolar dilatation and destruction. Breathlessness with exertion, chest tightness and wheeze are
the results of airway narrowing and impaired gas exchange. The loss of lung elastic tissue in
emphysema may result in airway wall collapse during expiration, leading to dynamic hyperinflation
and consequent increased work of breathing.
The irreversible component of airflow limitation is the end result of inflammation, fibrosis and
remodelling of peripheral airways. Airflow limitation leads to non-homogeneous ventilation, while
alveolar wall destruction and changes in pulmonary vessels reduce the surface area available for gas
exchange. In advanced COPD there is a severe mismatching of ventilation and perfusion leading to
hypoxaemia. Hypercapnia is a late manifestation and is caused by a reduction in ventilatory drive.
Pulmonary hypertension and cor pulmonale are also late manifestations and reflect pulmonary
vasoconstriction due to hypoxia in poorly ventilated lung, vasoconstrictor peptides produced by
inflammatory cells and vascular remodelling. The clinical features and pathophysiology of COPD can
overlap with asthma, as most COPD patients have some reversibility of airflow limitation with
bronchodilators. The follow up of a cohort of children aged 10 to 16 initially recruited in 1964
demonstrated that childhood participants who had wheezy bronchitis (n=53) and asthma (n=38) had
an increased risk (OR 1.81 and 6.37 respectively) of COPD by mean age of 61, compared to cohort
controls (n=239). Multivariate analysis details of adjustment for smoking were not provided (Tagiyeva
2016). A meta-analysis of six prospective cohort studies following children with or without wheezing
into adulthood found an association between childhood atopic wheezing and prevalence of COPD in
adulthood (RR 5.307, 95% CI 1.033 to 27.271, P=0.046) (Ma 2018). By contrast, some non-smokers
with chronic asthma develop irreversible airway narrowing. The overlap between chronic bronchitis,
emphysema and asthma and their relationship to airflow limitation and COPD are illustrated in Figure
1. This proportional Venn diagram presents data from the Wellington Respiratory Survey which
recruited participants over the age of 50 and invited them to have detailed lung function testing and
chest CT scans (Marsh 2008). It can be seen that almost all patients with both chronic bronchitis and
emphysema meet the GOLD definition of COPD, as do most with both chronic bronchitis and asthma.
Patients with chronic bronchiolitis, bronchiectasis and cystic fibrosis may also present with similar
symptoms and partially reversible airflow limitation.
17
Figure 1: COPD Phenotypes
The diagram (reproduced from Thorax 2008;63:761-7 with permission from the BMJ Publishing
Group and corrected in Thorax 2015;70:905 to now include the clear circle in the middle of the
emphysema circle) presents the different phenotypes within the Wellington Respiratory Survey study
population. The large black rectangle represents the full study group. The clear circles within each
coloured area represent the proportion of patients with COPD (post-bronchodilator forced expiratory
volume in 1 s/forced vital capacity (FEV1/FVC), 0.7). The isolated clear circle represents patients with
COPD who did not have an additional defined phenotype of asthma, chronic bronchitis or emphysema.
In recent years there has been a focus on the prevalence and implications of the coexistence of
asthma and COPD. A systematic review and meta-analysis of 19 studies found that the prevalence of
co-existing asthma in patients with COPD was 27% in population-based studies and 28% in hospital-
based studies (Alshabanat 2015). Both this review and systematic reviews by Gibson (Gibson 2015)
and Nielsen (Nielsen 2015) found an increased frequency of exacerbations in patients with features of
both asthma and COPD compared to those with COPD alone.
Treatable Traits
Treatable Traits is a new treatment paradigm proposed for the management of people with airway
diseases. The treatment approach has been suggested as a way to progress precision or personalised
medicine in COPD and asthma (Agusti 2017, Agusti 2016, McDonald 2019b). Patients are first
assessed through a detailed clinical history and identification of airway disease risk factors (e.g.
smoking history, history of allergies, occupational exposures, family history, respiratory disease in
early life); spirometry and measures of airway inflammatory biomarkers, including exhaled nitric oxide
fraction (FeNO) and blood eosinophils. These assessments will indicate a high or low probability of the
presence of an airway disease (Agusti 2016).
Following this confirmation, it is recommended that each individual undergoes a multidimensional

assessment to identify treatable traits and an individualised treatment plan is implemented based on
the presence of traits.
In order to be considered a trait, the following criteria should be met. Traits should be identifiable
using a trait identification marker, clinically relevant and modifiable (McDonald 2019b).
Traits are grouped into three domains – pulmonary and extrapulmonary traits and behaviours/ risk-
18
factors. While overall management according to treatable traits is a concept, the treatment of each
individual trait is supported in most cases through RCT evidence. A systematic review of interventions
targeting treatable traits in obstructive airways diseases found these interventions were effective in
improving HRQoL and were also associated with small to medium reductions in hospitalizations, 1-
year all-cause mortality, dyspnoea, anxiety, and depression (Sarwar 2022) [evidence level I]. Meta-
analysis of the 4 COPD-only studies demonstrated a significant improvement in SGRQ -5.82 (95% CI
-9.17 to -2.47).
C1. Aetiology and natural history

Smoking is the most important risk factor in COPD development (Fletcher 1977,
Burrows 1977) [evidence level I, strong recommendation]
Cigarette smoking is the most important cause of COPD (Fletcher 1977, Burrows 1977, Matheson
2018). There is a close relationship between the amount of tobacco smoked and the rate of decline in
forced expiratory flow in one second (FEV1), although individuals vary greatly in susceptibility (Fletcher
1977). Around half of all smokers develop some airflow limitation, and 15 to 20% will develop clinically
significant disability (Fletcher 1977). Even smokers who do not meet spirometric criteria for COPD may
have respiratory symptoms and reduced physical activity. They may have other subtle abnormalities
of lung function (Elbehairy 2016). Smokers are also at risk of developing lung cancer, and
cardiovascular disease such as ischaemic heart disease and peripheral vascular disease.
In susceptible smoker’s, cigarette smoking results in a steady decline in lung function, with a
decrease in FEV1 of 25–100 mL/year (Fletcher 1977). While smoking cessation may lead to minimal
improvements in lung function, more importantly it will slow the rate of decline in lung function and
delay the onset of disablement. At all times smoking cessation is important to preserve remaining lung
function (Fletcher 1977).
Impairment increases as the disease progresses but may not be recognised because of the slow pace
of the disease. The time course of development of COPD and disability and the influence of smoking
cessation are illustrated in Figure 2.
The annual decline in FEV1 has been measured in 5,041 patients with moderate to very severe COPD
followed for 4 years (Tashkin 2013). The decline in post-bronchodilator measurements was greater
than pre-bronchodilator, which might represent progression of disease or tachyphylaxis [evidence level
III-2].
19
Figure 2: Time-course of chronic obstructive pulmonary disease (COPD) (Fletcher 1977)
The figure (adapted from Fletcher C and Peto R. The natural history of chronic airflow obstruction. BMJ 1977;1:1645-
1648 and reproduced with permission from the BMJ Publishing Group) shows the rate of loss of forced expiratory flow in
one second (FEV1) for a hypothetical, susceptible smoker, and the potential effect of stopping smoking early or late in the
course of COPD. Other susceptible smokers will have different rates of loss, thus reaching “disability” at different ages.
The normal FEV1 ranges from below 80% to above 120%, so this will affect the starting point for the individual’s data
(not shown).
Hookah (a type of water pipe) smoking is increasing, particularly in developing countries. In an

Iranian study involving 245 adults aged ≥35 years who had at least 15 years of hookah smoking
history and matching controls, the prevalence of COPD among hookah smokers was 10.2%; higher
rates were found in older age, longer duration of hookah smoking; in men; history of ≥3 hookahs/day;
history of cough for ≥2 years; history of sputum for ≥2 years; and a history of dyspnoea for ≥2 years
(Bahtouee 2018).
In addition to cigarette smoking, there are a number of other recognised risk factors for COPD
(Omland 2014, Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2023) (see Box 2).
COPD almost always arises from a gene environment interaction. The best characterised genetic
predisposition is alpha1 antitrypsin deficiency, but multiple other genes each make a small contribution
and further investigation is required. The risk of COPD is related to the total burden of inhaled particles
and oxidative stress in the lung.
Analysing the lifetime job-histories of ∼100,000 individuals from a UK general population found that
the following specific occupation categories are associated with an increased COPD risk: sculptor,
painter, engraver, art restorer; gardener, groundsman, park keeper; food, drink and tobacco
processor; plastics processor, moulder; agriculture, and fishing occupations not elsewhere classified;
and warehouse stock handler, stacker. These associations were confirmed among never-smokers and
never-asthmatics and were influenced by employment duration. Gathering job-history and focused
preventive strategies in COPD high-risk jobs are warranted (De Matteis 2019).
Occupational dust exposure might be responsible for 20 to 30% of COPD. This is consistent with the
findings of a European study (Lytras 2018). This has long been recognised in coal miners (Santo Tomas
2011), but biological dust has also been identified as a risk factor, particularly in women (Matheson
2005). Non-smoking women involved in the spinning, weaving and knitting of cotton or silk have an
increased risk of death from COPD (Cui 2011). Biological dust exposure is also associated with chronic
sputum production, dyspnoea and work inactivity in male patients (Rodriguez 2008). Livestock farmers
20
are also at increased risk of developing chronic bronchitis and COPD (Eduard 2009). Dairy farmers
have increased wheeze and morning phlegm and increased rates of decline in FEV1 compared to
controls. These effects appear to be associated more with exposure to animal feed than handling hay
or straw (Thaon 2011). Lifetime cumulative exposure to pesticides is associated with risk of developing
COPD (De Matteis 2022). Each year of exposure to diesel exhaust increases the risk of dying from
COPD by 2.5% (Hart 2009). An analysis of a Swiss cohort of 4,267 patients without asthma found that
COPD was associated with high occupational exposures to minerals, biological dusts, vapours/fumes,
vapours, gases, dust or fumes (VGDF). The findings were clearer in non-smokers and those without
chronic bronchitis (Mehta 2012) [evidence level III-2]. A meta-analysis of 6 cross-sectional studies
found that occupational exposure to respirable quartz dust was associated with a pooled reduction in
FEV1 of -4.62 (95% CI -7.18, -2.06) % predicted (Bruske 2014). A case control study conducted within
a large managed care organisation found that self-reported exposures to vapours, gas, dust and fumes
on the longest held job were responsible for 31% of COPD (Blanc 2009). Joint exposure both to
smoking and occupational factors markedly increased the risk of COPD [evidence level III-2]. Evidence
of emphysema and gas trapping on CT scans was associated with self-reported occupational exposures
to dust and fumes in both men and women who were former or current smokers (Marchetti 2014). A
summary of the risks of COPD associated with biological or mineral dusts, gases, fumes / vapours,
diesel exhaust, irritant gases / vapours, chemical gas / fumes and various other occupational
exposures appears in Figure 3 (reproduced from Diaz-Guzman et al 2012 (Diaz-Guzman 2012) with
permission).
Figure 3: Risk of occupational exposure for COPD from selected studies
Pathak et al (2019) conducted a systematic review and meta-analysis of the risk of COPD due to
indoor air pollution from biomass cooking fuel. Eligible studies were case-control, retrospective cohort
and cross-sectional, conducted in adults. COPD was assessed using any diagnostic criteria. A total of
35 studies with 73,122 participants were included. The pooled analysis showed that exposure to indoor
air pollution due to solid biomass fuels increased the risk of COPD by 2.65 (95% CI 2.13–3.31).
Fortunately, the air quality in most Australian and New Zealand cities is relatively good and cooking
with biomass fuels (coal, wood, dung, crop waste etc.) is uncommon. However, a panel study of 84
moderate to severe COPD patients found that indoor pollutant exposure, including PM2.5 and NO2
(oxides of nitrogen) was associated with increased respiratory symptoms and risk of COPD
exacerbation (Hansel 2013) [evidence level III-2].
21
Prasad et al (2022) used modelling of exposure at an individual level and respiratory questionnaire
and respiratory function testing data to examine the effect of a 6-week period of coal fire PM2.5
exposure from a 2014 Hazelwood open cut coal mine. A dose–response association between particle
exposure and COPD in non-smokers and increased chronic cough in current smokers was observed
(Prasad 2022) [evidence level III-2].
Failure to achieve maximum lung function increases the risk of COPD in later life (Bui 2018, Lange
2015). Premature birth is associated with the development of COPD (Bui 2022). This association is
compounded by smoking [Evidence level III-B]. There is some evidence that women might be more
susceptible to the effects of tobacco smoke (Aryal 2014) [evidence level III-2]. Beyond the age of 45-
50 years, female smokers appear to experience an accelerated decline in FEV1 compared with male
smokers (Gan 2006) [evidence level II]. On the other hand, a family-based case control study involving
high resolution chest CT scans found that men demonstrated more low attenuation areas consistent
with emphysema than did women (Camp 2009) [evidence level III-2]. Nor is it known whether the
increased risk among lower socioeconomic groups is due to greater exposure to pollution, poorer
nutrition, more respiratory infection or other factors.
Novel risk factors for COPD have been reviewed by an assembly of the American Thoracic Society
(Eisner 2010a). Exposure to second-hand (Environmental) Tobacco Smoke was consistently associated
with various definitions of COPD; there was a temporal relationship, dose response gradient and
biological plausibility. Meta-analysis of 12 studies found a pooled odds ratio of 1.56 (95% CI 1.40 -
1.74). There was sufficient evidence that exposure to smoke from burning biomass fuels was
associated with development of COPD in women. Meta-analysis of 15 studies found a pooled odds ratio
of 2.23 (95% CI 1.72 - 2.90), but there was significant heterogeneity between studies. [evidence level
III-2]. Whilst the risk of biomass smoke in men has only been assessed in three studies, there also
appears to be a similarly increased risk of COPD (OR 4.3, 95% CI 1.85-10) (Hu 2010). Pulmonary
tuberculosis can lead to scarring and irreversible loss of lung function, however there is currently
insufficient evidence that this is clinically similar to COPD caused by cigarette smoking (Eisner 2010a).
After extensive adjustment for potential confounders, a self-reported past history of TB had an
adjusted odds of 3.78 (95% CI 2.87-4.98) of a diagnosis of COPD in a review of studies which were
exclusively of low- and middle-income countries. This review comprised 12396 people aged 35 to 95,
of cross-sectional data from 13 low- and middle-income countries and three continents. Overall
prevalence of COPD was 8.8%, and those with a history of TB had an overall COPD prevalence of
25.9% (Kamenar 2021) [evidence level III-2]. The authors suggested that previously underestimated
endobronchial spread and airway fibrosis as the mechanism.
22
Box 2: Risk Factors for COPD
• Genetic factors
• Age and sex
• Lung growth and development, premature birth
• Exposure to particles
o Tobacco smoke, active and passive
o Occupational dusts, organic and inorganic
o Indoor air pollution from heating and cooking with bio-mass in poorly vented dwellings
o Outdoor air pollution, including landscape fire smoke
• Socioeconomic status
• Asthma and airway hyper-reactivity
• Chronic bronchitis
• Infections, particularly tuberculosis and childhood respiratory infections
In the Tasmanian Longitudinal Health Study, there were five different asthma /allergy trajectory
patterns demonstrated in the prospective cohort of participants. This cohort included n=7380 initial
participants at seven years of age, to n=2689 of the original participants at 53 years of age. Those
with early onset-onset persistent asthma and allergies were most likely to develop COPD (OR 5.3,
95% CI 3.2-8.6.), followed by late-onset asthma and allergies (OR 3.8, 95% CI 2.4-4.6) (Bui 2021).
This highlights the need for a personal approach including the management of treatable traits to
potentially prevent progression to COPD. A past history of childhood asthma has been shown to be
independently associated with a 3-fold (95% CI 2.25-4.00) increase in prevalence of adulthood COPD
in a meta-analysis of 11 studies, which included 4294 people with and 44381 people without COPD
(Ali 2022) [evidence level III]. Smoking status and other recognised risk COPD factors were adjusted
for across this study.
Early life risk factors that could lead to lung problems in later life are discussed further by the European
Lung Foundation. https://europeanlung.org/en/information-hub/keeping-lungs-healthy/early-life-risk-
factors/
C1.1 Natural history
Although FEV1 has long been accepted as the single best predictor of mortality in population studies
in COPD (Fletcher 1977, Peto 1983) studies have suggested various other indices, which may also
predict mortality. In patients with established COPD, degree of hyperinflation as measured by
inspiratory capacity/ total lung capacity (IC/TLC) ratio was independently associated with all cause
and COPD mortality (Casanova 2005). Exercise capacity (as measured by the 6-minute walk distance
(6MWD), incremental shuttle walk distance (ISWD), or peak VO2 during a cardiopulmonary exercise
test, body mass index and dyspnoea score (measured with the modified Medical Research Council
Scale) have all been shown to predict mortality better than FEV1 in patients with established disease.
Several of these latter indices are incorporated together in a single score, the BODE index (Body mass
index, degree of Obstruction as measured by FEV1, Dyspnoea score and Exercise capacity measured
by 6MWD) or the i-BODE index, in which the ISWD replaces the 6MWD strongly predicts mortality
(Celli 2004, Williams 2012). A simplified ADO index (Age, Dyspnoea score and Obstruction) has been
developed in a Swiss cohort and shown to predict three-year mortality in a Spanish cohort (Puhan
2009b) [evidence level III-2]. Further studies are awaited including validation in an Australian cohort
of COPD patients. Nonetheless, FEV1 continues to have utility as a predictor of all-cause mortality in
COPD. In one study that followed patients after an exacerbation, the five-year survival rate was only
about 10% for those with an FEV1 <20% predicted, 30% for those with FEV1 of 20 to 29% predicted
and about 50% for those with an FEV1 of 30 to 39% predicted (Connors 1996). Patients with an FEV1
<20% predicted and either homogeneous emphysema on high resolution computed tomography
(HRCT) or a diffusing capacity of lung for carbon monoxide (D LCO) test <20% predicted are at high
risk for death after LVRS and unlikely to benefit from the intervention (National Emphysema Treatment
23
Trial Research 2001). A review of 15 COPD prognostic indices found that although the prognostic
information of some has been validated, they lack evidence for implementation. Impact studies will
be required in the future to determine whether such indices improve COPD management and patient
outcomes (Dijk 2011).
Continued smoking and airway hyperresponsiveness are associated with accelerated loss of lung
function (Tashkin 1996). However, even if substantial airflow limitation is present, cessation of
smoking may result in some improvement in lung function and will slow progression of disease
(Tashkin 1996, Anthonisen 2002).
The development of hypoxaemic respiratory failure is an independent predictor of mortality, with a

three-year survival of about 40% (Medical Research Council Working Party 1981). Long term
administration of oxygen increases survival to about 50% with nocturnal oxygen (Medical Research
Council Working Party 1981) and to about 60% with oxygen administration for more than 15 hours a
day (Nocturnal Oxygen Therapy Trial Group 1980) (see also section P). There may be a differential in
benefit between men and women. A study (Ekstrom 2010) of Swedish patients receiving long term
oxygen therapy demonstrated that overall, women had a lower risk of death than men; nonetheless,
when compared with expected death rates for the population, women had a higher relative mortality
with a standardised mortality rate (SMR) of 12 (95% CI;11.6-12.5) compared with 7.4 (95% CI 7.1-
7.6) [evidence level III-2].
The natural history of COPD is characterised by progressive deterioration with episodes of acute
deterioration in symptoms referred to as an exacerbation. A large study that included 4951 patients
from 28 countries found that health-related quality of life (HRQoL), measured by the St George’s
Respiratory Questionnaire (SGRQ), deteriorated faster in patients with more severe disease (Jones
2011a). Patients then classified as in GOLD stage II who received placebo showed an overall
improvement, while those in GOLD stages III and IV deteriorated. When all participants from the
different arms were included, the change in SGRQ at three years correlated weakly with change in
FEV1: r = -0.24, p < 0.0001 and there was no difference in this relationship between men and women.
However, a significantly faster deterioration in the SGRQ score relative to FEV1 % predicted was seen
in older patients (greater 65 years).
Admission to hospital with an exacerbation of COPD complicated by hypercapnic respiratory failure

is associated with a poor prognosis. A mortality of 11% during admission and 49% at two years has
been reported in patients with a partial pressure of carbon dioxide (PCO2) >50mmHg (Connors 1996).
For those with chronic carbon dioxide retention (about 25% of those admitted with hypercapnic
exacerbations), the five-year survival was only 11% (Connors 1996).
C2. Diagnosis
C2.1 History
A thorough history and examination is the first step in COPD diagnosis [evidence
level III-2, strong recommendation]
The main symptoms of COPD are breathlessness, cough and sputum production. Patients often
attribute breathlessness to ageing or lack of fitness. A persistent cough, typically worse in the mornings
with mucoid sputum, is common in smokers. Other symptoms such as chest tightness, wheezing and
airway irritability are common (Thompson 1992). Further, many people with COPD have low levels of
physical activity and demonstrate reduced exercise tolerance on formal testing (Watz 2014, Cote
2007b). People with chronic cough and sputum are at increased risk of exacerbation (Burgel 2009)
[evidence level III-2]. Exacerbations, usually infective, occur from time to time and may lead to a
sharp deterioration in coping ability. Fatigue, poor appetite and weight loss are more common in
24
advanced disease.
The effect of breathlessness on daily activities can be quantified easily in clinical practice using the
Modified Medical Research Council (mMRC) Dyspnoea Scale (see Box 3) (Celli 2004, Fletcher 1960).
Box 3: Modified Medical Research Council (mMRC) Dyspnoea Scale for grading the severity of
breathlessness during daily activities
Grade Description of Breathlessness
Grade 0 I only get breathless with strenuous exercise
Grade 1 I get short of breath when hurrying on level ground or walking up a slight hill
Grade 2 On level ground, I walk slower than people of the same age because of breathlessness, or I have
to stop for breath when walking at my own pace on the level
Grade 3 I stop for breath after walking about 100 metres or after a few minutes on level ground
Grade 4 I am too breathless to leave the house, or I am breathless when dressing or undressing
The COPD Assessment Test (CAT) (Jones 2009) is relatively short, easily scored and provides an
alternative to approximately 17 other reported and longer questionnaires such as the St George’s
Respiratory Questionnaire (SGRQ) and the Chronic Disease Respiratory Questionnaire (CRQ). It may
provide useful information when taking a history from patients. The CAT quantifies the impact COPD
has on a patient’s wellbeing and daily life, with the aim of facilitating communication between
healthcare professionals and patients. The test is comprised of eight questions pertaining to cough,
sputum, chest tightness, exercise tolerance, ability to perform activities of daily living, confidence in
leaving the home, sleep and energy levels. Each question is scored on a 6-point scale (0 to 5) yielding
a total possible score of 40 for the questionnaire. The total CAT score provides a broad clinical picture
of the impact of COPD on an individual patient with scores of >30, 21-30, 10-20 and <10
corresponding to very high, high, moderate and low impact respectively. A total score of 5 is the upper
limit of normal in a healthy non-smoker (Jones 2011b). A systematic review (Gupta 2014) that
included 36 studies carried out in 32 countries reported the CAT to be reliable, valid and responsive
as a health-related quality of life (HRQoL) instrument. The MCID for improvement is a difference of 2
(Cazzola 2015b). The CAT is freely available in many languages (see
https://www.catestonline.org/hcp-homepage.html). It is easy and quick to complete, and score. A
meta-analysis of eight studies of the CAT questionnaire demonstrates moderately strong predictive
values for aspects of COPD including a valid diagnosis, likelihood of exacerbations, depression, lung
function and mortality (Karloh 2016).
C2.2 Physical examination
The sensitivity of physical examination for detecting mild to moderate COPD is poor (Badgett 1993).
Wheezing is not an indicator of severity of disease and is often absent in stable, severe COPD. In more
advanced disease, physical features commonly found are hyperinflation of the chest, reduced chest
expansion, hyperresonance to percussion, soft breath sounds and a prolonged expiratory phase. Right
heart failure may complicate severe disease.
During an exacerbation, tachypnoea, tachycardia, use of accessory muscles, tracheal tug and
cyanosis are common.
The presence and severity of airflow limitation are impossible to determine by clinical signs (Badgett
25
1993). Objective measurements such as spirometry are essential. Peak expiratory flow (PEF) is not a
sensitive measure of airway function in COPD patients, as it is effort dependent and is dominated by
large airway resistance and has a wide range of normal values (Kelly 1988).
C2.3 Spirometry
COPD is confirmed by the presence of persistent airflow limitation (post-

bronchodilator FEV1/FVC< 0.7) [evidence level III-2, strong recommendation]
Because COPD is defined by demonstration of airflow limitation, which is not fully reversible,
spirometry is essential for its diagnosis (see Figure 4), and this may be performed in the
community or prior to discharge from hospital (Rea 2011). Most spirometers provide predicted
(“normal”) values obtained from healthy population studies, and derived from formulas based on
height, age, sex and ethnicity.
Airflow limitation is not fully reversible when, after administration of bronchodilator medication, the
ratio of FEV1 to forced vital capacity (FVC) is <70% and the FEV1 is <80% of the predicted value. The
ratio of FEV1 to vital capacity (VC) is a sensitive indicator for mild COPD. FEV1/FEV6 has a high level
of agreement with FEV1/FVC on both the fixed ratio and Lower Limit of Normal (LLN) criteria for the
diagnosis of COPD (Bhatt 2014a). There is controversy regarding the optimal cut-off to define airflow
limitation (FEV1/FVC less than 0.7 versus lower limit of normal). There is evidence that the fixed ratio
can lead to over diagnosis of COPD in older populations, under diagnosis in younger people (Cerveri
2008, Vollmer 2009, Swanney 2008) and may lead to gender imbalances as women have higher
FEV1/FVC than their male counterparts (Guerra 2009). A systematic review of 11 studies which
examined the relationship of each criterion with clinical outcomes found both were related to clinical
outcomes and concluded that on current evidence one could not be preferred over the other. The LLN
appeared to be a better criterion in older patients with less severe airflow limitation (van Dijk 2014);
however, a study by Bhatt (Bhatt 2014b) shows that the fixed cut-off of 0.7 identified more people
with CT diagnosed emphysema.
Concerning healthcare utilisation and COPD mortality, a population-based study of 11, 077 adults in
the US found that an FEV1/FVC ratio of <0.70 identified individuals who were at risk of COPD
hospitalisations and COPD-related mortality, with equal or better accuracy than other ratios ranging
from 0.75 to 0.65, and with more accuracy than the lower limit of normal (Bhatt 2019) [evidence level
III-2]. This study supported using the fixed FEV1/FVC ratio of <0.70 to identify individuals at risk of
clinically significant COPD.
26
Figure 4: Comparison of flow-volume curves for spirometry
The dotted line for all curves represents a normal flow–volume curve in a young adult. (a) and (b) depict typical flow–
volume curve shapes for spirometry within normal limits for a young adult and older person, respectively. Note that the
expiratory limb of (b) has some concavity despite the result being within normal limits. (c) shows an example of airway
obstruction with almost complete reversibility. The baseline curve (solid line) has concavity, typical of airflow
obstruction. The post-bronchodilator curve (dashed line) has returned to close to the ‘normal’ curve (dotted). (d) depicts
significant airflow obstruction. (e) represents the pattern often seen with restriction. The curve appears to be
compressed along the volume axis, but the expiratory limb does not appear to have any concavity. (f) portrays an
obstructive pattern. Note also that the volume appears to be reduced. This pattern may represent obstruction with a
reduced FVC due to gas trapping or may represent a mixed obstructive/restrictive ventilatory pattern. Measurement of
static lung volumes are required for determination.
(Figure reproduced from Interpreting Lung Function Tests: A Step-by-Step Guide, First Edition. Brigitte M. Borg, Bruce
R. Thompson and Robyn E. O’Hehir. © 2014 John Wiley & Sons, Ltd. with permission from Wiley)
The spirometric tests require high levels of patient effort and cooperation, and there are important
quality criteria that should be met in conducting spirometry (Miller 2005).
Indications for spirometry include:
● breathlessness that seems inappropriate;

● chronic (daily for two months) or intermittent, unusual cough;
● frequent or unusual sputum production;
● relapsing acute infective bronchitis; and
● risk factors such as exposure to tobacco smoke, occupational dusts and chemicals, and a strong
family history of COPD.
There is evidence of both underdiagnosis (Toelle 2013) and misdiagnosis of COPD in the community
(Zwar 2011). In a community-based study of 1615 participants with a range of respiratory symptoms,
but not recalling a diagnosis of respiratory disease, 8.4% had spirometry results consistent with
asthma and 12.1% subjects had spirometry results consistent with COPD (Alhabeeb 2022). This
highlights the prevalence of undiagnosed airways disease. These undiagnosed subjects also had more
severe respiratory symptoms as assessed by the COPD Assessment Test (CAT), and poorer health-
related quality of life as assessed by the St. George’s Respiratory Questionnaire (SGRQ) compared to
subjects with no airflow obstruction. This study highlights a beneficial yield of airways disease
27
diagnoses, in adults who have respiratory symptoms but without a diagnosis, by performing
spirometry.
In a systematic review examining under and overdiagnosis in primary healthcare settings Perrett et
al (2023) found that based on evidence from three studies of symptomatic smokers the prevalence of
spirometry-confirmed COPD without a diagnosis documented in their health records was 14%–26%.
The same review found substantial evidence of misdiagnosis. Based on four case series of COPD
diagnosed documented in primary healthcare records, only between 50% and 75% of subjects had
airflow obstruction on postbronchodilator spirometry performed by study researchers (Perret 2023)
[evidence level III-1]. In a general practice setting, patients with comorbidities may be more
commonly mis-diagnosed with COPD. In a study of 1,050 smokers or ex-smokers identified from 41
Melbourne general practices, two-thirds were current smokers (Liang 2018). More than one-third of
participants with a prior diagnosis of COPD did not meet the spirometric definition of the disorder. 1
in 6 participants not previously diagnosed with COPD had spirometry test results consistent with COPD.
Spirometric assessment is important in these patients to minimise this risk (Zwar 2011). Two
pulmonologists reviewed 333 patients with physician-diagnosed COPD and/or asthma. The patients
had two or more emergency room visits or admissions over the preceding 12 months, with prospective
evaluation over the next 10 months. The study found that a third of these patients had neither asthma
nor COPD, and a quarter may not even have any form of airflow limitation. The study highlighted the
importance of spirometry in making the correct diagnosis, which had been performed in less than a
third of the patients studied (Jain 2015). Respiratory symptoms are of clinical importance even in
those current or former smokers with preserved lung function (Woodruff 2016). Further evidence is
required for optimal management of these patients.
Inaccurate diagnosis related to lack of use of spirometry is also an issue in the hospital
setting. Habteslassie et al (2021) conducted a retrospective audit of inpatient separations in one
Victorian hospital. A total of 2239 inpatient separations occurred in 1469 individuals who had a clinical
diagnosis of COPD in the period October 2016 to March 2018. Spirometry results were not available
in 43.6% (n = 641) of the sample and a further 19.7% (n = 289) had spirometry results available at
the time of admission that did not demonstrate fixed airflow obstruction. The authors noted the risks
of inappropriate treatment related to the lack of diagnostic accuracy (Habteslassie 2021).
In a Danish study (Katsimigas 2019) of opportunistic screening for COPD carried out in symptomatic
smokers and ex-smokers (n=6,710), BMI <25 kg/m2 and BMI >35 kg/m2, increasing age and an
increasing number of pack-years smoked were all important predictors for COPD (diagnosed in 17.7%
in this study). GPs should target these patients for case finding to facilitate early diagnosis and initiate
early interventions.
Aaron et al (Aaron 2017) studied two longitudinal cohorts of patients with mild to moderate COPD
on post-bronchodilator spirometry at baseline and found that transient episodes of diagnostic
instability occurred commonly and that 12 to 27% of patients reversed their diagnosis of COPD over
a 4-to-5-year period. Diagnostic reversal was most common for patients who quit smoking during the
study period. These findings suggest there is considerable variability of spirometry results around
the FEV1/FVC threshold and that a single spirometric assessment may not be reliable for diagnosing
COPD in patients with mild to moderate airflow limitation. If spirometry results are around the
threshold, repeat spirometry should be performed to confirm diagnosis.
C2.4 Flow volume tests
Electronic spirometers allow for the simultaneous measurement of flow and volume during maximal
expiration. Reduced expiratory flows at mid and low lung volumes are the earliest indicators of airflow
limitation in COPD and may be abnormal even when FEV1 is within the normal range (>80%).
C2.5 COPD case finding
28
The US Preventive Services Task Force reviewed the evidence on screening asymptomatic adults for
COPD using questionnaires or office-based screening pulmonary function testing from January 2000
to January 2015. The review found no direct evidence to determine the benefits and harms of screening
or to determine the benefits of treatment in screen-detected populations. On this basis, screening of
asymptomatic adults was not recommended (Guirguis-Blake 2016, U. S. Preventive Services Task
Force 2016). A targeted systematic review commissioned by the USPSTF to update the evidence on
the effectiveness of screening asymptomatic adults found no new studies over the subsequent period
January 1, 2015, to March 25, 2021 (Webber 2022) [evidence level I].
Simple lung function tools can assist practitioners in the case finding of individuals who have
undiagnosed COPD. The devices measure the amount of exhaled air in the first 1 and 6 seconds of
expiration (FEV1, FEV6) and calculate FEV1/FEV6, which is the ratio of the amount of air forcibly exhaled
in the first second relative to the first 6 seconds. Schnieders et al (2021) published a systematic review
and meta-analysis of the performance of micro-spirometers or two questionnaires compared to post-
bronchodilator spirometry for detection of COPD. The meta-analysis included 17 studies. The overall
area under the curve (AUC) of micro-spirometers was 0.84 (95% CI 0.80–0.89). For questionnaires
the AUC for the COPD population screener (COPD-PS) questionnaire was 0.77 (95% CI 0.63–0.85)
and the COPD diagnostic questionnaire (CDQ) was 0.72 (95% CI 0.64–0.78) (Schnieders 2021). If
spirometry is unavailable either a micro spirometer or questionnaire are useful tests for early detection.
Lung Foundation Australia’s Position Paper: COPD case finding in community settings,
https://lungfoundation.com.au/resources/copd-case-finding-position-paper/ recommends that
previously undiagnosed individuals aged 35 years or older should be assessed with the symptom
checklist, followed by a ‘COPD screening device’ with an FEV1/FEV6 cut-off < 0.75. Individuals with an
FEV1/FEV6 ratio < 0.75 should undergo formal diagnostic spirometry. Symptomatic individuals with an
FEV1/FEV6 ratio ≥ 0.75 should be encouraged to visit their general practitioner as they may be at risk
of other diseases or lung conditions and may require more formalised testing.1
In a retrospective analysis of health data in Canada (Johnson 2020), over 99% of people with COPD
had incurred at least one visit in any of the previous 5 years prior to recording of the diagnosis. This
study highlights the potential for earlier diagnosis, and intervention.
COPD is commonly undiagnosed, until presentation requiring a hospital admission. A review of 39

studies with a variety of case finding strategies, including five studies comparing earlier diagnostic
strategies with usual care, has found that postal questionnaire approaches had poor results, while
active opportunistic case finding through primary care had greater chance of detection (Haroon 2015).
Practice led symptom questionnaires of patients clinically suspected to have COPD, followed by
diagnostic assessment, had the best diagnostic yields. Widespread population screening for COPD is
not recommended (Guirguis-Blake 2016, U.S. Preventive Services Task Force 2016).
Based upon an analysis of 4,484 COPD subjects in the ‘Genetic Epidemiology of COPD cohort’, DeMeo
et al demonstrated that females are more susceptible to the effects of COPD than males with respect
to symptom burden, including severity of dyspnoea, and exacerbation risk, especially in younger
females. Given this greater COPD burden, the study highlighted the potential of under diagnosis as
well as under treatment of COPD in females (DeMeo 2018). Retrospective data suggests that females
are at higher risk of presenting with a moderate or severe exacerbation than men (Stolz 2019). A
large study (29,678) of randomly selected residents of Copenhagen aged between 40 and 80 found
11% had FEV1/FVC <0.70 and FEV1 <80% of predicted on pre-bronchodilator spirometry. Treatable
problems were identified in many of these participants, including smoking (45%), insufficient physical
activity (12%), obesity (28%), undiagnosed hypertension (28%) and undiagnosed
1
Level of evidence could not be assigned due to heterogeneity
29
hypercholesterolaemia (48%) (Çolak 2022).
Patients that are added to a COPD register as a result of a systematic screening programme (Haroon
2020) received significantly higher levels of appropriate clinical care. However only one in five case-
found patients were actually registered in the database to potentially go on to receive such care. Case
finding is only likely to improve clinical care if patients with newly identified disease are promptly
added to an active primary care COPD register.
C3. Assessing the severity of COPD

Diagnosis of COPD should be accompanied by regular assessment of severity
[evidence level III-2, strong recommendation]
Spirometry is the most reproducible, standardised and objective way of measuring airflow limitation,
and FEV1 is the variable most closely associated with prognosis (Peto 1983). The grades of severity
according to FEV1 and the likely symptoms and complications are shown in Box 4. However, it should
be noted that some patients with an FEV1 >80% predicted, although within the normal range, may
have airflow limitation (FEV1/FVC ratio <70%).
A Spanish cohort study of 611 COPD patients found that the British Thoracic Society classification
(which is very similar to Box 4) had the optimal sensitivity and specificity against the criterion of all
cause and respiratory mortality over 5 years (Esteban 2009). There were also significant differences
in health-related quality (HRQoL) of life between different stages of the disease [evidence level III-2].
Exacerbations are an important complication of COPD (see X: Manage eXacerbations). The future
risk of exacerbations should be assessed in patients with COPD. Exacerbations are more frequent with
increased severity of COPD. The most important risk factor for exacerbations is a history of past
exacerbations; other factors include gastro-oesophageal reflux, poorer quality of life and elevated
white cell count (Hurst 2010). A systematic literature review that included data from 76 studies
confirmed that a past history of exacerbations is the most important predictor of future exacerbation
risk (Hurst 2022) [evidence level I].
30
Box 4: Classification of severity of chronic obstructive pulmonary disease (COPD)
MILD MODERATE SEVERE
Few symptoms Breathless walking on Breathless on minimal

level ground exertion
Typical Symptoms Breathless on Increasing limitation of Daily activities severely

moderate exertion daily activities curtailed
Cough and sputum Recurrent chest infections Exacerbations of

production increasing frequency
and severity
Little or no effect on Exacerbations requiring
daily activities oral corticosteroids and/or
antibiotics
Typical Lung FEV1 ≈ 60-80% predicted FEV1 ≈ 40-59% predicted FEV1 < 40% predicted
Function
FEV1=forced expiratory volume in one second

Box adapted from Lung Foundation Australia’s Stepwise Management of Stable COPD available at
https://lungfoundation.com.au/resources/?search=stepwise
C4. Assessing acute response to bronchodilators

The response to bronchodilators is determined to:
● assign a level of severity of airflow limitation (post- bronchodilator); and
● help confirm asthma.
The details for this assessment are outlined in Box 5.
The change in FEV1 after an acute bronchodilator reversibility test indicates the degree of reversibility
of airflow limitation. This is often expressed as a percentage of the baseline measurement (e.g., 12%
increase). An increase in FEV1 of more than 12% and 200 mL is greater than average day-to-day
variability and is unlikely to occur by chance (Sourk 1983, Pellegrino 2005). An analysis of cross-
sectional data from 3,922 healthy never smokers in the BOLD study (Tan 2012) found that the 95th
percentiles (95% CI) for bronchodilator response were 284 ml (263 to 305) absolute change in forced
expiratory volume in 1 second from baseline. However, this degree of reversibility is not diagnostic of
asthma and is frequently seen in patients with COPD (e.g., the FEV1 increases from 0.8 L to 1.0 L
when the predicted value is, say, 3.5 L). The diagnosis of asthma relies on an appropriate history and
complete, or at least substantial, reversibility of airflow limitation (see also below).
31
Box 5: Assessment of acute response to inhaled beta-agonist at diagnosis
Preparation
● Patients should be clinically stable and free of respiratory infection.
● Withhold inhaled short-acting bronchodilators in the previous six hours, long-acting beta-agonists in the
previous 12 hours, or sustained-release theophyllines in the previous 24 hours.
Spirometry
● Measure baseline spirometry (pre-bronchodilator). An FEV1 <80% predicted and FEV1/FVC ratio <0.70 shows
airflow limitation.
● Give the bronchodilator by metered dose inhaler (MDI) through a spacer device or by nebuliser.
● Give short-acting beta-agonist, at a dose selected to be high on the dose–response curve (e.g., 200–400mcg
salbutamol from MDI and spacer).
Repeat spirometry 15–30 minutes after bronchodilator is given and calculate reversibility.
FEV1=forced expiratory flow in one second. FVC=forced vital capacity.
C4.1 Confirm or exclude asthma
If FEV1 increases > 400 ml following bronchodilator, consider asthma, or

coexisting asthma and COPD [evidence level III-2, strong recommendation]
Some patients may have coexisting COPD and asthma (Global Initiative for Asthma 2019). Asthma
usually runs a more variable course and dates back to a younger age. Atopy is more common, and the
smoking history is often relatively light (e.g., less than 15 pack-years). Airflow limitation in asthma is
substantially, if not completely, reversible, either spontaneously or in response to treatment. By
contrast, COPD tends to be progressive, with a late onset of symptoms and a heavier smoking history
(usually >15 pack-years) and the airflow limitation is not completely reversible.
Long-standing or poorly controlled asthma can lead to chronic, irreversible airway narrowing even in
non-smokers, thought to be due to airway remodelling resulting from uncontrolled airway wall
inflammation with release of cytokines and mediators.
Patients with COPD and features of asthma should receive inhaled corticosteroid therapy (to treat the
asthma component), as well as long-acting bronchodilators. LABA monotherapy should be avoided in
patients who have a component of asthma (Global Initiative for Asthma 2019).
C5. Specialist referral

Further investigations may help a) confirm or exclude other conditions (either
coexisting or with similar symptoms to COPD) and b) assess the severity of
COPD [evidence level III-2, strong recommendation]
Referral to specialist respiratory services may be required [evidence level III-2,

strong recommendation]
Confirmation of the diagnosis of COPD and differentiation from chronic asthma, other airway diseases
or occupational exposures that may cause airway narrowing or hyperresponsiveness, or both, often
requires specialised knowledge and investigations. Indications for which consultation with a respiratory
medicine specialist may be considered are shown in Box 6.
Box 6:Indication for referral to specialist respiratory outpatient services
32
Reason Purpose
Diagnostic uncertainty and exclusion of Establish diagnosis and optimise treatment.
asthma
Check degree of reversibility of airflow
Obstruction
Unusual symptoms such as haemoptysis Investigate cause including exclusion of
Malignancy
Rapid decline in FEV1 Optimise management
Moderate or severe COPD Optimise management
Onset of cor pulmonale Confirm diagnosis and optimise treatment
Assessment of home oxygen therapy: ambulatory or Optimise management, measure blood gases and
long-term oxygen therapy prescribe oxygen therapy
Assessing the need for Pulmonary Rehabilitation Optimise treatment and refer to specialist or
community-based rehabilitation service
Bullous lung disease Confirm diagnosis and refer to medical or surgical units
for bullectomy
COPD <40 years of age Establish diagnosis and exclude alpha1- antitrypsin
deficiency
Assessment for lung transplantation or lung volume Identify criteria for referral to transplant Centres
reduction surgery
Frequent chest infections Rule out co-existing bronchiectasis

Dysfunctional breathing Establish diagnosis and refer for pharmacological and
non-pharmacological management
FEV1, forced expiratory volume in 1s; COPD, chronic obstructive pulmonary disease. Box adapted from British Thoracic Society Statement
(British Thoracic Society 2008)
C5.1 Complex lung function tests
Other measurements of lung function such as static lung volumes and diffusing capacity of lungs for
carbon monoxide assist in the assessment of patients with more complex respiratory disorders.
Measurements such as inspiratory capacity (IC), which indicate the degree of hyperinflation and relate
to exercise tolerance (O'Donnell 2001) and mortality (Casanova 2005) and forced oscillometry, have
not yet found clinical application.
C5.2 Exercise testing
Cardiopulmonary exercise tests may be useful to differentiate between breathlessness resulting from
cardiac or respiratory disease, and may help to identify other causes of exercise limitation (e.g.,
hyperventilation, musculoskeletal disorder). Exercise prescription and monitoring of outcomes from
drug or rehabilitation therapies are additional uses for these tests. Walking tests (6-minute walking
distance and shuttle tests) are also useful, and can indicate whether exercise oxygen desaturation is
occurring.
C5.3 Sleep studies
Specialist referral is recommended for patients with COPD suspected of having a coexistent sleep
disorder or with hypercapnia or pulmonary hypertension in the absence of daytime hypoxaemia, right
heart failure or polycythaemia. Continuous overnight oximetry (with appropriate sampling frequency
and averaging time) may be used to assess a need for overnight domiciliary oxygen therapy, and may
be indicated in patients receiving long-term domiciliary oxygen therapy to assess whether hypoxaemia
has been adequately corrected.
33
C5.4 Chest x-rays
A plain posteroanterior and lateral chest x-ray helps to exclude other conditions such as lung cancer.
The chest x- ray is not accurate for the diagnosis of COPD (den Harder 2017) as hyperinflation is not
specific and will not exclude a small lung nodule (<1cm).
C5.5 High resolution computed tomography
High resolution computed tomography (HRCT) scanning gives precise images of the lung
parenchyma and mediastinal structures. The presence of emphysema and the size and number of
bullae can be determined. This is necessary if bullectomy or lung reduction surgery is being
contemplated. HRCT is also appropriate for detecting bronchiectasis. Vertical reconstructions can
provide a virtual bronchogram.
Helical computed tomography (CT) scans with intravenous contrast should be used in other
circumstances, such as for investigating and staging lung cancer.
CT pulmonary angiograms are useful for investigating possible pulmonary embolism, especially when
the chest x- ray is abnormal.
C5.6 Ventilation and perfusion scans
The ventilation and perfusion (V/Q) scan may be difficult to interpret in COPD patients because
regional lung ventilation may be compromised leading to matched defects. If pulmonary emboli are
suspected, a CT pulmonary angiogram may be more useful. Quantitative regional V/Q scans are helpful
in assessing whether patients are suitable for lung resection and lung volume reduction surgery.
C5.7 Transcutaneous oxygen saturation

Oximeters typically have an accuracy of plus or minus 2%, which is satisfactory for routine clinical
purposes. They are more useful for monitoring trends than in single measurements. If continuous
overnight oximetry is required, standard oximeters are not appropriate (See section C5.3). Oximetry
does not provide any information about carbon dioxide status and is inaccurate in the presence of poor
peripheral circulation (e.g., cold extremities, cardiac failure) and when readings are consistently below
SpO2 80%.
C5.8 Arterial blood gas measurement

Arterial blood gas analysis should be considered in all patients with severe disease, those being
considered for domiciliary oxygen therapy (e.g., whose FEV1 is <40% predicted or <1 L, whose oxygen
saturation as measured by pulse oximetry [SpO2] is <92%), those with pulmonary hypertension, and
those with breathlessness out of proportion to their clinical status). Respiratory failure is defined as a
PaO2<60mmHg (8kPa) or PaCO2 >50mmHg (6.7kPa). The latter is termed ‘ventilatory failure’ and is
accompanied by either compensated (chronic) or uncompensated (acute) acidosis. Acute respiratory
acidosis indicates a need for assisted ventilation.
C5.9 Sputum examination
Routine sputum culture in clinically stable patients with COPD is unhelpful and unnecessary. Sputum
culture is recommended when an infection is not responding to antibiotic therapy or when a resistant
organism is suspected.
34
C5.10 Haematology and biochemistry
Polycythaemia should be confirmed as being secondary to COPD by blood gas measurement that
demonstrates hypoxaemia. The possibility of sleep apnoea or hypoventilation should be considered if
polycythaemia is present but oxygen desaturation or hypoxaemia on arterial blood gas tests are absent
when the patient is awake.
Hyperthyroidism and acidosis are associated with breathlessness. Hyperventilation states are
associated with respiratory alkalosis. Hypothyroidism aggravates obstructive sleep apnoea. Harrison
et al 2014 performed a multicentre prospective study of exacerbations of COPD requiring hospital
admission in 1343 patients with spirometry confirmed COPD. The authors reported the novel finding
of an association between thrombocytosis (>400/mm3 on admission) and mortality. Thrombocytosis
(after controlling for confounders) was associated with an increased 1-year all-cause mortality and an
increased in hospital mortality (OR 1.53 (95% CI 1.03 to 2.29, p=0.030) and OR 2.37 (95% CI 1.29
to 4.34, p=0.005)) respectively (Harrison 2014) [evidence level III-2].
The Thoracic Society of Australia and New Zealand Alpha1 Antitrypsin Deficiency Position Statement
indicates that testing for alpha1 antitrypsin deficiency (AATD) should be considered in all patients with
chronic airflow obstruction (Dummer 2020). The prevalence of severe homozygous AATD has been
estimated at approximately 1 in 4,500 in European populations (Blanco 2006). Available data from 15
cohorts in Australia and New Zealand suggest that the prevalence of affected individuals is around 1
in 4,000 (de Serres 2002). Tobacco smoking is still the most important risk factor for COPD even in
this group.
C5.11 Electrocardiography and echocardiography

Cardiovascular disease is common in patients with chronic obstructive pulmonary disease but is often
under-recognised. Electrocardiography (ECG) may be useful to alert the clinician to its presence. In a
retrospective Dutch study of patients entering pulmonary rehabilitation, ischaemic changes were
present on ECG in 21% of all patients and in 14% of those without reported cardiovascular co-
morbidity (Vanfleteren 2011). Electrocardiography is also indicated to confirm arrhythmias suspected
on clinical grounds. Multifocal atrial tachycardia is a rare arrhythmia (prevalence < 0.32% of
hospitalised patients) but over half the cases reported in the literature had underlying COPD (McCord
1998). Atrial fibrillation commonly develops when pulmonary artery pressure rises, leading to
increased right atrial pressure.
Echocardiography is useful if cor pulmonale is suspected, when breathlessness is out of proportion

to the degree of respiratory impairment or when ischaemic heart disease, pulmonary embolus or left
heart failure are suspected. Patients with COPD may have poor quality images on transthoracic
examination and transoesophageal echocardiography may be frequently needed.
Patients with COPD are prone to other conditions associated with cigarette smoking, including
accelerated cardiovascular, cerebrovascular and peripheral vascular disease, and oropharyngeal,
laryngeal and lung carcinoma. Conversely, there is a high prevalence of COPD among patients with
ischaemic heart disease, peripheral vascular disease and cerebrovascular disease and smoking-related
carcinomas (National Heart Lung and Blood Institute 1998). These patients should be screened for
symptoms of COPD, and spirometry should be performed.
35
C5.12 Trials of Therapy
The evidence supporting the utility of specific diagnostic tests in COPD is typically not of the same
strength as that for specific therapies reviewed in subsequent sections. The evidence base for tests
used in the diagnosis and monitoring of several respiratory diseases at one specialist referral clinic
was reviewed by Borrill et al (Borrill 2003). They were unable to identify any evidence to support the
use of peak flow charts to assess treatment with inhaled steroids in patients with pre-diagnosed COPD.
Studies were found that did not support the diagnostic use of trials of therapy with inhaled or oral
steroids in COPD. There was no evidence to support the diagnostic use of trials of therapy with short
or long-acting bronchodilators or oral theophyllines in COPD. However, it should be remembered that
absence of evidence is not the same as evidence of absence of utility.
36
O: Optimise function
Assessment is the first step to optimising function [evidence level III-2, strong
recommendation]
Optimise pharmacotherapy using a stepwise approach [evidence level I, strong

recommendation]
THE PRINCIPAL GOALS OF THERAPY are to stop smoking, to optimise function through symptom relief
with medications and pulmonary rehabilitation, and to prevent or treat aggravating factors and
complications. Adherence to inhaled medications regimes is associated with reduced risk of death
and admissions to hospital due to exacerbations in COPD (Vestbo 2009) [evidence level II].
Confirm goals of care

Addressing the goals of care is one of the most complex clinical issues in the management of COPD.
● Active therapy: In the early stages of the disease the goals of care must be to delay the
progress of the disease by aggressive treatment of exacerbations in order that patient function
is optimised, and their health is maintained. In this setting management of disease may provide
the best symptom control. Should the goal of health maintenance not result in adequate
symptom control then a palliative approach may also be required to augment active therapy.
During this period of the patient’s disease trajectory any change in therapy should be seen as
an opportunity to review the goals of care in general terms with the patient. Optimal
management of any individual patient with COPD must include careful management of
comorbidities and anticipation of increased risks associated with those comorbidities in the
presence of COPD.
● Active therapy with treatment limitations: The transition phase of health maintenance to
functional deterioration despite maximal therapy is difficult to define. The burden of disease
and care fluctuates, and it may be appropriate to encourage discussion about long term goals
prognosis and attitudes to future treatment and care plans can be encouraged. The initiation
of long-term oxygen therapy and functional deterioration have been found to be an important
point at which patient’s may be receptive to reviewing the goals of care, end of life care and
treatment limitations.
● Palliative and supportive care: Functional deterioration in the presence of optimum

treatment requires a reappraisal of the goals of care. Each exacerbation may be reversible until
there is a suboptimal or no response to treatment. At this point the patient may enter their
terminal phase and the goals of care may change rapidly to palliation with treatment limitations
or palliation alone with withdrawal of active therapy. In this setting (unstable, deterioration or
terminal care) the goals of care need to shift from active therapy to one of palliation. Should
the patient recover despite a palliative approach then the goals of care may continue to be
active management in preparation for the next crisis. A review of symptom management, end
of life care issues, and advanced directives should take place to prepare for the next crisis.
37
● Terminal care: Terminal care plans may be appropriate for patients who elect to avoid active
management. These plans need to be communicated to all services involved in the care of the
patient so that there is a continuity of care. In this situation the goals of care should be clearly
communicated and the advanced directive, terminal care plan and the location of care
documented. Patients may elect to be treated palliatively in their terminal phase 2 by their
respiratory physician owing to their long-standing relationship with the clinician. Terminal care
does not always require specialist palliative care unless there are problems with symptom
control or other complex needs. Hospice or specialist consultations should be available to
patients should they be required.
O1. Inhaled bronchodilators

See Appendix 1. Use and doses of long-term inhaled bronchodilator and corticosteroids determined
in response trials
O1.1 Short-acting bronchodilators
O1.1.1 Short-acting beta2-agonists (SABA)

Regular short-acting beta2-agonists improve lung function and daily breathlessness scores. A
systematic review of randomised controlled trials (Ram 2003) found a significant increase in post-
bronchodilator spirometry when compared to placebo; weighted mean difference = 140 ml (95% CI
40 to 250) for FEV1 and 300 ml (95% CI 20 to 580) for forced vital capacity (FVC). There were also
improvements in post-bronchodilator morning and evening PEF: weighted mean difference = 29.17
l/min (95% CI 0.25 to 58.09) for morning and 36.75 l/min (95% CI 2.57 to 70.94) for evening
measurements. The relative risk of dropping out of the study was 0.49 (95% CI 0.33 to 0.73), giving
a number needed to treat of 5 (95% CI 4 to 10) to prevent one treatment failure. There was no
significant benefit on functional capacity, measured by walking tests, or symptoms other than
breathlessness, although one randomised controlled trial has found a significant improvement in 6-
minute walking distance and quality of life (Guyatt 1987). Short-acting beta2-agonists are now usually
prescribed for use as “rescue” medication, i.e. for relief of breathlessness, rather than for regular use.
O1.1.2 Short-acting muscarinic antagonists (SAMA)

Bronchodilators such as ipratropium, tiotropium, glycopyrronium, aclidinium and umeclidinium are not
‘anticholinergics’ since they are unable to antagonize the effects of acetylcholine on nicotinic receptors.
They only block the muscarinic effects of acetylcholine. The word ‘anticholinergic’ suffers from
pharmacodynamic approximation and should be replaced by ‘antimuscarinic’ (if we consider the
involved receptor) or ‘atropinic’ (in relation to the pharmacodynamics effects of this drug class)
(Montastruc 2010).
The duration of action of short-acting muscarinic antagonists (formerly known as anticholinergics) is

greater than short-acting beta2-agonists. A systematic review of randomised controlled trials
comparing ipratropium bromide alone, or in combination with short-acting beta2-agonists, against
short-acting beta2-agonists alone found significant benefits for regimens containing ipratropium
bromide (Appleton 2006). Ipratropium bromide improved spirometry over short-acting beta2-agonists
alone, weighted mean difference = 30 ml (95% CI 0 to 60) for FEV1 and 70 ml (95% CI 10 to 140) for
forced vital capacity (FVC). Ipratropium bromide improved quality of life, with a statistically significant
2
Terminal Phase is characterised by the following criteria:
1. Profound weakness
2. Essentially bedbound (ECOG 4)
3. Drowsy for extended periods
4. Disorientated to time with poor attention span
5. Disinterested in food or fluids
6. Difficulty swallowing medications
38
improvement in all domains of the Chronic Respiratory Disease Questionnaire (CRQ). These benefits
occurred with fewer minor adverse drug effects, Number Needed to Harm (NNH) = 32 (95% CI 20 to
316). There was a lesser need to add or increase the dose of oral corticosteroids for participants
receiving ipratropium bromide, with 15 (95% CI 12 to 28) people requiring treatment with ipratropium
bromide to prevent one receiving additional oral corticosteroids.
However, some studies have found that ipratropium bromide is associated with an increased risk of
adverse cardiovascular effects (Lee 2008, Singh 2008, Ogale 2010). A nested case-control study (Lee
2008) [evidence level III-2] found an increased risk of cardiovascular death associated with the
prescription of ipratropium, OR 1.34 (95% CI 1.22 to 1.47). A meta-analysis of randomised controlled
trials (Singh 2008) found an increased risk for a combined cardiovascular endpoint of cardiovascular
death, myocardial infarction and stroke, estimated NNH for cardiovascular death 40 (95% CI 18 to
185) per year. The consistent finding across these studies suggests the cardiovascular adverse effects
are likely to be real [evidence level I].
A Cochrane meta-analysis comparing treatment with tiotropium [HandiHaler or Respimat] with

ipratropium bromide (via MDI) for patients with stable COPD found that tiotropium treatment, was
associated with improved lung function, fewer hospital admissions (including those for exacerbations
of COPD), fewer exacerbations of COPD and improved quality of life. There were both fewer serious
adverse events and disease specific events in the tiotropium group, but no significant difference in
deaths with ipratropium bromide when compared to tiotropium. Thus, tiotropium appears to be a
reasonable choice (instead of ipratropium bromide) for patients with stable COPD (Cheyne 2015).
O1.1.3 Short-acting bronchodilator combinations

For combination therapy with ipratropium bromide and short-acting beta2-agonists, there was no
significant difference in pre-drug spirometry compared to ipratropium bromide alone (Appleton 2006).
There was a significant benefit for the combination in post-drug spirometry measurements; weighted
mean difference = 70 ml (95% CI 50 to 90) for FEV1 and 120 ml (95% CI 80 to 160) for forced vital
capacity (FVC). There was no significant difference between interventions for quality of life or adverse
drug effects, but combination treatment decreased the need to add or increase oral corticosteroids
compared to ipratropium bromide alone, Number Needed to Treat = 20 (95% CI 12 to 108).
In summary, short-acting bronchodilators, either beta2-agonists or ipratropium bromide, significantly

increase lung function measurements in COPD. Ipratropium bromide has a significantly greater effect
on lung function compared to beta2-agonists alone; in addition to improving quality of life and
decreasing need for oral corticosteroid treatment. These benefits occurred with a decreased risk of
adverse drug effects. Combining two classes of bronchodilator may provide added benefits without
compounding adverse effects.
O1.2 Long-acting bronchodilators
Long-acting bronchodilators produce significant improvements in lung function, symptoms and quality
of life (Braido 2013), as well as decreasing exacerbations. These benefits come at a cost of increased
adverse effects, which are generally of mild to moderate severity.
O1.2.1 Long-acting muscarinic antagonists (LAMA)
39
Long-acting muscarinic antagonists (LAMAs) result in bronchodilation with a duration of action of 12
to 24 hours, depending on the agent. A number of LAMAs are available in Australia, which are delivered
via a range of devices:
- aclidinium (Genuair)
- glycopyrronium (Breezhaler)
- tiotropium (HandiHaler, Respimat)
- umeclidinium (Ellipta)
Aclidinium: Aclidinium is a twice daily LAMA. A Cochrane systematic review of 12 RCTs (9,547
participants) showed that, compared to placebo, aclidinium resulted in marginal improvements in
quality of life and FEV1, and reduced the number of patients with exacerbations requiring
hospitalisation (NNT 77, 95% CI 51 to 233) (Ni 2014) [evidence level I]. Aclidinium has also been
shown to reduce the rate of moderate to severe exacerbations (OR 0.80) (Wedzicha 2016a) [evidence
level I] without increasing major adverse cardiovascular events (Wise 2019) [evidence level II].
Glycopyrronium: Once daily glycopyrronium demonstrated significant improvement in spirometry

and a reduction in the rate of moderate to severe exacerbations, but no difference in quality of life,
compared with placebo (D'Urzo 2011, Kerwin 2012) [evidence level II]. In an RCT comparing
glycopyrronium to tiotropium, there was no difference in FEV1, dyspnoea, quality of life, exacerbation
rate or adverse effects (Chapman 2014) [evidence level II].
Tiotropium: Once daily tiotropium resulted in improved quality of life, and reduced exacerbation rates
(OR 0.78, 95% CI 0.70 to 0.87; NNT 16, 95% CI 10 to 36) compared to placebo, in a Cochrane
systematic review of 22 studies (23,309 participants) (Karner 2014) [evidence level I]. Tiotropium
improved FEV1 (mean difference 119 mL, 95% CI 113 to 125), and there was no overall difference in
mortality. In a 2-year RCT of 841 COPD patients with post-bronchodilator FEV1 >50% predicted,
tiotropium resulted in a significantly higher FEV1 (mean difference of 157 ml, 95% CI 123 to 192) and
reduced annual decline in post-bronchodilator FEV1 (mean difference 22 ml per year, 95% CI 6 to 37),
compared to placebo (Zhou 2017) [evidence level II]. However, there was a high withdrawal rate and
40% were current smokers.
Compared to ipratropium, tiotropium had beneficial effects for quality of life, dyspnoea and
exacerbation rates (Yohannes 2011b) [evidence level I]. Compared to LABAs, tiotropium reduced
exacerbation rates (Vogelmeier 2011, Decramer 2013) [evidence level II], whereas effects were
heterogeneous for quality of life, compared to various LABAs (Chong 2012, Decramer 2013) [evidence
level II].
Umeclidinium: Once-daily umeclidinium significantly improved lung function, dyspnoea and quality
of life, compared with placebo (Trivedi 2014) [evidence level II]. Umeclidinium resulted in a greater
improvement in FEV1 than tiotropium, but there were no significant differences between umeclidinium
and tiotropium for dyspnoea, St George’s Respiratory Questionnaire (SGRQ) or COPD Assessment Test
(CAT) scores (Feldman 2016) [evidence level II].
Adverse effects of LAMAs include dry mouth, constipation and urinary retention (Halpin 2015). A
safety study showed similar rates of death and exacerbations with tiotropium HandiHaler and
tiotropium Respimat (Wise 2013) [evidence level II].
Network meta-analyses of LAMAs: A network meta-analysis of LAMAs versus placebo showed that
there were no statistically significant differences among LAMAs in preventing moderate-to-severe
COPD exacerbations (Oba 2015) [evidence level I]. Tiotropium HandiHaler was the only LAMA
formulation which reduced severe exacerbations (HR 0.73; 95% CrI 0.60– 0.86). Another network
meta-analysis showed that current LAMAs have similar efficacy for change in FEV 1, SGRQ, dyspnoea
and rescue medication use (Ismaila 2015) [evidence level I]. However, with few head-to-head
40
comparisons of LAMAs available, the choice of LAMA and inhaler device depends on patient and clinician
preferences.
A meta-analysis of 9 studies of LAMA versus LABA inhalers (17,120 COPD patients, with tiotropium
as the most common LAMA) showed that LAMAs had reduced exacerbation rates (RR 0.88, 95% CI
0.84 to 0.93) and exacerbation-related hospitalisations (RR 0.78, 95% CI 0.69 to 0.87), compared to
LABAs (Maia 2017) [evidence level I].
O1.2.2 Long-acting beta2-agonists (LABA)

Long-acting beta2-agonists cause prolonged bronchodilatation with a duration of action of 12 to 24
hours. Indacaterol is available in Australia on PBS as a monocomponent LABA inhaler for the
management of COPD. This and other LABAs (salmeterol, formoterol, vilanterol, olodaterol) are also
available as combination LAMA/LABA, ICS/LABA or ICS/LABA/LAMA inhalers.
Indacaterol is an inhaled LABA that is given as a once daily maintenance therapy for COPD. Compared
to placebo, indacaterol improves dyspnoea, FEV1 and health-related quality (HRQoL) of life, and
reduces exacerbations (Geake 2015) [evidence level I]. Compared with twice daily beta2-agonists
(salmeterol and formoterol) indacaterol did not lead to a clinically significant difference in FEV 1,
dyspnoea or quality of life (Geake 2015).
The bronchodilator effects of indacaterol are at least as good as tiotropium (Donohue 2010). Once-
daily treatment with indacaterol via Breezhaler (150 μg) or tiotropium bromide via HandiHaler (18 μg)
in patients with severe COPD and a history of exacerbations gave equally effective and clinically
relevant improvements in lung function, health status, and breathlessness. Patients receiving
indacaterol had a 29% higher annual rate of exacerbations versus patients receiving tiotropium
(Decramer 2013).
Comparison with LAMAs: A meta-analysis of 16 randomised, double-blinded controlled trials which

included 22,872 patients with moderate to severe or very severe COPD with a treatment period ranging
from 12 to 52 weeks found that LAMAs were associated with a lower risk of acute exacerbations (OR
0.84, 95% CI 0.74–0.90; P = 0.004) and lower incidence of adverse events (OR 0.92, 95% CI 0.86–
0.98; P = 0.007) compared with LABAs (Chen 2017). There were no significant differences between
LAMAs and LABAs in terms of changes in lung function, symptom score, health status and serious
adverse events. LAMA may be preferable to LABA in patients with stable COPD, especially in those at
risk of frequent exacerbations.
Adverse effects: A meta-analysis of 24 clinical trials (Xia 2015) of inhaled LABAs (salmeterol,
formoterol, indacaterol, vilanterol, olodaterol, aformoterol) for COPD of any severity with at least 3
months follow-up (12,291 received a LABA and 7,784 received placebo) found that LABAs were
associated with a lower rate of fatal cardiovascular events compared with placebo (RR 0.65, 95% CI
0.50 to 0.86, P = 0.002). This is contradictory to the findings of a meta-analysis of 33 trials lasting
from 3 days to 1 year, in which beta2-agonist treatment significantly increased the risk for a
cardiovascular event (relative risk [RR], 2.54; 95% CI 1.59 to 4.05) compared to placebo (Salpeter
2004). The RR for sinus tachycardia alone was 3.06 (95% CI 1.70 to 5.50), and for all other events it
was 1.66 (95% CI 0.76 to 3.6). Post hoc analysis of the 3-year TORCH dataset found that the
probabilities of having a cardiovascular adverse event by 3 years were similar for placebo (24.2%),
salmeterol (22.7%), fluticasone propionate (24.3%) and salmeterol-fluticasone propionate
combination (20.8%) (Calverley 2010). Cardiac safety of LABAs is less clear when used inappropriately
(e.g. overdosing) or in patients with COPD and substantial cardiovascular disease, prolonged QTc
interval, or polypharmacy (Lahousse 2016a).
O1.2.3 Long-acting bronchodilator combinations (LAMA/LABA)
41
A number of LAMA/LABA fixed dose combinations in a single inhaler are available in Australia, which
are delivered via a range of devices:
● aclidinium/formoterol (Genuair)
● glycopyrronium/indacaterol (Breezhaler)
● tiotropium/olodaterol (Respimat)
● umeclidinium/vilanterol (Ellipta)
Aclidinium/formoterol: Twice daily aclidinium/formoterol had greater bronchodilation over placebo

(mean FEV1 up to 143 ml greater), and to a lesser extent, versus. formoterol (mean FEV1 53 ml greater)
or aclidinium (small differences at various timepoints) (Bateman 2015, D'Urzo 2014, Singh 2014b)
[evidence level II]. There were some improvements in dyspnoea and health-related quality of life
(HRQoL), measured by St George’s Respiratory Questionnaire (SGRQ). Aclidinium/formoterol reduced
the rate of moderate to severe exacerbations by 29%, when compared to placebo, but not when
compared to aclidinium or formoterol alone (Bateman 2015). In a systematic review of seven trials
(Ni 2018), the aclidinium/formoterol fixed dose combination (FDC) was found to improve dyspnoea
and lung function compared to the monocomponents or placebo. Quality of life (SGRQ) was better
with the combination compared to formoterol or placebo. There was no difference between the FDC
and monotherapy or placebo for hospital admissions, mortality, and non-fatal adverse events. A lower
risk of moderate exacerbations was observed with the FDC compared to formoterol but not with the
FDC compared with aclidinium [evidence level I].
Glycopyrronium/indacaterol: Once daily indacaterol/glycopyrronium had greater bronchodilation

compared with glycopyrronium, indacaterol, tiotropium (Bateman 2013) or placebo (Bateman 2013,
Dahl 2013, Wedzicha 2013) [evidence level II]. Moderate to severe exacerbations were reduced by
12% with indacaterol/glycopyrronium, compared to glycopyrronium (Wedzicha 2013). These benefits
were supported by systematic reviews (Ulrik 2014, Rodrigo 2014) [evidence level I].
Tiotropium/olodaterol: Once daily tiotropium/olodaterol significantly improved lung function,

quality of life (SGRQ total score) and breathlessness (transition dyspnoea index), compared to
tiotropium or olodaterol (Miravitlles 2017) [evidence level I]. However, patients taking
tiotropium/olodaterol 5 μg/5 μg and tiotropium 5 μg (two puffs once daily via the Respimat device)
had no significant differences in moderate and severe exacerbation rate (rate ratio [RR] 0·93, 99% CI
0·85–1·02;p=0·0498) and time to first moderate or severe event ([HR] 0·95, 99% CI 0·87–1·03;
p=0·12) over a 52-week treatment period compared to tiotropium alone (Calverley 2018b) [evidence
level II].
Umeclidinium/vilanterol: Once-daily umeclidinium/vilanterol improved lung function and

symptoms, when compared with placebo (Donohue 2013, Donohue 2014) [evidence level II].
Systematic reviews of umeclidinium/vilanterol have shown improved FEV 1, reduced dyspnoea and
reduced rate of exacerbations, when compared with umeclidinium or vilanterol (Rodrigo 2015, Guo
2016a) [evidence level I].
Systematic reviews of LAMA/LABA combinations: A meta-analysis and systematic review of

results of 8,641 participants in 22 double blinded RCTs comparing a once-daily LAMA/LABA
combination with placebo demonstrated similar clinically and statistically significant differences with
each of the inhalers with respect to St George’s Respiratory Questionnaire (SGRQ) quality of life (4.1
units), and improvement in FEV1 (200mls). Of the four once-daily LAMA/LABA combinations studied,
only the combination of umeclidinium/vilanterol (using the Ellipta inhaler device) was evaluated with
respect to the outcome of exacerbation rate, with an overall pooled rate reduction of 47% in three
studies (Maqsood 2019) [evidence level I].
A systematic review of 24 studies (n=45,441 participants) found statistically significant reductions in

hospital admissions (risk ratio 0.89, 95% CI 0.82 to 0.97) and exacerbations (risk ratio 0.80, 95% CI
42
0.69 to 0.92) with LAMA/LABA combination therapy, compared with LAMA or LABA monotherapy
(Mammen 2020b) [evidence level I]. Reductions in dyspnoea and health-related quality of life did not
reach MCID.
Network meta-analyses of LAMA/LABA: Because head-to-head studies of all relevant treatment

options may not be available, indirect comparisons of treatments using a technique comparing relative
effects against a common comparator (network meta-analysis) offers a way of comparing the relative
effects of treatment. A network meta-analysis was undertaken for dual combination inhalers compared
with single-agent long-acting bronchodilators (Oba 2018) [evidence level I]. In the network meta-
analysis, LAMA/LABA inhalers decreased the rate of moderate to severe exacerbations compared to
ICS/LABA (HR 0.86, 95% credible interval (CrI) 0.76 to 0.99), LAMA (HR 0.87, 95% CrI 0.78 to 0.99),
and LABA (HR 0.70, 95% CrI 0.61 to 0.80) in frequent exacerbators (moderate certainty of evidence),
with LABA being the least beneficial. However, the evidence was not statistically significant in some of
the pairwise meta-analyses between treatments.
Comparisons of LAMA/LABA versus ICS/LABA: In the FLAME study, indacaterol /glycopyrronium

once daily was compared to fluticasone/salmeterol twice daily in an RCT of 3,362 patients with
moderate to severe COPD, who had a history of at least one exacerbation in the previous year
(Wedzicha 2016b). Patients receiving indacaterol/glycopyrronium had a lower annual rate of
exacerbations (rate ratio 0.89; 95% CI 0.83 to 0.96). Trough FEV1 was 62 ml higher at 52 weeks and
SGRQ was 1.8 points lower with indacaterol/glycopyrronium although these changes were of unclear
clinical significance. The reduction of exacerbations was independent of baseline eosinophil count and
use of inhaled corticosteroids at time of recruitment (Roche 2017).
A Cochrane systematic review analysed 11 RCTs (9,839 patients) studying LAMA/LABA versus.
ICS/LABA therapy (Horita 2017). Compared to ICS/LABA, LAMA/LABA resulted in a small reduction in
the rate of exacerbations (OR 0.82, 95% CI 0.70 to 0.96), no significant change in mean SGRQ score
(although there was a higher proportion achieving the MCID) and a small improvement in FEV1 (mean
difference 0.08 L, 95% CI 0.06 to 0.09). Pneumonia rates were lower, and there was no change in
mortality. The studies were heterogeneous in study design and of relatively short duration, and the
evidence was of low to moderate quality. Even with these limitations, this systematic review supports
the use of LAMA/LABA fixed dose combinations over ICS/LABA inhalers, when initiating long-acting
inhaled medicines. Further RCTs of ICS/LABA/LAMA in a single inhaler are awaited, to clarify their
efficacy compared to LAMA/LABA. See Appendix 5. Table of Minimum Clinically Important Differences.
43
O1.3 Assessment of response and continuation of bronchodilator therapy
In some patients a response to bronchodilator therapy may require treatment for up to two months.
Symptomatic and functional benefits can often be demonstrated in the absence of an increase in FEV1.
Other objective measurements, such as an increase in exercise capacity (e.g., as measured using a
walking test such as the 6-minute walk test or the incremental or endurance shuttle walking test
(Pepin 2007, Pepin 2005) or an increased inspiratory reserve capacity, may be useful indicators of
physiological improvement.
Subjective measurements, such as quality of life, breathlessness and functional limitation (e.g. MRC
Dyspnoea Scale), can determine the patient’s perception of benefit. If there is no improvement:
● check inhaler technique;

● consider psychosocial issues and deconditioning; and
● exclude other causes of exercise impairment (consider specialist referral or a cardiopulmonary
exercise test).
O2. Oral bronchodilators

O2.1 Methylxanthines
Theophylline is rarely used for COPD in Australia. A small, randomised placebo-controlled trial in
China demonstrated that doses of 100mg twice daily reduced exacerbations compared with placebo
(Zhou 2006). In this study, patients were not on inhaled corticosteroids or long-acting bronchodilators
which limits the generalisability of the study findings. Devereux et al randomised 1,567 UK-based
COPD patients with a history of exacerbations to theophylline or placebo. All patients were receiving
inhaled corticosteroids and 80% of patients were on ‘triple-therapy’ (Devereux 2018). An RCT of low
dose theophylline plus low dose oral prednisone, theophylline or placebo in 1,670 patients with COPD
in China found no statistically significant differences in exacerbation rates, hospitalisations, FEV1,
SGRQ and CAT scores at 48 weeks (Jenkins 2020) [evidence level II].
A meta-analysis of 4 RCTs and 3 cohort studies (n=47,556) examined the addition of theophylline
to inhaled corticosteroids. Of the 7 studies reviewed, 4 used an ICS/LABA combination, 2 used ICS
alone and 1 trial did not specify. Theophylline was associated with a higher hospitalization rate (HR
1.12, 95% CI 1.10-1.15), and mortality (HR 1.19, 95% CI 1.14-1.25) (Shuai 2021) [evidence level
I].
Based on the available evidence, theophylline cannot be recommended for patients with COPD.
O2.2 Phosphodiesterase type-4 inhibitors
Phosphodiesterase type-4 (PDE-4) inhibitors act by increasing intracellular concentrations of cyclic

adenosine monophosphate (cAMP) to suppress inflammation and bronchoconstriction. A Cochrane
Review analysed results from RCTs of roflumilast (20 trials, 17,627 patients) and cilomilast (14 trials,
6,457 patients) (Chong 2017) [evidence level I]. Compared to placebo, PDE-4 inhibitors improved
FEV1 (mean difference 51 ml, 95% CI 43 to 60, moderate quality evidence) and reduced exacerbation
rates (OR 0.78, 95% CI 0.73 to 0.83, high quality evidence; NNTB 20, 95% CI 16 to 26), but had
relatively small effects on quality of life and symptoms. Gastrointestinal adverse effects were more
frequent with the PDE-4 inhibitors, and psychiatric adverse events such as insomnia and depressive
mood symptoms were more frequent with roflumilast (OR 2.13, 95% CI 1.79 to 2.54). These oral
agents are not currently available in Australia.
44
O3. Corticosteroids
O3.1 Oral corticosteroids
Long term use of systemic corticosteroids is not recommended (Postma 1988, Postma 1985,
Decramer 1996, Decramer 1994, Decramer 1992) [evidence level I]. Indeed, caution in the long-
term use of systemic corticosteroids is necessary because of limited efficacy and potential toxicity in
elderly patients. Some patients with stable COPD show a significant response to oral corticosteroids
(on spirometry or functional assessment). Therefore, a short course (two weeks) of prednisolone (20–
50mg daily) may be tried with appropriate monitoring. Short courses of oral corticosteroids (<14 days)
do not require tapering. A negative bronchodilator response does not predict a negative steroid
response (Senderovitz 1999). If there is a response to oral steroids, continued treatment with inhaled
corticosteroids is indicated, but these may fail to maintain the response (Senderovitz 1999, Vestbo
1999).
O3.2 Inhaled corticosteroids (ICS)
Exacerbations have a detrimental effect on quality of life, and patients with severe disease and
frequent exacerbations have an accelerated decline in their quality of life (Miravitlles 2004).
A Cochrane systematic review (Yang 2023a) of studies of long-term (more than 6 months) ICS
monotherapy compared to placebo, in people with stable COPD has found that ICS monotherapy likely
reduces the rate of clinically relevant COPD exacerbations (0.05 exacerbations per participant per
year, 95% CI −0.07 to −0.02; vs 0.88 exacerbations per participant per year, 95% CI 0.82 to 0.94),
and probably slows the rate of decline of lung function (FEV1) (MD 6.31 mL/year benefit, 95% CI 1.76
to 10.85), although the magnitude of this change is of unclear clinical relevance. ICS as monotherapy
likely results in a small improvement in health-related quality of life measures without meeting the
threshold for a clinically important difference (MD −1.22 units/year, 95% CI −1.8 3 to −0.60) but
there is probably no reduction in all-cause mortality (OR) 0.94, 95% CI 0.84 to 1.07). The potential
benefits of ICS as monotherapy must be weighed against the potential adverse events such as a likely
increase in the risk of pneumonia (OR 1.38, 95% CI 1.02 to 1.88), increased risk of oropharyngeal
candidiasis (OR 2.66, 95% CI 1.91 to 3.68) and hoarseness (OR 1.98, 95% CI 1.44 to 2.74) [evidence
level I].
A nested case-control analysis of a new-user database cohort of 103,386 patients treated with
inhaled corticosteroids in Quebec during 1999-2005 found that cessation of inhaled corticosteroids was
associated with a 36% decrease in the rate of severe pneumonia events defined as hospitalisation or
death from pneumonia during the study period (Suissa 2015). 14,020 patients had a serious
pneumonia episode during 4.9 years of follow-up (incidence rate 2.8/100/year). The decreasing rate
of serious pneumonia occurred rapidly, going from 20% reduction in the first month to 50% reduction
by the fourth month after discontinuation. The risk reduction was more marked with cessation of
fluticasone than cessation with budesonide.
Inhaled corticosteroids alone do not improve mortality, with pooled results from nine studies
involving 8,390 participants showing an odds ratio of death of 0.98 (95% CI 0.83-1.16). The effect of
inhaled corticosteroids on the rate of decline in lung function is inconsistent. Pooled results from studies
of six months duration or longer, show either no significant difference in the rate of decline in post-
bronchodilator FEV1 (generic inverse variance analysis: weighted mean difference of 5.8 ml/year (95%
CI -0.28-11.88, 2,333 participants) or a small statistically significant difference (pooled means
analysis: 6.88 ml/year, 95% CI 1.80-11.96, 4823 participants, with the inclusion of the TORCH study
(Calverley 2007, Yang 2023).
A comprehensive overview by Miravitlles et al (2021) of the risks associated with the use of ICS in
patients with COPD found an increased risk of local disorders such as oral candidiasis and dysphonia
45
and infectious adverse events such as pneumonia [evidence level I]. The pooled analysis of 16 RCTs
with n=33,725 participants showed that exposure to ICSs almost tripled the risk of oral candidiasis
(RR 2.89, 95% CI 2.36–3.55; p<0.00001). The pooled analysis of nine RCTs with 22 841 participants
showed that exposure to ICS increased the risk of dysphonia by 277% (RR 3.77, 95% CI 2.81–5.05;
p<0.00001; I2=0%). The pooled analysis of 19 RCTs with 66 485 participants showed that exposure
to ICSs for ⩾1 year increased the risk of pneumonia by 41% (RR 1.41, 95% CI 1.23–1.61; p<0.00001;
I2=55%). An interaction was found between the risk of pneumonia and the type of ICS used, with the
highest risk being associated with fluticasone (10 studies with 45870 participants), whereas exposure
to budesonide (six studies with 13 479 participants) was not associated with an increased risk of
pneumonia (Miravitlles 2021). A dose–response relationship was observed, indicating that lower doses
of ICS should be used in patients with COPD whenever possible. The risks of diabetes, osteoporosis,
bone fractures and eye disorders are less clear.
In people with COPD and diabetes mellitus, particular care should be taken not to exceed the
recommended dose of corticosteroids as there is some evidence of a direct relationship between
corticosteroid dose and glucose levels in such patients (Slatore 2009) [evidence level III-2]. In a large,
real-world, retrospective, Swedish cohort study, patients with COPD (n = 9651) were more susceptible
to bone fractures and osteoporosis than those of the same age and sex without COPD (Janson 2021).
The treatment of COPD patients, especially with high-dose ICS (⩾640 μg/day), was associated with a
higher risk of bone fractures and osteoporosis-related events (risk ratio 1.52 (95% CI 1.24–1.62).
Screening of patients with COPD for osteoporosis and identifying those at high risk of fracture (those
with comorbidities such as asthma, cardiovascular disease and depression), may be beneficial. In some
patients, reducing the dose or discontinuation of ICS might be warranted [evidence level III-2). The
treatment of people with COPD, especially with high-dose ICS (⩾640 μg/day), was associated with a
higher risk of bone fractures and osteoporosis-related events (risk ratio 1.52 (95% CI 1.24–1.62).
Screening of patients with COPD for osteoporosis and identifying those at high risk of fracture (those
with comorbidities such as asthma, cardiovascular disease and depression), may be beneficial. In some
patients, reducing the dose or discontinuation of ICS might be warranted [evidence level III-2).
Withdrawal of inhaled corticosteroids was not associated with any statistically significant increase in
exacerbation rate in a systematic review of 4 RCTs in 901 patients (Nadeem 2011) (OR 1.11, 95% CI
0.84 to 1.46) [evidence level I]. The 12-month Withdrawal of Inhaled Steroids during Optimized
Bronchodilator Management (WISDOM) trial, studied patients with severe COPD who were stable on
triple therapy (tiotropium, fluticasone propionate and salmeterol). Staged withdrawal of fluticasone
propionate over 12 weeks was compared to continuation of fluticasone propionate, plus salmeterol
and tiotropium (Magnussen 2014). 2,495 COPD patients with FEV1 <50% predicted and a history of
at least one exacerbation in the last 12 months were studied. The hazard ratio for the first COPD
exacerbation that was moderate or severe was 1.06 with ICS withdrawal (95% CI 0.94 to 1.19) which
was below the upper limit of the non-inferiority margin for the primary outcomes of exacerbation of
1.20 [evidence level II]. The mean reduction in FEV1 was 43 ml greater in the ICS withdrawal group
at 52 weeks, which was statistically significant. At 52 weeks there was no statistically different
significance in a mMRC dyspnoea score, and there was a small difference in change in SGRQ score,
favouring ICS continuation. Although the authors concluded that in patients with severe COPD
withdrawal of ICS in a tapered fashion was non-inferior to continuation of ICS, there were statistically
significant reductions in FEV1 and quality of life which may be clinically relevant to some patients.
In the 26 week SUNSET trial (Chapman 2018) abrupt withdrawal of ICS from long-term triple therapy
(tiotropium AND fluticasone/salmeterol administered via separate inhalers) to a LABA/LAMA
combination (indacaterol/glycopyrronium administered via Breezhaler) in COPD patients (mean FEV 1
57%) with no more than one moderate or severe exacerbation in the previous year led to a small but
significant decrease in trough FEV1 (26 ml; (95% CI −53 to 1 mL) with no differences in the rates of
COPD exacerbations (0.52 versus 0.48, rate ratio 1.08; 95% CI 0.83 to 1.40) or the time to first
moderate or severe COPD exacerbation (hazard ratio 1.11; 95% CI 0.85 to 1.46). Patients with high
blood eosinophils (≥ 300 cells/μL) at baseline showed greater differences in lung function (a mean
46
decrease of 69 ml) and were at increased risk of exacerbations after ICS withdrawal (rate ratio 1.86;
95% CI 1.06 to 3.29). The incidence of adverse events was similar across both treatment arms.
In patients with COPD without evidence of asthma and with infrequent exacerbations, ICS withdrawal
could be considered. Close follow-up is recommended following withdrawal. Post hoc analysis suggests
ICS withdrawal should be approached cautiously in patients with COPD and elevated eosinophil counts.
Patients with COPD with FEV1 50 to 80% predicted and no exacerbations in the past 12 months were
able to be switched to indacaterol with no significant differences in FEV1, dyspnoea score, SGRQ score
or frequency of exacerbations over six months, providing reassurance that switching from
salmeterol/fluticasone to indacaterol appeared to be safe in this group of milder COPD patients (Rossi
2014) [evidence level II].
In an RCT of 639 patients with COPD, the commencement of fluticasone propionate (250mcg bd)
and salmeterol (50mcg bd) within 14 days of the index exacerbation, compared to salmeterol alone,
was not associated with benefit in terms of incidence in moderate or severe exacerbations, over a 6-
month follow-up, although a 100 mL FEV1 benefit was demonstrated (Ohar 2014).
A systematic review of RCTs of ICS versus. non-ICS therapy for COPD showed an increased risk of
TB associated with ICS use (Peto OR, 2.29; 95% CI 1.04-5.03), and no excess risk of influenza with
ICS use (Peto OR, 1.24; 95% CI 0.94-1.63) (Dong 2014) [evidence level I]. The risk for TB was higher
in endemic areas (NNH 909), compared to non-endemic areas (NNH 1,667). Limitations of the
systematic review included: these outcomes were not the primary outcomes; limited number of trials
reporting TB events; lack of chest x-ray at recruitment; varying definitions for TB infection; and
differential withdrawal rate between ICS and non-ICS groups; and the authors recommended further
investigation (Dong 2014).
A systematic review of case-control and cohort studies also found that ICS use may increase the
odds of nontuberculous mycobacterial [NTM] infection in patients with chronic respiratory disease (OR
= 3.93, 95% CI 2.12–7.27. High-dose ICS use (OR = 2.27, 95% CI 2.08–2.48) and fluticasone use
(OR = 2.42, 95% CI 2.23–2.63) were in particular associated with increased odds of NTM infection.
ICS use also increased the odds of TB infection at high-doses (OR = 1.70, 95% CI 1.56–1.86) and in
COPD patients (OR = 1.45, 95% CI 1.29–1.63). When using ICS, clinicians should pay attention not
only to TB infection but also to NTM infection and also the types and dose of ICS (You 2022) [evidence
level III-2].
O3.3 Inhaled corticosteroids (ICS) versus long-acting beta2-agonists (LABA)
A systematic review of inhaled corticosteroids versus. long-acting beta-agonists in COPD found similar
benefits in exacerbation rates and mortality when comparing these treatments, but there was a higher
rate of pneumonia with inhaled corticosteroids (Spencer 2011) [evidence level I]. There were small
benefits in FEV1 (for long-acting beta-agonists) and quality of life (for inhaled corticosteroids). Overall,
the authors conclusions supported long-acting beta-agonists as part of frontline therapy for COPD,
with regular inhaled corticosteroid therapy as an adjunct in patients experiencing frequent
exacerbations (Spencer 2011).
O4. Combination therapies and biologic therapies

O4.1 Inhaled corticosteroids and long-acting beta2-agonists in combination
(ICS/LABA)
A systematic review of 19 randomised controlled trials involving 10,400 COPD patients of combined
corticosteroids and long-acting beta2-agonists in one inhaler (Nannini 2013a) [evidence level I] found
that, compared with placebo, both fluticasone/salmeterol and budesonide/formoterol reduced the rate
47
of exacerbations (rate ratio 0.73; 95% CI 0.69 to 0.78). It was estimated that treatment with
combined therapy would lead to a reduction of one exacerbation every two to four years. The three-
year number needed to treat for an additional beneficial outcome (NNTB) with fluticasone/salmeterol
to prevent one extra death was estimated at 42 (95% CI 24 to 775). Combined treatments improved
health status to a small extent and improved lung function. Increased risk of pneumonia was observed
with combined treatments compared with placebo (OR 1.62, 95% CI 1.36 to 1.94), with a three-year
NNTH for one additional case of pneumonia estimated to be 17. However, exacerbations,
hospitalisations or deaths did not increase. Overall, the authors concluded that there were no major
differences between combined inhalers in terms of benefits, but the evidence was currently not strong
enough to demonstrate that all are equivalent. Data from Kliber (Kliber 2010) [evidence level I] in
30,495 patients with COPD enrolled in trials of six months or greater duration found combination
therapy, compared with placebo, was associated with a reduction in all-cause mortality, relative risk
0.80 (95% CI 0.69, 0.94).
Studies have found conflicting results when the different combination therapies were compared with
the mono-components alone. A systematic review of 14 studies (Nannini 2012) (11,784 participants)
found low quality evidence for reduced exacerbation rates (rate ratio 0.76; 95% CI 0.68 to 0.84) with
ICS/LABA versus LABA alone [evidence level I]. There was no statistically significant difference in
hospitalisations or mortality. ICS/LABA improved quality of life and FEV1 to a small extent, compared
to LABA alone. High attrition rates from the studies limited the confidence in the results, except the
mortality result. Pneumonia was observed more commonly with ICS/LABA use (OR 1.55; 95% CI 1.20
to 2.01) with an annual risk of 4% on combination treatment, compared to 3% on LABA alone. A
network meta-analysis of 21 clinical trials of ICS/LABA demonstrated that these combinations, except
budesonide/formoterol and beclometasone/formoterol, reduced moderate-to severe exacerbations as
compared with placebo and LABA; however, none of the combinations reduced severe exacerbations
(Oba 2014) [evidence level I]. In 2012, Sharafkaneh et al reported that budesonide/formoterol 320/9
mg compared with formoterol alone prolonged the mean time to first exacerbation (277.9 days versus
249.8 days; p= 0.029). Higher pneumonia rates were noted with budesonide/formoterol 320/9 mg
6.4% compared with 2.7% for formoterol alone (Sharafkhaneh 2013). In a RCT of 26 weeks (Ferguson
2017) [evidence level II], twice daily budesonide/formoterol pMDI 320/9 mcg resulted in a 24%
reduction in exacerbation rate (rate ratio 0.76, 95% CI 0.62 to 0.92; P = 0.006) and a 22% reduction
in time to first exacerbation (hazard ratio 0.78; 95% CI 0.64 to 0.96; P = 0.0164) compared with
twice daily formoterol DPI 9 mcg. The study did not show any important difference between the groups
in their safety profile, including incidence of pneumonia (1% versus 0.5%).
A systematic review of 15 randomised controlled trials involving 7,814 COPD patients of combined
corticosteroids and long-acting beta2-agonists in one inhaler versus inhaled steroids alone (Nannini
2013b) [evidence level I] found that, compared with inhaled steroids, exacerbation rates were
significantly reduced with combination therapies (rate ratio 0.87, 95% CI 0.80 to 0.94). Mortality was
lower with combination therapy (OR 0.78, 95% CI 0.64 to 0.94), mainly due to results from the TORCH
study. There was a small improvement in lung function and health-related quality (HRQoL) of life. The
authors concluded that combination ICS/LABA inhalers offer some clinical benefits in COPD compared
with ICS alone, especially for reduction in exacerbations. The review did not support the use of ICS
alone when LABAs are available.
Compared to placebo, combination therapy did not significantly increase other adverse events, but
oral candidiasis was significantly more common, (NNH 16 [8-36], 1,436 participants). Combination
therapy was not associated with more adverse effects compared to long-acting beta2-agonists. Chen
et al (Chen 2011) conducted a retrospective cohort study of Veterans Affairs (VA) patients with COPD
who were admitted for pneumonia. Prior use of inhaled corticosteroids was associated with significantly
reduced 30- and 90-day mortality and need for mechanical ventilation. The analysis adjusted for age,
gender, race, marital status, primary care, classes of medications, smoking, comorbidities etc.
However, the patients were 98% male, and the most common inhaled steroids were flunisolide and
triamcinolone [evidence level III-2]. Studies by Calverley (Calverley 2007) and Kardos (Kardos 2007)
48
have found an increased rate of pneumonia (defined on clinical grounds) in the inhaled corticosteroid
arms, and this was also found in the Rodrigo systematic review, NNH = 48 (95% CI 31, 85) (Rodrigo
2009). These results contrast with the reductions in exacerbation rates induced by these drugs. A
nested case control study from Canada (Ernst 2007) [evidence level III-2] using databases linking
hospitalisations and drug dispensing information also found an increased risk of pneumonia and
hospitalisation from pneumonia in those prescribed and dispensed inhaled corticosteroids and that this
appeared dose-related. In the two-year RCT of salmeterol/fluticasone versus. tiotropium (Wedzicha
2008), the number of de novo pneumonias not preceded by symptoms of exacerbations was similar
between the two treatment groups (Calverley 2011). However, unresolved exacerbations preceding
pneumonia were more common in the salmeterol/fluticasone-treated patients (32 exacerbations in
658 patients), compared to the tiotropium-treated group (7 exacerbations in 665 patients) [evidence
level II]. Further prospective studies using objective pneumonia definitions may clarify the situation.
Meantime, increased vigilance and patient education about prompt treatment of infections would seem
prudent. A network meta-analysis of 71 RCTs of 73,062 patients with COPD showed that quality of life
and lung function improved most with combination ICS/LABA inhalers, with LABA or LAMA inhalers
next in efficacy, and ICS alone least effective (Kew 2014). Many of the patients in these studies had
FEV1 <50% predicted.
Fluticasone furoate/vilanterol is a new once daily ICS/LABA combination inhaled medicine. In short
term studies of 12 weeks duration, fluticasone furoate/vilanterol had comparable lung function and
quality of life effects as fluticasone propionate/salmeterol twice daily (Agusti 2014, Dransfield 2014).
Longer term studies (6 months) have shown that fluticasone furoate/vilanterol improves lung function
compared to fluticasone furoate alone or placebo, and was similar in effect to vilanterol (Kerwin 2013,
Martinez 2013). Patients with higher blood eosinophil count gain greater benefit from treatment with
fluticasone furoate to reduce exacerbation frequency than do those with a low eosinophil count.
Reductions in exacerbations with fluticasone furoate and vilanterol, compared with vilanterol alone,
were 24% in patients with baseline eosinophil counts of ≥ 2 to <4%, 32% for those with counts of 4
to < 6%, and 42% for those with eosinophil counts of ≥ 6%. In patients treated with vilanterol alone,
exacerbation rates increased progressively with increasing eosinophil count percentage category
(Pascoe 2015). However, prospective validation is required before routine clinical recommendations
can be made.
In a 12-month study of patient with COPD with a history of exacerbations, fluticasone

furoate/vilanterol reduced the rate of moderate to severe exacerbations by 20 to 30% compared to
vilanterol alone, whereas the rate of pneumonia increased approximately 2-fold (Dransfield 2013).
The study reported the event-based number needed to treat to prevent a moderate or severe
exacerbation per year of 3.3 to 5.6 for the 3 doses of fluticasone furoate/vilanterol used, compared to
vilanterol. In comparison, the event-based number needed to harm for pneumonia was 19 to 27 for
fluticasone furoate/vilanterol, compared to vilanterol. 8 deaths from pneumonia were observed in the
patients treated with fluticasone furoate/vilanterol (7 of whom were in the highest dose of 200/25
mcg), compared to no deaths from pneumonia in the vilanterol group. A higher number of fractures
was observed in the fluticasone furoate/vilanterol groups. The study authors advised that clinicians
should weigh up the benefit of reduced exacerbations with the risk of pneumonia when considering
fluticasone furoate/vilanterol and recommended that the 100/25 mcg dose be the maximum dose used
in future clinical trials.
The SUMMIT study randomised 16,590 patients with COPD with post-bronchodilator FEV1 50 to 70%
predicted, and history or increased risk of cardiovascular disease, to fluticasone furoate/vilanterol,
fluticasone furoate, vilanterol or placebo (Vestbo 2016a). Median study exposure was 1.8 years in this
event-driven RCT. No benefit for all-cause mortality was seen with any of the active treatments,
compared to placebo [evidence level II]. Because this primary outcome was not reached, the
secondary outcomes were considered to be descriptive. These included a clinically insignificant
reduction (8 ml/year) in the rate of decline of FEV1 with fluticasone furoate/vilanterol or fluticasone
furoate versus. placebo (Calverley 2018a). Fluticasone furoate/vilanterol reduced the rate of
49
exacerbations treated with corticosteroids alone (61% reduction, 95% CI 51 to 69%) or with
corticosteroids and antibiotics (45%, 95% CI 38 to 52%), but not those treated with antibiotics alone
(-2%, 95% CI -15 to 9%) (Martinez 2016). Rates of pneumonia were similar between fluticasone
furoate and placebo groups (Vestbo 2016a, Crim 2017).
Vestbo et al (Vestbo 2016b) performed an open label randomised trial in 75 UK general practices
where 2,799 patients were randomised to a combination of fluticasone furoate 100 μg and vilanterol
25 μg or usual care. The trial design was unique in that patients in the control group were permitted
to continue their current inhalers rather than all take the same treatment, the trial was performed in
general practice and the majority of patients only had contact with study staff at baseline and at 12
months. The rate of moderate or severe exacerbations was 8.4% lower (95% CI 1.1 to 15.2) with
fluticasone furoate–vilanterol therapy compared with usual care (P = 0.02). There was no increase in
pneumonia.
Addition of fluticasone furoate to vilanterol increased the risk of pneumonia, particularly in patients
with more severe airflow limitation (FEV1/FVC <0.46) and either BMI <19 (HR 7.8, 95% CI 4.7–13.0)
or previous history of pneumonia (HR 4.8, 95% CI 3.0–7.7) (DiSantostefano 2014) [evidence level
II]. Risk for pneumonia was significantly higher in all fluticasone furoate/vilanterol treatment groups
(fluticasone furoate/vilanterol 50 mcg/25 mcg, 100 mcg/25 mcg and 200 mcg/25 mcg) compared with
the vilanterol 25 mcg group when administered once daily in the morning. Factors associated with at
least a twofold increase in risk of pneumonia were low BMI (<25 kg/m2), 30% ≤ FEV1<50% predicted,
age >65 years, a prior exacerbation history, being a current smoker, and having a prior pneumonia
event (Crim 2015).
O4.2 Inhaled corticosteroids and long-acting beta2-agonists and long-acting

antimuscarinics in combination (ICS/LABA/LAMA)
More data are becoming available on the efficacy of multiple inhaled medications to guide the best
combination that will optimise patient’s lung function, improve symptoms and prevent/ reduce
exacerbations.
ICS/LABA plus LAMA: The GLISTEN three arm study compared the addition of glycopyrronium or
tiotropium or placebo to salmeterol/fluticasone propionate. The addition of either of the LAMAs
demonstrated statistically significant improvements to FEV1 (101 ml at 12 weeks), a statistically but
not clinically significant change in health status (2.15 units St George’s Respiratory Questionnaire
(SGRQ)) and reduced rescue medications (less than one puff per day) (Frith 2015).
A two-year double-blind, double dummy randomised controlled trial comparing tiotropium and
combination therapy with fluticasone/salmeterol (500/50 μg bd) (Wedzicha 2008) found no difference
in exacerbation rates between the groups (the primary aim of the study), but the combination therapy
group achieved a small, statistically significant benefit in quality of life as well as the unexpected
benefit of fewer deaths [evidence level II].
A Cochrane systematic review (Rojas-Reyes 2016) that compared tiotropium plus LABA/ICS
combination therapy versus tiotropium found no significant difference in risk of hospital admission with
the use of tiotropium + LABA/ICS (two studies; 961 participants; OR 0.84, 95% CI 0.53 to 1.33; I2 =
0%); the quality of evidence for this outcome is low because of the risk of bias in included studies and
imprecision of the estimates of effect [evidence level I].
Health-related quality of life (HRQoL) measured by SGRQ showed a statistically significant but not
clinically significant improvement in total scores with the use of tiotropium plus LABA/ICS compared
with tiotropium alone (mean difference (MD) -3.46, 95% CI -5.05 to -1.87; four studies; 1,446
participants). Statistically significant changes in FEV1 with the use of tiotropium plus LABA/ICS
compared with tiotropium plus placebo were observed (four studies; 1,678 participants; MD 0.06,
50
95% CI 0.04 to 0.08); however, the difference in treatment effect on FEV1 was 60 mL and did not
reach the MCID. Compared with the use of tiotropium alone, tiotropium plus LABA/ICS-based therapy
does not seem to increase adverse effects. Evidence is insufficient to support the benefit of “triple”
therapy for mortality or exacerbations (low-quality evidence). Not all people included in these studies
had COPD that was severe enough to be recommended “triple” therapy according to current guidelines
[evidence level I].
ICS/LABA/LAMA – single inhaler triple therapy
Beclometasone/formoterol/glycopyrronium: The TRINITY study evaluated the use of extra-fine

beclometasone dipropionate (BDP), formoterol fumarate (FF) and glycopyrronium bromide BDP/FF/GB
(fixed triple) (n=1078) compared to tiotropium, with a free combination of BDP/FF in one inhaler
(n=538) and tiotropium (n=1075) in a second inhaler as a control (Vestbo 2017). The rates of
moderate to severe COPD exacerbations were 0·46 (0·41–0·51) per patient per year for fixed triple,
0·57 (0·52–0·63) for tiotropium, and 0·45 (0·39–0·52) for open triple. Extra-fine particle fixed triple
was superior to tiotropium, with an adjusted rate ratio (RR) of 0·80 (95% CI 0·69–0·92; p=0·0025).
The time to first severe exacerbation was prolonged with fixed triple compared with tiotropium (HR
0·70 [95% CI 0·52–0·95]; p=0·0208), and was similar for fixed triple and open triple (1·05 [0·70–
1·56]; p=0·82). The adjusted mean changes from baseline in pre-dose FEV1 at week 52 were 0·082 L
(95% CI 0·065 to 0·100) for fixed triple, 0·021 L (0·003 to 0·039) for tiotropium and 0·085 L (0·061
to 0·110) for open triple. The incidence of adverse events (55 to 58%), including serious adverse
events (13 to 15%) and pneumonia (1 to 2%) were similar across the three groups.
In the TRILOGY study, escalation to ICS/LABA/LAMA in a single inhaler, in patients already taking
ICS/LABA, was tested in a 52-week RCT of 1,368 COPD patients who had FEV1 <50% predicted, one
or more exacerbations in the last 12 months, and significant dyspnoea and impact of COPD (Singh
2016a) [evidence level II]. Compared to ICS/LABA (beclometasone/formoterol), ICS/LABA/LAMA in a
single MDI (beclometasone 100µg/formoterol 6 µg/glycopyrronium 12.5 µg, two inhalations twice
daily) improved pre-dose FEV1 by 0.081 L (95% CI 0.052-0.109) at week 26, with no difference in
dyspnoea score. At week 52, beclometasone/formoterol/glycopyrronium was associated with a
reduced rate of moderate-severe exacerbations (rate ratio 0.77, 95% CI 0.65-0.92) and increased
proportion of patients having a beneficial improvement in SGRQ (rate ratio 1.33, 95% CI 1.06-1.66).
In patients with severe COPD and frequent exacerbations, ICS/LABA/LAMA in a single inhaler may be
more beneficial than ICS/LABA.
In the TRIBUTE study of COPD patients with severe airflow obstruction and frequent exacerbations,
ICS/LABA/LAMA in a single MDI (beclometasone/formoterol/glycopyrronium, twice daily) was
associated with reduced exacerbations over 52 weeks (rate ratio 0·85, 95% CI 0·72–0·99), compared
to once daily LABA/LAMA (indacaterol/glycopyrronium) (Papi 2018) [evidence level II]. Pneumonia
rates were similar.
Budesonide/formoterol/glycopyrronium: In patients with severe COPD and frequent

exacerbations, ICS/LABA/LAMA may be more beneficial than dual therapies ICS/LABA and LAMA/LABA.
In the 24-week KRONOS study, triple therapy (ICS/LABA/LAMA -
budesonide/formoterol/glycopyrronium MDI) was compared with dual therapies (ICS/LABA -
budesonide/formoterol as MDI or DPI, and LAMA/LABA MDI - glycopyrrolate/formoterol) (Ferguson
2018) [evidence level II]. Triple therapy improved lung function compared to budesonide/formoterol
and glycopyrrolate/formoterol. The rate of moderate or severe exacerbations was lower in the triple
therapy group.
In patients with moderate-to-very-severe COPD who are at risk of exacerbations, triple therapy with
a budesonide–glycopyrrolate–formoterol combination MDI (ETHOS Trial) showed significant benefits
over dual therapy with a LAMA–LABA or an ICS–LABA combination with respect to the annual rate of
moderate or severe COPD exacerbations (Rabe 2020) [evidence level II]. The rate was significantly
51
lower with 320-μg–budesonide triple therapy than with glycopyrrolate–formoterol (24% lower: rate
ratio 0.76; 95% CI 0.69 to 0.83; P<0.001) or budesonide–formoterol (13% lower: rate ratio 0.87;
95% CI 0.79 to 0.95; P=0.003). The rate was significantly lower also with 160-μg–budesonide triple
therapy than with glycopyrrolate–formoterol (25% lower: rate ratio 0.75; 95% CI 0.69 to 0.83;
P<0.001) or budesonide–formoterol (14% lower: rate ratio 0.86; 95% CI 0.79 to 0.95; P=0.002).
Triple therapy with a 320-μg dose of budesonide also resulted in a 46% lower all-cause mortality
than glycopyrrolate–formoterol group [28 vs 49 deaths; hazard ratio 0.54; 95% CI 0.34 to 0.87].
The incidence of any adverse event was similar across the treatment groups (range 61.7 to 64.5%);
the incidence of confirmed pneumonia was higher in the groups that included inhaled glucocorticoid
(range 3.5 to 4.5%) than the glycopyrrolate–formoterol group (2.3%).
A network meta-analysis of ETHOS, KRONOS, IMPACT, and TRILOGY studies (n = 21,909) comparing
triple ICS/LABA/LAMA FDC with dual LABA/LAMA and ICS/LBA FDCs administered via the same inhaler
device in COPD patients (Calzetta 2020) found that regardless of the level of blood eosinophil count
at baseline, the triple ICS/LABA/LAMA fixed dose combination (FDC) was the most effective treatment
in reducing the risk of exacerbation, compared to LABA/LAMA FDC (RR 0.45, 95% CrI 0.32–0.61, P <
0.05) and ICS/LABA FDC (RR 0.73, 95% CI 0.54–0.99, P < 0.05) [evidence level I]. In patients with
low level of blood eosinophil count at baseline, LABA/LAMA and ICS/LABA FDCs were equally effective
in preventing exacerbations (RR 1.12, 95%CrI 0.83–1.35, P > 0.05). FDCs including an ICS were
affected by an increased risk of pneumonia. No increased cardiovascular risk was detected in the FDCs
that included two bronchodilators.
The combinations of both beclometasone/formoterol/glycopyrronium and

budesonide/formoterol/glycopyrronium are now available in Australia and have been approved for
listing as PBS subsidised medications.
Fluticasone furoate/umeclidinium/vilanterol: In a 24-week RCT of 1,810 patients with

moderate to severe COPD, once daily fluticasone furoate/umeclidinium/vilanterol in a single inhaler
was compared to twice daily budesonide/formoterol (Lipson 2017). Fluticasone
furoate/umeclidinium/vilanterol improved FEV1 (mean difference 171 ml, 95% CI 148 to 194) and
SGRQ total score (mean difference -2.2 units, 95% CI -3.5 to -1.0), and reduced exacerbation rates
(rate ratio 0.65, 95% CI 0.49 to 0.86), supporting some benefits of single inhaler triple therapy.
The IMPACT trial (n=10,355) compared triple therapy (ICS/LABA/LAMA - fluticasone furoate,
umeclidinium and vilanterol) with dual therapies using the same molecules (ICS/LABA and
LAMA/LABA), all administered once-daily via an Ellipta dry powder single-inhaler (Lipson 2018). This
demonstrated a significantly lower rate of moderate or severe COPD exacerbations – 0.91 per year,
as compared with 1.07 per year in the fluticasone furoate–vilanterol group (rate ratio with triple
therapy, 0.85; 95% CI 0.80 to 0.90; 15% difference; p<0.001) and 1.21 per year in the umeclidinium–
vilanterol group (rate ratio with triple therapy, 0.75; 95% CI 0.70 to 0.81; 25% difference; p<0.001).
The annual rate of severe exacerbations (resulting in hospitalisation) in the triple therapy group was
0.13, as compared with 0.19 in the umeclidinium–vilanterol group (rate ratio 0.66; 95% CI 0.56 to
0.78; 34% difference; p<0.001). Overall, the adverse-event profile of triple therapy was similar to
that of the dual therapy comparators. Incidence of pneumonia was higher in the ICS groups than in
the umeclidinium–vilanterol group, and the risk of clinician-diagnosed pneumonia was also significantly
higher with triple therapy than with umeclidinium–vilanterol (hazard ratio 1.53; 95% CI 1.22 to 1.92;
p<0.001).
The difference in the mean change in trough FEV1 between the triple therapy and fluticasone furoate–
vilanterol groups was 97 ml (95% CI 85 to 109; p<0.001), and the difference between the triple
52
therapy and umeclidinium–vilanterol groups was 54 ml (95% CI 39 to 69; p<0.001). There were
significant differences between the triple therapy group and the fluticasone furoate–vilanterol and
umeclidinium–vilanterol groups in the mean change from baseline in the SGRQ total score (–1.8 [–2.4
to –1.1] and –1.8 [–2.6 to –1.0], respectively; both p<0.001) and in the percentage of patients who
had a response as defined by a decrease in the SGRQ total score of at least 4 points (1.41 [1.29 to
1.55] and 1.41 [1.26 to 1.57], respectively; both p<0.001). ICS regimens also showed a possible
signal toward lower all-cause mortality during treatment than umeclidinium–vilanterol.
In pre-specified secondary analyses of patients with eosinophil levels <150 cells/μL, the annual rate
of moderate or severe exacerbations was 0.85 (95% CI 0.80 to 0.91) with triple therapy, 1.06 (95%
CI 0.99 to 1.14) with fluticasone furoate–vilanterol and 0.97 (95% CI 0.88 to 1.07) with umeclidinium–
vilanterol. Among patients with eosinophil levels of at least 150 cells per microlitre, the annual rate
was 0.95 (95% CI 0.90 to 1.01) with triple therapy, 1.08 (95% CI 1.02 to 1.14) with fluticasone
furoate–vilanterol, and 1.39 (95% CI 1.29 to 1.51) with umeclidinium–vilanterol.
The results described above are further supported by systematic reviews of RCTs assessing the effects of
fixed and separate inhaled triple therapy versus dual therapy (of LABA and LAMA, LABA and ICS, or LAMA
and ICS) or monotherapy (LAMA, LABA, or ICS) (Calzetta 2019, Cazzola 2018b, Zheng 2018, Mammen
2020a). In a meta-analysis of 13 RCTs including 15,519 patients with COPD (Calzetta 2019) [evidence
level I], triple therapy was significantly more effective than the ICS/LABA combination in improving trough
FEV1, HRQoL and dyspnoea, and protecting against the risk of moderate or severe exacerbations, without
compromising cardiovascular safety. The NNT for a ≥100-mL increase from baseline in trough FEV1 of
ICS/LABA/LAMA combination versus ICS/LABA combination was 3.97 (95% CI, 3.25-5.13) and for
protection against the risk of a COPD exacerbation was 26.07 (95% CI, 16.79-152.70).
A network meta-analysis of 14 trials found that ICS/LABA/LAMA combination therapy significantly

(p<0.001) reduced the risk of moderate or severe COPD exacerbation compared to LABA/LAMA combination
therapy (relative effect 0.70, 95% CrI 0.53–0.94) and single long-acting bronchodilator therapy (relative
effect 0.62, 95% CrI 0.48–0.80) (Cazzola 2018b). No significant difference was found for the risk of
pneumonia when comparing ICS/LABA/LAMA combination therapy with LABA/LAMA combination therapy
(relative effect 1.36, 95% CrI 0.84– 2.00) and single long-acting bronchodilator therapy (relative effect
1.31, 95% CrI 0.76–2.32). Females with COPD seemed to be at higher risk of pneumonia and the risk of
pneumonia was greater when the value of FEV1 was high at enrolment.
In a meta-analysis of 21 trials, triple therapy reduced moderate or severe exacerbations compared to

LAMA/LABA (rate ratio 0.78, 95% CI 0.70 to 0.88) or ICS/LABA (rate ratio 0.77, 95% CI 0.66 to 0.91)
(Zheng 2018) [evidence level I]. A meta-analysis of 11 studies found that triple therapy reduced the risk
of exacerbations (relative risk 0.75, 95% CI 0.68 to 0.82) and increased the risk of pneumonia (relative
risk 1.48, 95% CI 1.23 to 1.79) (Mammen 2020a).
A meta-analysis of two trials (Bremner 2018, Vestbo 2017) directly comparing fixed triple therapy with
separate triple therapy found no statistically significant associations for all the outcomes, including
exacerbations of COPD, lung function, adverse events and HRQoL (Zheng 2018).
A systematic review and Bayesian network meta-analysis of 219 trials involving 228,710 patients with
stable COPD, comparing exacerbation, mortality, and adverse events among all regular inhaled drug
classes, including ICS/LAMA/LABA, LAMA/LABA, ICS/LABA, LAMA, LABA, ICS, and placebo found that all
drug classes showed significant benefits in reducing total exacerbations, compared to placebo (Lee 2019).
Triple therapy was the most effective treatment in reducing total exacerbations (odds ratio [OR] = 0.57;
95% credible interval [CrI] 0.50 to 0.64; and all-cause mortality OR = 0.74, 95% CrI 0.59 to 0.93, P[OR>1]
= 0.004 compared to placebo. However, ICS combinations had a high probability of pneumonia in
comparison to placebo (OR 1.58 (1.26 to 2) for triple therapy and for ICS/LABA 1.59 (1.36 to 1.91).
Different formulations of single inhaler triple therapy (ICS/LABA/LAMA) have similar efficacy for reducing
exacerbations, as shown in two network meta-analyses (Bourdin 2021, Lee 2021) [evidence level I]. A
53
meta-analysis of 60 RCTs (103,034 patients) suggested that compared with inhaled therapy without ICS,
inhaled therapy containing ICS (Peto OR 0.90; 95% CI 0.84-0.97), especially triple therapy (Peto OR, 0.73;
95% CI, 0.59-0.91) was associated with a reduction in all-cause mortality in patients with COPD. Further
subgroup analyses revealed that treatment duration ＞6 months (Peto OR 0.90; 95% CI 0.83-0.97),
medium-dose (Peto OR 0.71; 95% CI 0.56-0.91), and low-dose ICSs (Peto OR 0.88; 95% CI 0.79-0.97),
and budesonide (Peto OR, 0.75; 95% CI 0.59-0.94) were involved in this association. Eosinophil counts
≥200/μL or percentage ≥2%, documented history of ≥2 moderate and/or severe exacerbations in the
previous year, GOLD stage III or IV, age＜65 years, and BMI ≥25 were significant predictors, among which
eosinophil count ≥200/μL (Peto OR 0.58; 95% CI 0.36-0.95) was the strongest (Chen 2023) [evidence
level I].
Reduction in mortality with triple therapy in the IMPACT and ETHOS studies was mainly observed in the
first 3 months after randomization. As all the patients recruited for these two trials were frequent
exacerbators, and a proportion had ICS ceased prior to randomisation, it is possible that withdrawal from
ICS could have been a factor in the observed difference in mortality in those randomised to receive an ICS-
containing preparation (Suissa, 2022). Therefore, not all patients with COPD will necessarily achieve a
reduction in all-cause mortality as a consequence of ICS-containing triple therapy (Chen 2022) [evidence
level I].
In summary, triple therapy results in a lower rate of moderate or severe COPD exacerbations, and better
lung function and HRQoL than dual therapies. COPD subgroups whose all-cause mortality risk may be
reduced with the inhaled therapy containing ICS include those with eosinophil counts ≥200/mL or ≥2%,
documented history of ≥2 moderate and/or severe exacerbations in the previous year, GOLD stage III or
IV, age＜65 years old, and BMI ≥25. However, triple therapy could increase the risk of pneumonia, when
compared with dual bronchodilator therapy. Therefore, triple therapy should be limited to patients with
exacerbations and more severe COPD symptoms that cannot be adequately managed by dual therapy, and
to patients with COPD phenotypes most likely to respond to the triple therapy. In patients with COPD already
on ICS/LABA combination, the therapy can be improved without increase of cardiovascular adverse events
when a LAMA is added to the combination. Triple therapy delivered in a single inhaler is convenient for
patients and may improve adherence, but it is non-inferior to the use of multiple inhalers in terms of clinical
efficacy.
Triple therapy prescribing has been increasing since 2016. Retrospective analysis of de-identified
administrative data from the US between 2013 and 2018 found that almost three-quarters of patients with
COPD who were prescribed triple therapy did not meet guideline recommendations pertaining to prior
maintenance therapy and/or exacerbations. Relative to patients prescribed open triple therapy (multiple
inhalers collectively containing ICS, LAMA, and LABA), those prescribed closed triple therapy (a fixed-dose
single triple therapy inhaler containing fluticasone furoate/umeclidinium/vilanterol) were more likely not to
have used ICS, LAMA or LABA and/or their combinations (i.e. maintenance inhaler naïve) and to have no
evidence of at least 2 moderate or one severe exacerbation prior to initiating triple therapy. This guideline-
discordant prescribing behaviour occurred more often among generalist-specialty prescribers than
pulmonologists. Increasing prescriber awareness of guideline recommendations is warranted to counter the
continuing overprescribing of triple therapy in individuals with COPD (Bhatt 2022) [evidence level III-2].
In Australia, for initiation of triple therapy (ICS/LABA/LAMA) subsidised through the PBS, the patient
must have experienced at least one severe COPD exacerbation, which required hospitalisation, or two
or more moderate exacerbations in the previous 12 months, with significant symptoms despite regular
bronchodilator therapy with a long-acting muscarinic antagonist (LAMA) and a long-acting beta-2
agonist (LABA) or an inhaled corticosteroid (ICS) and a LABA; OR the patient must have been stabilised
on a combination of a LAMA, LABA and an ICS for COPD.
O4.2.1 Eosinophil count and inhaled corticosteroids
54
There is significant interest in the use of blood eosinophil count as both a prognostic marker and to
guide the use of inhaled corticosteroids in COPD.
In a US cohort study (Zeiger 2018), elevated blood eosinophils at baseline were independently
associated with COPD exacerbations and COPD-related ED visits or hospitalisations during a year of
follow-up. After adjusting for confounders, rate of future exacerbations were 25%, 48% and 76%
greater for patients with eosinophils ≥ 300 cells/ mm³ ≥ 400 cells/ mm³ and ≥ 500 cells/ mm³,
respectively. Analysis of data from the COPD Gene and ECLIPSE longitudinal studies (Yun 2018) also
found baseline blood eosinophils ≥ 300 cells/ mm³ to be associated with increased exacerbation
frequency. In a large group of patients (n=7,180) from the Danish Copenhagen General Population
Study (Vedel-Krogh 2018), blood eosinophils ≥ 0.34 x109 cells/L in people whose FEV1 was < 50%
predicted were associated with a higher risk of hospitalisation for pneumonia compared with those
with the same degree of airflow obstruction but a lower eosinophil count. In the Korean Obstructive
Lung Disease cohort study, patients with COPD who had persistently high blood eosinophils (≥ 300
cells/ mm³) had a better survival rate and improved symptoms and quality of life than those with
persistently low eosinophil counts (<300 cells/ mm³) while those with variable eosinophil counts had
survival rates similar to those with persistently low counts (Shin 2018). In an Australian study by
MacDonald et al (2019), low blood eosinophil counts (<50/uL) during admission for acute exacerbation
of COPD were associated with bacterial infection, increased length of stay and a higher 12-month
mortality, while just over half of exacerbations associated with higher eosinophil counts (>150/uL)
also demonstrated evidence of infection, likely requiring antibiotic therapy (MacDonald 2019). A
retrospective study from a single centre in China found no association between in hospital eosinophil
count and in hospital mortality or length of stay, or exacerbation within one year of discharge (Yu
2021) [evidence level III-B].
Higher eosinophil counts have also been shown to be associated with a higher rate of lung function
decline in individuals with and without COPD in the Canadian CANCOLD study, a prospective cohort
study based on the Canadian COPD prevalence study (COLD). CANCOLD evaluated 6000 males and
females ≥40 years, recruited through random sampling. The study included all subjects with COPD
from the original COLD study and an equal number of age and sex-matched peers without COPD. A
total of 1285 individuals had bloods drawn for eosinophil counts at 0 and 18 months as well as lung
function tests, and high-resolution CT scans. Baseline eosinophil count of ≥ 300 cells/uL was an
independent risk factor for accelerated decline in lung function in those with and without COPD,
independent of exacerbations, and was related to the presence of gas trapping, airway wall thickening
and reduction of total airway count base on CT (Tan 2021) [evidence level III-2].
In a post-hoc analysis of the FORWARD study, a double blind randomised controlled study which
compared 48 weeks of treatment with extra fine beclomethasone dipropionate (BDP) plus formoterol
furoate 100/6 ug two puffs bd with formoterol furoate (FF) 12 ug one puff bd in patients with COPD,
patients with eosinophil counts ≥ 279.8 cells/μL experienced the highest exacerbation rate with FF and
the greatest benefit from the BDP/FF combination (Siddiqui 2015). In a post-hoc review of data from
WISDOM, patients with higher blood eosinophil counts were more likely to develop exacerbations after
withdrawal of inhaled corticosteroids, with a significant treatment-by-subgroup interaction above an
eosinophil count of 4% or greater or above 300 cells/μL (Watz 2016). Bafadhel et al used negative
binomial regression analysis using splines to examine data from RCTs of budesonide/formoterol in
patients with COPD, a history of exacerbations and available eosinophil counts (n=4,528) (Bafadhel
2018). They found a treatment effect interaction between the budesonide-formoterol combination as
compared with formoterol alone and eosinophil count, with respect to exacerbations, lung function and
health status. At eosinophil counts of 100/μL or more, a significant treatment effect was found for
exacerbation reduction with budesonide/formoterol compared with formoterol alone (RR 0.75, 95% CI
0.57-0.99); p interaction =0.015).
Casanova et al examined the prevalence and stability of the finding of a blood eosinophil count ≥ 300
cells/μL and its relationship to outcomes over two years using hazard analysis in patients from the
55
CHAIN (patients with COPD and smokers without COPD) and BODE (patients with COPD only) cohorts
(Casanova 2017). 15.8% of COPD patients in CHAIN and 12.3% of those in BODE had persistently
elevated eosinophils during the period of follow-up (at least 3 measurements over two years). A similar
eosinophil blood pattern was observed in controls. Exacerbation rates did not differ in patients with
and without eosinophilia. All-cause mortality was lower in patients with high eosinophils compared
with those with values <300 cells/μL–1 (15.8% versus 33.7%; p=0.026). In the SPIROMICS database
of patients with COPD, smokers without COPD and 7% non-smokers, blood eosinophil count alone was
not a reliable biomarker for COPD severity or exacerbations (Hastie 2017). Although there was a
statistically significant relationship between blood and sputum eosinophils, blood eosinophil count did
not reliably predict the level of sputum eosinophilia. Sputum eosinophils were available in a subset of
just on 1,000 patients. The authors found that high sputum eosinophils, but not blood eosinophils,
identified a subset of patients with more severe airflow obstruction, worse quality of life, more
emphysema and gas trapping and more exacerbations. However, there were no differences in COPD
Assessment Test (CAT) scores noted with either blood or sputum eosinophil stratification. In the
prospective GLUCOLD study of patients with COPD using ICS or placebo during 30 months of follow
up, neither baseline blood eosinophil levels nor baseline eosinophil levels in sputum, bronchoalveolar
lavage (BAL) or bronchial biopsy predicted longitudinal changes in FEV 1 with or without ICS (Hartjes
2018).
Prospective studies that randomise patients based on eosinophil count are required to confirm these
associations.
A meta-analysis by You et al (2020) compared outcomes of acute exacerbations of COPD (AECOPD)

with and without eosinophilia (defined as an eosinophil count ≥2% or an absolute eosinophil count
≥0.34x109). Outcomes were better overall for eosinophilic AECOPD, with decreased hospital mortality
(OR 0.59, 95% CI 0.31-0.95, p=0.03), decreased length of stay (OR 0.72,95% CI-1.44 to -0.00,
p=0.05), higher FEV1 (mean difference =0.14, 95% CI 0.08-0.2, p<0.00001) and a lower risk of
arrhythmias 9 (OR 1.5, 95% CI 1.01-2.21, p=0.04). It was noted that there were more males among
the non- eosinophilic group (OR 1.34, 95% CI 1.15-1.56, p=0.0002), but that steroid use did not differ
between the groups (You 2020). The majority of studies in this meta-analysis were single centre and
retrospective in design.
O4.3 Biologic therapies
Post hoc analyses of data from a number of studies involving patients with COPD have highlighted the
blood eosinophil count as a potentially important biomarker of response to glucocorticoid treatment.
Several studies have examined whether depleting eosinophils with interleukin-5 (IL-5) or IL-5 receptor
antibodies could affect clinical outcomes in COPD. Pavord and colleagues compared the IL-5 inhibitor
mepolizumab with placebo in patients with COPD in two 12-month randomised, controlled, parallel-
group trials (METREX and METREO) (Pavord 2017). In METREX, the annual rate of moderate or severe
exacerbations was significantly lower in the mepolizumab group than in the placebo group (1.4 versus.
1.71 per year; rate ratio, 0.82; 95% CI 0.68 to 0.98; P=0.04). The time to first exacerbation was also
significantly longer in the mepolizumab group than in the placebo group, but there were no significant
differences in outcomes when patients were not stratified according to eosinophilic phenotype. In
contrast, no significant differences in exacerbation rates were detected in METREO. There was no
significant between-group difference in the rate of exacerbations that led to an emergency department
visit or hospitalisation or in measures of patients’ symptoms in either trial.
A phase 2a trial of benralizumab, a humanized monoclonal antibody to IL-5 receptor alpha, did not
demonstrate benefit in terms of exacerbations or quality of life in a group of patients with COPD who
had at least one exacerbation in the preceding year and a sputum count of ≥ 3% in the preceding
year; however the investigators felt that a prespecified subgroup analysis of patients with higher
blood eosinophil counts supported further investigation of the effects of this drug in patients with COPD
and eosinophilia (Brightling 2014). Nonetheless, large trials of benralizumab in patients with moderate
56
COPD and frequent exacerbations despite dual or triple therapy found no differences in annual rates
of COPD exacerbations in patients treated with benralizumab compared with placebo, and no
associations between baseline eosinophil counts and treatment effect (Criner 2019a). In a further pre-
specified analysis of the combined GALATHEA and TERRANOVA studies of benralizumab (Criner
2019b), a variety of statistical techniques were used to identify “efficacy associated factors” in the two
studies. These hypothesis-generating analyses were interpreted as suggesting that, in a subpopulation
of patients with COPD who had frequent exacerbations during treatment with triple therapy and higher
eosinophil counts might benefit from benralizumab 100 mg every 8 weeks.
A Cochrane Systematic review of randomised controlled trials by Donovan et al (2020) comparing

anti-IL-5 therapy with placebo in adults (≥40 years old) with a diagnosis of COPD (as defined by GOLD
2020) and with frequent exacerbations included three studies each of mepolizumab (1530 participants)
and benralizumab (4012 participants), both comparing anti-IL-5 therapy with placebo. No head-to-
head comparison trials were identified. Mepolizumab 100 mg reduced the rate of moderate or severe
exacerbations by 19% in those with an eosinophil count of at least 150/microlitre (RR 0.81, 95% CI
0.71 to 0.93; participants = 911; studies = 2, high-certainty evidence). In participants with lower
eosinophils, mepolizumab 100 mg might reduce exacerbations (RR 0.92, 95% CI 0.82 to 1.03;
participants = 1285; studies = 2, moderate-certainty evidence). Benralizumab 100 mg reduced the
rate of severe exacerbations requiring hospitalisation in those with an eosinophil count of at least 220/
microlitre (RR 0.63, 95% CI 0.49 to 0.81; participants = 1512; studies = 2, high-certainty evidence).
Anti-IL-5 therapies appeared to be safe in individuals with COPD and were likely to reduce the rate of
moderate and severe exacerbations in people with both COPD and higher levels of blood eosinophils.
Lung function and health-related quality of life were not improved (Donovan 2020) [Evidence Level I].
Further research is needed to elucidate the role of monoclonal antibodies in the management of
COPD. It is not clear whether there is a threshold blood eosinophil level above which these drugs may
be effective. Cost effectiveness data are also critical to inform clinical decision making, given the high
cost of these therapies.
O5. Inhaler technique and adherence

Adherence and inhaler technique need to be checked on a regular basis
[evidence level I, strong recommendation]
O5.1 Inhaler technique

Incorrect inhaler technique is common and is associated with worse outcomes. A systematic review
of articles reporting direct observation of inhaler technique in COPD and asthma reported that the
overall prevalence of optimal inhaler technique was only 31% (95% CI 28 to 35%), and that this
pattern had not improved over 40 years. Common errors were identified, for the MDI these were poor
coordination (45%; 95% CI 41 to 49%), inadequate speed and/or depth of inspiration (44%; 95% CI
40 to 47%), and the absence of post inhalation breath-hold (46%; 95% CI 42 to 49%). For the DPI,
common errors included incorrect preparation in 29% (95% CI 26-33%), inadequate expiration before
inhalation in 46% (95% CI 42 to 50%), and the absence of a post inhalation breath-hold in 37% (95%
CI 33-40%) (Sanchis 2016). These data highlight the importance of inhalation technique education.
Inhaler devices must be explained and demonstrated for patients to achieve optimal benefit. It is
necessary to check regularly that the patient has the correct inhaler technique as proficiency will wane
with time. There is no evidence to guide the optimal frequency of reviewing inhaler technique. Inhaler
proficiency may wane with time so we recommend at least 6 monthly inhaler technique reviews, or
after an exacerbation, or after a change in treatment.
57
Ensuring that patients are shown the correct inhaler technique requires the health professional to
have an understanding of the devices. Unfortunately, large gaps remain in health professionals’
knowledge and skill in this area. A systematic review that included 55 studies and evaluated health
professionals performing 9,996 tests demonstrating their inhaler technique confirmed this (Plaza
2018) [evidence level I]. Inhaler technique was only considered correct in 15.5% of health
professionals (95% CI 12-19.3) overall. Another finding of the review was that inhaler technique
proficiency of health professionals has decreased over time. In studies between 1975 and 1995, overall
proficiency was 20.5% (95% CI 14.9 to 26.8) compared to only 10.8% (95% CI 7.3-14.8) in the
period between 1996 and 2014. These data highlight the necessity of health professionals to develop
their knowledge and proficiency of inhaler device use.
A randomised cross over trial of 180 individuals hospitalized with COPD sought to understand the
determinants of incorrect inhaler technique by assessment technique with 10 different inhaler placebo
devices including: pressurised metered dose inhaler (pMDI), Aerolizer, Handihaler, Turbohaler, Discus,
Breezhaler, Ellipta, Easyhaler, Diskhaler and Respimat without receiving any instructions. The
strongest determinants of incorrect technique were: past-experience (OR 14.639, P<.001), type of
device (OR 10.397 at P<.001, 4.267 at P=.007, 2.664 at P=.057, 8.666 at P=.001, 10.250 at P<.001,
0.613 at P=.212 and 0.265 at P<.001 for pMDI, Aerolizer, Handihaler, Turbohaler, Discus, Breezhaler
and Ellipta, respectively), female gender (OR 0.310, P<.001), older age (OR 0.307, P<.001) and GOLD
group (OR 2.289, P=.005) (Harb 2021) [evidence level II]. Inhaler technique is poor in COPD and
determinants of technique are older age, female gender, severity of disease and the type of device. It
is important to tailor the inhaler device to the patients’ needs and preferences, as well as patient
education and repeated review.
Elderly and frail patients, especially those with cognitive deficits, may have difficulty with some
devices. Correct inhaler technique is essential for the optimal use of all inhaled medications (Melani
2011) [evidence level I] and is associated with fewer severe exacerbations. An observational study
involving 2,935 patients with COPD, reported that in individuals who were treated for at least three
months (n=2,760), the occurrence of prior (past three months) severe exacerbation was significantly
associated with at least one observed critical error using prescribed inhalers (OR 1.86, 95% CI 1.14-
3.04; p=0.0053) (Molimard 2017). Ease of operating and dose preparation were rated as being the
most important inhaler features leading to higher patient satisfaction and fewer critical errors in a
randomised, open-label, multicentre, cross-over study of two inhaler devices (van der Palen 2013)
[evidence level II]. An Australian cross-sectional study found that the proportion of patients with COPD
who made at least one error in inhaler technique ranged from 50 to 83%, depending on the device
used (Sriram 2016). Similarly, a systematic review and meta-analysis of 72 studies involving asthma
and COPD patients, reported that 50-100% of patients performed at least one handling error. The
pooled summary results for pMDI estimated an overall error rate of 86.6% (95% CI 79.4-91.9) and
for DPIs it was 60.9% (95% CI 39.3-79.0) (Chrystyn 2017) [evidence level I].
Consideration of cognitive impairment is important for the learning and retaining of inhaler technique
(Baird 2017, Iamthanaporn 2023) [evidence level I]. Ongoing training for re-enforcement, or
alternative inhaler device substitution, may be beneficial.
With the proliferation of new inhaler devices, inhaler device poly-pharmacy is becoming an increasing
problem amongst COPD patients and has a negative impact on outcomes (Bosnic-Anticevich 2017). A
study of 16,450 COPD patients compared exacerbation frequency and SABA use of patients who were
using similar style inhalers e.g. all MDI to those that were prescribed devices that required a different
technique. Those in the similar device cohort experienced fewer exacerbations (adjusted IRR 0.82,
95% CI 0.80 to 0.84; and used less SABA (adjusted OR 0.54, 95% CI 0.51-0.57), compared to the
mixed device cohort. Adherence may also be improved when using single inhaler therapy compared
to multiple inhaler therapies. A GSK-led retrospective study using a large US claims database involving
9942 patients demonstrated that those who initiated triple therapy with single-inhaler fluticasone
furoate/umeclidinium/vilanterol (FF/UMEC/VI) had significantly better adherence (46.5% vs. 22.3%;
58
RR 2.08, 95% CI 1.85–2.30) and persistence (35.7% vs. 13.9%; HR 1.91, 95% CI 1.81–2.01,
p<0.001) compared with patients who initiated multiple inhaler therapy (Mannino 2022) [evidence
level III-2]. These data support the recommendation to minimise the number of different devices
prescribed in COPD patients. Single combination inhaler devices have comparable efficacy to multiple
inhaler devices, delivering the same medications and doses without any additional safety concerns.
Retrospective and prospective studies have shown that using a single inhaler was associated with
decreased healthcare resource utilisation and improved cost-effectiveness compared with multiple
inhalers. However, due to the lack of long-term data, differences in outcome definitions and study
designs, robust conclusions regarding the differences between single- and multiple inhaler users
cannot be made (Zhang 2020) [Evidence level I].
An infographic highlighting important considerations for inhaler device prescription is included below.
Figure 5: Important considerations for inhaler device prescription
Content has been reproduced with permission from the Centre of Excellence in Treatable Traits, originally developed as
part of the Centre of Excellence in Treatable Traits (https://treatabletraits.org.au) in collaboration with the COPD-X
Guidelines Committee.
Lung Foundation Australia has developed a series of inhaler device technique videos and factsheets
for patients which provide step-by-step instructions on correct inhaler technique.
These are available at:
https://lungfoundation.com.au/resources/?user_category=32&search=inhaler%20device.
NPS Medicine Wise has also developed a checklist for inhaler device technique available at
https://www.nps.org.au/assets/NPS-MedicineWise-Inhaler-Technique-v2-jg-120320-ACC.pdf
The National Asthma Council has produced a number of “how-to” videos which are available on their
website at https://www.nationalasthma.org.au/living-with-asthma/how-to-videos. The Lung
Foundation Australia resource, Better Living With COPD: A Patient Guide contains an inhalation devices
chapter which can be accessed at https://lungfoundation.com.au/wp-content/uploads/2018/09/Book-
Better-Living-with-COPD-Dec2016.pdf.
59
The cost of inhaler devices varies between products. As there are no differences in patient outcomes
for the different devices, the cheapest device the patient can use adequately should be prescribed as
first line treatment (NHS Centre for Reviews and Dissemination 2003). The range of devices currently
available, the products and dosage, as well as their advantages or disadvantages, are listed in
Appendix 2. Brief counselling; monitoring and feedback about inhaler use through electronic
medication delivery devices; and multi-component interventions consisting of self-management and
care co-ordination delivered by pharmacists and primary care teams have been shown to improve
medication adherence (Bryant 2013) [evidence level I].
Pharmacist-led interventions comprising information provision, motivating patients and taught

necessary behavioural skills significantly improved medication adherence (1.41 [1.24 to 1.61],
P<.00001) and correct inhalation technique (Risk Ratio 1.85, 95% CI 1.57 to 2.17), compared with
the control group (Jia 2020) [evidence level I].
O5.2 Inhaler adherence
Bhattarai et al (2020) conducted a systematic review of 38 studies published from 2003 to 2019 that
examined rates of medication adherence and reported on barriers and enablers to adherence. Rates
of non-adherence ranged from 22% to 93%. The majority of studies identified the presence of
depression and subjects’ concern about the harmful effects of the medicine as barriers to adherence
(Bhattarai 2020).
A systematic review comprising predominantly retrospective database studies which measured

prescription refill adherence with one-to-two-year follow-up of patients with COPD found increased
hospitalizations, mortality, poor quality of life and loss of productivity among non-adherent patients
(van Boven 2014) [evidence level III-2]. Inhaler adherence and technique were found to be suboptimal
in an observational study of use of an ICS/LABA combination inhaler fitted with an electronic audio
recording device. Impaired lung function and cognition, as well as cough, predicted suboptimal
adherence and technique (Sulaiman 2017).
A large retrospective study examined medication use data of patients with asthma and COPD from a
digital health platform (smartphone App and electronic medication monitors). The authors compared
adherence rates using a once daily controller regimen compared to twice daily. In 1791 patients with
COPD, once daily was associated with higher median daily adherence than the twice daily regime
83.3% [IQR: 57.2 to 95.6] versus 64.7% [IQR: 32.8 to 88.9], p < .001). In COPD once daily regimen
was also associated with an increased odds of achieving ≥80% adherence [1.73 (95% CI: 1.38-2.17,
p < .001)]. Patients received electronic reminders via a mobile app if the medication was not taken,
therefore inflating real life adherence rates. These data highlight the importance of identifying the
regimen most likely to lead to improved adherence (De Keyser 2023) [evidence level III-I].
The National Asthma Council of Australia’s Australian Asthma Management Handbook contains
further information about adherence:
http://www.asthmahandbook.org.au/management/adherence.
O6. Non-pharmacological interventions

There is strong evidence for the benefits of regular exercise in individuals with COPD (McCarthy 2015,
Ries 2003, Spruit 2013, Alison 2017) [evidence level I]. All individuals with COPD should be
encouraged to engage in physical activity consistent with the recommendations for ‘healthy’ adults.
The current Australian and New Zealand guidelines for physical activity for adults at:
www.health.gov.au/internet/main/publishing.nsf/Content/health-pubhlth-strateg-phys-act-
guidelines#apaadult and www.health.govt.nz/system/files/documents/publications/eating-activity-
guidelines-for-new-zealand-adults-oct15_0.pdf recommend:
60
• Doing any physical activity is better than doing none;
• Be active on most, preferably all, days every week;
• Accumulate 150 to 300 minutes of moderate intensity physical activity or 75 to 150 minutes
of vigorous intensity physical activity, or an equivalent combination of both moderate and
vigorous activities, each week;
• Do muscle strengthening activities on at least 2 days each week.
Meeting current guidelines for physical activity is challenging for people with COPD due to exertional
dyspnoea and symptoms of fatigue. A large cohort study of 2,398 individuals with COPD (mean age
52.1 [11.5] years, 52.1% male) recruited as part of Health Surveys in England and Scotland (Cheng
2018) provide data demonstrating a reduction in mortality at a level of physical activity significantly
below that recommended by the current Australian and New Zealand guidelines for physical activity
for adults. Please refer to the Department of Health’s Australia's Physical Activity and Sedentary
Behaviour Guidelines at:
http://www.health.gov.au/internet/main/publishing.nsf/content/health-pubhlth-strateg-phys-act-
guidelines and the Ministry of Health’s Eating and Activity Guidelines for New Zealand Adults at:
https://www.health.govt.nz/publication/eating-and-activity-guidelines-new-zealand-adults.
Specifically, compared to those who reported no physical activity, over a mean follow up period of
8.5 ± 3.9 years, individuals who reported a level of physical activity below at least half that
recommended (i.e. 75 min/week of moderate or 32.5 min/week of vigorous physical activity or
equivalent combination) had a reduced risk of all-cause (hazard ratio [HR] 0.75, 95% CI 0.56-1.00)
and cardiovascular disease (CVD) mortality (HR 0.48, 95% CI 0.26-0.88). Individuals who met the
physical activity guidelines demonstrated the greatest reductions in all-cause (HR 0.56, 95% CI 0.45-
0.69), CVD (HR 0.48, 95% CI 0.32-0.71) and respiratory mortality risk (HR 0.40, 95% CI 0.24-0.67).
Dose response associations with mortality risk were found for walking and sport/exercise but not for
domestic physical activity. The majority of the study cohort (80.2%) had an FEV 1 >50% predicted
limiting the generalisability of the findings. These findings provide further support for encouraging
walking and structured exercise in people with COPD with the aim of reducing mortality risk.
O6.1 Pulmonary rehabilitation
Non-pharmacological strategies (such as pulmonary rehabilitation and regular

exercise) should be provided to all patients with COPD [evidence level I, strong
recommendation]
Pulmonary rehabilitation programs involve patient assessment, supervised exercise training,
education, behaviour change, nutritional intervention and psychosocial support (Spruit 2013). The aim
of pulmonary rehabilitation is to improve the physical and psychological condition of people with
chronic respiratory disease and to promote the long-term adherence to health-enhancing behaviours
(Spruit 2013). Exercise training is considered to be the cornerstone of pulmonary rehabilitation (Spruit
2013).
The benefits of pulmonary rehabilitation include a reduction in symptoms (dyspnoea and fatigue),
anxiety and depression, and improvements in health-related quality of life (HRQoL), peripheral
muscle function and exercise capacity. Following pulmonary rehabilitation, participants have been
shown to gain an enhanced sense of control over their condition (Bolton 2013, McCarthy 2015, Ries
2007, Alison 2017, Gordon 2019, Paneroni 2020) [evidence level I/II]. There is also evidence that
pulmonary rehabilitation reduces hospitalisation for exacerbations of COPD (Moore 2016) [evidence
level I]. A systematic review of 21 studies (Moore 2016) reported the effects of pulmonary
rehabilitation on subsequent hospitalisation for exacerbations of COPD. The meta-analysis included 18
studies (10 RCTs, five observational before and after studies, and three cohort studies) of which five
studies were carried out in Australia or New Zealand. Data from the RCTs, and from the five
observational studies that compared hospital admissions in the 12 months before and following
61
pulmonary rehabilitation, favoured rehabilitation (RCTs: mean [95% CI] number of
hospitalisations/patient-year 0.62 [0.33 to 1.16] PR group versus. 0.97 [0.67 to 1.40] control group;
before and after studies mean [95% CI] number of hospitalisations/patient-year 0.47 [0.28 to 0.79]
pre-PR versus. 1.24 [0.66 to 2.34] post-PR). Results of the cohort studies did not support this finding.
Pooled analysis of the three cohort studies showed a higher rate of hospitalisation (mean [95% CI]
number of hospitalisations/patient-year in the PR group 0.28 [0.25 to 0.32]) compared to the
reference group (0.18 [0.11 to 0.32]); however, this finding was influenced predominantly by the
results from one study. Pulmonary rehabilitation has also been shown to be cost-effective (Griffiths
2001) [evidence level II].
Most research has been undertaken with hospital-based programs which may use exercise machines
such as treadmills, stationary cycles, arm and rowing ergometers for aerobic training, and weight
machines for resistance training, but there is also evidence of benefit from pulmonary rehabilitation
provided to in-patients, and in community and home settings where programs involve regular face-
to-face contact to facilitate exercise participation and exercise progression (McCarthy 2015, Ries 2007,
Spruit 2013, Alison 2017). Travel and transport are consistently identified as barriers to participants
undertaking programs that include supervised exercise training (Keating 2011). A systematic review
and meta-analysis compared exercise training programs (ETPs) delivered in patients’ homes (7 trials,
n=319) or community settings (3 trials n=129) with out-patient (10 trials, n=486) ETPs in people with
stable COPD (Wuytack 2018). Trials selected for this review were ETPs of at least 4 weeks duration
with or without additional components often included in pulmonary rehabilitation programs such as
patient education and nutritional support. Programs were equally effective for improving quality of life
and exercise capacity irrespective of the setting (Wuytack 2018) [evidence level I]. A systematic
review and meta-analysis of 15 RCTs comparing home-based pulmonary rehabilitation of at least 4
weeks duration to usual care or centre-based pulmonary rehabilitation, demonstrated that home-
based pulmonary rehabilitation is as effective as centre-based pulmonary rehabilitation in improving
functional exercise capacity and quality of life compared to usual care (Uzzaman 2022) [evidence level
I]. A systematic review and meta-analysis of 19 RCTs comparing the effect of minimal equipment
programs with usual care or with exercise equipment-based programs, demonstrated that pulmonary
rehabilitation programs using minimal equipment elicit clinically significant improvements in 6-minute
walk distance and health-related quality of life and are comparable with exercise equipment-based
programs for improving 6-minute walk distance and upper limb and lower limb strength (Cheng 2023))
[evidence level I]. These systematic review findings are important because providing programs in
community and home-based settings where access to gymnasiums and equipment is limited may
enable greater access to pulmonary rehabilitation and overcome some of the barriers to program
uptake and completion.
Pulmonary rehabilitation should be offered to patients with COPD who are limited by shortness of
breath on exertion and can be relevant for people with any long-term respiratory disorder
characterised by dyspnoea (Ries 2007, Spruit 2013, Alison 2017). Patients with COPD, of all mMRC
grades, gain significant benefit from rehabilitation (Evans 2009, Altenburg 2012, Rugbjerg 2015).
However, those with the most severe dyspnoea, i.e. those who are breathless at rest or on minimal
activity (mMRC grade 3 and 4) are more likely to have difficulties attending out-patient programs for
reasons that include problems with transportation (Sabit 2008). Exacerbations of COPD are also an
indication for referral to pulmonary rehabilitation (Spruit 2013) and every effort should be made to
encourage patients to resume their rehabilitation program as early as possible following an
exacerbation (see section X3.6 Pulmonary rehabilitation).
Telerehabilitation may enable people with high symptom burden or travel restrictions to access
pulmonary rehabilitation. Telerehabilitation is the delivery of rehabilitation services at a distance using
information and communication technology (Kairy 2009). Communication between the health
professional and the patient in their home may utilise telephone (including text messaging), internet
or videoconferencing technologies (Hwang 2015).
In an Australian randomised controlled study comparing an initial 8 week, twice weekly, supervised
62
home-based pulmonary video-conferenced telerehabilitation program compared to a centre-based
pulmonary rehabilitation program, there were no significant differences between the groups for any
outcome at either 8 weeks or 12 months follow-up, and both groups achieved meaningful improvement
in dyspnoea and exercise capacity at the end of rehabilitation (Cox 2022) [evidence level II]. In a
Cochrane review including 15 studies, there was no difference between telerehabilitation and in-person
pulmonary rehabilitation for exercise capacity measured by 6-minute walking distance (6MWD) (mean
difference (MD) 0.06m, 95% CI -10.82m to 10.94m), quality of life measured by the St George’s
Respiratory Questionnaire (MD -1.26, 95% CI -3.97 to 1.45), or breathlessness measured by the
Chronic Respiratory Disease Questionnaire dyspnoea domain score (MD 0.13, 95% CI -0.13 to 0.40).
Telerehabilitation was associated with higher completion rates compared to in-person pulmonary
rehabilitation (93% vs 70%). Ongoing maintenance telerehabilitation was associated with a greater
6MWD by 78.1m (95% CI 49.6m-106.6m) (Cox 2021) [evidence level I]. Long-term telerehabilitation
consisting of two years of unsupervised exercise at home on a treadmill and strength training, plus
either supervised exercise sessions once/week for 8 weeks or supervised exercise sessions once/week
for 8 weeks followed by once/month for the two year duration of the study, reduced the rate of
hospitalisations and ED presentations compared to standard care (Zanaboni, 2023) [evidence level
II].
Exercise programs alone have clear benefits (McCarthy 2015) while the benefits of education or
psychosocial support without exercise training are less well documented (Ries 2007, Spruit 2013,
Alison 2017). There are few robust studies that have attempted to evaluate the role of disease specific
education within a pulmonary rehabilitation program in addition to exercise training. An RCT, carried
out in Australia, of 267 people with COPD failed to show any additional benefit with the combination
of an 8-week pulmonary rehabilitation program comprising exercise training and disease specific
education with a self-management focus, compared to exercise training alone. The outcomes assessed
in this study included disease specific and generic HRQoL, functional exercise capacity, dyspnoea,
health behaviours, self-efficacy and healthcare utilisation (respiratory-related hospital admissions,
physician consultations and prescriptions) (Blackstock 2014). Further, a sub-analysis undertaken
within the Cochrane Review of pulmonary rehabilitation for people with COPD showed no significant
differences in the magnitude of improvement in HRQoL between programs that delivered exercise
training alone (31 trials) when compared to those that delivered exercise training combined with any
form of education and/or psychosocial support (34 trials) (McCarthy 2015).
Some patients who experience marked oxygen desaturation on exertion may benefit from ambulatory
oxygen during exercise training and activities of daily living (see section P10 Oxygen therapy).
The duration of pulmonary rehabilitation programs reported in the literature ranges from 4 weeks to
18 months. Many programs within Australia and New Zealand are of 8 weeks duration, with patients
attending two supervised group sessions each week supplemented by an unsupervised home exercise
program (Alison 2017) consistent with the recommendations reported in pulmonary rehabilitation
statements (Spruit 2013) and international guidelines (Bolton 2013, Marciniuk 2010, Ries 2007). It
is unclear as to whether greater or more sustained benefits occur following programs of longer duration
because there are no RCTs that directly compare the outcomes of 8-week programs with those of
longer programs.
The improvements in functional exercise capacity and HRQoL begin to decline by 12 months following
completion of a pulmonary rehabilitation program (Brooks 2002, Ries 2003). For this reason, within
Australia, patients may be offered supervised exercise training at a lower frequency (≤1 session per
week) than the initial pulmonary rehabilitation program (unpublished data Lung Foundation Australia,
2015). Several studies have investigated maintenance strategies aimed at preserving the benefits in
exercise capacity and HRQoL (Spruit 2013, Alison 2017); however, more research is needed before
any specific strategy can be recommended. A Cochrane review of 21 studies comparing supervised
maintenance pulmonary rehabilitation programs with usual care showed an improvement in health-
related quality of life at 6-12 months (Chronic Respiratory Disease Questionnaire total score mean
difference (MD) 0.54 points, 95% CI 0.04-1.03, n=258, 4 studies, which exceeds the minimal
63
important difference of 0.5 points). It is uncertain whether supervised maintenance programs improve
6-minute walk distance (MD 26 meters, 95% CI -1.04 - 52.84, n=639, 10 studies) (Malaguti 2021).
Unsupervised home-based exercise for 12 months has been shown to improve 1 minute sit-to-stand
performance compared to usual care, had no effect on dyspnoea, but was well accepted by people
with COPD (Frei 2022) [evidence level III-2]. Whilst the optimal model for supervised maintenance
exercise programs is still unclear, some form of regular exercise should be encouraged following
completion of a pulmonary rehabilitation program to sustain the benefits gained (Alison 2017). There
is some evidence (n=2 RCT) that repeating a course of pulmonary rehabilitation within 12 months
following an initial program may be beneficial (Burge 2022) [evidence level I].
A list of pulmonary rehabilitation programs known to Lung Foundation Australia can be accessed at
Pulmonary Rehabilitation - Lung Foundation Australia. The individual contact details can be obtained
by calling the Lung Foundation’s Information and Support Centre (free-call 1800 654 301). An online
toolkit is available to assist health professionals to implement a Pulmonary Rehabilitation Program.
See www.pulmonaryrehab.com.au.
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O6.2 Exercise training
Exercise is defined as physical activity that is planned, structured and repetitive, and undertaken
with the aim of improving or maintaining physical fitness and for health benefits (Garber 2011).
Exercise training (whole body endurance training and strength training) is considered to be the
essential component of pulmonary rehabilitation (Ries 2007, Spruit 2013, Alison 2017). Numerous
RCTs in people with moderate to severe COPD have shown decreased symptoms (dyspnoea and
fatigue), increased maximal and functional exercise capacity and improved health-related quality of
life (HRQoL), emotional function and the individuals’ self-control over their condition following exercise
training alone (McCarthy 2015, Ries 2007, Spruit 2013, Alison 2017, Paneroni 2020) [evidence level
I]. Improvements in muscle strength and self-efficacy have also been reported (Bolton 2013, Ries
2007) [evidence level II]. Exercise training may confer a significant but small increase in physical
activity (Mantoani 2016) [evidence level I].
Recommendations for exercise training in people with COPD are based on those for healthy adults
(Garber 2011, Spruit 2013). However, since many individuals with COPD are unlikely to be able to
achieve the recommendation for moderate to vigorous intensity exercise involving large muscle groups
sustained for prolonged periods (i.e. 20-60 minutes) (Garber 2011) some modifications to these
recommendations are required. Specifically, for people with COPD to accumulate the recommended
dose (≥ 150 minutes per week of moderate intensity exercise, involving large muscle groups and
accumulated over ≥ 5 days) they frequently need to undertake periods of exercise interspersed with
rest periods in order to manage their dyspnoea. It is important to reassure patients that breathlessness
on activity is not harmful and a degree of breathlessness is necessary in order to gain the benefits of
exercise. When commencing an exercise program most individuals will need to gradually build up to
the recommended weekly dose of exercise. Walking (ground-based or treadmill) and or stationary
cycling are the forms of endurance exercise most commonly employed in exercise training programs
for people with COPD (Spruit 2013) with ground-based walking having the advantage that it requires
no equipment and can translate into improvements in walking capacity (Wootton 2014). Strength
training is also recommended on at least 2 days each week interspersed with at least one rest day
(Garber 2011). A systematic review and meta-analysis (de Lima 2020) including 3 studies and 145
participants suggests elastic resistance training may be an alternative to conventional resistance
training using weight machines for improving knee extensor muscle strength due to similar effects
[evidence level I]. In order to gain the most benefit from an exercise program it is likely that many
individuals with COPD will require supervision from a health professional who has a knowledge of lung
pathology and exercise prescription for people with chronic lung disease.
There is evidence from a multicentre, RCT (n=143) carried out in Australia that provides some
support for the use of supervised ground-based walking training as the sole modality of exercise
training in people with moderate to severe COPD (Wootton 2014). This trial demonstrated significant
benefits in HRQoL and endurance walking capacity favouring the walking training group [evidence level
II] however some of the benefits were of a lesser magnitude than reported following a comprehensive
pulmonary rehabilitation program. Supervised walking training in isolation has a therapeutic role where
access to pulmonary rehabilitation programs is limited or when specialised exercise equipment is
unavailable.
In an Australian study of telerehabilitation comparing 8 weeks of group exercise training thrice

weekly, compared to usual medical management involving pharmacotherapy and an action plan, the
endurance shuttle walk test improved significantly in the trained group compared with usual care: 340
seconds (95% CO 153-526, p<0.001) (MCID 180 seconds). However, there were no significant
differences in quality of life or physical activity measured as steps walked per day between the two
groups (Tsai 2017) [evidence level II], despite the control group not receiving an exercise intervention.
Most of the evidence for the benefits from exercise training has been gained from supervised
programs that involved land-based exercise training, however a Cochrane Review provides limited
65
evidence from RCTs conducted in a small number of patients with COPD that water-based exercise
may confer short-term benefits in exercise capacity and quality of life (McNamara 2013b) [evidence
level I]. The Australian study included in this Cochrane Review specifically recruited individuals with
COPD who had concurrent physical comorbidities such as obesity or significant musculoskeletal
problems that limited the ability to participate in a land-based exercise program (McNamara 2013a).
Thus, supervised water-based exercise training may provide an alternative for people with COPD
whose comorbidities preclude land-based exercise training or when pulmonary rehabilitation programs
are unavailable.
Unsupervised exercise training using a formal prescription of frequency, intensity, time and type can
significantly improve disease-specific quality of life in people with COPD, but not exercise capacity
(Taylor 2021) [evidence level I]. Supervised exercise training is required to improve exercise capacity.
O6.3 Inspiratory Muscle Training

Inspiratory muscle training (IMT), performed in isolation using a threshold loading device or target-
flow resistive device at loads equal to or greater than 30% of an individual’s maximum inspiratory
pressure generated against an occluded airway (PImax) has been shown to produce short-term gains
in inspiratory muscle strength and endurance, reduce dyspnoea, improve functional exercise capacity
(6 or 12 minute walk distance) and confer small gains in health-related quality of life (HRQoL) in
patients with COPD (Ammous 2023) [evidence level I]. Although IMT used in isolation is beneficial, it
does not appear to have any added benefits in terms of dyspnoea, functional exercise capacity or
quality of life when combined with whole body exercise training in people with COPD (Ammous 2023)
[evidence level I]. For this reason, IMT is not a replacement for whole body exercise training and is
not recommended as a routine component of a pulmonary rehabilitation program (Spruit 2013).
O6.4 Neuromuscular electrical stimulation

Neuromuscular electrical stimulation (NMES) uses an intermittent electrical current to elicit a
contraction of a superficial peripheral muscle. The main aim of NMES is to improve muscle power or
endurance. In people with COPD, NMES is generally applied to the thigh muscles. NMES is associated
with a very low ventilatory load and thus dyspnoea in contrast to whole body exercise training.
The findings of a Cochrane Review (Hill 2018) showed that NMES applied in isolation improved
peripheral muscle force (SMD 0.34, 95% CI 0.02 to 0.65, 6 trials, n=159) and endurance (SMD 1.36,
95% CI 0.59 to 2.12, 2 trials, n=35) and 6-minute walk distance (39.26m, 95% CI 16.31 to 62.22, 2
trials, n=76) [evidence level I]. These trials applied NMES over a 4 to 8-week period, 4 to 7 days a
week and for sessions lasting 30-60 minutes applied once or twice daily. The findings of studies that
applied NMES in addition to conventional exercise training compared to conventional exercise training
alone (6 trials) showed no additional gain in muscle performance. The quality of the evidence in this
review was rated as low. The main clinical applications for NMES are for patients unable to engage in
whole body exercise training, for example due to very severe dyspnoea including patients with an
exacerbation and those awaiting transplantation.
66
O6.5 Physical activity and sedentary behaviour
Physical activity is defined as any bodily movement generated by skeletal muscle that results in energy
expenditure above resting levels and is often classified as light, moderate or vigorous intensity
according to the energy level required (Garber 2011). In its broadest form, physical activity
encompasses exercise (physical activity) that is planned, structured and repetitive, undertaken with
the aim of improving or maintaining physical fitness and for health benefits), sports, and physical
activity done as part of daily living, work, leisure and transportation.
It is well-established that people with COPD participate in low levels of physical activity during daily
life. Data from meta-analyses indicate that, on average, people with COPD participate in 57% of the
total duration of physical activity undertaken by healthy controls (Vorrink 2011). Reductions in physical
activity commence early in the COPD disease trajectory (Waschki 2015). Over time, levels of physical
activity substantially decline across all severity stages of COPD and this decline is accompanied by
deterioration in lung function and health status (Waschki 2015). Levels of physical activity are reduced
further during hospitalisation for an exacerbation of COPD (Pitta 2006). An Australian study assessed
physical activity in 50 individuals during hospitalisation for an exacerbation of COPD, and at 1- and 6-
weeks following discharge (Tsai 2016). Although there was a significant improvement in physical
activity at one week following discharge when compared to activity levels during admission, the level
of physical activity at 6 weeks post-discharge showed no further significant improvement (Tsai 2016).
Low levels of physical activity are associated with increased mortality and exacerbations in people
with COPD (Gimeno-Santos 2014) [evidence level I]. In one cohort study of 341 patients hospitalised
for the first time with a COPD exacerbation, regular physical activity was related to a higher diffusing
capacity of lung for carbon monoxide (DLCO) test, expiratory muscle strength, exercise capacity (6-
minute walk distance (6MWD) and VO2 peak) as well as to lower levels of systemic inflammation, after
adjusting for confounders (Garcia-Aymerich 2009) [evidence level III-2]. In a population-based
sample of 2,386 individuals with COPD who were followed for a mean of 12 years, those who performed
some level of regular physical activity had a significantly lower risk of COPD admissions or mortality
than sedentary individuals (Garcia-Aymerich 2006) [evidence level III-2].
Regular physical activity is recommended for all individuals with COPD (Garcia-Aymerich 2009). In
the absence of instruction from a health professional (i.e. physiotherapist, exercise physiologist),
individuals with COPD should be encouraged to be physically activity (i.e. engage in at least moderate
PA for 30 minutes on 5 days each week, e.g. walking) and participate in activities of daily living that
require the use of muscle strength (e.g. lifting, squatting to complete tasks such as gardening) as well
as doing activities such as bowls, golf, swimming and Tai Chi that they enjoy.
There is some evidence that interventions comprising physical activity counselling, especially when
combined with coaching, can produce modest increases in physical activity in people with COPD
however the quality of the evidence was rated as very low (Mantoani 2016) [evidence level I].
A randomised controlled trial carried out in Spain in people with moderate COPD (predominantly
male) showed a significant increase in physical activity (mean difference 947 steps/day (95% CI 184
to 1731)) at the 12-month follow-up (per protocol analysis) in a group that received a multicomponent
Urban Training intervention compared to a group that received usual care (Arbillaga-Etxarri 2018).
Key components of the intervention included behavioural techniques and motivational interviewing,
maps of validated walking trails of different intensities, pedometer and calendar to record physical
activity, text messages every 2 weeks and option to participate in a monthly supervised walking group.
No between group differences were seen in any of the secondary outcomes that included 6MWD, QoL
and severe exacerbations.
Supervised exercise training alone or within the context of a pulmonary rehabilitation program has
been shown to produce significant but small increases in physical activity, however the benefits are
inconsistent and overall the quality of the evidence was rated very low (Mantoani 2016) [evidence
67
level I]. A systematic review and meta-analysis (Lahham 2016) found that activity counselling, when
added to pulmonary rehabilitation, increased physical activity as measured by daily step count, and
that this was both significant and exceeded the minimum important difference for daily step count
(mean difference 1,452 daily steps, 95% CI 549 to 2,356). Physical activity promotion with a wearable
activity monitor-based intervention (i.e., pedometer or accelerometer incorporated as a tool to monitor
and provide feedback on step-count throughout the intervention), improved steps per day (median
(IQR) 1153 (791-3199) steps per day) compared with usual care in a systematic review and meta-
analysis (Reilly 2023) [evidence level I]. Further studies are needed, but physical activity counselling
in the context of a pulmonary rehabilitation program shows promise in terms of increasing physical
activity in daily life.
In addition to low levels of physical activity, there is growing recognition that people with COPD
spend a large proportion of their waking hours in sedentary behaviours, (Hunt 2014) defined as those
behaviours which are undertaken in a sitting or reclined posture and have low energy requirements
(e.g. watching television, reading, playing cards, sitting at a computer) (Sedentary Behaviour
Research Network 2012). People with COPD who accumulate the greatest sedentary time during daily
life are more likely to live with someone else and be characterised by more frequent exacerbations,
lower exercise capacity, long-term oxygen use, lower motivation for exercise, and the presence of
physical comorbidities such as obesity, musculoskeletal or neurological conditions (Hartman 2013,
McNamara 2014).
In the general population, data from several large longitudinal studies have reported the deleterious
health consequences (e.g. both all-cause and cardiovascular mortality) of increased sedentary time
(Dunstan 2010, Thorp 2011) [evidence level I]. Sedentary behaviour defined as more > 8.5 hrs/ day
spent in sedentary behaviour in a cohort of 101 Brazilian patients with COPD was an independent risk
factor for mortality (Furlanetto 2017) [evidence level III]. Furthermore, data collected in 76,688
people from Japan, who were followed for 19.4 years show that, when compared with men who
watched television for < 2 hours/day, men who watched television for ≥ 4 hours/day had an increased
risk of COPD-related mortality (HR 1.63; 95% CI 1.04 to 2.55). However, this relationship was not
observed in females (HR 0.84; 95% CI 0.29 to 2.48) (Ukawa 2015). Data collected in 223 people with
COPD as part of the National Health and Nutrition Examination Survey (NHANES), showed modest
positive associations between sedentary time and markers of cardiometabolic risk such as waist
circumference and fasting glucose levels (Park 2014).
Given that people with COPD accumulate large amounts of sedentary time and this may have
deleterious health consequences, reducing sedentary time would seem to be an appropriate lifestyle
goal in this population. Compared with the goal of increasing physical activity, particularly moderate
or vigorous intensity physical activity, the goal of reducing sedentary time by increasing light intensity
physical activity is likely to be more feasible in those with marked reductions in exercise capacity who
are limited by dyspnoea during activities of daily living (Cavalheri 2016, Hill 2015). Of note, in people
with COPD, greater participation in light intensity physical activity, such as slow walking, has been
reported to reduce the risk of respiratory-related hospitalisations (Donaire-Gonzalez 2015). There is
a need to identify approaches that are effective at reducing sedentary time in people with COPD, and
most importantly, whether any reduction in sedentary time impacts health outcomes in this population.
The table in Appendix 4 provides some strategies aimed at avoiding prolonged sedentary time.
O6.6 Education and self-management
There is limited evidence that education alone can improve self-management skills, mood or health-
related quality of life (HRQoL). Education is often included with exercise training as part of a
comprehensive pulmonary rehabilitation program (Ries 2007) [evidence level III-2]. Delivering COPD-
specific information in a didactic style is unlikely to be beneficial and therefore is not recommended
(Blackstock 2007). Providing information and tools to enhance self-management in an interactive
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session is more effective than didactic teaching (Lorig 1999, Blackstock 2007).
A systematic review of self-management education for COPD (Schrijver 2022) concluded that self-
management education is associated with improvements in HRQoL measured by the SGRQ, compared
to usual care (mean difference -2.86 95% CI -4.87 to -0.85). This difference did not meet the MCID
of 4 units however. The intervention group was also at a lower risk of at least one respiratory hospital
admission, albeit the difference was small (OR 0.75 95% CI 0.57 to 0.98). This translates into a
Number Needed to Treat of 15 (95% CI 8-399) to prevent one respiratory related hospital admission
over a follow up period of 9.75 months. There were also improvements in exercise capacity (6MWD),
anxiety and depression, and antibiotic courses. However, because of the heterogeneity in
interventions, study populations, follow-up time and outcome measures, data are insufficient to
formulate clear recommendations regarding the format and content of self-management education
programs for individuals with COPD. Several more studies have not shown any benefit from self-
management interventions (Bucknall 2012, Bischoff 2012). One study found excess mortality in the
self-management group (Fan 2012). However, in the 2022 Cochrane review by Schrijver et al the
mortality meta- analyses, which included Fan et al (2021), showed no difference in respiratory related
mortality risk (risk difference RD 0.01 95%CI -0.02 to 0.04), or all-cause mortality risk (risk difference
RD 0.01 95%CI -0.03 to 0.01) between intervention and usual care.
The single most important intervention is assistance with smoking cessation. Good nutrition; task
optimisation for more severely disabled patients; access to community resources; help with control of
anxiety, panic or depression; instruction on effective use of medications and therapeutic devices
(including oxygen where necessary); relationships; end-of-life issues; continence; safety for flying;
and other issues may be addressed (Spruit 2013, Morgan 2001).
O6.6.1 Psychosocial support
Support groups may provide people with COPD and their carers with emotional support, social
interaction, and new knowledge and coping strategies, although studies specifically evaluating the
benefits of these groups for improving quality of life and psychological well-being are yet to be
conducted. Pulmonary rehabilitation provides a good opportunity to initiate support group attendance.
Lung support groups may provide patients and carers with emotional support, social interaction, and
other social outlets, and help them gain new knowledge and coping strategies. A list of Patient Support
Group names and locations can be accessed via Lung Foundation Australia’s website at
https://lungfoundation.com.au/patients-carers/get-support/support-groups/. Contact details can be
obtained from Lung Foundation Australia’s Information and Support Centre (free-call 1800 654 301).
In New Zealand, Asthma and Respiratory Foundation NZ list Pulmonary Rehabilitation and Support
Groups on their website: https://www.asthmafoundation.org.nz/about-us/support-groups, free-call
0800 100 506. Asthma New Zealand list COPD Support Groups and the 'Find your local group'
directory: https://www.asthma.org.nz/pages/copd-support-groups, free-call 0800 227 328.
People with COPD are vulnerable to developing symptoms of anxiety and depression, which then
worsen quality of life and disability (Xu 2008, Eisner 2010b) [evidence level III-2]. Pulmonary
rehabilitation has been associated with short-term reductions in anxious and depressive symptoms
(Coventry 2013, Yohannes 2017, Gordon 2019). Additional intervention by mental health specialists,
such as high-intensity cognitive behavioural therapy interventions, will be required for clinically
significant symptoms of anxiety or depression (Yohannes 2017, Williams 2020).
O6.7 Breathing exercises
A variety of breathing exercises are used in people with COPD. The aim of these exercises is to
reduce dyspnoea by altering respiratory muscle recruitment, reducing lung hyperinflation, improving
the functioning of the respiratory muscles and optimising thoraco-abdominal motion.
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A Cochrane Review of 16 studies involving a total of 1233 individuals with stable COPD (Holland
2012) evaluated the effects of a variety of breathing exercises alone, or together with other
interventions, on the primary outcome measures of dyspnoea, exercise capacity and health-related
quality of life (HRQoL). The review found some evidence that breathing exercises (pursed lip breathing,
diaphragmatic breathing, yoga involving pranayama timed breathing techniques) performed for
between 4 and 15 weeks when compared to no breathing exercises improved exercise capacity as
measured by 6-minute walking distance [evidence level I/II] but had inconsistent effects on dyspnoea
or HRQoL. Mixed results were found when breathing exercises were compared with other techniques,
namely inspiratory or expiratory muscle training, or whole-body exercise training, or when combined
with another intervention. Computerised ventilation feedback was less effective than exercise training
for improving exercise endurance [evidence level III-2] and when combined with exercise training did
not confer any additional benefits in dyspnoea compared to exercise training alone [evidence level III-
2]. No significant adverse effects were reported in the studies. A major limitation of the studies was
that assessor blinding could only be determined in two studies. In a systematic review of 15
randomised control trials (1098 people with COPD), daily pursed lip breathing combined with deep
breathing (2-5 times a day for 5-30 minutes) compared to usual care, showed statistically significant
improved pulmonary function (FEV1, FVC, FEV1/FVC) and 6-minute walk distance (mean difference
29m, 95% CI 19-38, p<0.001) compared to control (Yang 2022) [evidence level I].
Breathing exercises practiced daily may have a role to improve exercise capacity in people with COPD
who are unable to undertake exercise training, and their use during daily living activities can be
beneficial for breathlessness management by reducing respiratory rate at rest and shortening time
taken to recover from breathlessness.
O6.8 Chest physiotherapy (Airway clearance techniques)

Airway clearance techniques (ACTs) are only indicated for patients with COPD who have evidence of
sputum. This is likely to include individuals who have the clinical features of chronic bronchitis, those
with co-existent bronchiectasis and some patients during an exacerbation.
The aims of ACTs in patients with COPD are to assist sputum clearance in an attempt to reduce
symptoms and paroxysmal coughing, slow the decline in lung function, reduce exacerbation frequency
and hasten the recovery from exacerbations.
A variety of techniques are available that vary in terms of ease of learning and equipment-related
cost. These include the active cycle of breathing techniques (ACBT), (a cycle of breathing control,
thoracic expansion exercises and the forced expiration technique), positive expiratory pressure (PEP)
therapy (e.g. Astra PEP® or Pari PEP®), devices that combine PEP and an oscillatory vibration of the
air within the airways (e.g. Flutter®, Acapella® or Aerobika®) and autogenic drainage (AD). Autogenic
drainage is a more complex technique that is based on the principle of achieving the highest possible
airflow in different generations of bronchi, while preventing early airway closure, via the use of
controlled tidal breathing. Conventional chest physiotherapy (defined as any combination of gravity-
assisted drainage, percussion, vibrations and directed coughing /huffing) is now used less commonly.
Short-acting inhaled bronchodilators prior to treatment may assist with sputum clearance in some
patients. The Bronchiectasis Toolbox is an online resource which provides guidance for healthcare
professionals and people living with chronic lung disease which describes and demonstrates airway
clearance techniques (https://bronchiectasis.com.au/physiotherapy).
A Cochrane systematic review (Osadnik 2012) of 19 studies of ACTs in patients with stable COPD
found evidence from single studies suggesting that ACTs may reduce the need for hospital admission
and improve health-related quality of life (HRQoL) [evidence level II]. It is possible that ACTs may
also enhance sputum clearance and exercise tolerance, and reduce the longer-term need for antibiotics
[evidence level II] although further research is required. The trials included in the review were
generally of small sample size and the ability to pool data for meta-analyses was limited due to
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heterogeneity of outcome measures and inadequate reporting from cross-over studies.
It is unlikely that one ACT is appropriate or superior for all patients with COPD. The choice of
technique depends on the patient’s condition (e.g. extent of airflow limitation, severity of dyspnoea),
sputum volume and consistency, the effects of the different techniques on lung volumes, expiratory
flow and dynamic airway compression, presence of co-morbid conditions such as bronchiectasis,
cognitive status of the patient and acceptability of the technique to the patient especially where long-
term treatment is required (Holland 2006). Furthermore, the level of expertise of the therapist and
availability and cost of ACT devices are also factors affecting the choice of ACT prescribed.
A randomised controlled trial of oscillating positive expiratory pressure (OPEP) using the Acapella
device plus ACBT compared to ACBT alone in patients with COPD who frequently produce sputum
demonstrated significant improvements in cough-related QOL, genericQOL, and reduced fatigue
(Alghamdi 2022). In clinical practice, screening of patients who produce sputum on most days (i.e.
COPD with a sputum producing phenotype), can identify patients where the Acapella™, and perhaps
similar OPEP devices, can have a positive impact [evidence level II].
Patients with evidence of chronic sputum production should be referred to a physiotherapist for
assessment and education regarding the most appropriate ACTs for each individual based on their
clinical features.
O6.9 Smoking cessation

While smoking cessation has long been known to reduce the rate of decline of lung function (see
section P1.1), there is evidence it also has short-term benefits on lung function and quality of life. In
a randomised controlled trial of varenicline (Tashkin 2011b) participants who continuously abstained
from smoking compared to those who relapsed, had higher post-bronchodilator FEV1 at weeks 12
(mean 121.8 ml versus. 37.9 ml, p<0.007) and 24 (mean 58.4 ml versus. -19.1 ml, p=0.07) when
compared to baseline measurements, although the difference at the latter time point was not
statistically significant. Similarly, those who abstained, when compared to those who relapsed, had a
greater improvement in the total clinical COPD questionnaire score at 12 weeks (mean -1.04 versus.
-0.53, p<0.0001), and this significant benefit was also seen at 24 and 52 weeks. Benefits at all time
points were also found for the domain scores of respiratory symptoms, functional status and mental
state. Refer to P1.1 for additional information regarding smoking cessation.
O6.10 Nutrition
Nutritional management of COPD is complex, as both malnutrition and obesity are highly prevalent,
and both contribute to patient morbidity and mortality risk. In addition, poor eating habits, sedentary
lifestyle, smoking and corticosteroid use can lead to poor nutritional status in COPD, with deficiencies
in various nutrients such as vitamins and minerals, fatty acids and amino acids. The randomised
controlled trials (RCTs) that have been conducted with the aim of achieving a healthy weight,
improving nutritional status and functional outcomes in COPD are discussed below.
Malnutrition: Malnutrition is an independent predictor of mortality and healthcare use in COPD

patients (Hoong 2017) [evidence level III-2]. Low body weight and/or low-fat free mass (FFM) is
common in COPD, particularly in those patients with severe disease and those who are socially
deprived (Collins 2018), due to an inadequate nutritional intake compared to energy expenditure.
Energy intake may be reduced due to breathlessness during eating, hyperinflation of lungs causing
pressure on the stomach and loss of appetite induced by drugs (Sridhar 2006). At the same time,
energy demands may be increased due to factors such as the energy costs of breathing, the metabolic
costs of respiratory tract infections, increased nutrient-induced thermogenesis and catabolic effects of
systemic inflammation (Sridhar 2006, Akner 2016). As a result, low BMI and loss of FFM are common
in COPD patients and this increases COPD mortality risk, being inversely associated with respiratory
and peripheral muscle function, exercise capacity and health status (Vestbo 2006, Schols 2005). Two
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meta-analyses have shown that high calorie nutritional support has small, yet beneficial effects in
COPD, particularly in those who are undernourished. A systematic review which included 13 RCTs of
nutritional support included a meta-analysis that showed a pooled increase in mean weight, which was
greatest in undernourished patients [1.94 (95% CI 1.43-2.45) kg]. There were also increases in grip
strength 5.3% (p < 0.05) and small effects on fat free mass and skin fold thickness (Collins 2012)
[evidence level I]. In a follow-up meta-analysis which focused on functional outcomes, nutritional
support led to improvements in inspiratory muscle and expiratory muscle strength (Collins 2013)
[evidence level I]. A Cochrane Review updated in 2012 also demonstrated in a meta-analysis of data
from 17 RCTs, that nutritional therapy resulted in body weight gain in undernourished patients [1.65
(95% CI 0.14-3.16) kg] and improved FFM index and exercise tolerance (6-minute walk distance
(6MWD)) in all patients. Importantly, the increase in 6MWD reached the minimum clinically important
difference in severe COPD patients (Ferreira 2012) [evidence level I]. Hence high calorie nutritional
supplements should be considered in COPD, particularly those who are malnourished and/or have
severe disease. Importantly, those with undernutrition are most likely to benefit from nutrition therapy
before an undernutrition state is established (Akner 2016).
Obesity: At the other end of the spectrum, obesity is becoming increasingly prevalent in COPD.
Obesity complicates COPD management and in addition to the negative metabolic consequences, is
associated with decreased expiratory reserve volume (ERV) and functional residual capacity (FRC),
increased use of inhaled medications, increased dyspnoea and fatigue, decreased heath related quality
of life and decreased weight bearing exercise capacity (Cecere 2011, Ramachandran 2008, Ora 2009).
Despite these negative effects, obesity has been associated with reduced mortality risk in severe
COPD, (Landbo 1999, Guo 2016b) which may be due to a reduction in static lung volumes (Casanova
2005) and /or the increase in FFM (Poulain 2008) that occurs in obesity due to over-nutrition and
increased weight bearing. A meta-analysis of 17 studies evaluated the dose-response relationship
between BMI and mortality. Compared to healthy weight COPD individuals, the RR for death in the
underweight was 1.40 (95% CI 1.20-1.63; p=0.0001), whereas the risk of death was reduced in those
in that were overweight (RR 0.80, 95% CI 0.67-0.96; p=0.0001) and obese (RR 0.77, 95% CI 0.62-
0.95; p=0.0162). There was a nonlinear relationship between mortality and BMI categories. Those
with a BMI <21.75 kg/m2 had the greatest risk of dying. Once BMI exceeded 32 kg/m2 the protective
effect of high BMI was no longer evident (Guo 2016b).
No weight loss RCTs have been conducted in COPD to date, however, a recent pre-post study has
demonstrated the potential benefits of weight loss. In this uncontrolled trial, dietary energy restriction
coupled with resistance exercise training led to clinically significant improvements in BMI, exercise
tolerance and health status, while preserving FFM (McDonald 2016b) [evidence level III]. Definitive
RCTs are needed in this area in order to formulate clinical guidelines for managing obese COPD
patients.
Other nutritional interventions: A number of large observational cohort studies have

demonstrated that a healthy dietary pattern (including fruit, vegetables, fish and wholegrains) protects
against lung function decline and COPD onset, while an unhealthy eating pattern (including refined
grains, cured and red meats, desserts and French fries) has the opposite effect (Varraso 2015, Varraso
2007a, Varraso 2007b). Nutritional interventions targeting specific foods or nutrients in COPD are
limited and to date, the level of evidence supporting these interventions is level II or less.
Fruit and vegetables: Fruit and vegetables are recognised as being part of a healthy diet as they
are low in energy, yet dense in nutrients such as vitamins and minerals, fibre and phytochemicals. In
a cohort study in 44,335 men followed for 13.2 years, high fruit and vegetable intake was associated
with reduced risk of COPD. Current and ex-smokers with a high (≥ 5 serves per day) versus low (< 2
serves per day) had 40% and 34% lower COPD risk (Kaluza 2017) [evidence level III]. Two RCTs
manipulating fruit and vegetable intake have been conducted in COPD. A 12-week study in 81 COPD
patients showed no effect of a high fruit and vegetable intake on FEV1, systemic inflammation or airway
oxidative stress (Baldrick 2012) [evidence level III]. However, a 3-year study in 120 COPD patients
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revealed an improvement in lung function in the high fruit and vegetable group compared to the control
group (Keranis 2010) [evidence level III], suggesting that longer term fruit and vegetable intake
provides a therapeutic effect.
Vitamin E: Vitamin E is a nutrient with antioxidant and anti-inflammatory properties. The ability for
vitamin E to reduce biomarkers of oxidative stress in COPD has been demonstrated in one RCT (Daga
2003), but not another (Wu 2007) [evidence level II]. In a large-scale RCT (Women’s Health Study,
n=38597), the risk of developing chronic lung disease over a 10-year supplementation period was
reduced by 10% in women using vitamin E supplements (600 IU on alternate days), suggesting benefit
of long-term supplementation (Agler 2011) [evidence level III].
Omega-3 fatty acids: Omega-3 fatty acids have been demonstrated to have diverse anti-
inflammatory effects. Two RCTs have examined the effect of omega-3 polyunsaturated fatty acids
(PUFA) in COPD. One RCT randomised 32 COPD patients to supplementation with 0.6g omega-3PUFA
per day combined with low intensity exercise or a control group for 12 weeks. They reported an
improvement in weight, exercise capacity, quality of life and inflammation in the omega-3PUFA/
exercise group compared to controls (Sugawara 2010) [evidence level II]. The other study compared
the effects of 8 weeks supplementation with 2.6g omega-3PUFA/day versus a placebo in 102 COPD
patients undergoing pulmonary rehabilitation. They reported an increase in exercise capacity in the
omega-3PUFA group compared to the placebo group, but there were no effects on muscle strength,
FEV1 or inflammation (Broekhuizen 2005) [evidence level II]. Hence omega-3PUFA supplementation
may be a useful adjunct to COPD rehabilitation programs [evidence level II].
Vitamin D/ calcium: Vitamin D regulates calcium homeostasis and bone metabolism, as well as
having roles in immune function, inflammation, airway remodelling and muscle strength. Vitamin D is
frequently deficient in COPD due to factors including the use of oral corticosteroids, smoking, poor diet
and reduced exposure to sunlight due to physical limitations. Vitamin D deficiency was associated with
lower lung function and more rapid decline in FEV1 among smokers in a cohort of elderly men followed
for 20 years (Lange 2012) [evidence level III]. In another cohort of 18,507 participants, lung function
decline was faster, and COPD risk increased, in individuals with the lowest vitamin D levels (Afzal
2014). Corresponding with low vitamin D levels, osteoporosis is highly prevalent in COPD; in 658
COPD patients in the TORCH study, 23% were osteoporotic and 43% osteopenic (Ferguson 2009).
While there are no COPD-specific treatment guidelines for osteoporosis, standard treatment guidelines
apply, with patients using corticosteroids requiring treatment according to the guidelines for
management of corticosteroid-induced osteoporosis, including daily calcium intake of 1200-1500
mg/day and vitamin D doses of 800-1000 IU per day (Grossman 2010).
A meta-analysis of individual patient data from three RCTs of 468 patients (Jolliffe 2019) was
conducted to determine whether vitamin D supplementation reduced exacerbations of COPD. The
authors reported that vitamin D supplementation did not reduce overall moderate or severe
exacerbations, (adjusted IRR 0.94, 95% CI 0.78 to 1.13; p=0.52; n=469 in three studies, one step
IPD meta-analysis), and results were similar for the two-step analysis. There were however, protective
effects of vitamin D supplementation in patients considered vitamin D deficient, [those with a baseline
25-hydroxyvitamin D level of <25 nmol/l (1.23 versus 2.10 events per person per year, aIRR 0.55,
95% CI 0.36 to 0.84 n=87 in three studies; within sub-group p=0.006] but not in those with baseline
25-hydroxyvitamin D levels ≥25 nmol/l (2.01 versus 1.94 events per person per year, p=0.71, aIRR
1.04, 95% CI 0.85 to 1.27; p for interaction=0.015, n=382,) [evidence level I].
In people with COPD, vitamin D deficiency should be considered, and supplementation is

recommended in deficient patients, particularly those with a 25-hydroxyvitamin D level <25 nmol/l.
Amino Acids: Amino acids are the building blocks of protein and hence an integral component of
muscle tissue. Various types of amino acids and their derivatives have been assessed in intervention
trials in COPD. In a 12-week RCT in 88 COPD out-patients, those who received essential amino acid
supplementation had an improvement in FFM, muscle strength, physical performance and St George
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Respiratory Questionnaire (SGRQ) compared to placebo (Dal Negro 2010) [evidence level II]. Another
RCT in 28 COPD patients examined outcomes following 12 weeks pulmonary rehabilitation, in patients
with or without essential amino acid supplementation, including 5g/day branched chain amino acids.
Body weight and FFM increased in the supplemented group compared to controls (Baldi 2010)
[evidence level III]. Whey protein, rich in the amino acid cysteine and other essential amino acids,
was trialled in a 16-week RCT in COPD patients who were undergoing exercise training for the last 8
weeks of the intervention. This resulted in increased exercise capacity and quality of life compared to
placebo, but no changes in inflammation (Laviolette 2010) [evidence level II]. In a 6-week RCT in 16
COPD patients, the amino acid derivative L-carnitine was administered concurrent with pulmonary
rehabilitation and resulted in improved exercise tolerance and inspiratory muscle strength compared
to the placebo group (Borghi-Silva 2006) [evidence level II]. Conversely, the amino acid derivative
creatine, has been shown in meta-analyses to have no effect on muscle strength, exercise tolerance
or SGRQ in COPD (Al-Ghimlas 2010) [evidence level I]. In summary, based on level II evidence,
essential amino acids, whey protein and L-carnitine may be beneficial in COPD, particularly when
combined with exercise training.
Anabolic steroids: While anabolic steroids are not diet-derived, they have a potential role in FFM
accretion. A recent systematic review and meta-analysis reported that in COPD patients, 8-26 weeks
intervention with anabolic steroids led to improvements in body weight, FFM and SGRQ, while there
was no improvement in lung function, handgrip strength or 6-minute walk distance (6MWD) (Pan
2014) [evidence level I]. Hence some specific benefits are apparent, although possible adverse effects
also need to be considered.
In summary, level I evidence exists for the use of high calorie nutritional supplementation in COPD,
to achieve body weight gain, improve FFM index and exercise tolerance (6MWD), with results most
significant for patients who are undernourished. Benefits have been demonstrated for healthy eating
patterns, increasing fruit and vegetable intake and supplementing with n-3 PUFA, vitamin E, vitamin
D, essential amino acids, whey protein and L-carnitine in COPD, particularly when the supplements
are used in combination with a pulmonary rehabilitation program. However, level I evidence supporting
the use of these other interventions does not yet exist and further research is needed to confirm
efficacy.
Eating strategies
For all COPD patients, a key goal of nutritional management is to eat a balanced diet and to achieve
and maintain a healthy weight. Healthy eating means choosing a variety of foods from each of the five
food groups every day, in suitable proportions including: vegetables and legumes/beans; fruit; grain
foods, mostly wholegrain varieties, such as breads, cereals, rice and pasta; lean meats and poultry,
fish, eggs, tofu, nuts and legumes; and dairy products such as milk, yoghurt and cheese. At the same
time, foods that are high in saturated fat, sugar and sodium, such as highly processed and takeaway
foods, should be limited.
To prevent dyspnoea while eating, various strategies as shown in Box 7 have been recommended:
Box 7: Eating strategies which may prevent dyspnoea
● Clear the airways of mucus before eating
● If supplemental oxygen is used, make sure this is worn while eating
● Avoid eating large meals, instead eat small nutritious meals and snacks more frequently
● Avoid drinking with meals
● Eat slowly
● Choose softer foods that are easier to chew and swallow, e.g. mashed potato, soups, bananas
● Limit foods that can cause bloating, e.g. beans, onions, cauliflower, soft drinks
● Rest for at least 15-20 minutes after eating in an upright position
● In patients who are underweight, protein and calorie intake can be boosted using high energy,
nutrient-rich foods that are easily accessible, such as milk powder, cheese, cream, custard, peanut
butter and milkshakes or a nutritionally complete oral supplement (e.g. Sustagen)
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● Referral to a dietitian for individual advice may be beneficial
Other tips to avoid aspiration can be found in O7.6 Aspiration.
O6.11 Complementary therapies
A systematic review by Guo (Guo 2006) concluded there was no clear evidence supporting the
effectiveness of herbal medicines for treating COPD.
Tai Chi is a systematic callisthenic exercise that involves a series of slow and rhythmic circular
motions moving from one form to another. The styles of Tai Chi are differentiated by the varying forms
or postures, order of movement sequences, focus on muscle work, pace of movement and angle of
knee flexion during practice. Tai Chi is most commonly performed in a semi-squat position and is
recognised as an exercise of moderate intensity.
A Cochrane Review (Ngai 2016) in people with mild to very severe stable COPD included eight RCTs
that compared Tai Chi to usual care. One trial was undertaken in Australia (Leung 2013). The findings
provided very low to moderate quality evidence that when compared to usual care, Tai Chi improved
functional exercise capacity (6MWD) (6 trials, n=318,) mean difference 29.64m (95% CI 10.52 to
48.77m) and lung function (FEV1) (4 trials, n=258), mean difference 0.11L (0.02 to 0.20L) [evidence
level I]. There were no significant differences between Tai Chi and usual care in dyspnoea or quality
of life. No adverse events were reported. Tai Chi has also been shown to result in a significant
improvement in body sway and functional balance in patients with COPD (see O7.5 Falls in COPD). Tai
Chi did not show superiority when carried out in addition to breathing exercises (3 trials) or pulmonary
rehabilitation (1 trial) when compared with these interventions alone.
Tai Chi can be carried out in a wide range of settings and does not require equipment or a large
space. For these reasons, Tai Chi may be a potential treatment option when a pulmonary rehabilitation
program is not available or if a patient declines referral.
There is some evidence that acupuncture may reduce exertional dyspnoea and improve exercise
tolerance in people with moderate to severe COPD [evidence level II]. One placebo-controlled double
blinded randomised trial (n=68), carried out in Japan (Suzuki 2012), compared acupuncture applied
once a week for 12 weeks and sham acupuncture. Eleven standardised acupuncture points, including
those close to the respiratory accessory muscles, were used with treatment lasting 50 minutes each
session. Compared to sham acupuncture, real acupuncture reduced dyspnoea at the end of a 6-minute
walk test (6MWT) by -3.58 points (95% CI -4.27 to -2.90) on the Borg 0-10 dyspnoea scale and
improved 6-minute walk distance (6MWD) by 46 metres in the treatment group when compared to
the sham acupuncture group. A possible mechanism proposed for the benefits was an improvement in
rib cage mobility and accessory muscle function due to suppressed electromyogram activity of the
accessory muscles by the acupuncture. A well designed randomised controlled trial, including sham
acupuncture, with blinding of all involved apart from the acupuncturists themselves, demonstrated an
80-metre improvement in 6-minute walk distance as well as improvements in quality of life (Feng
2016). The effect of the lack of blinding of the acupuncturist is uncertain. Further studies are required
to evaluate the effects of acupuncture and to determine whether any longer-term benefits of treatment
occur.
O7. Comorbidities
Comorbid conditions are common in patients with COPD [evidence level III-2,
strong recommendation]
Optimal management of any individual patient with COPD should include identification and
management of comorbidities and anticipation of increased risks associated with those comorbidities
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in the presence of COPD (Gershon 2015). An American population based, nationally representative
survey of almost 15,000 people demonstrated that patients with self-reported COPD have significantly
higher prevalence of important medical co-morbidities (Schnell 2012). Higher prevalence of cardiac
disease, stroke, diabetes, depression, poly-pharmacy and mobility problems were reported. The
concept of multimorbidity has been increasingly discussed in primary care. Multimorbidity refers to co-
occurrence of two or more chronic medical conditions that may or may not directly interact with each
other within the same individual. Multimorbidity is the norm rather than the exception in older primary
care patients (Mercer 2009). Managing patients with multimorbidity effectively involves taking a
patient-centred approach to balancing multiple, and at times competing, priorities. Some of the
common comorbidities experienced by people with COPD (e.g. obesity, anxiety, depression,
osteoporosis and metabolic disease) are associated with poorer physical performance as measured by
the distance walked on the 6-minute walk test (6MWT) (Li 2014). Both comorbid chronic respiratory
conditions and comorbid psychiatric disorders have been found to be associated with a higher risk of
frequent (≥ 2 per year) exacerbations (Westerik 2017).
O7.1 Increased risks from comorbidities in the presence of COPD

Using a large dataset generated from 311 general practices in the UK, Feary et al (Feary 2010) found
COPD was associated with increased risks of cardiovascular disease (OR 4.98, 95% CI 4.85 to 5.81),
stroke (OR 3.34, 95% CI 3.21 to 3.48) and diabetes mellitus (OR 2.04, 95% CI 1.97 to 2.12). In the
follow-up analyses, after adjusting for confounding by sex and smoking status and stratifying for age,
the greatest increase in the rate of acute arteriovascular events was found in the youngest age groups.
Further supporting these findings, a prospective study examining in hospital mortality in patients with
acute ST segment elevation myocardial infarction found that COPD was a strong independent risk
factor for death (6.3% versus. 3.4% p=0.006) (Wakabayashi 2010). The most common comorbidities
differ between men and women. Specifically, women are more likely to demonstrate anxiety and
depression than men (Aryal 2014) [evidence level III-2]. In a cohort study in Spain, COPD was
associated with an increased number of comorbidities, occurring at an earlier age (on average 10 to
20 years earlier) compared to non-COPD controls (Divo 2018), suggesting accelerated ageing
[evidence level III-2]. A retrospective cohort study of COPD admissions in over 2,000 male US army
veterans found that comorbidity was associated with a higher 30-day readmission and mortality rate
and with lower rates of corticosteroid and antibiotic use whilst in hospital (Spece 2018).
A population-based cohort study in Ontario, Canada using linked datasets and including all patients
aged 35 years or older living in Ontario who underwent intermediate to high-risk elective non-cardiac
surgeries from April 2005 to March 2019, found that patients with COPD had lower survival and greater
health care costs in the year after scheduled surgery than patients without COPD. Within 30 days after
surgery, patients with COPD were more likely to die (n=5873, 3.4%) than those without (n=9429,
1.2%) (Sankar 2023) [evidence level III-2]. Perioperative patient care should include comprehensive
assessment and treatment tailored not only to COPD, but also to management of concomitant
conditions and surgical disease.
O7.2 Cardiac disease

COPD patients possess an increased burden of cardiovascular disease (CVD), cardiac arrhythmia and
heart failure when compared to the normal population. Chen’s systematic review and meta-analysis
pooled the results from 29 datasets and reported that COPD patients were more likely to be diagnosed
with cardiovascular disease (ischaemic heart disease, dysrhythmia, heart failure, pulmonary
circulatory disorders and arterial diseases) than controls (OR 2.46, 95% CI 2.02 to 3.00, p<0.0001).
This result was mainly driven by angina (OR 8.16) (Chen 2015) [evidence level III-2]. Feary’s
1,204,100 patients who were followed for a median of 895 days in the primary care setting also
demonstrated an association of COPD with increased rates of first myocardial infarction (MI) (HR
10.34, 95% CI 3.28 to 32.6), and stroke (HR 3.44, 95% CI 0.85 to 13.84), stratified by age and
adjusted for gender and smoking status (Feary 2010) [evidence level III-2]. Subsequently, sub-
analysis of the Canadian Cohort Obstructive Lung Disease (CanCOLD) data (n=1561) has
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demonstrated a higher prevalence (adjusted OR 1.55 (1.04-2.31), p=0.033) and incidence (HR 2.09
(1.10-3.98, p=0.024)) of CVD (defined as ischaemic heart disease or heart failure) in those with COPD
(Krishnan 2023) [evidence level III-2).
CVD is an important cause of mortality and hospital presentations in COPD, even affecting those with
mild disease. In addition to the high individual prevalence’s of COPD and CVD, these conditions share
conventional risk factors of advanced age, smoking, low socioeconomic status (SES) and sedentary
lifestyle. Systemic inflammation, autonomic dysregulation, hypoxia, acidosis and haemodynamic
derangements are likely to also contribute (Fuschillo 2012). Independent of smoking and other risk
factors, impaired lung function per se is a major risk factor for CVD and arrhythmia (on par with
hypercholesterolaemia), with the relationship being strongest for fatal CV events (Hole 1996, Agarwal
2012) [evidence level III-2]. Arterial stiffness has been proposed as one potential mechanism for this
excess of CVD as it strongly predicts CVD events and mortality. In COPD, arterial stiffness increases
during exacerbation and is associated with COPD severity (measured as airflow limitation or degree of
emphysema), inflammation, oxidative stress and sympathetic nervous system (SNS) tone. COPD also
predicted lipid core (OR 2, 95% CI 1.25 to 3.69, p=0.0058), plaque component vulnerable to rupture
(Lahousse 2013) [evidence level III-2], which increases risk of acute CVD events.
One review (Vivodtzev 2014) [evidence III-2] demonstrates results across multiple studies showing
increased arterial stiffness (n=18), endothelial dysfunction (n=4) and carotid intima-media thickness
(n=3) in COPD patients compared to controls. Several trials showed a gradated effect, with an increase
in COPD patients compared with non-COPD smokers, and in smokers compared with healthy non-
smokers. This group also summarised preliminary data suggesting that current therapeutic
interventions may impact on increased arterial stiffness; included studies reported a statistically
significant improvement in arterial stiffness after standard pulmonary rehabilitation, after treatment
with combination ICS/LABA or LAMA, and possible improvement with supplemental oxygen.
Konecny’s group sought to explore cardiac arrhythmia as a potential source of the excess CVD
mortality in COPD in a retrospective record review of 7,441 participants who underwent 24-hour Holter
monitoring and spirometry during the course of clinical assessment. The 3,121 (49%) COPD patients
demonstrated more arrhythmias than those without COPD; atrial fibrillation/flutter were identified in
23.3% versus 11% (p<0.0001), and non-sustained ventricular tachycardia in 13% versus 5.9%
(p<0.0001). Both results remained statistically significant after adjustment for multiple confounders
(Konecny 2014) [evidence level III-2]. The study population was a highly select group, which
potentially limits the broad application of the results. However, the study reports a “COPD dose effect”,
based on spirometry criteria, which adds weight to its conclusions.
Medications used in the treatment of COPD also have potential to impact cardiac morbidity and
mortality, due to intrinsic effects on chronotropy and muscle action potentials or due to side effects
such as hypokalaemia. Medications implicated include methylxanthines, beta-agonist and
antimuscarinic bronchodilators. Macrolide antibiotics, which in chronic dosing have been shown to
reduce respiratory exacerbations, have been added to the list, due to an association with QT
prolongation and bradycardia. Randomised controlled trials (RCT) of chronically dosed azithromycin
have not demonstrated adverse cardiac effects in the clinical setting, particularly when known drug
interactions are avoided. Likewise, for most inhaled bronchodilators, when used at therapeutic dose in
stable COPD, adverse cardiovascular effects are rare. However, a systematic review and meta-analysis
of RCTs in patients with moderate to severe COPD using inhaled LAMA combined with LABA (Yang
2023b) [evidence level I) reported an excess of major adverse CV events (MACE) (LAMA/LABA 1.2%
vs 0.9% control, RR 1.24, 95% CI 1.06-1.44; triple therapy 1.5% vs 1.3% control, RR 1.27, 95% CI
1.03-1.58). This finding should be considered in conjunction with the existing evidence base (see
O1.2.3 LAMA/LABA) for the efficacy of such medication to prevent COPD exacerbations, improve
symptoms and quality of life in well-designed prospective RCTs powered to measure these outcomes.
Similarly, the challenges of accurate MACE adjudication, inconsistency in the definitions of MACE across
trials and the reduced reliability of data extraction processes from safety reporting should be borne in
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mind. Importantly, none of the individual trials identified was powered or designed to investigate CV
outcomes. Hence, whilst these results provide grounds for careful individualised cardiovascular risk
evaluation for patients with COPD, they do not necessitate change to current treatment
recommendations. Despite being common clinical practice, there is even less evidence about the safety
of high dose, combined bronchodilator therapy in the setting of exacerbation of COPD.
Markers of cardiac involvement during an exacerbation of COPD may be an important determinant

of short-term prognosis. In a study of 250 consecutive admissions with an exacerbation of COPD and
no evidence of acute cardiac disease over 12 months, elevated NT-pro BNP >220 pmol/L and troponin
T >0.03 were present in 27% and 16.7% of patients and predicted 30-day mortality (OR 9, 95% CI
3.1-26.2) and (OR 6.3, 95% CI 2.4 – 16.5), respectively, after adjustment for other mortality
predictors. Elevated troponin T level lost significance with both cardiac biomarkers included in the
model, although the mortality association was additive for patients in whom both biomarker levels
were elevated (Chang 2011) [evidence level III-2]. Another prospective cohort study (Hoiseth 2012,
Li 2020) [evidence level III-2] reported results for 99 COPD patients with 217 exacerbations and a
median follow up duration of 1.9 years and found NT-pro BNP to be an independent risk factor for
mortality after an exacerbation of COPD. Dividing NT-pro BNP levels into tertiles, mortality rates were
8.6, 35 and 62 per 100 patient years (age-adjusted log-rank p<0.0001) and, compared to the lowest
tertile, adjusted HR for death were 2.4 (95% CI 0.95 to 6.0) and 3.2 (95% CI 1.3 to 8.1) in the
intermediate and highest tertiles, respectively.
High sensitivity troponin (hs-Tn) levels have now been associated with increased mortality in
prospective cohort studies in stable COPD (Neukamm 2016, Waschki 2019) [evidence level III-2]. In
a well characterised cohort of 2085 COPD patients, Waschki and colleagues report baseline hs-Tn level
to be independently associated with all-cause mortality at three years, whether considered as a
continuous variable [log hs-TnI, HR 1.28 (95%CI, 1.01 to 1.62)] or dichotomised at 6ng/L [HR 1.63
(95%CI, 1.10 to 2.42)] (as hs-TnI levels greater than 6ng/L identify individuals in the general
population who are at high risk of death during follow-up) (Waschki 2019). Similarly, in a population
with stable COPD and cardiovascular risk or disease, high sensitivity troponin I levels were associated
with increased cardiac events [adjusted HR 3.7 (1.3 to 10.1) p=0.012] and mortality [HR 20.1 (2.4 to
165.2), p= 0.005]. This effect was seen at troponin I >5ng/L; well below the threshold for diagnosis
of coronary events (Adamson 2018) [evidence level III-2].
Post hoc analysis of the SUMMIT cohort data (Kunisaki 2018) confirms a significantly increased risk
of CVD events, especially within 30 days following a COPD exacerbation. The study population was
selected for CVD or CVD risk factors but does represent the “real patients” seen in clinical practice.
The authors make a good case for heightened vigilance for CVD events in the immediate post-
exacerbation period.
Preliminary research suggests that cardiac pathology contributes to a proportion of exacerbations of

COPD. A small study (Bhatt 2012) [evidence level III-2] investigated a potential role for arrhythmia
in an exacerbation; comparing ECG indices during an exacerbation with stable state. They reported
that P wave duration was more variable during exacerbation. Moreover, “frequent exacerbator
patients” (defined as two or more exacerbations of COPD within 12 months) had increases in ECG P-
R interval during stable state compared with “infrequent exacerbators”. Although methodology was
not robust, the results probably justify further research into this issue. In addition, Abusaid et al
proposed a contributory role for diastolic dysfunction (DD) in an exacerbation of COPD (Abusaid 2009)
[evidence level III-2]. Their retrospective single centre cohort study reported that diastolic dysfunction
was associated with prolonged length of hospital stay (4.02 versus 3.24 days, p=0.005) and increased
frequency of hospitalisation for an exacerbation (1.28 versus 0.67 per patient year, p=0.0067) in the
absence of traditional precipitating factors.
Donaldson et al (Donaldson 2010) sought to quantify the increased risk of cardiac adverse events
associated with an exacerbation of COPD. Using self-controlled case series methodology, they
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identified 25,857 COPD patients and their cardiac adverse events (524 myocardial infarctions (MI) in
426 patients and 633 ischaemic strokes in 482 patients) using health care database diagnostic codes
and defining an exacerbation by receipt of systemic corticosteroid course (at minimum daily dose)
and/or specified antibiotics. Comparing cardiac adverse events incidence during the period
immediately after an exacerbation with that in stable state and adjusting for seasonality, they
demonstrated increased risk for MI (RR 2.27, 95% CI 1.1 to 4.7) in the five days following exacerbation
onset, if combined antibiotics and steroids were required and increased risk for stroke (RR 1.26, 95%
CI 1.0 to 1.6) for 49 days, for an exacerbation requiring antibiotics only [evidence level III-2].
Two studies have attempted to evaluate the extra morbidity burden conferred by heart disease in
COPD [evidence level III-2]. De Miguel Diez (de Miguel-Diez 2010) recruited patients meeting
diagnostic criteria for stable COPD from the Spanish primary health care setting and assessed chronic
morbidity and health resource utilisation according to the presence of ICD-9 codes for heart disease.
Of 9,390 COPD patients, 18.8% had documented heart disease. Compared to patients without heart
disease this group had worse lung function, worse quality of life (QoL), required more respiratory
medications, consumed more health resources and generated greater expenses - differences which
were all statistically significant. The authors identified admission duration as a major contributor to
increased costs in these patients [evidence level III-2]. In the study by Patel’s group (Patel 2012),
data from the London Cohort (1995 – 2009), comprising prospectively collected exacerbation data via
symptom diaries from 386 patients with COPD (as defined by spirometry) and at least 12 months’
diary data. Health status assessment occurred whilst in stable phase and comparison was made
regarding frequency and duration of an exacerbation of COPD between patients with and without
ischaemic heart disease (IHD). The 16% of the cohort with IHD scored worse on QOL assessment (St
George Respiratory questionnaire (SGRQ)), MRC dyspnoea scale and 6-minute walk distance. There
was no difference in frequency of respiratory exacerbations or the need for antibiotics and systemic
corticosteroid therapy. However, patients with IHD recovered more slowly and so endured more days
with increased levels of symptoms. The patients did not differ in COPD treatments received, but the
authors provided no information on treatments received for IHD [evidence III–2].
Conversely, two studies have looked at the impact of COPD on outcomes after first MI (Bursi 2010,
Andell 2014) [evidence level III–2]. Prevalence of clinically diagnosed COPD in these studies was 12%
and 6%, respectively. In Bursi’s American cohort, COPD prevalence increased significantly over time,
and was associated with increased mortality (adjusted HR 1.3, 95% CI 1.1 to 1.54), independent of
age, traditional indicators of poor prognosis and comorbidities. Likewise, Andell’s group reported worse
outcomes for COPD patients in their Swedish cohort: one year mortality [HR 1.14 (1.07 – 1.21)], and
development of heart failure [HR 1.35 (1.24 – 1.47)]. Bursi’s group found that the association of COPD
with survival remained unchanged over time, despite an overall decline in mortality after MI (seen
with improvements in medical care). The difference in clinical presentation and therapeutic
interventions received reported by Andell’s group, may partially explain the discrepant outcomes seen
in COPD patients (COPD patients were more likely to present with atypical symptoms, less likely to
undergo percutaneous revascularisation procedures or to receive secondary prevention medications).
O7.2.1 Heart failure

The diagnosis of heart failure coexisting with COPD is complicated by symptom overlap and the
technical challenges of echocardiography in COPD. The natriuretic peptides, including BNP and NT-pro
BNP, can assist in identifying heart failure in the setting of acute breathlessness, but do not exclude
comorbid COPD, and currently have an unclear diagnostic role in stable disease. The prevalence of
heart failure in COPD patients is estimated at 20 to 32%. For the converse situation in heart failure,
COPD prevalence has been previously quoted as 10 to 33%. A prospective multicentre sub study of
patients admitted with heart failure (Iversen 2008) [evidence level III-2] confirmed COPD in 35% of
participants using spirometry. Self-reported COPD diagnosis had poor sensitivity to identify these
individuals. Prevalence of COPD was higher in those heart failure patients with preserved left
ventricular ejection fraction (LVEF), but was also substantial in those with reduced LVEF (41% versus
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31%, p = 0.03). Potential mechanisms contributing to the high rates of heart failure in COPD include
coronary artery disease (CAD), hyperinflation, sympathetic nervous system and renin-angiotensin
system activation, pulmonary hypertension and right heart dysfunction. A study by Labaki et al found
levels of the natriuretic peptide, NT-proBNP to be an independent risk factor for COPD exacerbations
(Labaki 2018).
Barr and colleagues investigated a subgroup from the Multi-ethnic Study of Atherosclerosis (MESA):
a multi-centre, prospective, cross-sectional study of CVD. The group initially reported a linear
relationship between extent of emphysema and impairment of left ventricular filling, reduction of
stroke volume and of cardiac output, without a threshold effect, in “healthy” patients prospectively
assessed for cardiac disease with magnetic resonance imaging (MRI) (Barr 2010) [evidence level III-
2]. The same association was not present for LVEF. Smoking status was an effect modifier, with a
greater effect seen for current smokers. Similar relationships were obtained for measures of airflow
limitation. Mechanisms have been further explored (Stone 2016) in a randomised crossover trial of
combination ICS/LABA (fluticasone furoate/vilanterol) versus placebo in patients with at least
moderate COPD and bronchodilator-responsive gas trapping. Compared with placebo, active treatment
was associated with significantly reduced residual volume -429 ml, 95% CI 2.74-8.91, improved right
and left ventricular filling indices and cardiac index. In COPD, heart failure adversely impacts on
morbidity and prognosis. A prospective cohort study (Boudestein 2009) [evidence level III-2] further
clarifies this relationship; Boudestein’s group sought to quantify heart failure and its prognostic
implications in 405 Dutch general practice patients identified as having COPD. Extensive diagnostic
testing revealed occult heart failure in 20.5%; half of which half was systolic, half diastolic and none
was cor pulmonale. Similar proportions were found in the subset of 244 patients meeting GOLD criteria
for COPD. Not unexpectedly, comorbid heart failure proved a strong predictor of all-cause mortality
over the mean follow up duration of 4.2 years for the whole cohort (adjusted HR 2.1, 95% CI 1.2-3.6,
p=0.01) and for “GOLD COPD patients” (adjusted HR 2.0, 95% CI 1.0-3.7, p=0.04).
Since COPD and heart failure present with similar symptoms and frequently do coexist, the clinical
implication is that the opportunity for intervention will be missed unless both diagnoses are specifically
sought using careful clinical assessment in conjunction with appropriately directed investigations.
O7.2.2 Safety of beta-blockers

Beta-blockers have well established survival benefits in heart failure and after myocardial infarction
and have been long used in coronary artery disease and hypertension but have been considered
contra-indicated in patients with COPD. A Cochrane systematic review identified 20 RCTs of cardio-
selective beta-blockers which examined lung function and respiratory symptoms in 278 patients with
COPD (Salpeter 2005, Salpeter 2002) [evidence level I]. Eleven studies were of single dose and nine
were of prolonged treatment (mean 3.7 weeks, range two days to 12 weeks). The beta blockers
included atenolol, metoprolol, bisoprolol, practolol, celiprolol and acebutolol and were used at
therapeutic doses. There was no significant overall change in FEV1, respiratory symptoms or the
response to inhaled beta2 agonists. The authors concluded that cardio-selective beta-blockers were
safe and should not be withheld, even in patients with severe airflow limitation. However, even with
pooled data, the absolute patient numbers were small and failed to represent minority groups such as
females and the elderly. The longest duration included trial was 12 weeks, and so the meta-analysis
provides little guidance about long-term safety and potential morbidity of prolonged beta-blocker use
in COPD.
Despite a paucity of evidence to suggest harm, beta-blockers are still under-utilised in COPD for
guideline-based indications such as heart failure with reduced ejection fraction (HFrEF) (Lipworth
2016) [evidence level III-2]. Australian data from a COPD cohort hospitalised for a COPD exacerbation
also reflects this (Neef 2016) [evidence level III-2] as does a similar New Zealand study (Parkin 2020)
[both evidence level III-2]. In contrast, Parkin et al report much higher prescription rates for other
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medications used to reduce cardiovascular risk, such as aspirin and hydroxymethylglutaryl-CoA
reductase inhibitors (statins).
A number of observational studies also lend confidence to beta-blocker prescribing in COPD patients.
In Du et al’s meta-analysis (Du 2016) of 15 cohort studies with follow up ranging from one to 7.2
years beta-blocker treatment was associated with reduced mortality (RR 0.72, 95% CI 0.63 to 0.83)
and exacerbation risk (RR 0.63, 95% CI 0.57 to 0.71). Despite significant heterogeneity, sensitivity
analysis did not change the outcome [evidence level III-2]. Moreover, beta-blocker treatment did not
diminish the beneficial effects of inhaled treatments on post bronchodilator FEV1 or COPD
exacerbations (Dransfield 2018). However, a prospective randomised trial of metoprolol to prevent
exacerbations in moderate to severe COPD (Dransfield 2019) reported no benefit (adjusted HR 1.12,
95% CI 0.88 to 1.42), after early termination for futility and potential safety concerns about increased
respiratory symptoms and severe exacerbations (adjusted HR 1.91, 95% CI 1.29 to 2.83) in the active
treatment group. It is important to note that patients with heart failure and recent intervention for
ischaemic heart disease were excluded. Due to the study’s selection criteria, these results should only
apply to patients who have no therapeutic indication for beta-blockers. Prospective data for COPD
patients with cardiac disease are still needed.
O7.2.3 Stroke
The Rotterdam cohort study of 13,115 participants, studied for up to 22 years, included 1,566 patients
with COPD, who had a 20% higher incidence of stroke during the study, particularly following an
exacerbation of COPD. However, this association was no longer significant after adjusting for smoking,
which indicates that smoking is a common risk factor for both conditions. The risk may have been
higher, but COPD patients appear to be dying due to cardiovascular disease first, or early attention to
cardiovascular disease attenuates the risk of stroke (Portegies 2016). In a 2017 meta-analysis that
included eight longitudinal observation studies, patients with COPD had a significantly increased stroke
risk compared to controls (HR 1.30, 95% CI 1.18 to 1.42) (Kim 2018).
O7.2.4 Statins
Despite historic cohort studies suggesting a potential benefit of statins in COPD, a meta-analysis of
eight randomised controlled trials including 1,323 predominantly male patients with COPD showed no
change to mortality, exacerbation rates, lung function or quality of life with statin therapy compared
to placebo [evidence level I] (Walsh 2019). Several of the larger trials included in this meta-analysis
excluded patients with a conventional indication for statin therapy. Based on this data there is no
evidence to prescribe statins in patients with COPD outside of conventional indications.
O7.2.5 Coronary revascularisation procedures

Patients with COPD are at increased risk of death and complications following cardiac surgery
[evidence level III-2]. A study identified 1169 patients undergoing coronary artery bypass grafts and/
or valve replacement at one US centre who had preoperative lung function tests (Adabag 2010).
Operative mortality was 2% in those with no or mild airflow limitation, compared to 6.7% among those
with moderate or severe airflow limitation (FEV1/FVC < 70% and FEV1 < 80% predicted). Postoperative
mortality was 3.2 (95% CI 1.6-6.2) fold higher among those with moderate or severe airflow limitation
and 4.9 (2.3-10.8) fold higher among those with diffusing capacity < 50% predicted. These patients
were also more likely to require mechanical ventilation for > 48 hours and stayed longer in intensive
care and hospital than those with normal lung function.
COPD and COPD severity as defined by spirometry were also associated with increased mortality (OR
1.79, 95% CI 1.63 to 1.96), cardiac mortality (OR 1.57, 95% CI 1.35 to 1.81) and post-discharge MI
(OR 1.3, 95% CI 1.14 to 1.47) after percutaneous coronary intervention in multivariate analysis,
despite equivalent procedural success and complication rates (Konecny 2010) [evidence level III-2].
In this study, data prospectively collected for 14,346 patients (2001 COPD and 12345 non-COPD) from
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a single centre between January 1995 and August 2008 were subjected to retrospective cross-sectional
analysis. COPD patients were identified by ICD – 9 diagnostic codes and did possess significantly more
manifestations of CVD, including heart failure, than the control group. Unfortunately, preoperative
lung function data was only available in 60% of the COPD group.
O7.3 Osteoporosis
Patients with COPD are at increased risk for fracture due to the disease itself, the use of high dose
corticosteroids and coexisting risk factors such as hypogonadism (induced by corticosteroid therapy
itself in high doses in men and women), immobilisation reduced muscle mass and other factors. These
patients may have reduced bone mineral density (BMD) due to a reduction in bone formation and
perhaps increased bone resorption, the latter being primarily due to the underlying disease itself.
A systematic review of 58 studies of heterogeneous quality limited by largely cross-sectional designs

(8,753 patients with COPD) found a mean prevalence of 38% (95% CI 34-43) for osteoporosis in
patients with COPD, with increasing odds ratios for osteoporosis associated with lower BMI and
sarcopenia (Chen 2019), indicating that people with COPD are at special risk of osteoporotic
fracture. The overall OR for osteoporosis in COPD was 2.83 (95% CI 2.00-4.03) with particular risk
(OR 4.26, 95% CI 1.07- 16.99) for those with BMI of < 18.5 kg/m2. Although there is conflicting
evidence as to the strength of a causative relationship, oral or inhaled high dose corticosteroids,
coexisting risk factors such as hypogonadism (induced by corticosteroid therapy itself in high doses in
men and women), physical inactivity, repeated periods of immobilisation from hospital admissions,
and low dairy food intake may be potential contributory risk factors. Assessment of vitamin D status,
and other risk factors such as coexisting illnesses that may influence the skeleton (e.g. primary
hyperparathyroidism) may also be required, with bone densitometry to investigate further.
Patients with vertebral compression fractures, visualised on a lateral chest x-ray, have been
demonstrated to have more frequent admissions, longer length of hospital stay, and increased
mortality in the two years after admission (Pascual-Guardia 2017) [evidence level III-2]. A meta-
analysis by Kakoullis et al (2021) included 27 studies with a range of study designs, with 7662
participants and defined osteoporosis as a T-score of -2.5 SD where available. Participants with
osteoporosis and or vertebral compression fractures were found to be older (3.17 years, 95% CI 2.14-
4.19), lower BMI -3.15 (95% CI -4.41 to -1.88) and more likely to be female, which are recognised
general population risk factors. These participants had a mortality OR of 2.40 (95% CI 1.24-4.64) and
lower FEV1 -0.41L (95% CI -0.59 to -0.24) with a lower FEV1/FVC ratio. The authors note that it is
likely that osteoporosis is a marker of severity of COPD or patient frailty, with surrogate associations
with the outcomes demonstrated, rather than a direct cause of increased airflow obstruction or death
(Kakoullis 2021) [evidence level I]. Pro-active screening and preventative treatment of osteoporosis
are recommended.
There are contradictory findings of a small but deleterious effect of inhaled corticosteroids at
conventional doses on fracture risk. Triamcinolone was associated with reduced BMD in the Lung
Health Study (Lung Health Study Research Group 2000) [evidence level II]. However, a separate
study by Ferguson et al (Ferguson 2009) demonstrated that the combination of salmeterol and
fluticasone 1000 micrograms daily had no increase in decline in bone mineral density over three years
in compared with placebo in the subgroup of patients whose bone density was measured [evidence
level II].
Guidelines on the currently recommended screening, prevention and treatments of osteoporosis,

including corticosteroid-induced osteoporosis are available elsewhere including the eTG guidelines on
Osteoporosis and minimal trauma fractures:
https://tgldcdp.tg.org.au/guideLine?guidelinePage=Bone+and+Metabolism&frompage=etgcomplete.
O7.4 Frailty in COPD
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Frailty is a loss of resilience which means people affected may be physically or mentally vulnerable
and less able to recover quickly after illness or a stressful event (Clegg 2013). A consequence is that
people who have frailty have decreased function, health status and require additional health and social
care (Roe 2017).
Frailty can be assessed in a number of ways including a phenotypic approach or by noting the
accumulation of deficits. The phenotypic approach is defined by the presence of three or more of the
following five criteria: unintentional weight loss, self-reported exhaustion, weakness, slow gait speed,
and low energy expenditure (Fried 2001). Alternatively, the accumulation of deficits approach is based
counting the number of symptoms, diseases, conditions, and disability, which are used to calculate a
frailty index (Rockwood 2005), with higher scores indicating more frailty.
Frailty affects older people and particularly those with chronic conditions such as COPD. Although
there is no unified definition of frailty, a number of studies have demonstrated increased frailty in
COPD using different measurement tools including those based on phenotypes (Lahousse 2016b) or
accumulation of deficits (Gale 2018). A systematic review of frailty in COPD including 27 studies
demonstrated from pooled data that 19% of patients were frail and 56% were pre-frail (Marengoni
2018). Overall, patients with COPD have double the risk of becoming frail and frailty has been
associated with poorer lung function and reduced health status, increased length of stay following
exacerbations (Bernabeu-Mora 2017) and increased mortality (Galizia 2011). An additional meta-
analysis (Hanlon 2023) [evidence level I] on frailty, again highlighted the high prevalence of frailty in
people with COPD, according to a range of frailty measures, associated with a clinically significantly
increased risk of adverse outcomes. Proactive identification of frailty can identify candidates for
targeted intervention such as pulmonary rehabilitation, with evidence of frailty reduction in at least
one study when participants completed a programme (Maddocks, 2016).
The mechanism underlying increased frailty in COPD is likely to be multifactorial. COPD affects older
adults in whom other health conditions are more prevalent. In addition, COPD is associated with
inflammation that affects multiple body systems (Vanfleteren 2013), increased exacerbations, as well
as lifestyle factors such as smoking and reduced physical activity (GOLD 2023), all of which may
increase risk of frailty.
Although frailty can be difficult to manage, there is evidence from systematic reviews that exercise
can be beneficial for physical functioning, cognitive and psychological wellbeing in frail older adults
(Silva 2017). In addition, in older adults with frailty, multifactorial interventions including exercise and
nutritional support can minimise physical decline and can be cost effective for health care providers
(Apostolo 2018). In frail patients with COPD hospitalised for an acute exacerbation, exercise resulted
in improvements in strength and balance (Torres-Sanchez 2017). Frail patients with COPD have also
been shown to benefit from pulmonary rehabilitation with improvements in breathlessness, exercise
performance, physical activity level and health status (Maddocks 2016). However, frail patients were
twice as likely to not complete pulmonary rehabilitation. Given that smoking is a predictor of frailty
(Kojima 2015) and patients with frequent exacerbations have increased risk of frailty (Lahousse
2016b), smoking cessation as well as minimisation of exacerbations are additional key therapeutic
targets in COPD.
In a retrospective cohort study using publicly available Health and Retirement Study data frailty
prevalence measures such as BODE and Fried indices, were substantially higher in COPD than in those
without COPD. Prevalence of frailty among those aged 50–64 years using the Fried index was 7.5%,
and 11.0% for age ≥65. These measures identified patients with increased risk of poor outcomes
including more than doubling of mortality, as well as increased hospital admissions and nursing home
placement over the following 2 years (Roberts 2022) [evidence level III]. A study of 1,162 participants
with COPD and 3,465 participants without COPD by Lee et al (2022) also supported the use of a bundle
of physical frailty measurements in addition to lung function and dyspnoea scores in multidimensional
83
evaluation of COPD. The addition of frailty measures highlighted the associations with the inability to
perform daily tasks and mortality [evidence level III-2].
In summary, frailty is common in COPD and associated with poorer health outcomes, hospital
admissions and failure to complete pulmonary rehabilitation. Measuring frailty is useful in COPD and
may identify vulnerable patients and allow earlier interventions such as comprehensive medical or
geriatric review and pulmonary rehabilitation to minimise the development and impact of frailty on
patients and carers as well as health and social care services.
O7.5 Falls in COPD

Accidental falls are an important and underestimated problem in people with COPD. As in older adult
populations, falls in people with COPD are associated with increased injury-related mortality and risk
for hip fractures, which impose a substantial economic burden on health care systems worldwide (Berry
2008).
Chronic obstructive pulmonary disease was the second most prevalent condition among patients
presenting to emergency departments with hip fractures (Johal 2009). A higher risk of hip fractures
has been found in patients with COPD in comparison to a matched non-COPD sample (hazard ratio
1.78, p<0.001). In addition, patients who used inhaled bronchodilators and inhaled corticosteroids
(n=10,362) had an even higher falls risk (HR 2.04, 95% CI 1.72-2.41, p<0.001) in comparison to
those not using inhalers (n= 5,877, HR 1.63, 95% CI 1.40-1.89, p<0.001) (Huang 2016). Importantly,
one study with robust methodology suggests that a history of falls in the six months prior to hospital
admission is the strongest predictor of all-cause mortality in patients with severe COPD (odds ratio
3.05, 95% CI 1.40-6.66, p<0.005) (Yohannes 2016). A systematic review (Oliveira 2021) has reported
a falls incidence rate in COPD of 1.17 to 1.49 falls/person-year. In a large 4-year follow-up cohort
study, the incidence rate of falls in patients aged ≥35 years who had a new diagnosis of COPD was
higher compared with a matched cohort of non-COPD patients in primary care. Patients with COPD
were 55% more likely to have a fall compared to people without COPD (adjusted HR 1.55, 95% CI
1.50- 1.59) (Hakamy 2018).
The risk factors for falls identified in the COPD population are similar to those in older adults:
advanced age, previous fall history, female gender, increased number of medications and
comorbidities (Roig 2011). Risk factors specifically related to the physical and psychosocial effects of
COPD include muscle weakness, impaired postural balance, use of supplemental oxygen, increased
‘fear of falling’ and heavy smoking history (Oliveira 2015, Beauchamp 2009). Of these, polypharmacy
(use of ≥ 5 medications) is particularly important in those with multiple comorbidities, and was
identified as a falls risk factor in two prospective studies in people with COPD (Oliveira 2015, Roig
2011). The relationship between medication type and falls risk is well established in older adults (Park
2015). Particularly the use of the falls risk increasing drugs (FRID’s) including sedatives, hypnotics,
antidepressants and benzodiazepines (Park 2015). Of note, patients with COPD were 47% more likely
to have a fall than non-COPD patients when adjusting for smoking status, use of antidepressants and
diuretics (adjusted HR (aHR) 1.47, 95% CI 1.43-1.51) (Hakamy 2018). The adverse effects of systemic
corticosteroids on muscle strength (Decramer 1994) and consequently balance (Beauchamp 2012)
could also indirectly contribute to increased risk of falling in COPD.
The fact that COPD, consistent with many other chronic diseases, is associated with frailty and
increased falls risk suggests that these patients may benefit from generic falls prevention programs
designed for older adults. In addition, the findings of specific risk factors for falls in patients with COPD
highlights the need for specific preventive interventions in this patient population. The importance of
balance training has been increasingly recognised in COPD as an important fall’s prevention strategy.
For instance, Tai Chi exercises, which are characterised by posture alignment, weight shifting and
circular movements that incorporate elements of muscle endurance and strengthening, balance,
relaxation and breathing, have demonstrated significant improvement in body sway and functional
balance in patients with COPD (Leung 2013). The benefits of specific balance training added to a 6-
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week conventional pulmonary rehabilitation program have also been documented in a RCT
(Beauchamp 2013). Specific balance training including progressive stance tasks, transition, gait and
functional strengthening exercises was superior to PR alone in improving functional balance in patients
with COPD (Beauchamp 2013).
Given the higher fall frequency and prevalence of hip fractures in people with COPD, falls prevention
programs targeting modifiable risk factors should be considered for this patient population.
O7.6 Sleep-related breathing disorders

COPD has adverse effects on sleep quality, resulting in poor sleep efficiency, delayed sleep onset,
multiple wakening’s with fragmentation of sleep architecture, and a high arousal index. Arousals are
caused by hypoxia, hypercapnia, nocturnal cough and the pharmacological effects of methylxanthines
and b-adrenergic agents (Phillipson 1986). Intranasal oxygen administration has been shown to
improve sleep architecture and efficiency, as well as oxygen saturation during sleep (Meecham Jones
1995).
Indications for full diagnostic polysomnography in patients with COPD include persistent snoring,
witnessed apnoea’s, choking episodes and excessive daytime sleepiness. In patients with daytime
hypercapnia, monitoring of nocturnal transcutaneous carbon dioxide levels should be considered to
assess nocturnal hypoventilation. Patients with COPD with a stable wakeful PaO2of more than 55mmHg
(7.3kPa) who have pulmonary hypertension, right heart failure or polycythaemia should also be
studied. Overnight pulse oximetry is also useful in patients with COPD in whom long-term domiciliary
oxygen therapy is indicated (stable PaO2 <55mmHg, or 7.3kPa) to determine an appropriate oxygen
flow rate during sleep.
The overlap syndrome: The combination of COPD and obstructive sleep apnoea (OSA) is known
as the “overlap syndrome” (McNicholas 2009) [evidence level III-2]. The prevalence of COPD in
unselected patients with OSA is about 10%, while about 20% of patients with COPD also have OSA
(Chaouat 1995). Patients with COPD who also have OSA have a higher prevalence of pulmonary
hypertension and right ventricular failure than those without OSA (Chaouat 1995). Findings of a
systematic literature review suggest that COPD patients with overlapping OSA have higher mortality
and more frequent exacerbations of their disease than COPD patients without OSA (Shawon 2017).
Continuous positive airway pressure (CPAP) treatment reduced mortality and exacerbation rates
(Marin 2010) [evidence level III-2]. While oxygen administration may diminish the degree of oxygen
desaturation, it may increase the frequency and severity of hypoventilation and lead to carbon dioxide
retention.
As in other patients with OSA, weight reduction, alcohol avoidance and improvement of nasal patency
are useful in those with COPD. Nasal CPAP is the best method for maintaining patency of the upper
airway and may obviate the need for nocturnal oxygen. If nasal CPAP is not effective, then nocturnal
bi-level positive airway pressure ventilation should be considered, although the benefits of this in
chronic stable COPD remain to be established. The role of other OSA treatments, such as mandibular
advancement splinting, remains to be evaluated in the overlap syndrome.
O7.7 Aspiration
Aspiration of food and liquid is common in those with COPD, up to 70% of adults with COPD and
dysphagia (difficulty swallowing) aspirate (Good-Fratturelli 2000). Aspiration in those with COPD is
thought to be due to the disrupted coordination of the exhale-swallow-exhale respiratory cycle during
swallowing, cricopharyngeal muscle dysfunction, and changes in lung volume (Gross 2009, Zheng
2016). Silent aspiration has also been reported in those with COPD, which can complicate dysphagia
detection and management (Zheng 2016).
The prevalence of dysphagia in patients with COPD has been reported between 17% to 42%
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depending on the method of assessment and disease severity (Ghannouchi 2016, Gonzalez Lindh
2017, Kertscher 2015).
Dysphagia in COPD is thought to be due to the disrupted coordination of the exhale-swallow-exhale

respiratory cycle during swallowing (Gross 2009). This incoordination may place individuals with COPD
at a higher risk of aspiration, which may in turn contribute to COPD exacerbations (Gross 2009, Terada
2010) [evidence level III-2].
Dysphagia and aspiration risk can be determined by a speech pathologist with an adequate history
from patients and their partners or carers, clinical swallow examination and patient self-report scales
(Regan 2017). Instrumental swallowing assessments – videofluoroscopy and fibreoptic endoscopic
evaluation of swallowing (FEES) can be used to confirm aspiration (Ghannouchi 2016).
Further research characterising dysphagia in COPD has identified additional impairments in swallow
physiology including reduced tongue control, delayed pharyngeal swallow, reduced tongue base
retraction, impaired hyolaryngeal excursion, cricopharyngeal dysfunction, impaired laryngopharyngeal
sensitivity and slower bolus transit (Regan 2017).
Management for dysphagia and aspiration will be provided on an individual basis by a speech
pathologist and may involve the following (McKinstry 2010):
● Rehabilitation exercises
● Swallowing – breathing retraining (compensatory swallowing techniques)
● Texture modification of diet and fluids
● Postural strategies
● Safe swallowing strategies
O7.8 Gastro-oesophageal reflux disease (GORD)
In patients with COPD, hyperinflation, coughing and the increased negative intrathoracic pressures
of inspiration may predispose to reflux, especially during recumbency and sleep. Microaspiration of
oesophageal secretions (possible including refluxed gastric content) is a risk, especially with coexistent
snoring or OSA. Reflux and microaspiration exacerbate cough, bronchial inflammation and airway
narrowing. A nested case control study performed on a large primary care dataset found a modest
increased risk of gastro-oesophageal reflux in patients with a pre-existing diagnosis of COPD (RR 1.46,
95% CI 1.19-1.78) (Garcia Rodriguez 2008) although higher relative risks have been reported in other
studies and Sakae et al reported a RR of 13.06 (95% CI 3.64-46.87) in their systematic review and
meta-analysis of exacerbations of COPD and symptoms of GORD. In a large cross-sectional study of
patients with a wide range of COPD severity, forming part of the US COPD Gene Study, 29% of patients
reported a diagnosis of physician-diagnosed GORD (Martinez 2014). In this study, GORD symptoms
were associated with worse health-related quality of life (HRQoL) (St George’s Respiratory
Questionnaire (SGRQ)), increased dyspnoea and more frequent exacerbations. Two of these three
associations persisted after adjusting for the use of proton pump inhibitors (PPI) (although the latter
was associated with an improvement in HRQoL). It is noted that PPI use in the general population is
associated with a higher frequency of pneumonia (Gulmez 2007, Eurich 2010). Nonetheless, other
studies have suggested PPI use is associated with a reduction in exacerbations in GORD-sufferers
(Sakae 2013, Sasaki 2009). In the study by Martinez et al, patients with GORD were more likely to be
female, to have symptoms of chronic bronchitis and to have a higher prevalence of cardiovascular
disease. Over two years of follow-up the presence of GORD symptoms was associated with more
frequent exacerbations which was not altered by PPI use. ln another prospective cohort study, gastro-
oesophageal reflux symptoms were associated with an increased risk of exacerbation (Terada 2008).
Prospective data from users of inhaled medications in the COPD Gene cohort has shown that GORD is
a common risk factor for COPD exacerbations across all medication groups except for those using only
short-acting bronchodilator medications. Female gender was an independent risk factor across all
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groups (Busch 2016).
Further large prospective studies would seem to be required to clarify the relationships between
GORD, its treatment and COPD exacerbations. Diagnosis may be confirmed by 24-hour monitoring of
oesophageal pH, modified barium swallow or gastroscopy. However, a therapeutic trial of therapy with
H2-receptor antagonists or a proton-pump inhibitor may obviate the need for invasive investigations.
Lifestyle changes, including stopping smoking, limiting food intake within 4 hours of bed-time, reduced
intake of caffeine and alcohol, weight loss and exercise, will also help. Elevation of the head of the bed
is also recommended.
O7.9 Lung cancer
Lung cancer is a serious health problem in Australia (Cancer Council Australia 2004). In 2007, in
Australia, lung cancer was the fourth most commonly diagnosed cancer in both males and females
(excluding basal and squamous cell carcinoma of the skin), with a total of 9.703 diagnosed (AIHW &
Cancer Australia 2011). Lung cancer is the leading cause of cancer deaths for both sexes. The
occurrence of lung cancer was strongly related to age, with 84% of new lung cancers in males and
80% in females diagnosed in those aged 60 and over. Smoking is the largest single cause of lung
cancer, responsible for 90% of lung cancers in males and 65% of lung cancers in females in Australia.
Between 1982 and 2007, the incidence rate of lung cancer decreased in males by 32%, but increased
in females by 72%, reflecting historical differences in smoking behaviour.
The risk of lung cancer in people who have pre-existing lung disease has been studied using case-
control studies, which found an increased risk of lung cancer in people with bronchitis and emphysema,
even after correcting for the smoking history. A cohort study of 2,507 patients with COPD followed for
60 months found an incidence of lung cancer of 16.7 per 1000 patient years. The most frequent
histological type was squamous cell (44%) followed by adenocarcinoma (38%) and small cell (12%).
A diagnosis of lung cancer was associated with less severe GOLD stage, older age, lower BMI and a
diffusing capacity of lung for carbon monoxide (DLCO) test <80% predicted (de Torres 2011).
A much larger cohort study performed record linkage of Danish national hospital and cancer
registries. The investigators identified 236,494 patients admitted for COPD between 1980 and 2008,
who were followed for median of 3.5 years. During the first year of follow-up, the Standardised
Incidence Ratio (SIR) for any cancer was 3.1 (95% CI 3.0-3.2), and lung cancer 8.5 (95% CI 8.2-
8.8). The cumulative risks for lung cancer in this COPD cohort after 1, 5 and 10 years were 1.8% (95%
CI 1.7- 1.9%), 3.6% (95% CI 3.6-3.7%) and 4.9% (4.9%-5.0%) respectively (Kornum 2012)
[evidence level III-2].
During the longitudinal follow-up of the COPDGene Study [an average follow-up of 5.7 years (+/-
1.87 years)], a total of 169 subjects diagnosed with lung cancer were matched (for age, race, sex,
smoking status, average smoking pack-years and years since quitting smoking) against 671 control
subjects with no reported lung cancer diagnosis. Characteristics associated with a future risk of lung
cancer included airflow obstruction as measured by FEV1/FVC, history of exacerbations in the previous
year and the presence of visual emphysema. The results were similar when percentage predicted FEV1
was used as the measure of airflow obstruction (Carr 2018).
Research has suggested a mechanism for the association, through identification of single-nucleotide
polymorphisms (SNPs) on chromosome 15 in the nicotinic acetylcholine receptor subunit genes
(CHRNA3 and CHRNA5) that are associated with smoking behaviour and with an increased risk of lung
cancer and COPD (Bierut 2010). The SNPs on chromosome 15 appear to have an independent effect
on disease risk, as if you incorporate the smoking history into the statistical analyses, the genetic
variants continue to contribute to lung cancer risk above and beyond the smoking behaviour (Bierut
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2010).
O7.10 Bronchiectasis
Bronchiectasis is characterised by dilated, thick-walled bronchi that fail to clear airway secretions,
leading to a chronic productive cough, persistent bacterial infection and infective exacerbations. In
milder COPD patients, bronchiectasis may be an incidental, subclinical finding on CT chest, as observed
in the ECLIPSE study where the prevalence of bronchiectasis was 4% (Agusti 2010). In contrast,
patients with moderate to severe COPD have a higher prevalence of bronchiectasis of 30 to 60%
(O'Brien 2000, Patel 2004, Whitters 2013).
The presence of bronchiectasis influences the rate of respiratory infections and other adverse
outcomes in COPD. A meta-analysis of observational studies totalling 5,329 patients with COPD
showed that 30% had coexisting bronchiectasis, which increased the risk of exacerbations (OR 2.0),
potentially pathogenic microorganisms in sputum (OR 4.1), severe airway obstruction (OR 1.3) and
mortality (OR 2.0) (Du 2016).
These studies emphasise the clinical importance of coexisting bronchiectasis in some patients with
COPD. A high-resolution CT chest scan should be considered in patients with COPD who have chronic
bronchitis or frequent respiratory infections, to identify clinically important bronchiectasis which can
then be managed in addition to the COPD (Chang 2015, Hurst 2015).
O7.11 Combined pulmonary fibrosis and emphysema

Combined pulmonary fibrosis and emphysema (CPFE) is a syndrome defined by clustering of
pulmonary fibrosis and emphysema in a patient (Cottin 2022). Spirometry is frequently normal due to
opposing effects of hyperinflation from emphysema and restriction from fibrosis. Gas transfer,
however, is usually severely impaired due to the additive effect of dual pathology (Jankowich 2012,
Papaioannou 2016). Cigarette smoking is a major risk factor. CPFE occurs predominantly in males (up
to 9:1 male:female ratio). In non-smokers, CPFE has been described in people with occupational dust
exposure and genetic mutations (Jankowich 2012, Papaioannou 2016).
CPFE has a higher mortality than that of emphysema alone. Prognosis has been shown to follow the
course of patients with idiopathic pulmonary fibrosis (IPF) i.e. median survival between 2.1 and 8.5
years, or 5-year survival between 38% and 55% (Cottin 2017, Jankowich 2012, Papaioannou 2016).
Even in patients who do not fulfil criteria for IPF, the presence of interstitial features in addition to
emphysema carries a significantly higher mortality (Ash 2018).
In most cases, high resolution computed tomography (HRCT), spirometry and diffusing capacity of
lung for carbon monoxide (DLCO) test are adequate to diagnose CPFE. The prevalence of lung cancer
is higher in CPFE than COPD. Therefore, more vigilant follow up of pulmonary nodules is recommended,
though no specific screening guideline has been developed for CPFE (Jankowich 2012, Papaioannou
2016).
Currently, no specific treatment exists for CPFE. Post-hoc data from nintedanib trials (INPULSIS
(Richeldi 2014) and INPULSIS-ON (Crestani 2019), which included patients with concurrent
emphysema, showed attenuation of rate of decline in forced vital capacity (FVC) in IPF with
emphysema, similar to IPF without emphysema. An observational cohort study of real-world patients
who were commenced on pirfenidone also showed similar rate of progression between CPFE and IPF
without emphysema (Oltmanns 2014). Hence, antifibrotic therapy can be considered in CPFE, where
presence of IPF is confirmed. Early referral for lung transplantation should be considered in patients
with rapidly declining lung function.
O7.12 Alcohol and sedatives

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Patients with COPD have impaired gas exchange and an exaggerated fall in Po2 with recumbency
and sleep onset (Meecham Jones 1995, Chaouat 1995). Excessive use of alcohol and sedatives
exacerbates this and predisposes to sleep-disordered breathing.
Heavy cigarette smoking is associated with misuse of other substances in many individuals. Nicotine,
caffeine and alcohol also predispose to gastro-oesophageal reflux.
In a population-based cohort of 130,979 community-dwelling older adults with COPD, new opioid
users were associated with significantly increased risk of emergency room visits for COPD or
pneumonia (HR 1.14, 95% CI 1.00–1.29, p=0.04). Opioid use was also associated with significantly
increased risk for COPD or pneumonia-related mortality (HR 2.16, 95% CI 1.61–2.88) and all-cause
mortality (HR 1.76, 95% CI 1.57–1.98), but significantly decreased outpatient exacerbations (HR 0.88,
95% CI 0.83–0.94, p=0.0002). New opioid use and, in particular, use of the generally more potent
opioid-only agents, was associated with increased adverse respiratory outcomes and mortality. A
careful, individualised approach needs to be taken when administering opioids to older adults with
COPD, given the potential for adverse respiratory outcomes (Vozoris 2016).
O7.13 Testosterone deficiencies and supplementation

Observational studies in COPD patients have revealed reduced total testosterone levels compared with
matched controls [WMD -3.21nmol/L (95% CI -5.18 to -1.23)] (Atlantis 2013). The clinical significance
of this finding is unclear. Although testosterone supplementation therapy has been shown to increase
peak muscle strength and peak workload achieved in patients with COPD (not necessarily with
testosterone deficiency) maximal oxygen uptake and health-related quality of life (HRQoL) were not
improved. More data are awaited to determine whether screening patients with COPD for testosterone
deficiency is clinically necessary and whether supplementation in deficient patients can induce any
clinically relevant benefits.
O7.14 Cognitive impairment

Cognitive dysfunction has been described in people with COPD as in other chronic diseases such as
cardiac failure and diabetes. The frequency of cognitive dysfunction varies depending upon the battery
of neuropsychological tests used, with the domains most influenced being memory and attention. In
a population cohort of community dwelling elderly (age 70-89) with normal cognition, those who had
a diagnosis of COPD at baseline (based on medical record data), had an 83% increased risk of incident
non-amnesic mild cognitive impairment (hazard ratio 1.83, 95% CI 1.04-3.23) over 5 years (Singh
2014a). Cognitive function in patients admitted to hospital with an exacerbation of COPD was more
impaired than in patients with stable COPD which in turn was worse than in a matched control group
(Dodd 2013) [evidence level III-2].
In a meta-analysis of 655 patients with stable COPD and 394 control participants, cognitive function
was associated with severity of COPD only in those with severe to very severe disease (Schou 2012).
Baird et al performed a systemic review of 13 studies of the effect of cognitive impairment on self-
management in COPD and demonstrated high degrees of inhaler incompetency with cognitive
impairment, although dry powder inhalers are easier to learn to use (Baird 2017). As memory and
attention, as well as speed, co-ordination and learning ability were shown to be reduced, it may be
important to consider level of cognitive impairment when assessing capacity for self-management.
Potential aggregate anticholinergic effects of concurrent oral and inhaled medications should be
considered in patients with cognitive impairment.
O7.15 Anaemia
Anaemia is a relatively uncommon comorbidity of COPD (Schnell 2012, Barnes 2009, Yohannes 2011a,
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Almagro 2012), either attributable to erythropoietin resistance (Markoulaki 2011) or inflammation
(Markoulaki 2011, Rutten 2013, Boutou 2012), which may impair functional performance (Cote 2007a,
Krishnan 2006, Boutou 2011) and health status (Krishnan 2006, Boutou 2011), contribute to worse
survival (Haja Mydin 2013, Kollert 2013, Martinez-Rivera 2012, Boutou 2013, Cui 2012, Chambellan
2005), and be associated with increased health care utilization costs (Shorr 2008, Halpern 2006). Red
cell transfusion appears to be a reasonable strategy for those with severe anaemia (Schonhofer 1998),
though there is no evidence of benefit from RCTs.
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O8. Hypoxaemia and pulmonary hypertension
Hypoxaemia
Hypoxaemia in patients with COPD should be identified and corrected with long term oxygen therapy
as this has been shown to improve survival and quality of life (Nocturnal Oxygen Therapy Trial Group
1980, Medical Research Council Working Party 1981) (see O8.1). Hypoxaemia is best screened for
using pulse oximetry, however, should be confirmed using arterial blood gas (ABG) measurement. Use
of ABGs also allows for the detection of hypercapnia which may complicate long term oxygen use. The
indications for long term oxygen use are:
● Arterial PaO2 less than or equal to 55mmHg or

● Arterial PaO2 less than or equal to 59mmHg in the presence of pulmonary hypertension, right
heart failure or polycythaemia
Pulmonary hypertension
The definition of pulmonary hypertension (PHT) was revised in 2009. PHT is now defined as a mean
Pulmonary Artery Pressure (PAP) >25mmHg at rest measured by right heart catheterization
(Simonneau 2009). PAP assessed during exercise is no longer part of the definition. PHT was seen in
approximately 50% of patients with severe emphysema (FEV1 27% of predicted) studied as part of
the National Emphysema Treatment Trial (NETT) (Scharf 2002) but only 5% of these patients had
moderate to severe PHT (mean PAP > 35mmHg). In these patients, no correlation was found between
PaO2 and mean PAP although FEV1, Pulmonary Capillary Wedge Pressure and diffusing capacity of lung
for carbon monoxide (DLCO) test were correlated in a multiple regression model. In those COPD
patients with severe PHT, hypoxaemia, reduced DLCO and PAP are often more impaired than would be
expected for their degree of airflow limitation (Chaouat 2005). There are several postulated
mechanisms for PHT in COPD (Chaouat 2008). The presence of PHT is associated with a worse
prognosis (Chaouat 2008) and increased hospitalisation (Kessler 1999). This has resulted in several
small studies of non-selective and selective vasodilators.
No pharmacological therapies have shown to be effective to date. An early study of the non-selective
dihydropyridine calcium antagonist vasodilator felodipine in COPD showed improved haemodynamics
(Sajkov 1993). However, the low efficacy and high adverse effect profile make such drugs an
unattractive option. The first report of a selective pulmonary vasodilator, nitric oxide (NO) in stable
COPD (Barbera 1996) was disappointing in that hypoxia was exacerbated, presumably through the
mechanism of worsening ventilation/perfusion (V/Q) mismatching. A subsequent 40 patient
randomised trial assessed “pulsed” (a burst at the start of inspiration) NO and demonstrated that
improved haemodynamics without exacerbation of hypoxia (Vonbank 2003) was possible. No further
randomised controlled trials of selective pulmonary vasodilators in COPD patients have yet been
published. Although endothelin-1 receptor antagonists and other agents have been used to treat non-
COPD-related PHT, a trial of bosentan in COPD (Stolz 2008) once again induced adverse effects on gas
exchange and quality of life. Similarly, two randomised controlled trials of the phosphodiesterase-5
inhibitor sildenafil failed to demonstrate improvements in cardiac output, 6-minute walk test (6MWT)
or maximal workload on cardiopulmonary exercise testing in COPD patients (Holverda 2008, Rietema
2008). Well-designed trials of agents which selectively dilate the pulmonary vascular bed without
worsening V/Q mismatching are urgently needed.
PHT and right heart failure may be complications of exacerbations of COPD. Therapy in these patients
has generally been directed at reversing hypoxia and hypercapnia with bronchodilators,
corticosteroids, antibiotics as well as supplemental oxygen and ventilatory support. A 16-patient
randomised placebo-controlled trial of IV prostacycline showed no benefit, but exacerbated hypoxia in
patients receiving conventional therapy including mechanical ventilation for an exacerbation of COPD
(Archer 1996).
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Thus, there are no data at present that clearly support the use of vasodilators generally in COPD
patients with PHT. However severe PHT is uncommon in patients with even advanced emphysema. As
such, where appropriate, a careful search for other potential causes of PHT should be undertaken and
an alternative diagnosis considered.
Chest x-rays may show enlargement of proximal pulmonary arteries, but right ventricular
enlargement is difficult to detect because of hyperinflation. Right axis deviation and P pulmonale on
ECG may be difficult to detect because of low voltage traces (also a result of hyperinflation). Multifocal
atrial tachycardia and atrial fibrillation are common. A pulmonary artery to aorta ratio of greater than
one as measured on CT chest has been used as a marker of possible pulmonary hypertension. Wells
et al used this measure in over 1,000 patients and prospectively found its presence led to a significantly
increased risk of future exacerbations odds ratio, 3.44; 95% CI 2.78 to 4.25; p<0.001 (Wells 2012)
[evidence level III-2].
Retrospective data from 60 patients with severe COPD who had undergone CT chest, transthoracic
echocardiography and right heart catheterisation showed that a CT chest pulmonary artery to aorta
ratio greater than one was 73% sensitive and 84% specific for pulmonary hypertension with right
heart catheter as the gold standard. This was significantly more sensitive and specific than
transthoracic echocardiography (Iyer 2014) [evidence level IV].
Echocardiography is the best non-invasive method of assessing pulmonary hypertension, but image
quality is reduced by hyperinflation. This can be clarified using the more invasive procedure of trans-
oesophageal echocardiography. Patients with COPD may have poor quality images on transthoracic
examination and transoesophageal echocardiography may be frequently needed. Echocardiography is
indicated in patients with severe disease, or when symptoms seem out of proportion to the severity
of airflow limitation. Estimation of pressure relies on at least some tricuspid regurgitation. Other
findings include mid-systolic closure of the pulmonic valve and increased right ventricular wall
thickness.
O8.1 Treatment of hypoxaemia and pulmonary hypertension
Treat underlying lung disease: The logical first step is to optimise lung function and treat all
potential aggravating conditions.
Oxygen therapy: Long term, continuous (>18h/day) oxygen therapy to treat chronic hypoxaemia
prolongs survival of patients with COPD, presumably by reducing pulmonary hypertension (Medical
Research Council Working Party 1981, Nocturnal Oxygen Therapy Trial Group 1980, Weitzenblum
1985, Gorecka 1997, Zielinski 1998). (For a detailed description of oxygen therapy in COPD, see
Section P).
Diuretics: Diuretics may reduce right ventricular filling pressure and oedema, but excessive volume
depletion must be avoided. Volume status can be monitored by measuring serum creatinine and urea
levels. Diuretics may cause metabolic alkalosis resulting in suppression of ventilatory drive.
Digoxin: Digoxin is not indicated in the treatment of cor pulmonale and may increase the risk of
arrhythmia when hypoxaemia is present. It may be used to control the rate of atrial fibrillation.
Vasodilators: Vasodilators (hydralazine, nitrates, nifedipine, verapamil, diltiazem, angiotensin-

converting enzyme [ACE] inhibitors) do not produce sustained relief of pulmonary hypertension in
patients with COPD (Barbera 1996, Jones 1997). They can worsen oxygenation (by increasing blood
flow through poorly ventilated lung) and result in systemic hypotension. However, a cautious trial may
be used in patients with severe or persistent pulmonary hypertension not responsive to oxygen
therapy. Some vasodilators (e.g., dihydropyridine calcium antagonists) have been shown to reduce
right ventricular pressure with minimal adverse effects and increased well-being, at least in the short
92
term (Sajkov 1993, Sajkov 1997). Nitric oxide worsens V/Q mismatching and is therefore
contraindicated in patients with COPD (Barbera 1996, Jones 1997).
O9. Surgery
None of the current surgical approaches in patients with COPD provides a survival advantage (Benditt
1997). In view of the potential for serious morbidity and mortality, all surgical treatments require
careful assessment by an experienced thoracic medical and surgical team.
O9.1 Bullectomy
This operation involves resection of large bullae (larger than 5cm). The procedure is most successful
where there are very large cysts compressing adjacent apparently normal lung (Mehran 1995). Giant
bullae can be defined as occupying more than 50% of the hemithorax with definite displacement of
adjacent lung tissue (Laros 1986).
O9.2 Lung volume reduction surgery and bronchoscopic interventions

van Geffen et al performed a meta-analysis of data from randomised controlled trials across all
modalities of lung volume reduction (surgical and endobronchial) (van Geffen 2019). The mean
differences compared with the control were an increase in FEV1 of 15∙87% (95% CI 12.27-19.47),
improvement in 6-minute walk test (6MWT) of 43∙28m (31∙36 to 55∙21), and reduction in the St
George’s Respiratory Questionnaire (SGRQ) of 9∙39 points (–10∙92 to –7∙86) [evidence level I]. The
authors noted a high risk of bias due to lack of blinding. The odds ratio for a severe adverse event,
which included mortality, was 6∙21 (95% CI 4∙02-9∙58) following intervention.
Surgical Lung Volume Reduction
The National Emphysema Treatment Trial (NETT) was a large randomised multicentre study which
investigated the effectiveness and cost-benefit of this procedure (NETT 1999). A total of 1,218 patients
with severe emphysema underwent pulmonary rehabilitation and were then randomised to lung
volume reduction surgery (LVRS) or continued medical therapy. Pulmonary rehabilitation plays an
important role in preparing patients for interventions such as lung volume reduction (Ries 2005). There
was no overall survival advantage of surgery, but after 24 months there was significant improvement
in exercise capacity in the surgical group. Patients allocated to LVRS took significantly longer (median
2 vs. 1 year) than those who continued medical therapy to reach a composite endpoint of death or
meaningful deterioration in disease related quality of life (Benzo 2009). Among patients with
predominantly upper lobe emphysema and impaired exercise capacity, mortality was significantly
lower in the surgical than the medical group. However, high risk patients with diffuse emphysema
and well-preserved exercise capacity are poor candidates for surgery because of increased mortality
and negligible functional gain (Fishman 2003) [evidence level II].
A 2016 Cochrane Review on lung volume reduction surgery was very heavily influenced by data
from the NETT study (van Agteren 2016) [evidence level I]. The authors concluded that short-term
mortality was higher for LVRS (odds ratio (OR) 6.16, 95% CI 3.22-11.7) than for control, but long-
term mortality favoured LVRS (OR 0.76, 95% CI 0.61-0.95) 96% of the patients contributing to the
long-term mortality data was from patients enrolled in the NETT study. The authors made note of high
post-operative complications, especially persistent air leak and pneumonia. A retrospective analysis of
2,815 LVRS cases performed in America demonstrated an in-hospital mortality rate of 5.5% (Attaway
2019). Pulmonary hypertension was associated with an increased risk in mortality (adjusted OR 4.4,
95% CI 1.7-1.5).
Buttery et al (Buttery 2023) performed the first RCT comparing endobronchial valves to surgical
lung volume reduction in a highly selected group of 88 people with COPD who were suitable for both
procedures. The trial was performed at 5 expert centres in the UK. At 12 months there was no
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significant difference in the primary end point, the 'i-BODE' score [evidence level II]. This composite
disease severity measure includes BMI, airflow obstruction, dyspnoea and exercise capacity
(incremental shuttle walk test). The CAT score was a secondary end point and the surgical lung volume
reduction group experienced a larger reduction in CAT score (treatment effect −6, 95% CI –9– −2;
p=0.005). The group undergoing lung volume reduction surgery had a longer median length of
hospital stay (9 vs 3 days p = 0.006), however the group undergoing valve placement had a 30%
pneumothorax rate and 15% required further procedures. There were no deaths within 30 days of
treatment in either group. There was a death at day 44 in an individual that received valves due to
complications of the procedure. This trial does not demonstrate that either approach is superior. A
larger trial is currently underway.
Endobronchial lung volume reduction

A variety of nonsurgical techniques have been investigated. These include endobronchial one-way
valves, self-activating coils, targeted destruction of emphysematous tissue, bypass tract airway
stenting and transpleural ventilation. Of these techniques, only valves are in regular clinical use in
Australia.
van Geffen performed a meta-analysis of endobronchial lung volume reduction surgery (van Geffen
2019). Six trials were included in the analysis of endobronchial valves (620 participants) and 3 trials
were included in the analysis of endobronchial coils (458 participants). The authors reported
improvements in lung function, 6-minute walk distance and symptom scores with both modalities. The
odds ratio for an adverse event for trials examining endobronchial valves was (9.58, 95% CI 5.56–
16.50). The most frequent adverse events with endobronchial valve treatment were pneumothorax
(1.4 - 25%) and COPD exacerbations (4 - 20%). A large multi-centre randomised controlled trial
reported a 27% pneumothorax rate and a 3% 45-day mortality rate (Criner 2018). The odds ratio
(OR) for an adverse event for trials examining coils was 8.73, 95% CI 2.69-28.32). The most common
adverse events were pneumonia (5 - 20%), COPD exacerbations (7 - 28%) and pneumothorax (5 -
10%). There was no difference in early mortality between valves/coils and control in this meta-
analysis. However, a 2021 randomised controlled study of coils in patients with severe COPD (FEV1
15-45% predicted) was terminated early with only 120 of the > 200 planned participants recruited.
There were 6 month follow up results available for 57 coil and 34 control participants, demonstrating
clinically significant improvements in SGRQ of -10.6 (95% CI -15.9 to -5.4) and improvement in FEV1
+10.3% predicted (95% CI 4.7-16.0) in the coil arm. There were no deaths in the control arm, whilst
there were 5 deaths in the coil arm. Also, the incidence of serious adverse events was higher in the
coil arm (n=30 of the coil participants, n=3 of the control participants) (Klooster 2021) [Evidence level
II]. Overall, these results indicate mixed results for coils.
There was concern regarding the lack of sham bronchoscopy and/or unclear status of blinding in
some studies that may cause a risk of bias (van Agteren 2017).
Endobronchial valves may be appropriate in highly selected patients with severe COPD and
hyperinflation if collateral ventilation can be excluded (intact fissure on imaging and Chartis negative
during bronchoscopy). Based on the data above the role of coils is unclear.
LVRS therapy should only be considered in high volume specialised centres (Herth 2017). All patients
being considered for lung volume reduction surgery and bronchoscopic interventions should be
referred for pulmonary rehabilitation and discussed by an expert panel that includes a radiologist,
respiratory physician, interventional pulmonologist, and thoracic surgeon (Herth 2017).
O9.3 Lung Transplantation

Lung transplantation is a complex therapy for selected patients with severe COPD and it is indicated
to improve quality-of-life and most likely improve survival. International guidelines (Weill 2015) and
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national consensus guidelines from the Australian Organ and Tissue Donation and Transplantation
Authority http://www.tsanz.com.au/organallocationprotocols and NHRMC Ethical Guidelines for Organ
Donation from Deceased Donors https://www.nhmrc.gov.au/guidelines-publications/e76 recommend
COPD patients be referred to one of Australia’s four lung transplant centres for consideration of lung
transplantation where the majority of the following are present:
● Progressive symptoms, despite maximal treatment including medication, pulmonary

rehabilitation, and oxygen therapy
● Patient is not a candidate for endoscopic or surgical lung volume reduction surgery (LVRS).
Simultaneous referral of COPD patients for both lung transplant and LVRS evaluation is
appropriate
● BODE index of 5-6
● PaCO2 > 50 and/or PaO2 < 60 mmHg
● FEV1 < 25% predicted
The absolute contraindications include recent malignancy, untreatable advanced dysfunction of

another major organ system, psychological/psychiatric conditions associated with poor compliance,
substance abuse or dependence (including ANY tobacco/marijuana) in the prior six months, absence
of social support and poor rehabilitation potential. According to Weill, the Australian Organ and Tissue
Donation and Transplantation Authority and the NHMRC, relative contraindications include age older
than 65 years, obesity, malnutrition, severe symptomatic osteoporosis, and colonisation with
resistant/virulent organisms/viruses.
If successful transplantation is possible, a detailed multi-disciplinary medical assessment and

eventual wait-listing for transplant may follow. Not all potential patients will be suitable or appropriate.
Based on specific patient and donor variables, waiting times vary from one month to years. The 2017
Australian and New Zealand Cardiothoracic Organ Transplant Registry Report states that the expected
one, five and ten-year survival rates post bilateral lung transplant are 91%, 67% and 52%. Complex
medications, regular investigations (e.g.: blood work, spirometry etc.) and Transplant Centre follow-
up are required indefinitely post-operatively.
O9.4 Pre-operative work-up for surgery

Patients with COPD are at increased risk of post-operative pulmonary complications after any thoracic
or non-thoracic surgery. A US database analysis has shown that COPD is associated with increased
post-operative mortality and morbidity with major surgical procedures (Gupta 2013), including
abdominal operations (Fields 2016). Careful pre-operative work-up of patients with COPD minimises
post-operative complications. As no specific thresholds of lung function are mandated for non-thoracic
surgery, the risk/benefit ratio for individual patients needs to be estimated for elective and urgent
surgery. For lung resection to treat lung cancer, spirometry and diffusing capacity should be measured
to estimate predicted post-operative lung function, and if required, exercise tests should be performed
(Brunelli 2013).
COPD management should be optimised in the pre-operative period, including smoking cessation,
inhaled bronchodilators, and pulmonary rehabilitation. Specific peri- and post-operative management
strategies have been suggested for patients with severe COPD. These strategies include early
mobilisation and, where appropriate, minimising medications leading to respiratory depression,
regional anaesthesia, and controlled oxygen delivery in the post-operative period (Diaz-Fuentes 2016,
Lakshminarasimhachar 2016).
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O10. Palliative and supportive care
Palliative care - ideally from a multidisciplinary team which includes the
primary care team - should be considered early, and should include symptom
control and addressing psychosocial issues [evidence level II, weak
recommendation]
Palliative care
Palliative care aims to improve the quality of life of patients and their families when facing life-
threatening illness, through the prevention and relief of suffering by controlling symptoms and
addressing physical, psychosocial and spiritual issues (WHO 2002). Palliative care encompasses early,
supportive care in addition to offering the traditional model of high-quality, end-of-life care for patients
close to death.
The provision of early palliative care can improve survival (Higginson 2014, Temel 2010). Early
access to palliative care is now recommended for patients with COPD and persisting symptoms.
General palliative care practices such as symptom management and aligning treatment with patients’
goals should be routine aspects of care. For patients with complex symptoms, referral to specialist
palliative care may be required (Quill 2013). Specialist palliative care services often work as
interdisciplinary teams and may include a wide range of health professionals offering support in
hospitals, community, or hospices.
Patients with COPD experience many distressing symptoms including breathlessness, fatigue,
depression, anxiety, and insomnia. However, these symptoms are often poorly controlled and
undertreated in advanced disease (Ahmadi 2016, Johnson 2012, Mullerova 2014, Walke 2007). In
Australia only 17.9% of COPD patients access any palliative care in their last year of life and only 2.6%
of palliative care admissions are for COPD (Rosenwax 2016). A review of COPD patient deaths
occurring in the ICU in 15 hospitals in the USA identified that patients with COPD were less likely to
receive specialist palliative care input or have opportunities to discuss end of life care preferences
related to resuscitation in the ICU, compared with cancer patients. This occurred despite patients with
COPD having longer hospital and ICU stays than patients with cancer. Therefore, there is a need to
improve patient and carer access to palliative care approaches both generally and more specifically
also within ICU (Brown 2016). Furthermore, a Belgian population cohort study (Faes 2018) identified
that during the last six months of life, patients with COPD used resources which focused on
preservation of life, with less use of resources or medications to alleviate symptoms or address end-
of-life care needs.
Well-described barriers to patients with COPD accessing palliative care include:
● Difficulty prognosticating in COPD

● Patients’ fears of abandonment by their usual physician (Knauft 2005)
● Perceptions that palliative care is only for end-of-life care or patients with cancer
● Clinicians’ lacking time to discuss palliative care, being reluctant to take away hope, and having
insufficient knowledge (Hardin 2008, Knauft 2005)
● Current palliative care services are already over-stretched (Quill 2013).
New models of well organised, integrated respiratory and palliative care may overcome these barriers
(Crawford 2013, Higginson 2014). In the randomised controlled trial by Higginson et al, patients with
advanced lung disease (including COPD) who received integrated palliative care together with care
from a respiratory medicine team had improved disease mastery and survival, but no change in quality
of life, when compared with patients who received standard care alone (Higginson 2014). Further
research is needed to evaluate new models of integrated care.
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Retrospective data from a study including two Victorian hospitals (Smallwood 2018) demonstrated
that in the last two years of life, only 18% of patients with severe COPD accessed specialist palliative
care, with 6% prescribed opioids as outpatients, despite most having severe chronic breathlessness.
Similarly, only 5% wrote an advance directive. In a substudy of the same population, Ross et al
reported that investigation burden was still significant at end of life for patients dying in hospital with
COPD, with many patients still undergoing diagnostic investigation even in the last 2 days of life (Ross
Given the difficulty in determining prognosis in an individual with COPD, including palliative care
principles and practices into COPD management should not be dependent on making an accurate
prognosis. Instead, symptom palliation and palliative care approaches should be considered earlier as
patients become more symptomatic, occurring concurrently with disease directed, active treatment.
A retrospective cohort study from Belgium demonstrated that receiving one or more home specialist
palliative care (PHC) visits more than 30 days before death was associated with increased appropriate
patient-centred medical resource use and lower inpatient and total costs in the last 30 days before
death for COPD compared to no PHC (Scheerens 2020). Notably, very few patients with COPD accessed
any PHC.
Supportive care - symptom control

Breathlessness is almost universal in severe COPD; however, this symptom remains under-recognised
and undertreated (Ahmadi 2016, Blinderman 2009, Gysels 2008). Therefore, it is important to
specifically ask about breathlessness and consider using a simple scoring tool (such as the modified
Medical Research Council Breathlessness scale – see Box 3 in C2.1 History above) to quantify
breathlessness. Patients with a score of 3 or higher have severe breathlessness.
When breathlessness persists at rest or on minimal exertion, despite optimal treatment of all
underlying causes, it is deemed refractory (Abernethy 2003). Refractory breathlessness requires a
comprehensive approach, including pharmacological and non-pharmacological strategies.
Non-pharmacological management of breathlessness
Evidence-based, non-pharmacological strategies include smoking cessation, self-management

education, physical activity and pulmonary rehabilitation, breathing exercises and the use of a
handheld fan to move cool air on the face (Box 8) (Galbraith 2010, Johnson 2016, Marchetti 2015,
Marciniuk 2011). Additionally, other management strategies such as chest wall vibration (Marciniuk
2011), neuromuscular electrical stimulation (Vieira 2014), activity pacing and energy conservation
may be helpful.
There is little evidence to support the use of “palliative” oxygen therapy in patients with
breathlessness and mild hypoxaemia (Abernethy 2010), however, the prescription of oxygen in these
clinical situations should be made on an individual basis.
Pharmacological management of breathlessness – opioids and benzodiazepines
In COPD, there is growing evidence that regular low dose oral morphine (<30mg/day) may safely and
effectively be used to treat refractory breathlessness in patients with advanced COPD (Abernethy
2003, Barnes 2016, Currow 2011, Ekstrom 2015a, Ekstrom 2014).
A 2015 systematic review and meta-analysis comparing opioids with placebo in 16 studies (271
participants, of whom 95% had COPD) found small short-term benefits in dyspnoea with minimal
adverse effects and unclear effects on quality of life (Ekstrom 2015a). A review in 2016, which included
26 RCTs with 526 participants, identified a small but beneficial effect from oral and parenteral (but not
nebulised) opioids on breathlessness (Barnes 2016). Abdallah et al (Abdallah 2017) have
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demonstrated improvements in exertional dyspnoea and exercise endurance, as measured by
cardiopulmonary exercise testing with single dose immediate release morphine syrup (0.1mg/kg) up
to a maximum of 10mg. Adverse effects from opioids include predictable gastrointestinal effects
(constipation, nausea and vomiting), drowsiness and light-headedness. However, in the reviewed
studies there were no cases of hypoventilation, respiratory depression, treatment-related
hospitalisations or death. Nevertheless, opioids should be used with care in COPD (Barnes 2016,
Ekstrom 2015b). Low dose morphine SR, 10mg twice day, with up-titration after 1 week if required,
in a double blind RCT with 111 patients, over 4 weeks, significantly improved health status as
measured by the CAT score (-2.18 95% CI -4.14 to -0.22). Overall, there was no effect on
breathlessness measures; however, in the subgroup of people with MMRC 3-4, there was a significant
difference in change of worst breathlessness in the previous 24 hours between the treatment groups
(-1.33, 95% CI -2.5 to 0.16; p=0.03). The only adverse effect demonstrated was constipation
(Verberkt 2020) [evidence level-II].
While there is good quality evidence to support a once daily, extended-release morphine dosing
schedule (Abernethy 2003), some patients may prefer to use immediate-release morphine as required
for breathlessness. Morphine dosing should therefore be individualised, taking into consideration
comorbidities, starting at a low dose and up titrating weekly until efficacy is achieved, or to a maximum
of 30mg/day. Laxatives should be prescribed to prevent constipation and patients should be warned
of side effects. Both patients and carers require both verbal and written education regarding how to
use morphine for breathlessness. Additionally, early medical review within 1-2 weeks is recommended
on initiating morphine or increasing the dose. Morphine sulfate pentahydrate (modified release)
capsules are approved for use in people with severe chronic breathlessness, despite optimal treatment
of all the underlying causes contributing to dyspnoea. Please refer to PBS criteria for further detail:
http://www.pbs.gov.au/medicine/item/11760Y-8349K.
There is no evidence to support a beneficial effect from benzodiazepines for the relief of
breathlessness in patients with COPD, however, they may be considered as a second- or third-line
treatment when non-pharmacological strategies and opioids have failed (Simon 2016).
As breathlessness management is complex, requiring multiple approaches, in addition to significant

self-management education of patients and their carers, individualised written breathlessness
management plans may be useful.
A retrospective single-centre study (Taverner 2019) found overuse of antibiotics occurred commonly
at the end of life in patients with COPD dying in hospital.
Goals of care
Discussing goals of care and future treatment wishes should occur early, in a non-acute setting and
should involve their General Practitioner. The option of including carers or family members should be
raised.
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Topics to consider:
● Disease severity, symptoms, quality of life and possible prognosis
● Patients’ and carers’ values and beliefs
● Treatment options including non-invasive ventilation, admission to an intensive care unit, and
intubation for mechanical ventilation (specialist input may be required)
● What death might be like
● End-of-life care wishes, including place of death preferences
These conversations occur as several discussions over multiple appointments. This has the advantage
of gently adding each new topic gradually, thereby reducing the chance of causing distress.
As a result of discussing goals of care, some patients may wish to appoint a medical power of attorney
or write an advance treatment directive (which must also be signed by a medical practitioner). It is
vital that other health professionals involved in the patient’s care and family members, or carers are
fully aware of the person’s future care wishes and of the existence of any advance treatment directive.
All patients should routinely and regularly be asked if they wish to discuss or update their goals of
care. More than a third of patients with severe medical problems were observed to change their
preferences regarding life supporting measures at least once over a period of twelve months (Janssen
2012).
End-of-life care
Patients with distressing symptoms or other challenging situations may benefit from referral to a
specialist palliative care team for:
● Management of persisting refractory symptoms

● Psychosocial, spiritual or existential care
● Co-ordination of care
● Active management of the terminal phase (at home or in a hospice)
● Emotional care and bereavement support of relatives and carers
Key points
1. Palliative care should be considered early and should include symptom control and addressing
psychosocial and spiritual issues.
2. Active treatment of persisting symptoms or challenging issues may require a multidisciplinary
team (which includes primary care, respiratory medicine, and palliative care)
3. The introduction of palliative and supportive care principles and discussion of goals of care
should be routine in patients with persisting symptoms despite optimal disease-directed
treatment.
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Box 8: Breathlessness management strategies
Non-pharmacological strategies
Smoking cessation
Physical activity
Pulmonary rehabilitation
Exercise training
Self-management education
Breathing exercises e.g. pursed lip breathing, breathing control, timed breathing techniques
Use of walking aids
Activity pacing
Use of breathlessness recovery positions e.g. sitting upright, forward lean
Handheld fans to move cool air on the face
Energy conservation including using equipment to perform tasks
Pharmacological options
Low dose morphine
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P: Prevent deterioration
Preventing exacerbations has a key role in preventing deterioration [evidence

level III-2, strong recommendation]
REDUCING RISK FACTORS FOR COPD is a priority, and smoking is the most important of these. A
systematic review of 47 studies with an average follow-up of 11 years found a significantly higher
decline in FEV1 in people who continued to smoke compared to those who ceased (Lee 2010) [evidence
level I]. The annual decline in FEV1 for those who stopped at the beginning of follow-up was 12.4
ml/year (95% CI 10.1-14.7) and for those who stopped during the period of follow-up 8.5 ml/year
(95% CI 5.6-11.4), both less than people who continued to smoke. While there were limitations to the
data, the review clearly found that in people who continue to smoke the annual decline in FEV1 is >10
ml/year greater than in people who have never smoked or stopped smoking. Reduction of exposure
to occupational dust, fumes and gases and to indoor and outdoor air pollutants is also recommended.
Influenza immunisation reduces the risk of exacerbations and death [evidence level I], while long term
oxygen therapy reduces mortality [evidence level I].
Avoidance of passive smoking is also recommended to prevent deterioration. In a cohort study

exposure to second-hand smoke (SHS) was found to be associated with worse clinical outcomes for
people with COPD. Living with a smoker was associated with poorer health-related quality of life
(HRQoL) (on both St George’s Respiratory Questionnaire (SGRQ) and COPD Assessment Test (CAT)
scores) and increased risk of severe exacerbations (OR 1.51, 95% CI 1.04-2.17), while SHS exposure
in the last week was associated with worse SGRQ and more symptoms (Putcha 2016) [evidence level
III-2].
P1. Risk factor reduction
P1.1 Smoking cessation

Smoking cessation is the most important intervention to prevent the worsening
of COPD [evidence level II, strong recommendation]
Australia has made substantial progress in reducing the prevalence of tobacco smoking. In 2017-18
the prevalence of daily smoking in adults (people aged 18 and over) was 13.8% compared to 16.1%
in 2011-12 and 23.8% in 1995. The proportion of First Nations people aged 15 years and over was
37% in 2018-19, a decrease from 41% in 2012-13. Despite the decrease in prevalence in 2018 tobacco
use remained the leading risk factor contributing to disease burden and death (8.6% of total disease
burden). In 2018 tobacco use was estimated to be the cause of death for almost 20,500 Australians.
The Australian National Tobacco Strategy 2023-2030 (Commonwealth of Australia 2023) aims to
achieve a national daily smoking prevalence of less than 10% by 2025 and 5% or less by 2030. For
First Nations people the goal is to reduce daily smoking to 27% or less by 2030. One of the priorities
of the strategy is to provide greater access to evidence-based cessation services to help people quit
tobacco. Actions related to this priority include improving and extending Quitline services, providing
policy guidelines and accredited training in smoking cessation and reviewing restrictions on and the
access to smoking cessation pharmacotherapies on the PBS.
Comprehensive treatment of tobacco dependence involves providing both behavioural support and
pharmacotherapy (Zwar 2014). International data show that smoking cessation strategies are cost
effective but with a 10-fold range in cost per life-year gained depending on the intensity of the program
and the use of pharmacological therapies (Ekpu 2015). A range of health professionals can help
smokers quit (Rice 2013, Stead 2013a, Carr 2012, Sinclair 2004) but relapse is common [evidence
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level I].
Currently accepted best practice is summarised in the 5-A strategy: (Zwar 2014).
• Ask and identify smokers. Document smoking status in the medical record.
• Assess the degree of nicotine dependence and motivation or readiness to quit
• Advise smokers about the risks of smoking and benefits of quitting and discuss options
• Assist cessation — this may include specific advice about pharmacological interventions or
referral to a formal cessation program such as the Quitline
• Arrange follow-up to reinforce messages.
Brief interventions for smoking cessation involve opportunistic advice, encouragement and referral.
Quit Victoria has summarised this as Ask, Advise, Help.
The brief advice model has three steps:
• Ask all patients about smoking status and document this in their medical record.
• Advise all patients who smoke to quit in a clear, non-confrontational and personalised way,
focusing on the benefits of quitting and advising of the best way to quit.
• Help by offering referral to behavioural intervention through Quitline (13 7848) and prescribe
(or help patients to access) pharmacotherapy, such as nicotine replacement therapy.
Cessation rates increase with the amount of support and intervention, including practical counselling
and social support arranged outside of treatment.
People with COPD often have barriers to smoking cessation. There is evidence that smokers with COPD
report lower self-efficacy and lower self-esteem, impairing their ability to quit. Co-existing depression is
common with depression reported in 44% of hospitalised patients with COPD (Jimenez-Ruiz 2015).
Despite this there is evidence that smoking cessation interventions can be effective. The 2016 update
of the Cochrane Review (van Eerd 2016) on smoking cessation for people with COPD includes 16 studies
involving 13,123 participants. Only two studies were rated as high quality. The review found high-quality
evidence from a meta-analysis of four (1,540 participants) of the 16 studies that a combination of
behavioural treatment and pharmacotherapy is effective in helping smokers with COPD to quit smoking.
A systematic review of behaviour change techniques to support smoking cessation in patients with
COPD found that four techniques were associated with higher rates of cessation. The behaviour change
techniques found to be effective (usually in comparison to usual care) were; facilitate action
planning/develop treatment plan, prompt self-recording, advise on methods of weight control, and
advise on/facilitate use of social support. In addition, linking COPD and smoking was found to result
in significantly larger effect sizes (Bartlett 2014) [evidence level I]. Personalising smoking cessation
advice based on lung function results increase cessation rates (Parkes 2008) [evidence level II].
AAAASmoking tobacco can alter the metabolism of a number of medicines. This is primarily due to
substances in tobacco smoke, such as hydrocarbons or tar-like products that cause induction of some
liver enzymes (CYP 1A2, in particular). When a person stops smoking, the enzyme activity returns to
normal, which may result in increased levels of these medicines in the blood. Monitoring and dosage
reduction may often be required. For information on medicines affected by smoking see Appendix 3
of the RACGP smoking cessation guidelines (http://www.racgp.org.au/your-
practice/guidelines/smoking-cessation/). Heavy marijuana smoking (> 20 joint-years of exposure)
increases the risk of COPD and accelerates FEV1 decline in concomitant tobacco smokers beyond that
observed with tobacco alone (Tan 2019).
P1.2 Treatment of nicotine dependence

Pharmacotherapies for nicotine dependence are effective and should be offered to all nicotine
dependent smokers who express an interest in quitting, except when contraindicated (Tobacco Use
102
and Dependence Guideline Panel 2008, Cahill 2013) [evidence level I]. Caution is recommended in
people with medical contraindications, pregnant women and adolescent smokers. Nicotine patches,
varenicline and bupropion sustained release are all PBS listed for smoking cessation. Details of PBS
listing are available are available in the RACGP smoking cessation guidelines
(http://www.racgp.org.au/your-practice/guidelines/smoking-cessation/) and the Australian Medicines
Handbook (https://shop.amh.net.au/).
A Cochrane network analysis concluded that combination NRT (nicotine patch combined with a quick-
acting oral form) and varenicline (used as monotherapy) are the most effective forms of drug
treatment and work equally well. It has been shown that varenicline is more effective than bupropion
in a number of studies. Head-to-head comparisons between bupropion and NRT monotherapy have
shown these medicines are equivalent to each other in efficacy (Cahill 2013).
In a study of 690 current smokers identified from Melbourne general practices (Liang 2018), 52.2%
self-reported attempts to quit at least once during the previous 12 months. The pharmacological
treatments most frequently tried were nicotine replacement therapy (205, 57.4%) and varenicline
(110, 30.8%). However, non-evidence-based treatments such as hypnotherapy (62, 17%) and
electronic cigarettes (38, 11%), were also frequently tried. Under-utilisation of evidence-based
smoking cessation pharmacotherapies during admission and at the time of discharge was observed in
a Tasmanian study of smokers admitted for an acute exacerbation of COPD (Pham 2019). Limited
access to formal smoking cessation training for doctors and poor uptake of nurse-led smoking
cessation services were also reported.
P1.2.1 Nicotine replacement therapy

All forms of nicotine replacement therapy (NRT) appear to be useful in aiding smoking cessation and
increase the rate of quitting by 50 to 70% (Stead 2012) [evidence level
I]. NRT is most suitable for nicotine dependent smokers who are motivated to quit. All forms of NRT
(at equivalent doses) are similarly effective in aiding long-term cessation. Evidence for efficacy of NRT
is strongest in in those who smoke more than 15 cigarettes daily but there is also evidence of benefit
in lighter smokers who choose to use pharmacotherapy (Shiffman 2005) [evidence level II). There are
a range of forms available in Australia (transdermal patch, gum, inhalator, lozenge, and mouth spray).
The choice of type of NRT depends on patient preference, needs and tolerance. NRT is more effective
when combined with counselling and behavioural therapy (Schwartz 1987). All forms of NRT should
be used for at least eight weeks. Information on the forms of NRT available, PBS listing and initial
dosing guidelines are available in the RACGP smoking cessation guidelines
(http://www.racgp.org.au/your-practice/guidelines/smoking-cessation/) and the Australian Medicines
Handbook (https://shop.amh.net.au/).
NRT is safe in patients with stable cardiac disease such as angina pectoris (Joseph 1996, Mahmarian
1997, Nitenberg 1999) [evidence level II]. NRT should be used with caution in people with recent
myocardial infarction, unstable angina, severe arrhythmias and recent cerebrovascular events (Meine
2005) [evidence level III-2]. NRT produces lower peak levels of nicotine than active smoking, so
theoretically, should be safer than smoking, even in patients with unstable disease.
Combination NRT. Combining two forms of NRT (patch plus oral form, such as gum or lozenge) has
been shown to be more efficacious than a single form of nicotine replacement. The patch provides a
steady background nicotine level, and the oral forms provide relief for breakthrough cravings as
needed. There is evidence from nine trials that this type of combination NRT is more effective than a
single type (Stead 2012) [evidence level I]. Combination NRT can be recommended:
• as first-line treatment for those who smoke and are nicotine dependent
• for those unable to quit using NRT monotherapy alone
• for those who experience cravings using NRT monotherapy alone.
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Pre-cessation nicotine patch. There is evidence to support use of the nicotine patch prior to smoking
cessation. A meta-analysis found that the nicotine patch used prior to quit day increased success rates
compared to standard therapy (Shiffman 2008) [evidence level I].
Reduce to quit. There is also evidence for use of NRT to help smokers who are not willing to quit
immediately to reduce their tobacco and then progress to quitting. A meta-analysis found that reducing
cigarettes smoked before quit day versus quitting abruptly, with no prior reduction, produced
comparable quit rates (Lindson 2010).
P1.2.2 Nicotine receptor partial agonists

The addictive properties of nicotine are considered to be mediated through its action as an agonist at
alpha4beta2 nAnti-Cholinergic Receptors (α4β2 nAChR), which stimulate the release of dopamine (Coe
2005). Varenicline was developed to counteract the effects of nicotine on the nAChRs, and its efficacy
in smoking cessation has been assessed in a Cochrane systematic review (Cahill 2008). In five trials
of varenicline compared to placebo for smoking cessation, it was found to be significantly more
effective for continuous abstinence at 12 months than placebo (n= 2023, OR 3.22, 95% CI 2.43-4.27,
NNT= 8, 95% CI 6-11). A 12-week course of treatment is recommended, starting 1–2 weeks before
the quit date and titrating the dose as follows: days 1–3: 0.5 mg daily; days 4–7: increase to 0.5 mg
twice daily; and continue with 1 mg twice daily from day 8 to the end of a 12-week treatment course.
Efficacy has also been demonstrated in people with COPD in a double-blind, multinational study of 504
patients with mild to moderate COPD (Tashkin 2011a). The primary end point of carbon monoxide-
confirmed continuous abstinence rate (CAR) for weeks 9 to 12 was significantly higher for patients in
the varenicline group (42.3%) than for those in the placebo group (8.8%) (OR 8.40, 95% CI 5-14,
p<.0001) [evidence level II]. Although adverse effects could not be pooled for analysis in the
systematic review, multiple trials reported an increased incidence of minor effects, particularly nausea,
which was mostly at mild to moderate levels and usually subsided over time, but also insomnia and
abnormal dreams. People planning to use the drug should set a date to stop smoking and be warned
that varenicline frequently causes nausea which may settle over time and taking it with food and a full
glass of water may help reduce nausea. Varenicline has no known clinically meaningful interactions
with other drugs. Two trials have tested the use of varenicline beyond the 12-week standard regimen
and found the drug to be well-tolerated and effective during long-term use. Three studies comparing
varenicline with bupropion found it to be significantly more effective in achieving continuous abstinence
at one year (n= 1,622, NNT= 14, 95% CI 9-32). An open-label study comparing varenicline with NRT
did not find any difference in one-year cessation rates, despite higher abstinence at the end of
treatment (Aubin 2008). There have been questions about the safety of varenicline in people with
mental health conditions. Psychiatric comorbidity is common in those who smoke, and in a large
randomised trial varenicline was found to be safe in those with stable mental illness or a past history
of mental illness (Anthenelli 2013). There is also evidence that varenicline is safe and effective to
assist cessation in people with schizophrenia (Pachas 2012, Williams 2012). Varenicline can be used
in those who smoke with mental health problems, but these patients should be monitored during quit
attempts. These patients should be advised to report unusual mood changes, depression, behaviour
disturbance and suicidal thoughts, and stop using the medicine if these occur.
Cytisine, a naturally occurring substance chemically related to varenicline, has been used for
smoking cessation for decades in parts of Eastern Europe. In the Cochrane meta-analysis of trials
comparing cytisine with placebo, the risk ratio for cessation was 3.98 (95% CI 2.01-7.87). A non
inferiority trial conducted in Australia compared standard cytisine treatment (25 days) with standard
varenicline treatment (84 days). The verified 6-month continuous abstinence rates were similar
(11.7% for the cytisine group vs 13.3% for the varenicline group) but the difference did not meet the
noninferiority margin of 5% (Courtney 2021). Cytisine is not currently registered for use in Australia
or New Zealand but importation is possible.
P1.2.3 Antidepressants
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Antidepressants for smoking cessation have been shown to be effective in a number of trials which
have been pooled in a Cochrane systematic review (Hughes 2014). This review included a total of 90
trials, 44 of which assessed the effect of bupropion and 10 nortriptyline. Pooling six available trials
using nortriptyline as the only pharmacotherapy showed evidence of a significant benefit for over
placebo in achieving cessation in the longer (6-12 months) term (NNT= 10, 95% CI 6-21).
Nortriptyline has the potential for serious adverse effects, but it was not possible to pool adverse
effects from the few small trials for smoking cessation. While none of the included trial reported major
adverse effects, individual studies did report an increased incidence of antimuscarinic adverse effects
such as dry mouth and constipation.
Bupropion, when used as the sole pharmacotherapy, doubled the odds of smoking cessation
compared to placebo at ≥ 6 months (44 trials, NNT= 16, 95% CI 13-20). There were few serious
adverse effects reported, although it is known there is a risk of about 1 in 1000 of seizures associated
with bupropion use. As a result, it is contraindicated in patients with past seizures, known CNS
tumours, bulimia, alcohol abuse or a history of head trauma. Bupropion may interact with other
antidepressants, especially monoamine oxidase inhibitors, which require a 14-day washout. While
minor adverse effects could not be pooled, individual trials frequently reported insomnia, dizziness and
headache to be more common with bupropion than placebo. Initial concerns that bupropion may
increase suicide risk are currently unproven. It is recommended as first-line pharmacotherapy for
smoking cessation alongside NRT (Hughes 2014) [evidence level I] and is of similar efficacy as NRT
monotherapy (Cahill 2013). The recommended dose is 150 mg orally once daily for three days, then
150 mg twice daily (at least eight hours apart) for between seven and nine weeks, in combination with
counselling. A quit date should be set (e.g. Day 5–10). The drug works equally well in smokers with
and without a past history of depression. It is also effective in people who have relapsed and are
motivated to quit again. There is insufficient evidence that adding bupropion or nortriptyline to nicotine
replacement therapy provides an additional long-term benefit. Pooled results from four trials
comparing bupropion to varenicline showed significantly lower quitting with bupropion than with
varenicline (RR 0.68, 95% CI 0.56-0.83). Three trials of extended therapy with bupropion to prevent
relapse after initial cessation did not find evidence of a significant long-term benefit.
The Cochrane systematic review included four trials of selective serotonin reuptake inhibitors or their
own (two of fluoxetine, one of sertraline and one of paroxetine) and two trials of fluoxetine as an
adjunct to NRT. None of these detected significant long-term effects, and there was no evidence of a
significant benefit when results were pooled. There was one trial of the monoamine oxidase inhibitor
moclobemide, and one of the atypical antidepressant venlafaxine, neither of which detected a
significant long-term benefit. Two trials of the herbal therapy St John’s Wort also showed no benefit.
Based on a Cochrane meta-analysis of six trials, the tricyclic antidepressant nortriptyline doubles
cessation rates compared with placebo treatment at six months when used as sole pharmacotherapy
(RR 2.03, 95% CI 1.48-2.78) (Hughes 2014). All studies included in the Cochrane Review were
placebo-controlled and used doses of 75 to 100 mg/day or titrated doses to serum levels recommended
for depression during the week prior to the quit date. Side effects include dry mouth, constipation,
nausea, sedation, and headaches. Nortriptyline is not licensed for smoking cessation. It is dangerous
in overdose and can increase the risk of arrhythmia in patients with cardiovascular disease.
P1.2.4 Other agents

A number of other agents have been shown to be effective in smoking cessation but are not commonly
used in clinical practice. Clonidine, an antihypertensive agent, increased smoking cessation 12 weeks
following the end of treatment compared to placebo, although abstinence was not objectively
confirmed in all studies (NNT= 12, 95% CI 6-32). There was a high incidence of dose-dependent
adverse effects, particularly dry mouth and sedation (Gourlay 2004). Anxiolytics have not been shown
to be effective in smoking cessation. A Cochrane systematic review including one trial each of
diazepam, meprobamate, metoprolol and oxprenolol and two trials of buspirone concluded there was
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no strong evidence of an effect for any of these drugs, but confidence intervals were wide, and an
effect of anxiolytics cannot be ruled out on current evidence (Hughes 2000).
P1.2.5 Electronic cigarettes (e-cigarettes)

E-cigarettes are battery-powered devices that may deliver nicotine in a vapour without tobacco or
smoke. Nicotine e-cigarettes can relieve cravings and symptoms of nicotine withdrawal as well as
simulating the behavioural and sensory aspects of smoking.
Concerns about e-cigarettes include limited evidence for short-term efficacy and short-and long-term
safety, particularly in patients with current chronic disease. Rather than cessation, concurrent use with
smoking may continue. A 2022 NHMRC CEO Statement on electronic cigarettes was informed by a
systematic review of global evidence by Banks et al (Banks 2022) [evidence level I]. The statement
was based on evidence reviews commissioned by the NHMRC on the topics of e-cigarette use and
smoking behaviour (uptake and cessation), the effects of e-cigarette advertising, promotion and
sponsorship, and e-cigarette use and health outcomes. Relevant evidence statements from the
publication are:
• E-cigarettes can be harmful. All e-cigarette users are exposed to chemicals and toxins that
have the potential to cause adverse health effects.
• E-cigarette-related poisonings have substantially increased over the past 5 years. E-cigarette
related calls to Australian Poisons Information Centres have more than doubled between 2020
and 2021.
• There are no health benefits of using e-cigarettes if you do not currently smoke tobacco
cigarettes.
• Short-term e-cigarette use may benefit smokers if they are able to quit smoking and have
been previously unsuccessful with other smoking cessation aids.
• There are other proven safe and effective options available to help smokers quit.
In November 2022 the Cochrane Library published an update of its review on electronic cigarettes
for smoking cessation (Hartmann-Boyce 2022). The review included 78 studies of which 17 were new
to the update. The comparison of nicotine e-cigarettes versus NRT was of studies comparing smoking
cessation at six months or more and measures of harm at one week or longer of e-cigarette use. There
were six studies in the analysis including one study in a pregnant population. The total number of
participants was 2378. The risk ratio was 1.63 (95% CI: 1.30 to 2.04) favouring nicotine e-cigarettes
over NRT. Using the Grade criteria, the authors rated the certainty of evidence as high meaning that
further studies would be unlikely to change the effect estimate in a way that would alter its clinical
interpretation. A key factor in the rating of the evidence was the rating of risk of bias in the included
studies. The review authors rated the risk of bias as low in five of the six studies, including the largest
study (Hayek et al 2019) which exerted the greatest influence on the risk estimate.
There are limited studies of nicotine e-cigarettes in populations of people with COPD. An
observational study of more than 4,500 current or former smokers aged 45 to 80 years (at least 10
pack years) has found that starting around 2010, there has been a rapid rise in the prevalence of e-
cigarette use among older adults with or at risk for COPD (Bowler 2017). Patients with mild, moderate,
and severe COPD were just as likely to try and continue to use e-cigarettes as those without COPD.
E-cigarette users had a heavier conventional cigarette smoking history and worse respiratory health,
were less likely to reduce or quit conventional cigarette smoking, had higher nicotine dependence, and
were more likely to report chronic bronchitis and exacerbations. As stated in the e-cigarettes position
paper from the Forum of Respiratory Societies, since electronic cigarettes generate less tar and
carcinogens than combustible cigarettes, use of electronic cigarettes may cause less disease related
to these components. However, the health risks of electronic cigarettes have not been adequately
studied and evidence on the safety and efficacy of e-cigarettes is still emerging (Hartmann-Boyce
2016). Until long-term safety and efficacy is established, e-cigarettes cannot be recommended as a
harm minimisation strategy among smokers with, or at risk of COPD.
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All e-cigarette users are exposed to chemicals and toxins that have the potential to cause adverse health
effects. In some cases, doctors may choose to prescribe nicotine e-cigarettes as a means of supporting
smoking cessation. TGA approved pharmacotherapy combined with behavioural support should be
offered as first line therapy. Nicotine e-cigarettes are an unapproved product, meaning that unlike
other forms of nicotine replacement therapy, they have not been assessed by the TGA for safety,
quality and efficacy. From 1 October 2021, the Australian government introduced restrictions aimed
at reducing access to the use of nicotine e-cigarettes among adolescents and young adults while
making them available for supporting smoking cessation. The arrangements include requiring a valid
prescription in order to get access to nicotine vaping products whether dispensed in Australia or
imported from overseas. A focussed update of the RACGP Smoking Cessation guidelines was
undertaken to provide guidance about the rescheduling of nicotine e-liquids. Therapeutic Goods
(Standard for Nicotine Vaping Products) (TGO 110) Order 2021 (TGO 110) came into effect on 1
October 2021. TGO110 sets minimum standards for nicotine vaping products supplied in Australia.
Refer to the following to access these guidelines: https://www.racgp.org.au/clinical-

resources/clinical-guidelines/key-racgp-guidelines/view-all-racgp-guidelines/supporting-smoking-
cessation/pharmacotherapy-for-smoking-cessation
Therapeutic Goods Administration provides information: https://www.tga.gov.au/resource/nicotine-

vaping-products-and-vaping-devices
Lung Foundation Australia has a position statement about electronic cigarettes:

https://lungfoundation.com.au/lung-health/protecting-your-lungs/e-cigarettes-and-vaping/e-
cigarettes-for-smoking-cessation/
https://lungfoundation.com.au/health-professionals/clinical-information/smoking-cessation/
The rapid uptake of nicotine vaping in young people, including people who have never smoked, has
prompted the federal health minister to propose further restrictions on access to nicotine vaping
products. If passed, the legislation will:
• ban the importation of vaping products (including devices, e-liquids and pods, whether
they contain nicotine or not), except by pharmacies who will be permitted to dispense
them under a prescription
• introduce minimum quality standards for vaping products, including restricting
flavours, colours and other ingredients
• require all vaping products to have pharmaceutical-like packaging
• reduce permissible nicotine concentrations and volumes
• ban all single-use disposable vaping devices
• allow all GPs to write prescriptions for vaping products without applying to become an
“authorised prescriber” of NVPs.
P1.3 Prevent smoking relapse

Family, friends and workmates should be advised of the intention to quit and asked to provide
understanding and support. The relapse rate is increased if there are other smokers in the household.
Success is more likely if all the smokers agree to quit together. Suggest the patient ring the Quit Line
or other local services (Australia 137 848 www.quitnow.gov.au/; NZ, 0800 778 778).
Former smokers who attend for follow-up are more likely to be successful in the long term. Support
is most needed in the first few weeks, so regular follow-up visits then and over the first three months
should be encouraged.
P2. Immunisations
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Vaccination reduces the risks associated with influenza and pneumococcal
infection [evidence level I, strong recommendation]
P2.1 Influenza immunisation

In people aged 65 years and older, annual influenza immunisation may lower the risk of influenza and
probably lowers the risk of influenza-like illness (Demicheli 2018). A Cochrane systematic review has
shown that in people with COPD, inactivated influenza vaccine reduced the total number of
exacerbations per vaccinated person, compared to placebo (mean difference -0.37, 95% CI -0.64 to
-0.11, n=180 patients; rated as low-quality evidence due to only 2 RCTs) (Kopsaftis 2018a) [evidence
level I]. There was no change in rates of hospital admission or mortality. Adverse effects are mild,
local, transient and self-limiting and include sore arm, mild fever and arthralgia. Please see the link to
The Australian Immunisation Handbook on the NHMRC’s website for the latest details about available
vaccines and timing of influenza vaccination: https://immunisationhandbook.health.gov.au.
P2.2 Pneumococcal immunisation

Pneumococcal immunisation is recommended for all patients with COPD. Pneumococcal immunisation
with conjugated vaccines covering 13 virulent serotypes (13vPCV) is highly effective in preventing
community-acquired pneumococcal pneumonia in older adults (Bonten 2015). In contrast, the
pneumococcal polysaccharide vaccine covering 23 virulent serotypes (23vPPV) is less effective in
elderly or immunosuppressed patients (Simberkoff 1986). People with COPD vaccinated with injectable
polyvalent pneumococcal vaccines are less likely to experience an episode of community-acquired
pneumonia (OR 0.62, 95% CI 0.43-0.89) with a NNTB of 21 to prevent one episode of pneumonia
(95% CI 15-74) and vaccination also reduces the likelihood of an exacerbation of COPD (OR 0.6, 95%
CI 0.39-0.93), NNT of 8 to prevent one exacerbation (95% CI 5-58) (Walters 2017) [evidence level
I]. Evidence was insufficient in this meta-analysis by Walters et al for comparison of different
pneumococcal vaccine types.
For those with newly diagnosed COPD who have never received pneumococcal immunisation: a first
dose of 13vPCV (conjugated vaccine) is recommended at diagnosis followed by up to two additional
doses of 23vPPV regardless of age. The number of lifetime doses of 23vPPV is now limited to 2 doses
for all people who are recommended to receive 23vPPV. The doses of 23vPPV received in the past are
also counted when deciding how many more are required. If a person has already received at least
two doses based on previous recommendations, no further doses of 23vPPV are to be given.
In the current national immunization program (NIP) patients under the age of 70 years with COPD and
chronic emphysema are not included in the risk conditions for National Immunisation Program (NIP)
funded pneumococcal vaccination. Consequently, they are not eligible for reimbursement. The NIP
provides funding for 13vPCV followed by 23vPCV vaccine for Aboriginal and Torres Strait Islander
adults 50 years and over.
Please see The Australian Immunisation Handbook for further details.
The additive effect of pneumococcal immunisation to annual influenza immunisation has been studied
in one small randomised, controlled trial over two years in Japanese patients with chronic lung disease
(Furumoto 2008). They found a significant additive effect of receiving both vaccines on exacerbations
in patients with COPD (influenza vaccine alone = 26% versus both vaccines =10.3%, p=0.037),
supporting current recommendations for dual immunisation.
P2.3 Haemophilus influenzae immunisation

A Cochrane Review/meta-analysis of six placebo-controlled RCTs evaluating 557 patients, conducted
to test the efficacy of enteric-coated, killed preparations of H. influenzae in populations prone to
recurrent exacerbations of chronic bronchitis or COPD, concluded that there was no significant
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reduction in exacerbations in the vaccinated group when compared to the placebo group (Teo 2017)
[evidence level I].
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P3. Immunomodulatory agents
The available evidence suggests that the putative immunomodulatory agent OM-85 BV is well tolerated
(Sprenkle 2004) [evidence level I]. However, consistent results across important clinical outcomes,
such as exacerbation and hospitalisation rates, are lacking to determine whether it is effective. Further
randomised, controlled trials enrolling large numbers of persons with well-defined COPD are necessary
to confirm the effectiveness of this agent.
P4. Macrolides
For patients with moderate-severe COPD and recurrent exacerbations, trials have found that long-
term low-dose oral macrolides reduce the number of patients experiencing an exacerbation and the
frequency of exacerbations. The number needed to treat to prevent one exacerbation (NNT) was 8
(95% CI 5-18) (Herath 2018).
A systematic review of prophylactic macrolide treatment in severe COPD, which included 6 RCTs
involving 1,485 COPD patients, showed that regular treatment of at least 6 months in duration results
in a significant decrease in COPD exacerbations (RR 0.65, 95% CI 0.43-0.89, p=0.01). Participants
treated with macrolides were more likely to experience non-fatal adverse (gastrointestinal reactions,
ototoxicity, rash, and liver injury) events compared to the placebo treated group (Yao 2013) [evidence
level I]. However, prudence would suggest this treatment should be reserved for patients who have
severe disease with recurrent exacerbations, in whom other treatments (for example: smoking
cessation, pulmonary rehabilitation, vaccination and optimal use of other preventive pharmacotherapy
known to reduce exacerbations) have been optimised. Retrospective analysis of the trial by Albert et
al found no evidence of treatment benefit among current smokers, with the greatest benefit seen in
milder COPD and older patients (Han 2014). Prospective data in predefined groups is required before
any sub-group treatment recommendations can be made.
A Cochrane network meta-analysis of various prophylactic antibiotics for patients with COPD (12
studies, n=3,405 patients) found beneficial effects of macrolides for reducing exacerbations (hazard
ratio 0.67, 95% credible interval 0.60 –0.75) compared to placebo and improving quality of life (mean
difference in SGRQ of -2.30, 95% credible interval -3.61 to -0.99, although this difference did not
reach the MCID) (Janjua 2021) [evidence level I]. No significant benefits were associated with use of
long-term quinolones or tetracyclines, compared to placebo.
Given the potential significant adverse effects of such regimens (including cardiac toxicity,
ototoxicity, diarrhoea, and the development of antibiotic resistance which affects both the individual
and the community), expert advice is recommended before starting long-term antibiotic therapy. It
should be noted that azithromycin is not available on the PBS for long term use.
P5. Long-acting bronchodilators
P5.1 Antimuscarinics
A Cochrane Review of nine RCTs (6,584 patients) found that tiotropium reduced the odds of a COPD
exacerbation (OR 0.74, 95% CI 0.66-0.83) and related hospitalisations (OR 0.64, 95% CI 0.51-0.82)
compared to placebo or ipratropium. The number of patients who would need to be treated with
tiotropium for one year was 14 (95% CI 11-22) to prevent one exacerbation and 30 (95% CI 22-61)
to prevent one hospitalisation (Barr 2005) [evidence level I]. Another systematic review of 22 trials
with 15,276 participants found that anticholinergic (antimuscarinic) use also significantly reduced
respiratory deaths (RR 0.27, 95% CI 0.09-0.81) compared with placebo. It would be necessary to
treat 278 patients with antimuscarinic agents to prevent one death (Salpeter 2006) [evidence level I].
A randomised double-blind placebo-controlled trial of four years duration found that tiotropium was
associated with a reduced risk of death at end of treatment (hazard ratio 0.84, 95% CI 0.73-0.97)
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(Celli 2009). It would be necessary to treat at least 53 patients to prevent one death. The precise
statistical significance varied with the period of analysis. The hazard ratio for tiotropium compared to
placebo varied from 0.87 (95% CI 0.76-0.99, p=0.034) for the full 4 years to 0.89 (0.79-1.02,
p=0.086) for 4 years+ 30 days [evidence level II]. A pre-specified subgroup analysis of this four-year
trial (Decramer 2009) found that tiotropium reduced the rate of decline of post-bronchodilator FEV1 in
patients with GOLD II COPD (43 ml/year versus 49 ml/year, p=0.024). However, the of pre-
bronchodilator FEV1 decline was not different between the groups.
P5.2 Comparison of inhaled medications

A systematic review examined the relative effectiveness of inhaled medications to reduce the risk of
exacerbations of COPD (Puhan 2009a). The authors identified 35 randomised controlled trials of at
least 4 weeks duration that enrolled 26,786 patients with COPD of whom 27% had one or more
exacerbations. All regimes significantly reduced the odds of exacerbation compared with placebo - no
single inhaled medication was more effective than another. If FEV1 was ≤ 40% predicted, long acting
antimuscarinics, inhaled corticosteroids and combination treatment reduced exacerbations
significantly compared with long-acting beta agonists alone. However the authors did not have FEV 1
data for individual patients.
In 2012, Chong et al (Chong 2012) performed a meta-analysis that compared tiotropium to a range
a long-acting beta-agonists, data from over 11,000 patients were included and trials were at least 3
months long. Chong reported that tiotropium was more effective in preventing COPD exacerbations
leading to hospitalisation (OR 0.86, 95% CI 0.79-0.93). There was no difference in mortality, all-cause
hospitalisations, quality of life and lung function. There were fewer serious adverse events with
tiotropium (OR 0.88; 95% CI 0.78-0.99).
P6. Corticosteroids
The effect of inhaled corticosteroids on the disease progression in COPD has been the subject of a
series of controlled trials and systematic reviews and the effect remains unclear. A Cochrane
systematic review found benefits of inhaled corticosteroids in reducing exacerbations and reducing
decline in quality of life, but no consistent benefit on rate of decline in lung function or mortality (Yang
2012) [evidence level I]; see Section O3.2 Inhaled corticosteroids for details). While these data do
not support the use of inhaled corticosteroids in all people with COPD, they are indicated for those
with more severe disease (FEV1 <50% predicted) and a history of frequent exacerbations.
P7. Mucolytic agents

Mucolytics may benefit certain patients with COPD [evidence level I, strong
recommendation]
Mucolytics, including N-acetylcysteine (NAC), ambroxol (3), sobrerol, carbocysteine, sobrerol,

letosteine, cithiolone, iodinated glycerol, N-isobutyrylcysteine (NIC), myrtol and erdosteine have
multiple possible actions in COPD including decreasing sputum viscosity, and antioxidant, anti-
inflammatory or antibacterial activity.
A 2019 Cochrane Review (Poole 2019) [evidence level I] included 38 trials involving 10,377
participants with COPD or chronic bronchitis, who were randomised to receive at least daily oral N-
acetylcysteine, carbocysteine, erdosteine, ambroxol, or placebo. The authors found treatment with
mucolytics was associated with an increased likelihood of being exacerbation free during the period of
study (OR 1.73, 95% CI 1.56-1.91) and calculated the number needed to treat with mucolytics for an
average of nine months to keep an additional participant exacerbation free was eight (NNTB 8, 95% CI 7-
10). For this outcome there was high heterogeneity I2 = 62%), and the authors recommend caution
with the interpretation of the results. Overall, the effect size of the more recent trials was smaller.
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Further the number of people with one or more hospitalisation was reduced, but study results were
not consistent (Peto OR 0.68, 95% CI 0.52-0.89; I2 = 58%). Mucolytic use resulted in a reduction of
0.43 days of disability per participant per month compared to placebo (95% CI -0.56 to -0.30; I2 =
61%). The authors concluded that the use of mucolytics in patients with chronic bronchitis or COPD
may produce a small reduction in the likelihood of an exacerbation, in days of disability per month,
and possibly hospitalisation. There was no clinically or statistically significant effect on quality of life.
In another meta-analysis of 10 RCTs involving 1,278 patients, Cazzola reported that compared to
placebo, erdosteine improved the clinical condition of COPD, as measured by global overall clinical
scores comprising a number of measures (SMD -0.56, 95% CI -0.94 to 0.17; p=0.001) (Cazzola
2018a). Erdosteine treatment also reduced the risk of COPD exacerbation and the risk of experiencing
at least one exacerbation compared to control.
There is evidence to support the use of high dose oral N-acetylcysteine in the reduction of COPD
exacerbations and improvements in lung function. This is supported by the results of a systematic
review and meta-analysis by Cazzola et al (Cazzola 2015a). In their meta-analysis of 13 studies
involving 4155 COPD patients, both low (<600mg/day) and high doses (>1200mg/day) of N-
acetylcysteine significantly reduced the frequency of exacerbations (relative risk 0.75, 95% CI 0.66–
0.84; p<0.01). The effectiveness of N-acetylcysteine in reducing exacerbations was also confirmed by
seven RCTs performed in patients who were enrolled based on ATS/ERS or GOLD guidelines,
spirometry confirmed COPD (relative risk 0.78, 95% CI 0.65–0.93; p<0.01) [evidence level I]. In
patients with COPD, high dose (≥ 1200mg/day) N-acetylcysteine should be considered as an effective
therapy for reducing exacerbations. In patients with chronic bronchitis but without airflow limitation,
a dose of 600mg/day leads to reduced exacerbations.
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P8. Humidification and nasal high flow (NHF) therapy
Several trials have shown that nasal high flow (NHF) humidified air in stable COPD patients reduces
transcutaneous CO2 (PtCO2) and respiratory rate (Fraser 2016, Biselli 2017, McKinstry 2018,2019).
A randomised trial by Rea et al (Rea 2010) found that NHF for up to 2 hours daily reduced annual
exacerbation days and days to first exacerbation but not hospital admission compared with usual care
in a group of 108 patients, with COPD/ bronchiectasis. Quality of life and lung function also improved.
No sham treatment was given.
In a small study crossover by Nagata et al (Nagata 2018), use of nocturnal HFNC in addition to LTOT
also demonstrated significant benefit in quality of life (St George’s Respiratory Questionnaire COPD
(SGRQ-C)) score improved by 7.8 points; (95% CI 3.7-11.9; p<0.01) and measured PCO2 (-4.1, 95%
CI -6.5 to -1.7), other studies have not demonstrated benefits in patient related outcomes. In a 12-
month multi-centre study of just over 100 patients with severe COPD and resting hypercapnia on LTOT
in Japan by Nagata (2022), reductions were found in annual moderate to severe exacerbation rates
and days to first exacerbation in the group receiving high flow nasal oxygen in addition to long term
oxygen therapy, but there were no changes in breathlessness scores, for example, between the
groups, over the duration of the study. No sham treatment was given in these studies by Rea and
Nagata, and in the 2022 Nagata study, hospitalisation rate was not reported. The arm without the
high flow nasal canula intervention had significantly higher combined moderate and severe
exacerbations, which was the primary outcome of interest, by an adjusted odds ratio of 2.85 (95% CI
1.48-5.47). Hospital admissions were classed as severe exacerbations but were not significantly
reduced (Nagata 2022) [evidence level II].
In a 12-month study by Storgaard et al (Storgaard 2018), 200 Danish patients with stable
hypoxaemic COPD who had commenced long term oxygen therapy (LTOT) within the preceding 3
months were randomised to LTOT alone or LTOT plus high flow nasal cannula (HFNC) at 20
litres/minute with oxygen flow unchanged (mean 1.75 (0.8) L) for at least 6 hours per day. 67 patients
in the HFNC group completed the trial and 71 in LTOT group. Analysis was by intention to treat.
Exacerbation rate was decreased in the HFNC group but not hospitalisations.
The role of long term domiciliary HFNC is as yet still unclear. Prospective randomised controlled
trials in the appropriate COPD patient population with meaningful clinical endpoints are required before
long term domiciliary NHF can be broadly recommended.
In the acute setting, high flow nasal oxygen has a role in hypoxic respiratory failure where
hypercapnia has been excluded (Frat 2015, Stephan 2015). Please see section X3.2.1 for further
details.
P9. Regular review

Regular review, with objective measures of lung function, health status (COPD Assessment Test
(CAT)), consideration of referral to pulmonary rehabilitation and medication review, is recommended.
This may reduce complications and the frequency or the severity (or both) of exacerbations and
admissions to hospital. Please see comments in section D.
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P10. Oxygen therapy
Long-term oxygen therapy has survival benefits for COPD patients with
hypoxaemia [evidence level I, strong recommendation]
Long term oxygen therapy (LTOT) reduces mortality in COPD (Medical Research Council Working Party
1981, American Thoracic Society 1995, Gorecka 1997, Nocturnal Oxygen Therapy Trial Group 1980,
Siafakas 1995, Tarpy 1995, Zielinski 1998). It may also have a beneficial impact on haemodynamics,
haematological status, exercise capacity, lung mechanics and mental state (Weitzenblum 1985,
Zielinski 1998, Tarpy 1995). Although effective, it is a potentially expensive and cumbersome therapy
that should only be prescribed for those in whom there is evidence of benefit (see below). Information
on prescribing oxygen therapy is given in Appendix 3.
Long-term continuous oxygen therapy (ideally at least 18 hours a day) is appropriate for
patients who have PaO2 consistently < 55 mmHg (7.3 kPa; SpO2 less than 88%) (Medical Research
Council Working Party 1981, Nocturnal Oxygen Therapy Trial Group 1980) when breathing air, at rest
and awake [evidence level I]. If oxygen is prescribed when the patient’s condition is unstable (e.g.,
during an exacerbation), then the requirement for it should be reviewed four to eight weeks after
initiation as it has been demonstrated in several studies that patients frequently do not fulfil the criteria
for LTOT at subsequent follow up (Eaton 2004, Levin 2018, Khor 2019). The studies by Khor and Levin
demonstrated that approximately 50% of patients no longer required LTOT at review 1-2 months after
discharge. At assessment for ongoing therapy, the patient’s condition must be stable, all potentially
reversible factors must have been treated and the patient must have stopped smoking at least one
month previously.
Polycythaemia (haemoglobin level > 170 g/L), clinical or electrocardiographic evidence of pulmonary
hypertension, as well as episodes of right heart failure, are consistent with the systemic effects of
chronic hypoxaemia, and continuous oxygen should be supplied if the stable PaO2is 55– 59 mmHg
(7.3–7.9 kPa; SpO2 < 90%) (Siafakas 1995, American Thoracic Society 1995). Continuous oxygen
therapy is of most benefit for patients with increased arterial PaCO2 (> 45 mmHg, or 6 kPa) (Nocturnal
Oxygen Therapy Trial Group 1980).
Government funding is available on the basis that the prescribing doctor is an approved prescriber
(usually a respiratory physician). Oxygen is usually supplied to patients meeting specific criteria and
means testing by state or regional health departments in Australia and New Zealand (Serginson 2009).
Oxygen in patients with moderate hypoxaemia
A large study of patients with moderate hypoxaemia (SpO2 89 to 93%) was powered originally to
determine whether continuous oxygen therapy improved mortality (Long-Term Oxygen Treatment
Trial Research Group 2016). Subsequently, inclusion criteria were altered to include those who
desaturated with exertion but were minimally hypoxaemic at rest (SpO2 ≥ 94% resting but
desaturating to <90% for >10 seconds and with SpO2 ≥ 80% for ≥ 5 mins). The study demonstrated
no difference between groups in the composite outcome of mortality or time to first hospitalisation,
nor in any other outcome including quality of life.
738 participants were randomised to receive oxygen at 2 litres per minute or no oxygen. 57% had
resting hypoxaemia and were prescribed continuous oxygen at 2 litres per minute and 43% were
prescribed oxygen at 2 litres per minute during exercise and sleep. Over a median follow-up of 18.4
months, the median use of oxygen was 15.1 ± 6.2 hours per day in the continuous group and 11.3 ±
5 hours per day in the exercise and nocturnal group. 51 adverse events were noted, with three patients
requiring hospitalisation on account of these. The majority of adverse effects were slips and falls, but
fire and burns also occurred.
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Limitations to this study included an absence of blinding, no placebo arm, and lack of clarity as to
whether the study was adequately powered for the modified composite primary outcome.
The findings from this study and its accompanying editorial are consistent with clinical practice
guidelines on adult domiciliary oxygen provided by the Thoracic Society of Australia and New Zealand
which recommend provision of long-term continuous oxygen therapy only in those who are significantly
hypoxaemic (see P10 above) and recommend use of ambulatory oxygen only in the few patients who
demonstrate benefit in a blinded test (McDonald 2016a).
In a systematic review and meta-analysis of the effects of home oxygen (delivered either as LTOT
or nocturnally) in patients with moderate hypoxaemia, six high quality studies were included. The
results demonstrated the effect of home oxygen in reducing 3 year mortality was small or absent and
the authors concluded the data did not support the widespread use of home oxygen in this population
of patients with moderate hypoxaemia (Lacasse 2022) [evidence level I].
Ambulatory oxygen therapy
In patients who qualify for long-term oxygen therapy (LTOT), ambulatory oxygen therapy can be
used in order to maximize usage achieve an average usage of 18 hours day (Nocturnal Oxygen Therapy
Trial Group 1980).
In patients who do NOT qualify for LTOT, available evidence does not allow any firm conclusions to
be made about the use of long-term intermittent ambulatory domiciliary oxygen therapy in patients
with COPD who do not meet the criteria for LTOT. This conclusion is based on a Cochrane Review
comprising four studies (total of 331 patients) (Ameer 2014) who received oxygen or air (blinded) for
between two and 12 weeks in the home setting. This review found no significant difference in exercise
tolerance or mortality in those receiving supplemental oxygen compared to breathing air supplied by
a cylinder. Although statistically significant benefits favouring oxygen were found in health-related
quality of life (HRQoL) (dyspnoea and fatigue domains of the Chronic Respiratory Disease
Questionnaire (CRQ)), the improvements did not reach the threshold for clinical significance. A
clinically significant reduction in end exercise dyspnoea favouring oxygen was found in two studies
[evidence level I].
Ambulatory oxygen should not be routinely offered to patients who are not eligible for LTOT.
However, the use of short-term intermittent oxygen therapy may be considered for:
People who experience oxygen desaturation on exertion
A Cochrane Review of 31 studies found that ambulatory oxygen was efficacious in single assessment
studies (in the hospital or laboratory setting) when comparing an exercise test performed breathing
oxygen or air in patients with moderate to severe COPD (Bradley 2005) [evidence level I]. Benefits
were shown in endurance exercise capacity, dyspnoea at isotime and oxygen saturation. However, the
minimum clinically important difference in these variables with oxygen therapy is unknown. Due to
the heterogeneity of the studies, subgroup analyses were not possible to determine which patients
were more likely to benefit. Acute benefit may be established by comparing exercise tolerance, oxygen
saturation and dyspnoea on a field walk test or treadmill test when breathing oxygen and when
breathing air (blinded). A cycle ergometry test should not generally be used for this purpose as oxygen
desaturation is significantly greater in COPD patients when walking as compared to cycling (Turner
2004, Poulain 2003). It is important to consider that most patients will walk further on a repeat walk
test and hence a practice test is usually necessary (Singh 2014c). The endurance shuttle walk test
(ESWT) has been shown to be more responsive than the 6-minute walk test when assessing the
benefits of ambulatory oxygen (Revill 2010) and it would appear that a practice ESWT may not be
necessary when two ESWTs are performed on the same day (Singh 2014c). However, the ESWT
requires patients to first perform the incremental shuttle walk test in order to determine the walking
speed for the ESWT. Ideally, the oxygen system used in the assessment should be the same as the
system the patient would use if oxygen were prescribed at home (e.g. trolley or shoulder bag to
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transport the cylinder). It is to be noted that short-burst oxygen i.e. oxygen inhaled immediately prior
and/or following exertion with the aim of relieving breathlessness or improving exercise tolerance is
not effective (O'Neill 2006) [evidence level I], (O'Driscoll 2008) [evidence level II].
The prescription of supplemental oxygen should not be based solely on an improvement in the
distance achieved on a walk test. Factors such as a reduction in dyspnoea and agreement to use
oxygen within the home and outdoors during activity should also be considered. As the relationship
between single assessments and long-term benefits is unclear, the acute assessment should form only
part of the determination and benefit of ongoing ambulatory oxygen therapy. Long-term review and
determination of oxygen usage are also important (Bradley 2007).
Ambulatory oxygen therapy during pulmonary rehabilitation
In the absence of need for LTOT there is no direct evidence that the treatment of exercise-induced
hypoxaemia retards long-term pulmonary hypertension or prolongs life. Nevertheless, in patients who
desaturate during exercise training, supplemental oxygen has been proposed with the aim of delaying
the onset of dynamic hyperinflation and the associated dyspnoea (O'Donnell 1997, O'Donnell 2001),
and to improve the benefit from training (Emtner 2003). However, neither a 2019 RCT (Alison 2019),
nor a systematic review of earlier studies (Nonoyama 2007) [evidence level I] support this approach.
In the Australian RCT (Alison 2019), 111 subjects with moderate to severe COPD who had oxygen
desaturation to <90% during 6-minute walk tests were randomised to either air or oxygen via nasal
prongs at 5L/minute for 8 weeks of 3X/week treadmill and cycle exercise sessions. Both groups
improved with respect to outcomes of Chronic Respiratory Disease Questionnaire and endurance
shuttle walk test, however there was no additional benefit with supplementary oxygen. This RCT
provides strong evidence that the provision of supplementary oxygen does not improve these
important outcomes in such exercise programs even when subjects are known to desaturate to <90%.
Other indications for intermittent oxygen therapy
Patients living in isolated areas or prone to sudden life- threatening episodes while they are awaiting
medical attention or evacuation by ambulance.
Patients travelling by air: Flying is generally safe for patients with chronic respiratory failure who are
on long- term oxygen therapy, but the flow rate should be increased by 1-2 L/minute during the flight
(see also below).
Nocturnal oxygen therapy
A large multicentre randomised controlled trial of nocturnal oxygen therapy versus air delivered via
concentrator or sham concentrator (the so-called INOX trial) was performed in patients with COPD
who did not fulfil criteria for LTOT (Lacasse 2020). Exclusion criteria included smoking cessation less
than 6 months previously, significant obstructive sleep apnoea (AHI>15), BMI>40, known left heart
failure and bronchiectasis. Inclusion criteria included desaturating to SPO2<90% for at least 30% of
the recording time on nocturnal oximetry. Recruitment to this trial was stopped early because of
recruitment and retention difficulties after n=243 patients, of a planned n=600, had undergone
randomisation. At three years of follow up there was no difference between the groups in the
composite endpoint of death from any cause or a requirement for long-term oxygen therapy as defined
by the Nocturnal Oxygen Therapy Trial (NOTT) criteria in the intention-to-treat population Although
this trial was underpowered, based on these results and those of two previous studies by Fletcher et
al (Fletcher 1992) and Chaouat et al (Chaouat 1999) current evidence does not support the
prescription of nocturnal oxygen therapy to improve survival or slow disease progression in patients
with COPD. However, the confidence intervals around the pooled treatment effects from a meta-
analysis of these three studies performed by the authors of this recent INOX trial and presented as
supplementary to this study concluded that the confidence limits around these outcomes are wide,
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and clinically significant effects are plausible [evidence level I]. More research is needed. In the
meantime, some patients with hypoxaemia during sleep may benefit from nocturnal oxygen therapy.
Nocturnal hypoxaemia should be considered in patients whose arterial gas tensions are satisfactory
when awake, but who have daytime somnolence, polycythaemia or right heart failure. Oxygen may
be indicated for patients whose nocturnal arterial oxygen saturation repeatedly falls below 88%. Sleep
apnoea should be excluded and treated independently.
P10.1 Fitness to fly

Commercial aircraft operate at altitudes of up to 12 500 metres, with the plane’s interior pressurised
to 2100–2400 metres. At this “altitude” the alveolar PaO2 for healthy individuals decreases from
103 mmHg (13.7 kPa) to 64 mmHg (8.5 kPa) and oxygen saturation declines from 97% to 93%.
As a general rule, supplemental oxygen is unlikely to be required if the resting oxygen saturation is
95% or higher, and likely to be required if oxygen saturation is 88% or lower. Patients with oxygen
saturation values between these levels might require specialist assessment.
Before flying, patients should ideally be clinically stable. Patients recovering from an exacerbation
are particularly at risk. Those already on long-term oxygen therapy need an increase in flow rate of
1–2 L per minute during flight. Careful consideration should be given to any comorbidity that may
impair delivery of oxygen to the tissues (e.g., cardiac impairment, anaemia). Exertion during flight
will exacerbate hypoxaemia.
The American Thoracic Society currently recommends that PaO2 during air travel should be
maintained at more than 50 mmHg (6.7 kPa). At altitude, PaO2can be estimated from PaO2at sea level
by means of published nomograms. If the PaO2at sea level is less than 70 mmHg (9.3 kPa), PaO2 at
2300 metres is less than 50 mmHg (6.7 kPa). The natural conclusion is that all patients with a PaO2
less than 70 mmHg (9.3 kPa) at rest at ground level should receive supplemental oxygen (American
Thoracic Society 1995, Ahmedzai 2011).
Many lung function laboratories perform high altitude simulation tests (HAST) to assess fitness to
fly. These measure arterial blood gas levels or transcutaneous oxygen saturation while breathing a
mixture of 15% oxygen and 85% nitrogen, mimicking conditions at 2800 metres.
P11 Long-term home non-invasive ventilation

Raveling et al (2021) performed a meta-analysis of chronic non-invasive ventilation use in patients
with COPD and hypercapnia compared to usual care. The analysis was separated into studies where
NIV was commenced in a stable phase and studies where NIV was commenced after an
exacerbation. Data was included from 13 stable COPD studies (n= 778) and 3 post exacerbation
studies (n =364). There is a high risk of bias due to lack of blinding. Note is made of significant
differences in trial design and NIV pressures delivered. Smoking status was not reported. Most studies
excluded people with obstructive sleep apnoea. For the outcomes of quality of life and mortality sub-
group analyses based on NIV pressures and baseline PaCO2 were not performed.
In the stable COPD group, quality of life scores improved with NIV, after three months (SMD 0.39,
95% CI 0.15-0.62, 5 studies, 259 participants); however, the improvement in quality of life was not
sustained to 12 months. There was no effect of NIV on exercise capacity. The risk for all-cause
mortality is reduced by NIV (adjusted hazard ratio 0.75, 95% CI 0.58-0.97; 3 studies, 405
participants; moderate-certainty evidence).
In the group where NIV was commenced after an exacerbation there was no improvement in quality
of life or mortality however, NIV did lead to an improvement in admission-free survival (adjusted
hazard ratio 95% CI 0.54-0.94; 2 studies, 317 participants) (Raveling 2021) [Evidence level I].
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There was no effect of NIV on lung function in either group. There was no improvement in lung
function in either group.
Long term NIV can be considered in patients with severe stable COPD and hypercapnia. Such
patients should be referred to a centre with expertise in home NIV.
P12 Alpha1-antitrypsin deficiency

Alpha1-antitrypsin deficiency (AATD) is an inherited condition that increases the risk of developing
pulmonary emphysema. Evidence for the diagnosis and treatment of patients with AATD-related lung
disease has been comprehensively reviewed in a position statement endorsed by the Thoracic Society
of Australia and New Zealand (TSANZ) (Dummer 2020).
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D: Develop a plan of care
Good chronic disease care anticipates the wide range of needs in patients with
COPD [evidence level I, strong recommendation]
IN THE EARLY STAGES OF DISEASE, patients with COPD will often not recognize and perhaps may ignore
mild symptoms, and this contributes to delay in diagnosis. As the disease progresses, impairment and
disability increase. As a health state, severe COPD has the third-highest perceived “severity” rating,
on a par with paraplegia and first-stage AIDS (Mathers 1999). Depression, anxiety, panic disorder,
and social isolation add to the burden of disease as complications and comorbidities accumulate.
Patients with severe COPD often have neuropsychological deficits suggestive of cerebral dysfunction.
The deficits are with verbal (Incalzi 1997) and visual short-term memory (Crews 2001), simple motor
skills (Roehrs 1995), visuomotor speed and abstract thought processing (Grant 1982). Severe COPD
is also associated with lower cognitive performance over time (Hung 2009) [evidence level III-2]. One
of the most effective means of improving the patient’s functional and psychological state is pulmonary
rehabilitation.
People with chronic conditions are often cared for by partners or family members. There is evidence
that family carers of people with COPD experience significant psychological and physical burdens
(Strang 2018).
Health systems around the world are reorienting health care delivery in ways that continue to provide
services for people with acute and episodic care needs while at the same time meeting the proactive
and anticipatory care needs of people with chronic diseases and multiple morbidities. Wagner and
colleagues have articulated domains for system reform in their Chronic Care Model (Wagner 1996).
These include Delivery System Design (e.g. multi-professional teams, clear division of labour, acute
versus planned care); Self-Management Support (e.g. systematic support for patients / families to
acquire skills and confidence to manage their condition); Decision Support (e.g. evidence-based
guidelines, continuing professional development programs) and Clinical Information Systems (e.g.
recall reminder systems and registries for planning care) (Adams 2007). Many of these domains are
addressed in the following sections.
D1. Support team
Clinical support teams working with the primary healthcare team can enhance
quality of life and reduce disability for patients with COPD [evidence level III-2,
weak recommendation]
Patients and their family and friends should be actively involved in a therapeutic partnership with a
range of health professionals (Celli 1995, Spruit 2013, Ries 1995, Lorig 1999). In advanced disease,
the many comorbidities, social isolation and disability mean that a multidisciplinary approach to
coordinated care may be appropriate. Studies have demonstrated the potential benefits of an
interdisciplinary approach on patient quality of life, symptom control, exercise tolerance and hospital
episodes (Chavannes 2009, Kruis 2014). Many different healthcare professionals are involved in the
crucial components of COPD management, including case finding, smoking cessation support,
pharmacotherapy, exercise training and self-management and education and exercise training. A
program with an emphasis on co-operation and collaboration between these providers should be
established for more effective patient care.
Multidisciplinary collaboration can improve the diagnosis and management of COPD in primary care.
Structuring collaboration and communication between primary care professionals involved in the
management of COPD (i.e. general practitioners (GP), nurses, physiotherapists, pharmacists and
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dieticians) is elementary to achieve this. Links should also be built between primary and secondary
care in order to accomplish optimal multidisciplinary care for COPD patients (Schermer 2008).
The general practitioner plays a key role in the delivery and coordination of care for people with
chronic disease including COPD and can access a range of Medicare items to support the delivery of
multi-disciplinary care. The multidisciplinary team, depending on local resources, may include the
members listed below. The role of respiratory specialists is outlined in Section C.
D1.1 General Practitioner

As the primary healthcare provider, the general practitioner (GP) is uniquely placed to identify smokers
and help them quit, diagnose COPD in its early stages and coordinate care as the disease progresses
(Johnston 2011). Improving GP uptake of spirometry for COPD diagnosis and recommendation of
evidence-based behavioural treatments, including smoking cessation and pulmonary rehabilitation,
are key to better management of COPD in Australian primary care.
Smoking cessation: A doctor’s advice is an important motivator for smoking cessation, especially if
the doctor is the family physician. The GP can help initiate the cycle of change by repeated brief
interventions. Since relapse to smoking is common, GPs should make enquiries about smoking status
routinely at each visit. There are several smoking cessation programs that have been developed for
use in general practice. The GP is also the appropriate health professional to recommend or prescribe
nicotine replacement therapy and pharmacological and/or non-pharmacological treatment of nicotine
addiction (for a detailed discussion of smoking cessation interventions, see Section P).
Early diagnosis: Simple questions relating to smoking history, daily cough and degree of
breathlessness should lead to lung function testing. A study in 31 general practice clinics in Melbourne
found that although GPs recognised the value of spirometry in differentiating between asthma and
COPD, most general practices only used spirometry in diagnostically difficult cases leading to more
accurate diagnosis of asthma (69%), but substantial underdiagnosis of COPD (14%) (Abramson 2012).
Spirometry needs to be more widely used to improve the accuracy of respiratory diagnoses in general
practice.
A national survey of Australian GPs in 2014 identified reactive, relatively passive and delayed
approach to diagnosis of COPD, potentially delayed smoking cessation advice and under-utilisation of
pulmonary rehabilitation. Less than half of the GP respondents reported using COPD management
guidelines (Bereznicki 2017).
In a cluster-randomised controlled trial of general practices in the UK, routine practice identified
fewer new cases of COPD, while an active targeted approach to case finding including mailed screening
questionnaires before spirometry was found to be a cost-effective way to identify undiagnosed patients
and had the potential to improve their health (Jordan 2016).
Coordinate investigation and management: GPs will manage patients with mild to moderate
COPD. Referral to a respiratory physician may be indicated to confirm the diagnosis, exclude
complications and aggravating factors, and to help develop a self-management plan (Section C, Box
6).
Coordinate care in advanced disease: GPs play a crucial role coordinating services provided by a
range of healthcare professionals and care agencies (the “multidisciplinary team”).
A cluster randomised controlled trial of an interdisciplinary COPD intervention in 43 Australian

primary care clinics coordinated by general practitioners (GPs) and involving smoking cessation
support, home medicines review (HMR) by a consultant pharmacist and home-based pulmonary
rehabilitation delivered by a specially trained physiotherapist did not improve health-related quality of
life (HRQoL), symptom severity or lung function in a cohort of patients with predominantly mild COPD
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(Liang 2019) [evidence level II]. Uptake of the intended intervention components by both GPs and
patients was suboptimal (31% completed the full intervention, 26% partially completed the
intervention). Exploratory analyses of the 31% who received the intended full intervention showed
statistically and clinically significant differences in HRQoL over usual care at 6 months (adjusted mean
difference 5.22, 95% CI 0.19–10.25, p=0.042).
D1.2 Other specialist physicians

COPD is an important morbidity in older people which impacts on comprehensive medical management
and quality of life. It is important to note that the support team involved in the management of COPD
patients may include a geriatrician, cardiologist, endocrinologist and psychiatrist amongst others.
D1.3 GP practice nurse/ nurse practitioner/ respiratory educator/ respiratory

nurse
Nurses play an integral role in the assessment and delivery of education and management for people
living with COPD. The training, expert knowledge and skills of respiratory nurses allow them to
undertake multidimensional assessments and to work with patients to tailor specific therapeutic
interventions and to co-ordinate the delivery of person-centred care (McDonald 2018).
Specific aspects of COPD care provided by nurses may include:
● respiratory assessment, including spirometry and pulse oximetry;

● assessment of comorbidity and delivery of interventions for comorbid disease, for example
cognitive behavioural therapy for anxiety, and education for diabetes and heart failure;
● evaluation of risk factors and the provision of evidence-based interventions, such as smoking
cessation techniques and education to promote physical activity, good nutrition and
appropriate vaccination;
● symptom assessment and management in the context of the community, primary and tertiary
care settings and pulmonary rehabilitation;
● implementation of, or referral for interventions such as exercise training, pulmonary
rehabilitation, airway clearance techniques and oxygen therapy;
● skills training with inhalation devices;
● assessment of adherence and implementation of interventions to improve adherence;
● patient education and skill development regarding the importance of exacerbation avoidance,
recognition and treatment;
● education to promote better self-management;
● organisation of multidisciplinary case conferences and participation in care-plan development;
● assessment of the home environment;
● end of life planning;
● respiratory nurses also deliver specialised assessments and treatments such as, oxygen
assessment and the provision of NIV.
Nurse led self-management programs have led to improved outcomes for people with COPD. Patients
discharged from a Hong Kong hospital after a COPD exacerbation were randomised to an intervention
group (IG) or usual care group (UG). The IG received a comprehensive, individualised care plan which
included education from a respiratory nurse, physiotherapist support for pulmonary rehabilitation,
three-monthly telephone calls by a respiratory nurse over one year, and follow-up at a respiratory
clinic with a respiratory specialist once every three months for one year. The UG was managed
according to standard practice. At 12 months, the adjusted relative risk of readmission was 0.668
(95% CI 0.449–0.995, p=0.047) for the IG compared with the UG. At 12 months, the IG had a shorter
length of stay (4.59±7.16 versus 8.86±10.24 days, p≤0.001), greater improvement in mean Modified
Medical Research Council Dyspnoea Scale (-0.1±0.6 versus. 0.2±0.6, p=0.003) and St George's
Respiratory Questionnaire (SGRQ) score (-6.9±15.3 versus. -0.1±13.8, p=0.003) compared with the
UG (Ko 2017). Another nurse led RCT of an intensive self-management intervention resulted in a
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reduction in hospitalizations (at 12 months) and in emergency department visits at 6 and 12 months.
Additionally, exercise capacity improved as measured by the 6MWD, as did health related quality of
life (Wang 2019). See self-management section.
D1.4 Physiotherapist
Physiotherapists are involved in a broad range of areas, including exercise testing and training,
assessment for oxygen therapy, patient education, airway clearance techniques, breathing retraining,
mobility, non-invasive ventilation (NIV), postoperative respiratory care and assessment and treatment
of musculoskeletal disorders commonly associated with COPD. Please refer to O6 for more detailed
information.
D1.5 Occupational therapist

Occupational therapists provide specific skills in task optimisation and prescription for those with
severe disease of adaptive equipment and home modifications. Some therapists also teach energy
conservation for activities of daily living and can help in the set-up of home and portable oxygen.
The effect of individualised occupational therapy in patients with moderate to severe COPD was
evaluated in an RCT (Martinsen 2017). 52 patients were randomly assigned to the intervention group
(occupational therapy) or control group (treatment as usual). Participants were recruited from the
outpatient and inpatient pulmonary department at a hospital in Norway and through advertisements
in local newspapers and distribution of leaflets to GPs’ offices. The primary outcome was assessed
using the Canadian Occupational Performance Measure (COPM), and participants were assessed at
baseline and after four and 12 months. The results indicate that compared with the usual care,
occupational therapy did not improve occupational performance or satisfaction with performance.
Small but significant changes in activity performance in favour of the intervention group were found
in some of the secondary outcomes.
In a randomised controlled trial, activity training by occupational therapists combined with exercise
improved functional status more than exercise alone or together with education, especially in elderly
people with moderate to severe COPD (Norweg 2005).
D1.6 Social worker

Social workers can provide counselling for patients and their carers, organisation of support services,
respite and long- term care.
D1.7 Clinical psychologist/psychiatrist

Anxiety and depression are common disorders in patients with COPD (Di Marco 2006, Gudmundsson
2006, Kunik 2005, Laurin 2007, Schane 2008), which worsen quality of life and add to disability
(Gudmundsson 2005, Ng 2007, Xu 2008, Laurin 2009, Giardino 2010, Eisner 2010b) [evidence level
III]. The prevalence of panic attacks and panic disorder in COPD are particularly high (Yellowlees 1987,
Pollack 1996, Kunik 2005, Laurin 2007) [evidence level III]. There is promising evidence that anxiety
and depression can be treated by clinical psychologists and psychiatrists using approaches such as
cognitive behaviour therapy (Kunik 2001, de Godoy 2003, Hynninen 2010, Yohannes 2017) [evidence
level II]. Psychiatrists can also advise whether pharmacological treatment may be appropriate.
A systematic review of various psychological interventions in patients with COPD showed some
improvements in psychological outcomes, especially with cognitive behavioural therapy (CBT). In
contrast, for physical outcomes, only mind-body interventions (e.g. mindfulness-based therapy, yoga,
and relaxation) revealed a statistically significant effect. These findings favour psychosocial
intervention as a tool in the management of COPD (Farver-Vestergaard 2015).
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A directed psychological intervention consisting of six sessions of group-based CBT delivered by a
psychologist added to an eight-week pulmonary rehabilitation program, showed significant
improvements in the CBT group in the 6-minute walk test (6MWT), fatigue, depression and stress
measures (Luk 2017).
Telephone-administered CBT can reduce depression symptoms in people with COPD. People with
COPD who have mood disorders would prefer to have CBT than befriending (Doyle 2017).
D1.8 Speech pathologist/therapist

Speech pathologists are involved in the assessment and management of dysphagia (difficulty
swallowing) in individuals with COPD and can be accessed in the community or in a hospital setting
(inpatient or outpatient). Early identification of dysphagia in those with COPD and adequate
management can minimise COPD exacerbations and hospital admissions (Kobayashi 2007, Schermer
Speech Pathologists use case history from patients and their partners or carers, clinical swallow
examinations, patient self-report scales and instrumental swallowing assessments - videofluoroscopy
and fibreoptic endoscopic evaluation of swallowing (FEES) to assess and diagnose dysphagia
(Ghannouchi 2016, Regan 2017). Strategies for the management of dysphagia are listed in O7.6
Aspiration.
Management of dysphagia in individuals with COPD is dependent on the individual’s swallowing

difficulties and is prescribed by the Speech Pathologist (McKinstry 2010).
D1.9 Pharmacist
Community pharmacists are medicines experts in the primary care setting and are well placed to
engage in early detection/case finding of COPD, and COPD care programs due to their frequent
interactions with patients during prescription refill. Monitoring and optimising COPD maintenance
therapy in a community pharmacy has the potential to improve COPD management. Evidence from
overseas suggests that such interventions significantly improved both inhalation technique and
medication adherence, and significantly decreased the estimated annual severe exacerbation rate
(Tommelein 2014). Structured education about COPD provided by a clinical pharmacist and a
comprehensive pharmaceutical care program significantly improved medication adherence, improved
quality of life, decreased severe exacerbation and hospitalisation rate, and higher quit rates (Xin
2016). Such interventions have not been evaluated in Australian community pharmacies in large trials.
A pharmacist-led medication adherence management intervention in 53 Spanish community
pharmacies comprising motivational interviewing principles to assess adherence, identification of
barriers for medication adherence and tailored strategies to address identified barriers, and monthly
follow-ups was effective at improving medication adherence (self-reported data) compared to usual
care in patients with COPD at 6 months (92.9% (87.0%-96.2%) vs 72.5% (62.3%-80.7%); 4.93 (2.20
- 11.1) p=0.0001). Patients in the intervention group also had lower Clinical COPD Questionnaire
(CCQ) scores (MD −0.50, 95% CI −0.82 to −0.18, p<0.05) when compared with the control group
(Torres-Robles 2022) [evidence level II].
Community pharmacists are ideally positioned to play a vital role in all key stages of an integrated
COPD patient care pathway, smoking cessation support, support/monitoring of management plans to
the provision of advice and counselling regarding medications, inhaler technique and treatment
adherence (van der Molen 2017). The skill sets, frequency of contact with patients, expertise regarding
available treatments, and convenience to patients, in terms of the location, opening times and ‘open
door’ consultation opportunities are the strengths of community pharmacists (Fathima 2013).
Australian community pharmacists, with adequate training could play a bigger role in optimising
medicine use by patients with chronic respiratory conditions.
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Pharmacists are involved in education about medications and supply of medications. They can help
smokers quit by advising about nicotine replacement and can counsel patients requesting over-the-
counter salbutamol. They are well placed to monitor for medication problems and complications and
suggest solutions (e.g., individual dosing dispensers) (Beney 2000). This is particularly important
where multiple comorbid conditions require treatment with multiple medications that have potential
interactions, or when confusion exists about timing of medication administration.
D1.10 Dietitian/Nutritionist
Excessive weight-loss is a common problem in patients with end-stage COPD. Conversely, obesity
in patients with COPD is associated with sleep apnoea, CO2 retention and cor pulmonale. Dietitians
play a central role in managing these problems.
A Cochrane Review of 17 studies (632 participants) that provided nutritional supplementation for
patients with COPD for more than two weeks found growing evidence that nutritional supplementation
improved body weight, respiratory muscle strength, walking and quality of life, especially if
malnourished (Ferreira 2012).
In obese (body mass index ≥ 30 kg/m2) COPD patients a 12 week weight reduction program
involving meal replacements and dietary counselling by a dietitian and resistance exercise training
prescribed and supervised by a physiotherapist, with face to face review by the dietitian and
physiotherapist every two weeks for counselling, achieved modest weight loss of 6.2%, and improved
clinical outcomes including health status, symptoms, exercise and functional capacity, whilst
preserving skeletal muscle mass (McDonald 2016b).
D1.11 Exercise physiologist

Exercise physiologists are predominantly involved in exercise testing, exercise prescription and
supervision of exercise rehabilitative programs. They also provide patient education on the importance
of regular exercise and on activity/behavioural modification. They may also play a role in the
assessment of exertional oxygen and the exercise rehabilitation of associated co morbidities.
D1.12 Non-medical care agencies

Many patients with COPD have difficulties with activities of daily living and may require a range of non-
medical support services, including governmental and non-governmental organisations. Availability of
services varies between states and between areas within states (e.g., urban, rural, remote). Some
examples include:
● financial support and organisation of oxygen, CPAP machines, nebulisers, etc.;

● Homecare;
● Government-supported assistance with activities of daily living (showering, cleaning, shopping,
etc.);
● home maintenance;
● Meals on Wheels;
● exercise programs; and
● support groups.
D2. Multidisciplinary care plans

A multidisciplinary care plan involves documentation of the various medical, paramedical and non-
medical services required to keep a patient functioning in the community. Various generic and disease-
specific proformas are available. The care plan may be initiated in the context of a multidisciplinary
case conference involving the GP and at least two other health professionals (one of whom is not a
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doctor).
GPs are remunerated for their involvement in case conferences. This is supported by Extended
Primary Care (EPC) item numbers, which vary according to the level of involvement of the GP and the
location of the patient. The GP may participate by telephone. A consultant physician is also entitled to
claim rebates for organising or participating in case conferences. Further information about item
numbers is available at http://www.health.gov.au/mbsprimarycareitems.
The multidisciplinary care plan may include a component of self-management with appropriate
support.
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D3. Chronic Disease Self-management
Patients may benefit from self-management support [evidence level I, strong
recommendation]
Chronic disease management can broadly be defined as a comprehensive strategy for improving
overall health status and reducing health care costs (Hunter and Fairfield 1997). It is well suited to
chronic conditions as it takes a holistic approach, treating patients as individuals throughout the clinical
course of a disease rather than viewing their care as a series of discrete episodes (Hunter 2000). The
essence of disease management includes a system of patient education and self-management,
implementation of practice guidelines, appropriate consultation, and supplies of medications and
services (Hunter 2000). Self-management support is the systematic provision of education and
supportive interventions by health care staff to support patients increase their skills and confidence in
managing their health problems (Institute of Medicine Committee on the Crossing the Quality Chasm:
Next Steps Toward a New Health Care, 2004).
Disease management approaches in COPD include a number of the Chronic Care Model domains. A
systematic review by Peytremann-Bridevaux (2008) assessed the impact of COPD management
programs attended by patients, which they defined as interventions with two or more different
components (e.g. physical exercise, self-management, structured follow-up), at least one of which
continued for 12 months, were delivered by two or more health care professionals and incorporated
patient education. It found such programs improved exercise capacity and health-related quality of
life (HRQoL), and reduced hospitalisation [evidence level I]. However, it is unclear from this review
which specific components of the disease management programs contribute the most benefit to
patients. A Cochrane Review (Kruis 2013) examined 26 trials of integrated disease management
programs defined as "a group of coherent interventions designed to prevent or manage one or more
chronic conditions using a systematic, multidisciplinary approach and potentially employing multiple
treatment modalities." The review found positive effects on disease-specific QoL measured by the
Chronic Respiratory Questionnaire (all domains) and on the impact domain of the St George’s
Respiratory Questionnaire (SGRQ). There were also positive effects on exercise tolerance, hospital
admissions and hospital days per person [evidence level I].
An updated Cochrane Review of RCTs and clusters RCTs of self-management support interventions
published since 1995 included 27 studies and 6008 participants. Follow-up time ranged from 2.5 to 24
months. The review found improvement in HRQoL measures by the SGRQ with a mean difference from
usual care of -2.86 points (95% CI -4.87 to -0.85). This is less than the minimal clinically importance
difference of 4 points. There was also a lower risk of at least one respiratory-related hospital admission
(OR 0.75, 95% CI 0.57-0.98). The NNT to prevent one respiratory hospital admission over a mean of
9.75 months follow-up was 15 (95% CI 8-399). No excess respiratory-related and all-cause mortality
risks were observed. The review had stricter inclusion criteria than previous reviews (Schrijver 2022).
A cluster RCT conducted in Canadian primary care of an integrated disease management

intervention aimed at patients with frequent and/or severe exacerbations and comprising on-site
spirometry, case management, education, and skills training including self-management education by
a certified respiratory educator resulted in improved disease-related quality of life, improved disease
knowledge and FEV1 and fewer exacerbations and unplanned service use compared to usual care
(Ferrone 2019) [evidence level II]. In another large multicentre randomised controlled trial (Rice 2010)
involving veterans who received a single education session, an action plan for self-treatment of
exacerbations and monthly follow-up calls from a case manager, found that, when compared to usual
care, the intervention group had a significant reduction in hospitalisation and ED visits for COPD,
mortality and quality of life, measured with the Chronic Respiratory Questionnaire [evidence level II].
An alternative approach of home care outreach nursing was studied in a systematic review by Wong
(Wong 2012), in which the intervention included home visits to provide education and social support,
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identify exacerbations and reinforce correct inhaler technique. They also found a significant benefit in
quality of life, measured by the St George’s Respiratory Questionnaire (SGRQ), but no significant effect
on mortality or hospitalisations [evidence level I]. In all these studies, it remains unclear which specific
components contribute the most benefit to patients, are the most cost effective or should be combined
to provide optimal benefit on the many different outcomes.
Box 9: Comparison of outcomes for COPD management programs
Study/Outcome Mortality Hospitalisation QOL Exercise

Peytremann-Bridevaux OR = 0.85 Benefit in 7/10 Not reported WMD = 32.2
(0.54 to 1.36) studies (4.1 to 60.3)
Rice #MD = 3.7 *MD = 0.34 MD = 5.1 Not reported
(-1.4 to 8.8) (0.15 to 0.52) (2.5 to 7.6)
Wong OR = 0.72 OR = 1.01 WMD = -2.60 WMD = 5.05

(0.45 to 1.15) (0.71 to 1.44) (-4.81 to - (-15.08 to
0.39) 25.18)
McLean OR = 1.05 OR = 0.46 WMD = -6.57 Not reported
(0.63 to 1.75) (0.33 to 0.65) (-13.62 to
0.48)
Outcome presented as OR = odds ratio or (W)MD = (weighted) mean difference, with 95% confidence intervals in brackets.
*Hospitalisation and ED visits. # difference per 100 patient years.
A number of systematic reviews have been undertaken to evaluate the effect of self-management in
COPD (See Figure 6 for abbreviated table and Appendix 6 for full table). Whilst these have
consistently reported improvements to quality of life, there have been conflicting findings in terms of
their effect on healthcare utilisation (Jolly 2016, Jonkman 2016a, Jonkman 2016b, Majothi 2015,
Schrijver 2022).
A Cochrane review found self-management interventions that included action plans for exacerbations
were associated with reduced probability of respiratory-related but not all-cause hospitalisation, all-
cause mortality, dyspnoea or exacerbation rate (Lenferink 2017). However, exploratory analysis
showed a small but significantly increased respiratory-related mortality. The differences may be
related to differences in the study populations, study context and extent of self-management support
provided. Other reviews of self-management in COPD have found reductions in both respiratory-
related, ED (Schrijver 2022), and all-cause hospitalisations (Jonkman 2016b), a reduction in urgent
health care, improved exercise capacity measured by the 6-minute walk distance (6MWD) (Cannon
2016, Schrijver 2022), and improved anxiety and repression (Schrijver 2022). However, reviews have
also reported no differences in 6MWD, anxiety and depression, hospital admissions and mortality
(Majothi 2015, Cannon 2016, Jolly 2016, Jonkman 2016b). A systematic review and meta-analysis of
nurse-led COPD interventions concluded that such interventions were associated with improvements
in 6MWD, activities of daily living, and anxiety and depression, but failed to reduce the number of
hospital admissions or improve HRQoL measured using the SGRQ. Interventions carried out by hospital
and respiratory nurse-led interventions were associated with greater effectiveness compared to
community nurses (Aranburu-Imatz 2022) [evidence level I]. These systematic reviews should be
interpreted with caution due to the methodological weaknesses of the studies and heterogeneity of
the interventions and outcome measures.
In 2019, Aboumatar et al reported an RCT that showed increased rates of exacerbation in the
intervention group without any change in health status. They recruited patients admitted to hospital
with a COPD exacerbation, or patients who had a previous diagnosis of COPD who were hospitalised
and were receiving treatment for an increase in COPD symptoms (Aboumatar 2019). Patients (n=240)
were randomised to a three-month intervention that involved: 1. A transition support aimed at
preparing patients and caregivers for discharge and ensuring they understood the post discharge plan
of care, 2. Individualised COPD self-management support to help patients take medications correctly,
recognise exacerbation signs and follow action plans, practice breathing exercises and energy
conservation techniques, maintain an active lifestyle, seek help as needed, and stop smoking, and 3.
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Facilitated access to community programs and treatment services. The intervention was delivered by
COPD nurses. Usual care involved a general transition coach to follow the patient for 30 days after
discharge, with a focus on adherence to the discharge plan, and connecting to outpatient care. The
intervention resulted in an increased number of COPD-related acute events per participant at 6 months
compared to usual care (difference 0.68, 95% CI 0.22-1.15, p=0.004). There were no differences
observed in health status measured by the SGRQ at 6 months (difference 5.18, 95% CI 2.15-12.51,
p=0.11). The interventions included assessment and management of knowledge and skills, physical
activity, pharmacological and nonpharmacological interventions and health behaviours.
A RCT reported in 2022 evaluated the effect of self-management strategies delivered by health care
professionals compared to a dual intervention of self-management delivered by health care
professionals and peer supporters (defined as patients with COPD and their family- caregivers who
were nominated by pulmonary clinic and rehabilitation program staff). Of the 1061 patients identified
as eligible, only 292 were randomised. There was no effect on the primary outcome of quality of life
measured by the SGRQ at 6 months (unadjusted difference of 1.26 points with 95% CI -5.44 to 7.96,
p=0.591), nor at nine months. The intervention did however improve the secondary outcome of COPD-
related acute care events during the 6-month intervention (Aboumatar 2022) [evidence level II],
signalling the potential role of peers and family carers in the management of COPD.
The high degree of heterogeneity within interventions and study designs limits the ability to analyse
which characteristics of self-management programs are associated with the most significant
improvements. However, a meta regression review of complex interventions identified that general
education, exercise and relaxation therapy components contributed to reduced use of urgent
healthcare (Dickens 2014) [evidence level I]. Additionally, Jonkman et al (2016a) demonstrated that
intervention duration, regardless of composition, displayed the strongest association with reduction in
all cause hospitalisations in COPD patients. Newham et al. identified that interventions targeting
mental health were the most effective in improving health-related quality of life (HRQoL) and reducing
ED visits (Newham 2017).
Health coaching, when using motivational interviewing methods, and including components of goal
setting and education, when delivered in person, has been demonstrated in a meta-analysis of 10
RCTs, to lead to significant improvements in quality of life, as well as COPD–related hospital admissions
(54% reduction [OR 0.46, 95% CI 0.31-0.69]). However, the benefit appears not to be sustained
beyond 12 months post-intervention (Long 2019).
Overall, COPD self-management programs appear to improve HRQoL. The effect of these
interventions on exacerbations remains unclear. Studies have reported positive outcomes, whilst
others have reported increased rates of exacerbations associated with self-management interventions
(Aboumatar 2019). Due to the heterogeneity of the study designs, setting and outcomes, and
conflicting results, we are unable to make recommendations regarding the essential elements of a
COPD self-management program.
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Written COPD Action Plans
The concept of written action plans for patients with COPD is derived from their success in asthma
management indicating doses and medications to take for maintenance therapy and for exacerbations.
Instructions for crises are often also included. Lung Foundation Australia has developed a COPD Action
Plan which can be downloaded from https://lungfoundation.com.au/resources/copd-action-plan. The
Action Plan should be completed in partnership with the clinician and patient and guides patients in
recognising when their symptoms change and what action they should take. Written action plans are
often included as an integral part of COPD self-management programs described above but have also
been tested as independent interventions.
A Cochrane systematic review by Howcroft et al synthesized the findings of seven RCTs conducted
in people with COPD in which the intervention included the provision of actions. A single short
educational component was included in the interventions in which the clinician personalised the plan
according to management needs and symptoms. Ongoing support directed at the use of the action
plan was permitted, however studies with a broader self-management approach or exercise
intervention were excluded. The comparator was usual care. Action plans reduced ED visits and
hospital admissions (Howcroft 2016). The number needed to treat to reduce one hospital admission
was 19. A subsequent RCT not included in this review confirmed a reduction in ED visits in patients
who utilised an action plan (Zwerink 2016).
A multicentre RCT (Lenferink 2019) (n=201) evaluated the effect of patient-tailored symptom-based
written action plans embedded within a multi-disease self-management intervention on COPD
exacerbation days compared to usual care in patients with COPD and one or more comorbidity. Patients
were given written action plans to prompt management of both COPD exacerbations and comorbidities
(congestive heart failure (CHF), ischaemic heart disease (IHD), anxiety, depression and diabetes),
together with a self-management education program. No difference in the primary outcome of COPD
exacerbation days/patient/year was observed (intervention median 9.6 (interquartile range (IQR) 0.7
to 31.1) versus usual care 15.6 days (3.0 to 40.3); (Incidence Rate Ratio (IRR) 0.87, 95% CI 0.54-
1.30 (p=0.546)). There were however observed differences in the secondary outcome of duration of
COPD exacerbations, in favour of the intervention (8.1, IQR 4.8 to 10.1 versus 9.5, IQR 7.0 to 15.1
days; p=0.021). There was no difference in overall HRQoL between groups, and the intervention group
reported poorer emotional function on the CRQ compared to usual care.
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Figure 6: Table of Systematic Reviews Evaluating the Effect of Self-Management in COPD
Authors Design Studies Participants HRQoL All-cause Respiratory- Mortality ED Anxiety & Dyspnoea 6M Respiratory- Medication Urgent
included n= hospitalisations related pres depression WD related use healthcare
hospitalisations mortality
Dickens et RCT 32 studies, 3941 ☺
al., 2014 database
inception-2013
Zwerink et RCT, 29 studies, 3688 ☺ ☺ ☺ 😐 ☺ 😐
al., 2014 CCT 1995-2014
Majothi et RCT 9 studies, 1466 ☺ 😐 😐 😐

al., 2015 Moderate-
severe COPD,
database
inception-2012
Cannon et RCT 25 studies, 4082 ☺ 😐 😐 ☺
al., 2016 1990-2016
Howcroft RCT, 7 studies, 1550 ☺ 😐 ☺ 😐 ☺

et al. 2016 quasi Database
RCT inception -2015
Jolly et al., RCT 173 studies, n/a ☺ 😐
2016 database
inception-2012
Jonkman et RCT 14 studies, 3282 ☺ ☺ ☺ 😐
al., 2016 1985-2013
Lenferink RCT 22 studies, 3854 ☺ 😐 ☺ 😐 😐 😐 ☹

et al., 2017 1995-2017
☺= improved, 😐= no change, ☹= worsened., grey shading indicates outcome was not analysed. HRQoL= health related quality of life,
6MWD= 6-minute walk distance, RCT= randomized controlled trial, CCT= controlled clinical trials, COPD= chronic obstructive pulmonary
disease, ED= emergency department, PR = pulmonary rehabilitation.

D3.1 Maintenance therapy
Detailed discussion of the maintenance therapy for COPD appears in Section O. In general, the use
of drugs in COPD does not involve back-titration, which is a core principle in asthma management.
The exception is when oral corticosteroids have been given for an exacerbation. There is at present
no evidence for back titration and further clinical trials are required.
D3.2 Exacerbation prevention

Detailed discussion of the management of exacerbations is found in Section X.
Committee Commentary (see below)
COPD Exacerbation Terminology
In patient education and for effective patient-clinician partnerships, the words we use as
clinicians’ matter. This is particularly important when discussing COPD exacerbations.
COPD exacerbations are common and have deleterious impacts on patients at the time
of the event, on their recovery and on their future risk (McDonald 2019). Unfortunately,
exacerbations of COPD are frequently under-reported and untreated (Calderazzo 2019,
Jones 2014). It has been proposed that patients and clinicians do not recognise the need
for urgent treatment of these events or their impact on future outcomes (Holverda 2020,
Bafadhel 2020, Jones 2019). For example, COPD mortality risk at one year following a
hospitalisation for an acute exacerbation is approximately 25% (García-Sanz 2017, Ho
2014), which is greater than the mortality risk of someone hospitalised for an acute
myocardial infarction (McDonald 2019, Halpin 2008).
Patients in part may not understand the impact of exacerbations due to language
clinicians use to describe these events (Holverda 2020, Bafadhel 2020). Terms such as
‘exacerbations’ and ‘flare ups’ trivialise these events in asthma and may do the same in
COPD (Holverda 2020, Bafadhel 2020, Jones 2019, Pavord 2018). Furthermore, most
patients do not understand the term exacerbation. In a qualitative study of 125 people
with moderate to severe COPD <2% understood what the term ‘exacerbation’ actually
meant (Kessler 2006). This is a similar concern in asthma (Jones 2019).
There are calls for the abandonment of the terms exacerbations and flare ups and to
replace these with terms such as attack, lung attack or COPD crisis (Holverda 2020,
Bafadhel 2020, Jones 2019, Pavord 2018, Fitzgerald 2011). We recognise that it is
important to agree on the most appropriate person-centred language to improve
response to COPD exacerbations and suggest that this is an area for future collaborative
work among the respiratory community and patients.
For severe exacerbations there is evidence for the use of bronchodilators, antibiotics, systemic
corticosteroids and supplemental oxygen (if patients are hypoxaemic). Selected patients may benefit
from early intervention with these agents according to a predetermined plan developed by a GP or
respiratory specialist, that is a COPD action plan as described above. Some patients can be instructed
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to start using a “crisis medication pack” while awaiting medical review. They may also be instructed
to contact a particular member of the multidisciplinary care team as part of their overall care plan. For
a COPD action plan template see, https://lungfoundation.com.au/resources/copd-action-plan/
Controlled trials are required to document the efficacy of self-management plans in patients with
stable COPD, but, drawing on the success of asthma action plans, education of patients with COPD in
self-management is recommended. Written plans are usually required to complement such
interventions (see examples at https://lungfoundation.com.au/resources/copd-action-plan/)
D4. Telehealth
Telemonitoring interventions ranging from simple telephone follow-up to daily telemonitoring of
physiological or symptom scores, to more complex telemonitoring interventions with greatly enhanced
clinical support; have been evaluated in patients with COPD. A Cochrane Review found that telehealth
may have an impact on quality of life and emergency attendances in COPD, however, further research
is needed to clarify its precise roles, as to date trials have included telecare as part of more complex
packages (McLean 2011) [evidence level I]. The positive effect of telemonitoring seen in some trials
could thus be due to enhancement of the underpinning clinical service rather than to the telemonitoring
communication.
Pinnock et al separated the effects of telemonitoring from the effects of existing services by adding
telemonitoring alone to background self-management and clinical support in the usual care group.
Adults registered with general practices in Scotland who had been admitted to hospital with an
exacerbation of COPD in the previous year and who were thus at risk of future admissions were
randomised to telemonitoring or usual care. All participants received self-management advice -
education on self-management of exacerbations reinforced with a booklet, a written management
plan, and an emergency supply of antibiotics and steroids, integrated within the standard clinical care
service for the region. The telemonitoring package consisted of touch screen operated daily
questionnaires about symptoms and drug use, with an instrument to measure oxygen saturation. Data
were transmitted daily by an internet connection to the clinical monitoring team, which contacted
patients whose score reached a validated threshold. Algorithms, based on the symptom score, alerted
the clinical monitoring team if daily readings had not been submitted or if a high symptom score had
been recorded. Clinicians responded by advising rescue drugs, a home visit, admission to hospital, or
further review. Intervention fidelity was high. After 12 months, no difference was seen in hospital
admissions for COPD between the two groups (hazard ratio 0.98, 95% CI 0.66-1.44). Furthermore,
no differences were seen in health-related quality of life (HRQoL), anxiety or depression, self-efficacy,
knowledge, or adherence to drugs. This trial suggested that the addition of telemonitoring to the
management of high-risk patients, over and above the backdrop of self-management education and a
good clinical service, is costly and ineffective (Pinnock 2013) [evidence level II]. These findings are in
agreement with a 2011 systematic review of telemonitoring, which suggested that in the absence of
other care packages the benefit of telemonitoring is not yet proven and that further work is required
before its wide-scale implementation (Bolton 2011). A systematic review (Gregersen 2016) examined
the effects of telehealth on quality of life in COPD. Of 18 suitable studies found, only three
demonstrated significant improvements in quality of life as a consequence of a telehealth intervention.
A further study of telehealth with multiple components (COMET) also failed to demonstrate reduction
in hospitalisation based on intention to treat analysis (Kessler 2018). It is noted there was reduced
mortality as a safety/secondary outcome in the per-protocol analysis.
A number of RCTs have been published since the McLean et al (2011) systematic review. An RCT of
577 patients with mild COPD, obtained from UK primary care COPD registers of 71 general practices
evaluated a telephone health coaching program which included the provision of a pedometer, written
educational documents, diary, inhaler use education and encouragement of medication adherence
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(Jolly 2018). Most potential participants did not respond to the study invitation. While there was no
benefit on the primary outcome of quality of life as measured by the St George’s Respiratory
Questionnaire (SGRQ), nor the secondary outcomes of anxiety and depression, other secondary
outcomes of self-reported physical activity and inhaler usage did improve [evidence level II]. In
contrast, in an RCT of 375 people with COPD, a 12-week remote patient monitoring system focusing
on daily step count and exercise practice along with weekly health coaching telephone calls utilising
motivational interviewing, improved health-related quality of life measured by the Chronic Respiratory
Disease Questionnaire which was maintained to 24 weeks (Benzo 2022) [evidence level II].
PROMETE II was a randomised control trial of a telehealth package offered to 229 patients, recruited
from across 5 centres, over 12 months, with a comprehensive range of outcomes (Soriano 2018)
[evidence level II]. The intervention included an educational home visit, and provision of home
oximeter, blood pressure gauge, spirometer, and oxygen therapy compliance monitor. It was rated as
highly satisfactory with most patients as well as clinicians, and followed on from the earlier single site,
7-month, n=30 participants ‘PROMETE’ study, which had demonstrated a reduction in acute
exacerbations. Despite the earlier study’s promising positive finding, the larger PROMETE II study
failed to demonstrate any such benefit in any of the diverse range of outcomes, including costs. This
calls into question the generalisability of a single site positive finding (Segrelles Calvo 2014), where a
very small number of highly motivated staff may be able to achieve extraordinary positive results, but
which may prove difficult to replicate elsewhere.
An RCT that evaluated a simple nurse-initiated telephone follow-up of COPD patients following
admission to hospital with an acute exacerbation of COPD or pneumonia (n=224), did not demonstrate
any reduction in readmission or mortality at 30- or 84-days post discharge. The intervention group
received a nurse-initiated phone call at two days post discharge and further calls if deemed necessary.
At 30 and 84 days the proportion of those readmitted in the intervention and control groups was 33
and 34% (p=0.84), and 32 and 27% (p=0.66), respectively. The intervention group did however
report more confidence in disease management (Lavesen 2016).
In another RCT, 470 people with COPD with at least 2 comorbidities were recruited from a
metropolitan and a rural centre. The intervention comprised a combination of telephone consults,
action plans, and other components and was found to have no effect on the number of emergency
department visits and hospital admissions; however, mortality was reduced (Rose 2018) [evidence
level II]. A further RCT including telemonitoring to detect deteriorations over 9 months reported no
benefit on outcomes including time to first hospitalisation or quality of life (Walker 2018) [evidence
level II].
Baroi et al reviewed feasibility and comparative studies, which used a heterogeneous range of
measurement devices (including spirometers, respiratory rate sensors, impedance oscillometers,
auscultation microphones, pedometers, capnometers, and oximeters), which aimed to identify COPD,
and/or to detect early exacerbations of COPD. Information communication methods between subjects
and clinicians included videoconferencing and questionnaires. The studies that did report positive
results were more likely to be those that were more integrated into existing respiratory outpatient
services, and in people with high risk of readmission due to a COPD exacerbation. The combination
of online consultations with availability of home-based nebuliser and medical therapies could provide
an effective “virtual hospital” (Baroi 2018).
An intensive, comprehensive health coaching intervention that included motivational interviewing-

based intervention delivered via telephone, a written action plan for exacerbations including the use
of antibiotics and oral steroids, and an exercise prescription decreased COPD-related hospitalisations
at 1, 3, and 6 months after hospital discharge, but not at one year after discharge. The absolute risk
reductions of COPD-related rehospitalisation in the health coaching group were 7.5% (p=0.01), 11.0%
133
(p=0.02), 11.6% (p=0.03), 11.4% (p=0.05), and 5.4% (p=0.24) at 1, 3, 6, 9, and 12 months,
respectively, compared with the control group. Disease-specific quality of life improved significantly in
the health coaching group compared with the control group at 6 and 12 months, based on the Chronic
Respiratory Disease Questionnaire (CRQ) emotional score (emotion and mastery domains) and
physical score (dyspnoea and fatigue domains) (p<0.05). There were no differences between groups
in measured physical activity at any time point (Benzo 2016). It should be noted that several of these
individual components have been shown to be effective in isolation.
Similar to the studies of self-management support, the COPD telehealth studies are heterogeneous
in design and outcome, and the results are also conflicting, again making it difficult to make
recommendations regarding the essential elements of telehealth program in COPD. Telehealth has
become an increasingly important aspect of COPD care, particularly during periods of pan/epidemics,
as such an important area for further research.
D5. Assessment and management of anxiety and depression

Symptoms of anxiety and depression and associated disorders are common in people with COPD (Ng
2007, Xu 2008, Weiss 2022) and have a range of negative impacts [evidence level III-2].
A retrospective cohort study of 80,088 U.S. Medicare recipients found a 34% higher 30-day
readmission rate in COPD patients with depression, and 43% higher in those with anxiety (Singh
2016). These and other co-existing psychological disorders were also associated with being less likely
to have follow up appointments (23.8% versus 16.25%). Although the study design had the potential
for confounding by severity of disease, the relationships of psychological disorders with readmissions
were much higher than index admission ICU length of stay or need for mechanical ventilation. The
results therefore support the case that depression and anxiety are important independent predictors
of readmission.
Anxiety symptoms in COPD are associated with worse quality of life (Blakemore 2014), self-
management (Dowson 2004) and exercise performance (Eisner 2010) [evidence level III], and with
increased medical symptom reporting (Katon 2007), exacerbations (Laurin 2012), hospitalisations
(Gudmundsson 2005), length of hospitalisations (Xu 2008), medical costs (Katon 2007), and mortality
(Celli 2008) [evidence level III]. The prevalence of one anxiety disorder in particular, panic disorder,
is approximately 10 times greater in COPD than the population prevalence of 1.5 to 3.5%, and panic
attacks are commonly experienced (American Psychiatric Association 2004, Smoller 1996).
Cognitive behaviour therapy has been shown to be an effective treatment for panic disorder in the
physically healthy (Mitte 2005) [evidence level I]. There is consistent evidence from randomised
controlled trials supporting the positive effect of cognitive behaviour therapy on anxiety and/or
depressive symptoms in people with COPD (Williams 2020), in preventing the development of panic
attacks and panic disorder (Livermore 2010), and reducing ratings of dyspnoea (Livermore 2015,
Yohannes 2017). A nurse-delivered minimalist version of cognitive behaviour therapy (1-2 home visits
of 20-60 minutes duration) provided clinically and statistically significant improvements on the Hospital
Anxiety Depression Scale (HADS) and also the Chronic Respiratory Disease Questionnaire (CRQ)
Mastery scale at 3 month follow up in the intervention arm (n=22) compared to the control arm (n=22)
(Bove 2016). In a larger RCT, self-help leaflets for anxiety management were compared to a brief
nurse led CBT intervention with self-help leaflets in 279 patients with COPD. At 3 months the CBT
groups had greater improvements in the HADS Anxiety subscale [3.4 (95% CI 2.62–4.17, p<0.001)]
compared to the active control (leaflets) [1.88 (95% CI 1.19–2.55, p<0.001)]. The effect was
maintained at 12 months. The CBT intervention was also cost effective (Heslop-Marshall 2018). In a
trial of 28 patients undergoing pulmonary rehabilitation, cognitive behaviour therapy was associated
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with an improvement in fatigue, stress, depression and anxiety scores over the 3 month follow up
period (Luk 2017).
A record linkage study in Canada found that elderly COPD patients prescribed benzodiazepines for
anxiety were at increased risk of an outpatient exacerbation (NNH 66, 95% CI 57–79) or an emergency
department visit for COPD or pneumonia (NNH 147, 95% CI 123–181). There was also a slightly
elevated albeit not significant risk of hospital admission (Vozoris 2014) [evidence level III-2]. Caution
is warranted in using these medications, due to their potential depressive effects on respiratory drive
(Shanmugam 2007), and their inherent risks in the elderly of dependence, cognitive impairment, and
falls (Uchida 2009).
People with COPD are not only at high risk of symptoms of depression and mood disorders but are at
higher risk than people with other chronic conditions (Ng 2007 [evidence level III], Siraj 2020
[evidence level III-2]). When depressive symptoms are comorbid with COPD they are associated with
worse health-related quality of life (HRQoL) (Ng 2007, Hanania 2011) and difficulty with smoking
cessation (Ng 2007) [evidence level III], and with increased exacerbations (Laurin 2012),
hospitalisations (Bula 2001, Xu 2008, Hanania 2011), length of hospitalisations (Ng 2007) [evidence
level III], medical costs (Bula 2001), and mortality (Bula 2001, Ng 2007) [evidence level III].
Depressive symptoms have been more strongly associated over four years with patient reported
outcomes, including symptom control and physical activity related dyspnoea, than with change in FEV1
(O'Toole 2022) [evidence level II]. Depression may also influence decisions about end-of-life issues
(Stapleton 2005). In summary, these findings support the benefit of screening for symptoms of
depression and anxiety in people with COPD and of providing mental health care as a component of
comprehensive multidisciplinary care.
A systematic review of randomised controlled trials has shown that symptoms of depression and
anxiety can be decreased by cognitive behaviour therapy (Williams 2020) [evidence level I].
Mindfulness-based cognitive therapy in conjunction to pulmonary rehabilitation also improved
depressive symptoms compared to pulmonary rehabilitation alone (Farver-Vestergaard 2018). A 2019
Cochrane review concluded that, while cognitive behaviour therapy may be an effective treatment for
depression in COPD, the quality of the evidence is currently limited (Pollok 2019).
In a 2018 Cochrane systematic review conducted to assess the effectiveness and safety of
pharmacological interventions for depression in patients with COPD, there was not enough evidence
relating to efficacy and safety to make recommendations on use of SSRIs (Pollok 2018) [evidence
level I]. In a meta-analysis involving two RCTs of 148 participants there was no difference in the
primary outcome of change in depressive symptoms post-intervention (SMD 0.75, 95% CI -1.14 to
2.64; I2 = 95%). Due to the risk of bias and high level of heterogeneity in depression levels, as well
as in the types of medication and doses used, these results should be interpreted with caution (Pollok
2018). Case management to support adherence to antidepressant medication in conjunction with
attending pulmonary rehabilitation has been associated with improvements in both depression and
dyspnoea-related disability (Alexopoulos 2016). As for anxiety symptoms, psychiatrists can advise on
the most appropriate medications for particular patients (Shanmugam 2007).
Multiple systematic reviews have demonstrated that pulmonary rehabilitation is associated with short-
term reductions in anxious and depressive symptoms (Coventry 2013, Yohannes 2017, Gordon 2019).
The existing evidence warrants the referral of anxious and depressed people with COPD to clinical
psychologists and psychiatrists for assessment and treatment. Depressed COPD patients referred to
mental health specialists have lower odds of two-year mortality than those treated in primary care
settings (Jordan 2009). Screening for clinically significant anxiety and depression, given their serious
impacts, should therefore be part of routine care (including during admissions for exacerbations)
(Lecheler 2017). The Hospital Anxiety Depression Scale (HADS) is an example of an easily
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administered, widely used screening questionnaire, developed for use with medical patients (Zigmond
1983), and used in numerous studies of people with COPD (Ng 2007, Xu 2008, Bock 2017) [evidence
level III]. Another screening option is the Patient Health Questionnaire (PHQ), which screens for
symptoms of the most seen mental disorders in medical patients – depression, generalised anxiety,
panic attacks, somatoform and eating disorders. The full scale, or the depression and anxiety
subscales, may be administered (Spitzer 1994). The PHQ has the advantages of high statistical
reliability and validity, while being an easily administered measure that is available on the internet at
no cost (Kroenke 2010).
D6. Referral to a support group

Patients may benefit from support groups and other community services
[evidence level III-2, weak recommendation]
Greater improvements in exercise performance and self-efficacy for exercise have been shown for
people with COPD who received education and psychosocial support than for those who received
education without support (Ries 1995). Patient support groups aim to empower participants to take a
more active role in the management of their healthcare, and thus reduce the psychosocial impact of
their disease. Benefits of support groups on quality of life and psychological outcomes in people with
COPD have not yet been demonstrated, although studies of other chronically ill patient groups indicate
that positive effects can be expected (Kennedy 2007). One pathway to initiate attendance of support
groups is through pulmonary rehabilitation programs. The likely benefits of support groups for people
with COPD are summarised in Box 10.
Box 10: Patient Support Groups
Typical support group activities

Regular meetings
Guest speakers providing information on a range of topics
Receiving and distributing lung health education information
Education and information days
Exercise programs
Social or recreational activities
Group newsletters
Member to member support (through telephone calls, hospital, and home visits)
Benefits of support groups

Reinforce and clarify information learnt from health professionals
Provide access to new information on lung health
Share experiences in a caring environment
Empower patients to be more actively involved in their healthcare through self-management
techniques
Participate in social activities and exercise programs
Encourage patients to think more positively about their lung disease
Help carers understand lung disease
A list of Patient Support Group names and locations can be accessed via Lung Foundation Australia’s
website at https://lungfoundation.com.au/patient-support/support-for-you/patient-support-groups/.
Contact details can be obtained from Lung Foundation Australia’s Information and Support Centre
(free-call 1800 654 301).
In New Zealand, Asthma and Respiratory Foundation NZ list Pulmonary Rehabilitation and Support
Groups on their website: https://www.asthmafoundation.org.nz/about-us/support-groups, free-call
0800 100 506. Asthma New Zealand list COPD Support Groups and the 'Find your local group'
directory: https://www.asthma.org.nz/pages/copd-support-groups, free-call 0800 227 328.
X: Manage eXacerbations
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A COPD exacerbation is characterised by a change in the patient’s baseline
dyspnoea, cough, and/or sputum that is beyond normal day-to-day variations,
is acute in onset and may warrant a change in regular medication or hospital
admission [evidence level III-2, strong recommendation]
EXACERBATIONS of COPD which are more frequent in the winter months in temperate climates (Jenkins
2012) [evidence level II] often require hospital admission for treatment of respiratory failure. A record
linkage study in WA (Geelhoed 2007) demonstrated that the rate of hospital admission for COPD has
been declining. The risk of readmission was highest within three months of discharge, and more than
half of all patients were readmitted within 12 months. About 10% of patients with a primary diagnosis
of COPD died either during admission or within the same year. Median survival from first admission
was five years in men and eight years in women. The poorest survival was among older patients with
recognised emphysema. In one study of more than 1,000 patients admitted to several hospitals with
an exacerbation of severe COPD, about 50% were admitted with a respiratory infection, 25% with
congestive cardiac failure, and 30% with no known cause for the exacerbation (Connors 1996). A
study of 173 patients with COPD reported an average of 1.3 (range 0 to 9.6) exacerbations annually.
An ecological study of hospital admissions for COPD in Victoria found higher rates of admission in rural
and remote areas with greater socioeconomic disadvantage and higher rates of smoking (Ansari 2007).
Exacerbations become more frequent as severity of COPD worsens (Hoogendoorn 2010a). In the
study by the ECLIPSE investigators, exacerbation rate increased with increasing GOLD stage, such
that 22% of patients with GOLD stage 2 disease had two or more exacerbations during one year of
follow-up, whereas 47% of patients with GOLD stage 4 disease had frequent exacerbations over the
same period. The single best predictor of exacerbations across all GOLD stages was prior
exacerbations. Other predictors included a history of heartburn, poorer quality of life and elevated
white cell count (Hurst 2010). ECLIPSE data also showed that a history of prior hospitalisation for
COPD is the strongest predictor of subsequent hospitalisation. Han et al prospectively examined
exacerbation rates in 1,105 patients with COPD over a three-year period from the SPIROMICS cohort
(Han 2017). Contrary to the ECLIPSE study, Han reported that individual exacerbation rates vary
significantly from year to year, and very few patients experience two or more exacerbations over
successive years. In addition to a history of past exacerbations, Han reported that interleukin-15 (IL-
15) and interleukin-8 (IL-8) levels in blood as well as small airway abnormalities on CT chest predicted
frequent exacerbations (Han 2017).
The ECLIPSE data also confirmed 12-month mortality rates were significantly higher in patients
hospitalised for COPD (15%) compared to those without hospitalisation (5%) (p<0.001) (Mullerova
2015). In a Spanish cohort of (predominantly male) patients prospectively followed, Guerrero et al
demonstrated that re-admission to hospital within 30 days following discharge for an exacerbation of
COPD increased 12-month mortality rates (37% in readmitted versus. 17% in non-readmitted
patients, p=0.001) and was an independent risk factor for mortality at one year (HR 2.48, 95% CI
1.1-5.59) (Guerrero 2016).
Studies have confirmed that although the prognosis of exacerbations is poor, the prognosis post-
exacerbation is improving. Hoogendoorn et al (Hoogendoorn 2010b) identified six cohort studies that
followed the survival of COPD patients for at least 1.5 years after a severe exacerbation resulting in
hospitalisation. A meta-analysis resulted in a weighted average case-fatality rate of 15.6% (95% CI
10.9-20.3). The excess risk of mortality continued after discharge from hospital. Almagro et al
(Almagro 2010) prospectively examined three-year mortality after a severe exacerbation resulting in
hospitalisation in two well matched cohorts seven years apart (1996/97 and 2003/04). The 1996/97
three-year survival rate was 53% and the 2003/4 three-year survival rate was significantly improved
at 61% (log rank p = 0.017). The 2003/4 cohort had increased usage of tiotropium, long acting beta2
agonists, angiotensin receptor blockers, statins and anti-platelet therapy. The authors speculated that
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the increased survival may be due to improved treatment options for COPD and co-morbidities
including cardiac disease [evidence level III-2].
Soltani et al (Soltani 2015) prospectively evaluated a cohort of 150 severe COPD patients admitted
with an exacerbation of COPD at an Australian tertiary hospital and reported a 28% readmission rate
at three months and a 12-month mortality rate of 24.5%. It should be noted that patients requiring
invasive or non-invasive ventilation were excluded from this study. A retrospective database study of
over 2 million COPD admissions among American Medicare recipients above the age of 65 reported a
12-month mortality rate of 26.2% (Lindenauer 2018). The 12-month mortality rate for those requiring
invasive and non-invasive ventilation was 45.7% and 41.8% respectively. This study showed a 12-
month readmission rate of 64% (Lindenauer 2018). Analysis of over 1 million COPD admissions from
a US national database that included patients of all age groups and all healthcare providers
demonstrated a 19.2% 30-day readmission rate (Jacobs 2018). A systematic review of over 40 studies
reported a 30-day COPD related readmission rate of 11% and a 12-month readmission rate of 37%
(Ruan 2023) [evidence level III-2].
DECAF (see Figure 7) is a 30-day mortality prediction score for COPD admissions (Steer 2012).
DECAF was derived with data from 920 consecutive patients admitted with a COPD exacerbation from
two neighbouring hospitals in the UK. COPD had been confirmed on spirometry. The five strongest
predictors of mortality that comprise the score are extended MRC Dyspnoea Score, eosinopenia,
consolidation, acidaemia, and atrial fibrillation. The score showed high discrimination for mortality with
an area under the receiver operator characteristic curve =0.86, 95% CI 0.82-0.89. A DECAF score of
3 predicts confers a 27.2% 30-day mortality risk. Echevarria et al examined the performance of the
DECAF score in 2,645 patients with an admission of COPD across 6 hospitals in the UK and reported a
similarly high performance for mortality prediction (Echevarria 2019).
Figure 7: The DECAF Score

The DECAF Score
Variable Score
Dyspnoea
eMRCD 5a* 1
eMRCD 5b** 2
Eosinopenia (<0.05 X109/l) 1
Consolidation 1
Acidaemia (pH <7.3) 1
Atrial fibrillation 1
Total DECAF Score 6
DECAF: Dyspnoea, Eosinopenia, Consolidation, Acidaemia and atrial Fibrillation; eMRCD: extended MRC
dyspnoea
* eMRCD 5a - too breathless to leave the house unaided but independently able to manage
washing and/or dressing
**eMRCD 5b - too breathless to leave the house and requiring assistance with both washing and dressing
Table (see Figure 6) reproduced from Steer J et al. The DECAF Score: predicting hospital mortality in exacerbations
of chronic obstructive pulmonary disease. Thorax 2012; 67: 970-976 (Steer 2012) with permission from the BMJ
publishing Group Ltd.
In patients with COPD the normally sterile lower airway is frequently colonised by Haemophilus
influenzae, Streptococcus pneumoniae and Moraxella catarrhalis. While the number of organisms may
increase during exacerbations of COPD, the role of bacterial infection is controversial (Macfarlane 1993,
Smith 1980, Soler 1998, Wilson 1998, Stockley 2000, Walsh 1999, Mogulkoc 1999, Murphy 1999,
Miravitlles 1999).
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Exacerbations can also be caused by viral infection (Seemungal 2001). Retrospective data from an
Australian tertiary hospital demonstrated that influenza virus and rhinovirus were the most common
viral pathogens found in patients admitted to hospital with an exacerbation of COPD (Biancardi 2016).
Given the current COVID-19 pandemic, it is recommended that patients with COPD take adequate
precautions to stay well (https://lungfoundation.com.au/lung-health/protecting-your-
lungs/coronavirus-disease-covid-19/what-you-need-to-know/). Guidance for diagnosis and
management of COVID-19 infection is highly relevant to patients with COPD. Living guidelines from
the National COVID-19 Clinical Evidence Taskforce are available at
https://covid19evidence.net.au/#living-guidelines.
Other causes of exacerbations of COPD include left ventricular failure and pulmonary embolus (PE).
A systematic review comprising seven studies with a total of 880 patients who were hospitalised with
an exacerbation of COPD and underwent a CT pulmonary angiogram (CTPA) found that 16% had a PE
(Aleva 2017). There was large variation in the prevalence of PE between studies (3% to 29%). One
third of patients had only small, isolated, sub-segmental PE. A prospective study of 740 patients with
COPD with an acute worsening of respiratory symptoms presenting to 7 French hospitals found a
prevalence of 5.9% of PE on CTPA, based on a predefined diagnostic algorithm including clinical
probability based on the Geneva score and D-dimer testing (Couturaud 2021). A diagnosis of PE should
be considered in patients presenting with an exacerbation of COPD when signs of respiratory infection
are absent, and chest pain or cardiac failure are present.
A panel study of patients with moderate to severe COPD demonstrated that exacerbations could also
be triggered by urban air pollutants such as PM10, black smoke and NO2 (Peacock 2011) [evidence
level II]. Chest trauma and inappropriate use of sedatives can lead to sputum retention and
hypoventilation.
Early diagnosis and treatment of exacerbations may prevent hospital

admission and delay COPD progression (Wilkinson 2004) [evidence level III-2,
strong recommendation].
Prolonged COPD exacerbations are associated with worse health status and the exacerbation that
follows occurs sooner. Exacerbations of COPD are associated with accelerated loss of lung function,
particularly in patients with mild disease. In patients with mild COPD each severe exacerbation was
associated with an additional FEV1 loss of 87 ml/year (95% CI 23-151) (Dransfield 2017).
Retrospective analysis of data from the UPLIFT study also demonstrated an accelerated loss of lung
function after a single COPD exacerbation (Halpin 2017).
Early diagnosis and prompt management of exacerbations of COPD may prevent progressive
functional deterioration and reduce hospital admissions (Lorig 1999, Shepperd 1998). Education of the
patient, carers, other support people and family may aid in the early detection of exacerbations. A
self-management plan developed in conjunction with the patient’s GP and specialist to indicate how to
step-up treatment may be useful (see examples at https://lungfoundation.com.au/resources/copd-
action-plan-for-hps/). This plan might indicate which medications to take, including antibiotics and
oral corticosteroids. The plan should also require patients to contact their GPs or community nurses to
allow rapid assessment (see section D).
Statins have been shown to reduce rates of hospitalisation (for COPD or any other reason), lung-
function decline, the need for mechanical ventilation, and all-cause mortality in observational studies
of COPD patients. The Prospective Randomized Placebo-Controlled Trial of Simvastatin in the
Prevention of COPD Exacerbations (STATCOPE) examined the effect of daily treatment with simvastatin
in patients with moderate-to-severe COPD who were at high risk for exacerbations and had no other
139
indications for statin treatment. Simvastatin at a daily dose of 40 mg for at least 12 months did not
affect exacerbation rates or the time to a first exacerbation (Criner 2014) [evidence level II].
Hospital admissions are indicators or failed prevention and are highly expensive to health care
systems. Hospitalisations are being included increasingly as an outcome measure in randomised
controlled trials of a range of interventions. Box 11 below summarises the interventions that have
been demonstrated, in such randomised control trials to statistically significantly reduce
hospitalisation.
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Box 11: Reducing hospital utilisation: current level I and II evidence from COPD-X
Intervention Demonstrated impact Effect estimate Where to find it
Level I
LAMAs “…LAMAs had reduced exacerbation rates…and exacerbation-related 22% improvement O1.2.1
hospitalisations…compared to LABAs” (RR 0.78, 95% CI 0.69 to 0.87) Maia 2017
NB: most participants in this analysis had Tiotropium as their LAMA
Tiotropium “… tiotropium reduced the odds of a COPD exacerbation … and related 36% improvement P5.1
hospitalisations compared to placebo or ipratropium.” (OR 0.64, 95% CI 0.51 to 0.82 Barr 2005
NNT 30, 95% CI 22 to 61)
"… tiotropium was more effective in preventing COPD exacerbations 14% improvement P5.2
leading to hospitalisation [compared to a range of other LABAs]” (OR 0.86, 95% CI 0.79 to 0.93) Chong 2012
Aclidinium “…Aclidinium resulted in marginal improvements in quality of life and FEV1, NNT 77, 95% CI 51 to 233 O1.2.1
and reduced the number of patients with exacerbations requiring Ni 2014
hospitalisation”
Systemic “… systemic corticosteroids reduce treatment failure (defined as 52% improvement X2.2.2
corticosteroids additional treatment, hospital admission/re-admission for index (OR 0.48, 95% CI 0.35 to 0.67 Walters 2014
episode, return to emergency department, unscheduled physician NNT 9)
visit for the index episode), improve lung function, shorten recovery and
reduce the severity of exacerbations of COPD … reduced the risk of
treatment failure by over half compared with placebo in … median
treatment duration 14 days”
Non-invasive “The use of NIV reduces hospital length of stay.” MD -3.39 days, 95% CI X3.2
ventilation -5.93 to -0.85 Osadnik 2017
Hospital at “… compared to standard care, participants allocated to hospital in the 24% improvement X1
home home were significantly less likely to be readmitted to hospital within the (RR 0.76, 95% CI 0.59 to 0.99) Jeppesen 2012
next 1 to 6 months.”
Multi-faceted “… integrated disease management programs defined as ‘a group of Admissions: D
care plans coherent interventions designed to prevent or manage one or more chronic 32% improvement Kruis 2013
conditions using a systematic, multidisciplinary approach and potentially (OR 0.68, 95% CI 0.47 to 0.99
employing multiple treatment modalities.’ … found positive effects on NNT 15)
disease-specific QoL … exercise tolerance, hospital admissions and
hospital days per person…” Length of stay:
MD -3.78 days, 95% CI -5.90 to -
1.67

Pulmonary “Pulmonary rehabilitation following hospitalisation for an exacerbation also 56% improvement X3.6
rehabilitation reduced hospital readmissions.” OR 0.44, 95% CI 0.21 to 0.91 Puhan 2016
Intervention Demonstrated impact Effect estimate Where to find it
Level II
LAMA/LABA/IC “In selected COPD patients with a history of exacerbations there was a 34% improvement O4.2
S 34% reduction in admissions with triple therapy using a single inhaler (RR 0.66, 95% CI 0.56 to 0.78) Lipson 2018
(umeclidinium/ (fluticasone [ICS], vilanterol, umeclidinium – IMPACT study), as well as
vilanterol/ other benefits, regardless of baseline bronchodilator responsiveness,
fluticasone compared to dual therapy (no ICS), and with even greater benefits in some
furoate) outcomes demonstrated in those with high eosinophil counts (>150 cells/
microlitre).”
Airway “The use of ACTs was associated with a significant short-term reduction MD - 0.75 days, 95% CI -1.38 to - X3.4
clearance in the need for increased ventilatory assistance … duration of ventilatory 0.11 Osadnik 2012
techniques assistance …and hospital length of stay.”
Discharge “… the use of COPD discharge bundles reduced hospital readmissions 20% improvement X3.7
bundles …” (RR 0.80, 95% CI 0.65 to 0.99) Ospina 2017
Supported “…has been shown to reduce re-admissions for COPD exacerbations 45% improvement X3.8
discharge compared to usual care …” (HR 0.55, 95% CI 0.35 to 0.88) Casas 2006
programs &
medication “Adherence to inhaled medication regimes is associated with reduced risk 44% improvement O
adherence of death and admissions to hospital due to exacerbations in COPD...” (RR 0.56, 95% CI 0.48 to 0.65) Vestbo 2009

X1. Home management
Multidisciplinary care may assist home management of some patients with an

exacerbation [evidence level I, weak recommendation].
The shortage of hospital beds, especially in winter, has prompted interest in home care for
management of COPD exacerbations, with involvement of multidisciplinary teams assisting GPs. Such
“Hospital in the Home” schemes were studied in a systematic review by Jeppesen (Jeppesen 2012)
that included eight randomised controlled trials which entered patients into a hospital in the home
scheme within 72 hours of presenting to hospital. The review found that compared to standard care,
participants allocated to hospital in the home were significantly less likely to be readmitted to hospital
within the next 1 to 6 months (risk ratio =0.76, 95% CI 0.59-0.99) [evidence level I]. There was no
significant difference in mortality (risk ratio = 0.65, 95% CI 0.40-1.04), and while there was no
difference in satisfaction levels for patients or carers, these comparisons were based on small numbers.
Economic studies of such programs have shown mixed results.
X2. COPD exacerbation management

X2.1 Confirm exacerbation and categorise severity
Assessment of severity of the exacerbation includes a medical history, examination, spirometry and,
in severe cases (FEV1 < 40% predicted), blood gas measurements, chest x- rays and
electrocardiography.
Patients should be provided with and bring a summary of their medical problems and treatment (e.g.,
a personal health record). If available, results of previous stable lung function tests and arterial blood
gas measurements are invaluable for comparison.
Spirometry: Because COPD is defined by demonstration of airflow limitation, which is not fully
reversible, spirometry is essential for its diagnosis, and this may be performed prior to discharge from
hospital to confirm the diagnosis (Rea 2011).
Assess Oxygenation
Pulse oximetry should be recorded routinely, in conjunction with other vital signs
Arterial blood gases: Measurement of pulse oximetry and venous blood gases has significant
limitations, particularly when assessing ventilation, Arterial blood gasesshould be considered if the
FEV1 is less than 1.0 L or less than 40% predicted, if percutaneous oxygen saturation is less than 92%
in the presence of adequate peripheral perfusion, in patients where SpO2 is falling and increased
fraction of inspired oxygen (FiO2) is required and in patients at risk of hypercapnia. . Values obtained
while breathing room air are the most useful for assessing ventilation–perfusion inequality. A PaO2 less
than 60 mmHg (8 kPa) indicates hypoxaemic respiratory failure, while a PaCO2 greater than 45 mmHg
indicates ventilatory failure. Respiratory acidosis indicates acute respiratory failure warranting
consideration for assisted ventilation.
All prospective RCTs that have demonstrated a mortality advantage with the use of NIV in
exacerbations of COPD have used ABG (arterial blood gas), not VBG (venous blood gas) samples to
determine need for NIV. McKeever et al examined paired ABG-VBG (venous blood gas) samples in 234
patients admitted to hospital with a doctor diagnosed exacerbation of COPD (McKeever 2016). A VBG
pH ≤7.34 gave a sensitivity of 88.9% and specificity of 95.6% for an ABG pH ≤7.35. The authors
argued that all patients presenting with an exacerbation of COPD should initially be assessed with a
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VBG and only go on to an ABG if the VBG pH ≤7.34. The primary reasons for preferring VBG samples
cited by the authors were less pain and lower risk of bruising. The general applicability of these findings
is limited by the fact that this cohort had relatively few patients with pH below 7.30. The authors did
not propose that VBGs should replace ABGs to assess severity of respiratory failure or be used to
monitor patient response to treatment/ NIV. Caution is required due to the lesser precision with VBGs
compared to ABGs.
Chest x-ray and electrocardiogram: These help to identify alternative diagnoses and
complications, such as pulmonary oedema, pneumothorax, pneumonia, empyema, arrhythmias,
myocardial ischaemia and others.
Studies have identified a simple clinical prediction score, the BAP-65, based on age, basal urea
nitrogen, acute mental status change and pulse, which predict in-hospital mortality (Tabak 2009, Shorr
2011). In-hospital mortality in both studies increased as patient classification escalated from 1 (no
risk factors, age <65 years) to 5 (3 risk factors present), the highest class being associated with an
in-hospital mortality between 14.1% and >25%.
A 2012 prospective single centre study of 920 patients admitted with an exacerbation of COPD found
that those with CXR confirmed pneumonia had a far higher mortality (20.1% versus. 5.8%, p<0.001).
Severity of dyspnoea in the stable state was strongly associated with both in-hospital mortality and
early re-admission (Steer 2012) [evidence level III-2].
X2.2 Optimise treatment

An exacerbation of COPD may involve an increase in airflow limitation, excess sputum production,
airway inflammation, infection, hypoxia, hypercarbia and acidosis. Treatment is directed at each of
these problems.
● Bronchodilators: Inhaled beta-agonist (e.g., salbutamol, 400–800mcg; terbutaline, 500–

100mcg) and antimuscarinic agent (ipratropium, 80mcg) can be given by pressurised metered
dose inhaler and spacer, or by jet nebulisation (salbutamol, 2.5–5 mg; terbutaline, 5 mg;
ipratropium, 500mcg). The dose interval is titrated to the response and can range from hourly
to six-hourly. There is a lack of evidence in favour of one mode of delivery over another for
bronchodilators during exacerbations of COPD. In a Cochrane Review by van Geffen (van
Geffen 2016) there were no differences between nebulisers and pressured metered dose
inhalers plus spacer regarding the primary outcomes of FEV1 at one hour (MD 36 ml, 95% CI
−38 to 110, n=40) and serious adverse events (OR 1.00, 95% 0.18-5.53, n=70) [evidence
level I].
● Corticosteroids: Oral corticosteroids hasten resolution and reduce the likelihood of relapse.
Up to two weeks’ therapy with prednisolone (40–50 mg daily) is adequate. Longer courses add
no further benefit and have a higher risk of adverse effects.
● Antibiotics: Antibiotics are given for purulent sputum to cover for typical and atypical
organisms.
● Controlled oxygen therapy: This is indicated in patients with hypoxia, with the aim of
improving oxygen saturation to 88 to 92%. Use nasal prongs at 0.5–2.0 L/minute or a Venturi
mask at 24% or 28%. Minimise excessive oxygen administration, which can worsen
hypercapnia.
● Ventilatory assistance: This is indicated for increasing hypercapnia and acidosis. Non-
invasive ventilation by means of a mask is the preferred method.
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Although the adherence to pharmacological, rehabilitation and vaccination management as
recommended in GOLD have each been shown to reduce health care costs, uptake of GOLD
recommendations has had little evaluation. A study in a Victorian hospital setting demonstrated
significant overuse of antibiotics and oxygen therapy, as well as a greater evidence practice gap in
general medical units than respiratory medical units (Tang 2014) [evidence level III-2].
X2.2.1 Inhaled bronchodilators for treatment of exacerbations
Inhaled bronchodilators are effective for initial treatment of exacerbations

[evidence level I, strong recommendation]
In exacerbations of COPD, the immediate bronchodilator effect is small, but may result in significant
improvement in clinical symptoms in patients with severe obstruction.
Studies of acute airflow limitation in asthma indicate that beta-agonists are as effectively delivered
by metered dose inhaler and spacer as by nebuliser (Cates 2006) [evidence level I]. The applicability
of this evidence to patients with COPD is unknown. There is evidence in patients with a COPD
exacerbation that a dry powder inhaler delivering formoterol is as effective in improving lung function
as a metered dose inhaler delivering salbutamol, with or without a spacer device (Selroos 2009)
[evidence level II]. An adequate dose should be used. The dose equivalent to 5 mg of salbutamol
delivered by nebuliser is 8–10 puffs of 100mcg salbutamol by metered dose inhaler and spacer. Limited
evidence indicates dry powder inhalers are as effective as other delivery devices for the administration
of short-acting bronchodilators in the setting of exacerbations of COPD (Selroos 2009) [evidence level
II]. Airflow in the nebuliser should be 6 L per minute or higher to achieve an appropriate aerosol, but
using high- flow oxygen should be avoided as this may worsen carbon dioxide retention (Bardsley
2018).
People with COPD often have cardiac co-morbidities, although these may be undiagnosed at the time
of presentation with a COPD exacerbation. Such patients may be susceptible to adverse events from
high dose, frequent short acting beta agonists. A review by Kopsaftis (Kopsaftis 2018b) identified 10
relevant randomised or controlled trials and demonstrated that higher (5mg versus 2.5mg) doses of
salbutamol were associated with increased risk of tremors, elevated heart rate, palpitations and lower
blood pressure, but without evidence of any additional benefit. Given that elevated cardiac stress
markers during COPD exacerbations are predictive of 30-day mortality (Chang 2011), the review
authors recommend caution in prescribing frequent high doses of short-acting beta agonists, such as
doses of salbutamol exceeding 2.5mg, when treating exacerbations of COPD [evidence level I].
A small (n=30) single centre pilot randomised controlled trial performed in New Zealand (Mukerji
2015) [evidence level II] showed that 2g IV magnesium when added to standard bronchodilator
therapy in an exacerbation of COPD significantly improved FEV1 at 120 mins (mean percentage change
in FEV1 was 27.07% with magnesium versus 11.39% in the placebo group, 95% CI 3.7-27.7,oxygen
titration p=0.01). Asthma was excluded on clinical grounds on review of past spirometry. Larger trials
with meaningful clinical endpoints are required before this can be recommended as standard therapy.
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X2.2.2 Systemic corticosteroids for treatment of exacerbations
Systemic corticosteroids reduce the severity of and shorten recovery from mild
to severe exacerbations (Walters 2014) [evidence level I, strong recommendation]
Walters et al report that there is high-quality evidence that systemic corticosteroids reduce treatment
failure (defined as additional treatment, hospital admission/re-admission for index episode, return to
emergency department, unscheduled physician visit for the index episode), improve lung function,
shorten recovery and reduce the severity of exacerbations of COPD (Walters 2014) [evidence level I].
Systemic corticosteroids reduced the risk of treatment failure by over half compared with placebo in
nine studies (n=917) with median treatment duration 14 days, odds ratio (OR) 0.48 (95% CI 0.35-
0.67. The number needed to treat to avoid one treatment failure is 9. There is no evidence that
treatment with corticosteroids alters mortality.
Unlike earlier reviews this review included four papers that compared intravenous corticosteroids
with oral corticosteroids and two papers with ventilated patients in ICU. In patients requiring
ventilation in ICU, pooled data did not show a reduction in length of stay, duration of ventilation or
mortality in those receiving corticosteroids compared with placebo (Walters 2014). Walters et al
concluded that there is no evidence of benefit for intravenous treatment compared with oral treatment
with corticosteroids on treatment failure, relapse or mortality. Hyperglycaemia rates were higher with
intravenous corticosteroids.
With regards to duration of treatment, a meta-analysis by Walters et al (Walters 2018) concluded

that five days of oral corticosteroids is likely to be sufficient [evidence level I].
In summary, a 5-day course of oral prednisolone of 30mg to 50mg is adequate. In patients who have
been on oral corticosteroids for longer than 14 days, tapering may be necessary. Patients on long-
term oral corticosteroid therapy (> 7.5 mg prednisolone daily for more than 6 months) are at risk of
developing osteoporosis. Prevention and treatment of corticosteroid-induced osteoporosis should be
considered. Longer courses of prednisolone may increase mortality and pneumonia (Sivapalan 2019).
There is emerging evidence that blood eosinophil levels can be used as a biomarker to determine
which patients require oral corticosteroids for exacerbations of COPD. A small, single centre, double
blind randomised controlled trial used blood eosinophils as a biomarker to determine if prednisolone
would be given for an exacerbation of COPD. In the intervention arm, only patients with blood
eosinophils above 2% received prednisolone. In the standard arm all patients received prednisolone.
The prednisolone dose was 30mg for 14 days and both groups received oral antibiotics. There was no
difference in treatment failure or health status between the biomarker and standard groups (Bafadhel
2012). Bafadhel re-analysed data from 3 additional randomised controlled trials that examined the
use of oral corticosteroids in COPD exacerbations (n=243) (Bafadhel 2014). Patients had blood
eosinophil levels measured at the time of COPD exacerbation. Blood eosinophils >2% were a useful
biomarker to determine which patients benefit from systemic corticosteroids. The trial designs had
considerable heterogeneity. Further, larger studies with long term follow up are required before any
firm recommendations can be made.
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X2.2.3 Antibiotics for treatment of exacerbations
Independent of the severity and practice setting, exacerbations with clinical

features of infection (increased volume and change in colour of sputum and/or
fever) benefit from antibiotic therapy [evidence level I, strong recommendation].
Bacterial infection may have either a primary or secondary role in about 50% of exacerbations of
COPD (Macfarlane 1993, Wilson 1998, Miravitlles 1999, Patel 2002). Haemophilus influenzae,
Streptococcous pneumoniae and Moraxella catarrhalis are most commonly involved (Macfarlane 1993,
Soler 1998, Murphy 1999). Mycoplasma pneumoniae and Chlamydia pneumoniae have also been
reported (Macfarlane 1993, Mogulkoc 1999). As lung function deteriorates (FEV1 < 35%),
Pseudomonas aeruginosa and Staphylococcus aureus are often encountered (Macfarlane 1993, Soler
1998, Miravitlles 1999). Multi drug resistant Ps. aeruginosa is associated with 6-fold increased risk of
death (Montero 2009) [evidence level III-2].
A re-examination of data from the placebo arm of a Spanish antibiotic trial that recruited patients
with mild to moderate COPD from primary care confirmed that sputum purulence increased the
likelihood of treatment failure 6-fold. A CRP elevated greater than 40 mg/L was also independently
associated with a 13-fold increase in the risk of treatment failure (Miravitlles 2013) [evidence level
III-2].
A study of 220 patients hospitalised with exacerbations of COPD with clinical features of infection,
randomised to CRP-guided antibiotic therapy (antibiotics if CRP ≥ 50mg/L) or GOLD criteria based
antibiotic treatment found a significant reduction in antibiotic use in the CRP guided group, with an
absolute reduction in antibiotic use of 14.5% (Prins 2019) [evidence level II]. An open label RCT
(n=653) of patients in the UK showed that in patients with COPD exacerbations treated in primary
care, use of point-of-care CRP testing to guide prescribing of antibiotics lowered patient-reported
antibiotic use (OR 0.31, 95% CI 0.20-0.47) (Butler 2019) [evidence level II]. The judicious use of CRP
testing in primary or tertiary care may assist in determining the need for antibiotics for exacerbation
management.
El Moussaoui et al (El Moussaoui 2008) conducted a systematic review of 21 randomised controlled

trials of antibiotics in exacerbations of chronic bronchitis and COPD. There were similar rates of clinical
or bacteriological cure with short courses (≤ 5 days) and longer courses of antibiotics [evidence level
I]. A related systematic review (Falagas 2008) found that patients receiving short courses experienced
fewer adverse effects than those receiving longer courses. It would be necessary to treat 26 (95% CI
15-134) patients with short course antibiotics to prevent one adverse effect. However, the antibiotics
evaluated were late generation cephalosporins, macrolides and fluoroquinolones, which are not those
recommended in Australia.
Procalcitonin is an acute phase reactant. Procalcitonin levels increase in bacterial infections but do
not increase in viral infections or auto-immune inflammation (Gilbert 2011). Procalcitonin has been
proposed as a measure to determine if patients with an exacerbation of COPD require oral antibiotics.
In most clinical trials, use of antibiotics was discouraged if procalcitonin was 0.1ng/ml or lower and
encouraged if procalcitonin was above 0.25ng/ml.
A meta-analysis of eight randomised or quasi-randomised trials, evaluating 1,062 patients, compared

procalcitonin-based protocols to initiate or discontinue antibiotics, versus standard care in COPD
exacerbation (Mathioudakis 2017). Procalcitonin-based protocols decreased antibiotic prescription
(relative risk (RR) 0.56, 95% CI 0.43–0.73) without affecting clinical outcomes such as rate of
treatment failure, length of hospitalisation, exacerbation recurrence rate or mortality (low to moderate
quality evidence). Since the publication of this meta-analysis, a further trial has also reported that
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procalcitonin-based protocols reduce antibiotic use without increasing complications (Wang 2016).
A meta-analysis of RCTs and observational studies investigating the impact of a procalcitonin-based

protocol on antibiotic prescription and clinical outcomes in patients with COPD exacerbations, found
that the use of procalcitonin-based protocols significantly reduced the length of antibiotic treatment in
COPD exacerbation (MD = -2.01 days, 95% CI -3.89 to -0.14 days, p=0.04, moderate quality, and
MD = -1.64 days, 95% CI -2.91 to -0.36 days, p=0.01, very low quality for RCTs and observational
study, respectively), while no apparent effects were found on length of hospital stay, treatment failure
and all-cause mortality. The effect of procalcitonin on antibiotic duration was no longer significant (MD
= -1.88 days, 95% CI -3.95 to 0.19 days, p=0.08, and MD = -1.72 days, 95% CI -4.28 to 0.83 days,
p=0.19, respectively), when studies with high risk of bias were excluded. Procalcitonin has limited
value in guiding antibiotic use in COPD exacerbation (Chen 2020) [evidence level I].
It is important to note that patients with pneumonia were excluded from these trials. Based on the
evidence from these trials, it may be possible to withhold antibiotic therapy in patients presenting to
the emergency department with an exacerbation of COPD, who are afebrile, have no pneumonia on
chest imaging, and have a serum procalcitonin level of <0.1ng/ml. This test is not currently funded by
Medicare in Australia and is only available in some centres. Despite promising data from multiple
clinical trials, cross-sectional and longitudinal analysis of over 200,000 COPD admissions from 505 US
hospitals did not show a change in antibiotic prescribing rates or duration of use in hospitals that had
begun using procalcitonin testing (Lindenauer 2017). The authors conclude that further
implementation research is required.
Therapeutic guidelines: Antibiotic (Therapeutic Guidelines Limited 2019) recommend the use of oral
agents such as amoxycillin or doxycycline.
A retrospective cohort study from the Danish registry of COPD by Bagge et al (2021) examined
outcomes following patients redeeming prescriptions for amoxycillin (AMX) or amoxycillin clavulanic
acid (AMC) for presumed community exacerbations of COPD. They found pneumonia hospitalisation or
death by all cause after 30 days was decreased with AMX compared to AMC (adjusted HR 0.6, 95% CI
0.5-0.7, p<.0001). This was also observed for all cause hospitalisation or death (aHR 0.8, 95% CI
0.8-0.9, p<0.0001). Although confounding by severity is not excluded, the findings of this study
support the recommendation broad -spectrum antibiotics such as AMC should not be the drug of first
choice for outpatient exacerbations of COPD (Bagge 2021) [evidence level III-2].
If pneumonia, Pseudomonas or staphylococci or resistant organisms are suspected, appropriate

antibiotics should be used.
Typically, a course of antibiotics should be five days. A systematic review and meta-analysis by Llor
et al (2022) including only patients with spirometrically-proven COPD (n=eight trials) concluded that
there were no significant differences in clinical cure rates or bacterial eradication rates of short courses
of antibiotics (≤5 days) compared with longer courses (≥6 days). Nonetheless, the majority of studies
included fluroquinolones as first line therapy, which is not common practice in Australia, raising
questions about the face validity of this study [evidence level I] (Llor 2022). A historical population-
based cohort study found that co-treatment of an exacerbation with oral corticosteroids and oral
antibiotics significantly increased the time to subsequent exacerbations (median 312 versus 418 days,
p<0.001 to next compared to oral corticosteroids alone) (Roede 2008) [evidence level III-2].
Two Australian retrospective case series of hospitalised COPD patients have found that antibiotic
treatment was guideline concordant in less than 15% of cases (Brownridge 2017, Fanning 2014). This
was due to over-use of intravenous antibiotics and prescription of dual antibiotics. Further efforts are
needed to increase adherence to the use of oral antibiotics in patients hospitalised with exacerbations
of COPD, where appropriate.
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Radiologically proven pneumonia in patients with COPD, especially in those who have been frequently
hospitalised, may not be restricted to the above organisms. Gram-negative organisms, Legionella spp.
and even anaerobic organisms may be responsible. Initial empiric antibiotic therapy should be tailored
according to clinical and radiographic criteria.
X2.2.4 Combined systemic corticosteroids and antibiotics for treatment of exacerbation

A randomised placebo-controlled trial (Daniels 2010) has provided evidence to support the traditional
practice of treating exacerbations with a combination of systemic corticosteroids and antibiotics. In
this study, hospitalised patients were commenced on a tapering dose of prednisolone and randomised
to receive doxycycline 200mg daily or placebo for 7 days. Clinical cure, defined as complete resolution
of signs and symptoms, at day 10 was significantly higher in the antibiotic treated group compared to
placebo (OR 1.9, 95% CI 1.2-3.2, NNT=7, 95% CI 4-523). By day 30, the primary end point, there
was no significant difference in clinical cure. Serious adverse effects occurred in 9% of the doxycycline
group (7 deaths) and 5% of the placebo group (3 deaths). Medication adverse events were similar
between groups, 3% in the doxycycline group and 4% in the placebo.
X3. Refer appropriately to prevent further deterioration (‘P’)

The risk of death from exacerbations of COPD increases with acute carbon dioxide retention
(respiratory acidosis), the presence of significant comorbid conditions (e.g., ischaemic heart disease)
and complications (e.g., pneumonia and empyema). Depending on the nature and severity of the
exacerbation, the patient may require urgent specialist review, hospital assessment or admission to a
high-dependency or intensive care facility for ventilatory support and appropriate monitoring (see
Boxes 12 and 13).
Box 12: Indications for hospitalisation of patients with chronic obstructive pulmonary disease
Marked increase in intensity of symptoms

Patient has acute exacerbation characterised by increased dyspnoea, cough or sputum production, plus one or
more of the following:
Inadequate response to ambulatory management
Inability to walk between rooms when previously mobile
Inability to eat or sleep because of dyspnoea
Cannot manage at home even with home-care resources
High risk comorbidity condition — pulmonary (e.g., pneumonia) or non-pulmonary
Altered mental status suggestive of hypercapnia
Worsening hypoxaemia or cor pulmonale
Newly occurring arrhythmia
Box 13: Indications for non-invasive or invasive ventilation
Severe dyspnoea that responds inadequately to initial emergency therapy

Confusion, lethargy or evidence of hypoventilation
Persistent or worsening hypoxaemia despite supplemental oxygen, worsening hypercapnia (PaCO 2 > 70 mmHg), or
severe or worsening respiratory acidosis (blood pH < 7.3)
Assisted mechanical ventilation is required.
X3.1 Controlled oxygen delivery
Controlled oxygen delivery (0.5–2.0 L/min) is indicated for hypoxaemia in

patients with exacerbations (Beasley 2015) [evidence level II, strong
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recommendation]
In the emergency setting, supplemental oxygen may be required to relieve hypoxaemia. Oxygen flow
should be carefully titrated to achieve a target SpO2 range of 88 to 92%. Nasal cannulae deliver a
variable concentration of oxygen, but a flow of 0.5–2.0 L per minute is usually sufficient. The TSANZ
position paper on acute oxygen use in adults highlights the importance of assessment of hypoxia,
prescription of oxygen and always implementing SpO2 targets to prevent over-oxygenation (Barnett
2022).
High flow oxygen via a Hudson mask or non-rebreather mask should be avoided, as it is rarely
necessary and may lead to hypoventilation and worsening respiratory acidosis and increased mortality.
A randomised study has demonstrated that in the pre-hospital emergency setting titrated oxygen via
nasal cannula compared with high flow oxygen reduced mortality by 78% in COPD patients (NNH=14)
(Austin 2010) [evidence level II]. In an observational study from the UK of 1027 patients admitted
across 6 hospitals with an exacerbation of COPD and receiving supplemental oxygen, Echevarria et al
reported that in-hospital mortality was lowest in those with admission oxygen saturations between 88
and 92%. This mortality effect was dose-responsive with mortality rates highest in the sub-group with
oxygen saturations 97-100%. The effect was also present in patients with normocapnia. The authors
recommend that all patients with COPD receiving supplemental oxygen should have an oxygen
saturation target of 88-92% independent of the presence of hypercapnia (Echevarria 2020). In a
Victorian retrospective case file emergency department audit of patients admitted to hospital with an
exacerbation of COPD between Jan 2012 and March 2013, 84.4% had a final ambulance oxygen
saturation reading of ≥ 93% (95% CI 79.5-88.3%) (Chow 2016). A retrospective Australian study
examined oxygen use in 111 patients admitted with hypercapnia due to an exacerbation of COPD.
Over-oxygenation was common and was significantly more likely to occur on non-respiratory ward
admissions (76% vs 57%, p=0.03) (Anderson 2020). In Wellington, New Zealand, an audit of patients
with an exacerbation of COPD transferred by ambulance to hospital before and after an education
program to reduce high concentration oxygen delivery was undertaken (Pilcher 2015). Significantly
fewer patients received high concentrations of oxygen in 2010; however, concern was voiced by the
authors about the continued use of high concentration oxygen to drive nebulisers. Education may be
the key to changing practice.
Where there is evidence of acute respiratory acidosis (or a rise in PaCO2) on ABG, together with signs
of increasing respiratory fatigue and/or obtunded conscious state, assisted ventilation should be
considered. Early non-invasive positive pressure ventilation (NIV) may reduce the need for
endotracheal intubation (see below for more detail).
X3.2 Non-invasive ventilation

Non-invasive ventilation (NIV) is effective for patients with rising paCO2
levels [evidence level I, strong recommendation].
Non-invasive ventilation (NIV) should be strongly considered in patients with

an exacerbation of COPD who present with hypercapnic respiratory failure as
defined on an arterial blood gas with a PaCO2 above 45mmHg and a pH less
than 7.35 (Osadnik 2017) [evidence level I].
NIV is an effective and safe means of treatment of ventilatory failure. Its use allows preservation of
cough, physiological air warming and humidification, and normal swallowing, feeding and speech.
Applying NIV in addition to conventional therapy reduces the risk of mortality by 46% (risk ratio (RR)
0.54, 95% CI 0.38-0.76); NNT 12 and decreases the risk of needing endotracheal intubation by 65%
(RR 0.36, 95% CI 0.28-0.46; NNT 5) (Osadnik 2017). This benefit is similar for patients with mild
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acidosis (pH 7.30 to 7.35) versus. a more severe nature (pH < 7.30), and when NIV is applied in a
ward or intensive care unit (Osadnik 2017). The use of NIV reduces hospital length of stay mean
difference -3.39 days (95% CI -5.93 to -0.85) (Osadnik 2017).
A local prospective observational cohort study demonstrated that ward-based NIV (managed by
respiratory medical and nursing staff) compared with high dependency unit (HDU) and ICU-based NIV
achieved equivalent clinical outcomes and was substantially more cost-effective (Parker 2018). These
findings were replicated in a similar but retrospective study based in a teaching hospital in China (Hong
2020). The optimal location for provision of NIV should be determined by local experience and
availability of expertise.
Hartley et al used a derivation cohort of 489 patients to derive a mortality prediction score for
patients with an exacerbation of COPD and hypercapnic respiratory failure receiving NIV. The NIVO
score was then validated in a group of 733 patients from across 10 hospitals in England and Wales. The
NIVO score consisted of 6 measures that should be available at the bedside (see below). The area
under the curve form predicting mortality was 0.79. The score also allowed for mortality risk
stratification - see table below. The NIVO score performed better in this patient group than all other
mortality prediction scores tested. Use of this score may assist clinicians, patients and their carers in
making decisions regarding acute non-invasive ventilation (Hartley 2021) [evidence level III].
X3.2.1 Humidified nasal high flow therapy (hNHF)

Humidified nasal high flow therapy (hNHF) delivering flows of up to 60 L/minute has been used
successfully for the management of acute hypoxaemic respiratory failure, while in acute exacerbations
of COPD associated with hypercapnia and acidemia, NIV is accepted as standard of care.
In a multi-centre Italian study of hNHF (Cortegiani 2020), (Optiflow and MR850 or Airvo) patients
(n=80) with mild-moderate AECOPD and hypercapnia (PaCO2 > 55mmHg, pH 7.25-7.35) before
support were randomised to receive NIV or hNHF, with oxygen titrated to oxygen saturations of 88-
92%. hNHF was statistically non-inferior to NIV as initial ventilatory support in reducing PaCO2 at 2
hrs (-6.8mmHg HFNT + 8.7, v -9.5 mmHg +8.5), p=0.4, considering a non-inferiority margin of 10
mmHg. However, by 6 hours 32% of patients in hNHF group had switched to NIV due to worsening or
no improvement of respiratory failure; n=1 due to intolerance, while from the NIV group only one
patient switched to hNHF due to intolerance and one to invasive ventilation. The authors of this study
concluded that further trials with a superiority design examining patient related outcome measures
are needed. NIV remains standard of care at present as it has been consistently shown to reduce
mortality [evidence level I].
In a multi-centre RCT of patients from 16 hospitals in China admitted with AECOPD and mild
hypercapnia (pH 7.35 and PCO2>45mmHg) there was no difference in the primary outcome of
proportion of patients needing intubation in the HFNC group (AirVo2 started at 25L/min and increased
to maximal tolerance with maximal humidification and maintaining SPO2 90-95%) versus the
controlled oxygen group (low flow oxygen at 1-5L/min to maintain SPO2 90-95%). There was no
difference between the groups in rate of treatment failure (15.8% versus 14.5%) and the most
common reason for treatment failure in the HFNC group was intolerance, whereas in the controlled
oxygen group it was need for NIV. The numbers of patients upgraded to NIV in both groups were
comparable. However, the median duration from randomisation to commencement of NIV was longer
in the HFNC group. Patients in the HFNC group had longer lengths of stay (9 v 8 days) and increased
treatment costs (by 14.6%) compared to those on controlled oxygen therapy (Xia 2022) [evidence
level II].
Overall, taking together the results of these two studies, there was no clear benefit to the use of
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HFNC in these patients hospitalised with mild-moderate exacerbations of COPD, and potential for harm.
X3.3 Invasive ventilation (intubation)
NIV is contraindicated in patients who are unable to protect their airways, are not spontaneously
breathing or who have severe facial injury or burns (Esteban 2000). Relative contraindications
(situations where NIV may be less effective) include life-threatening refractory hypoxaemia (PaO2
< 60 mmHg, or 8 kPa on 100% inspired oxygen), bronchiectasis with copious secretions, severe
pneumonia, and haemodynamic instability. These patients may require intubation. Patients who need
mechanical ventilation have an inpatient mortality of up to 39% (Wildman 2009). A multi-centre
Spanish study (Rivera-Fernandez 2006) that followed surviving patients for 6 years found that
subsequent mortality was related to age, Acute Physiology and Chronic Health Evaluation (APACHE)
score and quality of life. Although quality of life deteriorated over time, 72% of the survivors remained
self-sufficient [evidence level III-2]. A multi-centre UK study (Wildman 2009) that followed surviving
patients up to 180 days found that 80% rated their quality of life unchanged compared to pre-
admission and 96% would elect to receive the same treatment again under similar circumstances.
Overall patients’ functional capacity was slightly reduced at 180 days, but broadly predicted by, pre-
admission function. Doctors’ prediction of survivors’ quality of life was pessimistic and agreed poorly
with their patients rating.
Weaning from invasive ventilation can be facilitated by the use of non-invasive ventilation. In a
Cochrane meta-analysis of patients with predominantly COPD, the use of non-invasive ventilation for
weaning resulted in decreased mortality (RR 0.55, 95% CI 0.38-0.79), reduced ventilator-assisted
pneumonia (RR 0.29, 95% CI 0.19-0.45), reduced length of stay in ICU (WMD -6.27 days, 95% CI -
8.77 to -3.78) and reduced hospital length of stay (WMD -7.19 days, 95% CI -10.8 to -3.58) (Burns
2013).
The patient’s wishes regarding intubation and resuscitation should ideally be documented before an
admission for management of respiratory failure. Patients who require ventilatory support during
exacerbations of COPD may have impaired control of breathing or apnoeas during sleep, even when
well. Therefore, performing a diagnostic sleep study when the patient’s condition is stable should be
considered. Narcotic analgesics and sedatives should be avoided, as these may worsen ventilatory
failure and hasten the need for positive pressure ventilation.
X3.4 Clearance of secretions
Patients who regularly expectorate sputum or those with tenacious sputum may benefit from airway
clearance techniques (ACTs) during an exacerbation. However, the choice of ACTs during
exacerbations requires careful consideration as these episodes result in worsening of airflow limitation
and lung hyperinflation, which lead to acute increases in dyspnoea. Patients are also likely to
experience significant physical fatigue during an exacerbation and this impacts on the choice of ACT.
A Cochrane Systematic Review of 9 trials examined the efficacy of ACTs in patients experiencing an
exacerbation of COPD (Osadnik 2012). The use of ACTs was associated with a significant short-term
reduction in the need for increased ventilatory assistance (odds ratio 0.21, 95% CI 0.05-0.85, data
from 4 studies involving 171 patients) NNT 12, 95% CI 10-66 [evidence level I], the duration of
ventilatory assistance (mean difference of -2.05 days, 95% CI -2.60 to -1.51 compared to control,
data from 2 studies of 54 patients) [evidence level I] and hospital length of stay (mean difference -
0.75 days, 95% CI -1.38 to -0.11 compared to control, data from one study of 35 patients) [evidence
level II]. Airway clearance techniques that utilised positive expiratory pressure (PEP) tended to be
associated with a greater reduction in the need for increased ventilatory assistance and hospital length
of stay compared to non-PEP based ACTs however the difference was not significant.
With the exception of chest wall percussion, which has been associated with a decrease in FEV1 and
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one report of vomiting during treatment involving a head-down tilt position ACTs were not associated
with serious adverse effects (Hill 2010, Tang 2010, Osadnik 2012) [evidence level I]. Airway clearance
techniques applied during an exacerbation do not appear to improve measures of resting lung function
or produce any consistent changes in gas exchange (Osadnik 2012) [evidence level I]. However, the
limitations of the studies included in the systematic reviews (i.e. considerable diversity in patients’
characteristics and application of specific techniques, small sample sizes in some of the studies, large
variety of outcome measures) limited the ability to pool data for meta-analysis. A multicentre RCT that
involved 90 patients hospitalised with an exacerbation of COPD investigated whether the addition of
PEP therapy to usual medical care that included a standardised physical exercise training regimen
improved symptoms, QoL and incidence of future exacerbations (Osadnik 2014). Individuals in this
study were characterised by evidence of sputum expectoration or a history of chronic sputum
production with over 50% of those recruited expectorating purulent sputum, however individuals with
primary bronchiectasis were excluded. The authors found no significant between group differences in
symptoms or quality of life assessed over a 6-month period following hospital discharge. The incidence
of exacerbations during the follow-up period was low and similar in both groups. The findings of this
study (Osadnik 2014) do not support a routine role for PEP therapy even in patients with purulent
sputum who are hospitalised for an exacerbation of COPD.
Given the negative impact that exacerbations have on symptoms such as dyspnoea and fatigue, it
is important to decide whether performing ACT is appropriate, and if so, choosing the most appropriate
technique during this time. The choice of ACT should be guided by a physiotherapist experienced in
this type of clinical presentation.
X3.5 Develop post-discharge plan and follow-up

The aim is to relieve hypoxaemia and obtain improvement in clinical signs and symptoms.
● Clinical examination: Reduction in wheeze, accessory muscle use, respiratory rate, distress.
● Gas exchange: Arterial blood gas levels and/or pulse oximetry levels should be monitored
until the patient’s condition is stable (SpO2 88 to 92%).
● Respiratory function testing: FEV1 should be recorded in all patients after recovery from an
exacerbation.
● Discharge planning: Discharge planning should be commenced within 24–48 hours of
admission.
As individual non-pharmacological interventions have shown some promise in reducing COPD

admissions, diverse attempts have been made at “bundling” various combinations of these
interventions. A large Canadian cohort study of hospitalised COPD patients compared those exposed
(n=796) to a bundled intervention (inhaler device technique, follow up with primary care, medication
optimization, written discharge management plan, referral to pulmonary rehabilitation, comorbidities
and frailty screen, and smoking cessation) to patients not exposed (n=3344). The bundled intervention
resulted in an 83% reduced risk of 7-day readmission (RR 0.17, 95% CI 0.07-0.35) and 26% reduced
risk of 30-day readmission (RR 0.74, 95% CI 0.60-0.91). There was no difference in 90-day
readmissions. The transition bundle however was also associated with a 7.3% (RR 1.07, 95% CI 1.0-
1.15) relative increase in length of stay and a 76% (RR 1.76, 95% CI 1.53-2.02) greater risk of a 30-
day ED revisit. Within this cohort was a nested RCT where patients exposed to the bundled
intervention were randomised to a case coordinator (n=392) in addition to the bundled intervention
versus the bundled intervention only (n=404). There was no difference in readmission between these
groups, although 7.6% more patients in the care co-ordinator group visited their primary care
physician within 14 days of discharge. The care co-ordinator did not provide ongoing case management
beyond contact between 48 to 72 hour and 7 to 10 days after discharge (Atwood 2022) [evidence
level III-2]. These data highlight the importance of COPD discharge bundles.
Jennings et al (2015) randomised 173 patients admitted to hospital with an exacerbation of COPD to
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usual care or a pre-discharge care bundle. The care bundle included smoking cessation counselling,
screening for gastroesophageal reflux disease and depression or anxiety, standardised inhaler
education, and a 48-h post-discharge telephone call. The intervention did not reduce 30 or 90-day
COPD readmission rates. Where bundles have omitted proven components such as pulmonary
rehabilitation, there has been no benefit for readmissions (Jennings 2015) [evidence level II]. A
Tasmanian retrospective cohort study by Njoku et al (2022) demonstrated that being male (odds ratio
[OR] 1.49, 95% CI 1.06–2.09), or Indigenous (OR 2.47, 95% CI 1.31–4.66) and living in a lower
socioeconomic region (OR 1.80, 95% CI 1.20–2.69) were risk factors for 30-day readmission (Njoku
2022) [evidence level III-B]. Efforts to find effective interventions are needed particularly for those at
high risk of readmission.
Supportive discharge care, sometimes known as transitional care, has been demonstrated to reduce
COPD admissions (OR 0.60, 95% CI 0.42-0.85) and all cause re-admissions (OR 0.72, 95% CI 0.53-
0.98), with greatest likelihood of success with greater intervention duration (longer the better), use
of phone calls, and multidisciplinary professional involvement (Ridwan 2019) [evidence level I].
X3.6 Pulmonary rehabilitation

Consider pulmonary rehabilitation at any time, including during the recovery
phase following an exacerbation [evidence level I, strong recommendation]
Exacerbations of COPD are characterised by worsening dyspnoea and fatigue, decreased exercise
tolerance and a reduction in health-related quality of life (HRQoL) (Seemungal 2000, Spencer 2003).
Individuals are typically less active following hospitalisation for an exacerbation of COPD and this low
level of activity may persist for several weeks (Pitta 2006). Quadriceps muscle strength is often
reduced during an exacerbation and may be a contributor to inactivity (Spruit 2003).
Pulmonary rehabilitation should be offered to people with COPD following hospitalisation for an
exacerbation of COPD. A systematic review of 17 studies (Puhan 2016) reported the effects of
pulmonary rehabilitation in 1,477 participants who were in the recovery phase of a recent
hospitalisation for an exacerbation of COPD. Rehabilitation was commenced between two days and
two weeks after the exacerbation, and was provided in inpatient, outpatient, and home settings, with
a program duration between four days and six months. Pulmonary rehabilitation significantly improved
HRQoL and exercise capacity in the short-term (median of five months for HRQoL and a median of
three months for exercise capacity). Pulmonary rehabilitation also reduced hospital readmissions
(pooled odds ratio 0.44, 95% CI 0.21- 0.91, n=810 participants). The follow-up period for collection
of hospitalisation data ranged from three to 18 months, with a median duration of nine months. There
was no significant effect on mortality (pooled odds ratio 0.68, 95% CI 0.28- 1.67). In another
systematic review (Ryrso 2018), early supervised pulmonary rehabilitation (initiated within four weeks
after a COPD exacerbation) reduced mortality (four studies, RR=0.58, 95% CI 0.35-0.98) after the
end of treatment. There was no effect of early supervised pulmonary rehabilitation on mortality over
the longer-term, most likely due to the small sample (three trials, 127 participants) [evidence level
I].
In the Australian and New Zealand health care context, inpatient pulmonary rehabilitation is not
easily accessible, whereas access to outpatient pulmonary rehabilitation is more feasible. Accordingly,
the authors of the Australian and New Zealand Pulmonary Rehabilitation Guidelines (Alison 2017)
performed a meta-analysis of five outpatient pulmonary rehabilitation studies (program duration 6-12
weeks), commenced within two weeks of hospital discharge. Consistent with the Puhan review (Puhan
2016) and confirmed by the Ryrso review (Ryrso 2018), large benefits for HRQoL and exercise capacity
were found. Importantly, no adverse events were reported. Overall, the Australian and New Zealand
Pulmonary Rehabilitation Guidelines recommend that outpatient pulmonary rehabilitation is provided
after an exacerbation of COPD, commencing within two weeks of hospital discharge (weak strength of
154
recommendation, moderate quality of evidence) (Alison 2017). The Ryrso review (Ryrso 2018)
reported a decrease in the number of COPD-related hospital admissions in the three to 12 months
following early supervised pulmonary rehabilitation programs initiated after discharge (RR=0.41, 95%
CI 0.11-1.47), and no difference in the drop-out rate between early supervised pulmonary
rehabilitation and usual care. Given the personal and health-system benefits of pulmonary
rehabilitation commenced shortly after an exacerbation, it is important to have appropriate screening
and referral processes to increase participation in early pulmonary rehabilitation.
Information about pulmonary rehabilitation including a list of programs known to Lung Foundation
Australia can be accessed on the website. The individual contact details can be obtained by calling the
Lung Foundation’s Information and Support Centre (free-call 1800 654 301).
X3.7 Discharge planning

Patients with COPD discharged from hospital following an exacerbation should
receive comprehensive follow-up led by the primary healthcare team [evidence
level I, strong recommendation].
Discharge planning involves the patient, external lay and professional carers, the multidisciplinary
hospital and community team and the patient’s regular GP. It should commence on admission and be
documented within 24–48 hours (see Box 14).
Lung Foundation Australia has developed the Managing COPD Exacerbation Checklist available at:
https://lungfoundation.com.au/resources/?search=managing%20a%20copd%20exacerbation%20ch
ecklist which provides guidance on managing a patient at three stages – in hospital; prior to leaving
hospital; and on an ongoing basis 1-4 weeks post-discharge (See Figure 8).
Appropriate patient education and attention to preventive management are likely to reduce the
frequency of further exacerbations. Assessment of social supports and domestic arrangements are
critical in discharge planning. Medicare items support aspects of discharge planning. See
http://www.health.gov.au/internet/main/publishing.nsf/Content/mbsprimarycare-
chronicdiseasemanagement-qanda
A discharge pack, which includes general information about COPD, advice on medication use and
written instructions on use of inhalation and oxygen devices, if appropriate, as well as a plan for
management of worsening symptoms, should be provided. The GP (and respiratory outreach program,
if available) should be notified during the patient’s admission. A case conference involving the
multidisciplinary team and GP may assist successful transition to the community. Medicare Benefits
Schedule Enhanced Primary Care item numbers may be claimed for “participation in a case conference”
and “contribution to a care plan” (see Section D).
Before discharge, referral to a comprehensive pulmonary rehabilitation program should be

considered.
155
Box 14: Criteria for discharge
Suggested criteria for a patient’s readiness for discharge include:

The patient should be in a clinically stable condition and have had no parenteral therapy for 24 hours
Inhaled bronchodilators are required less than four-hourly
Oxygen delivery has ceased for 24 hours (unless home oxygen is indicated)
If previously able, the patient is ambulating safely and independently, and performing activities of daily living
The patient is able to eat and sleep without significant episodes of dyspnoea
The patient or caregiver understands and is able to administer medications
Follow-up and home care arrangements (e.g., home oxygen, home-care, Meals on Wheels, community nurse,
allied health, GP, specialist) have been completed.
A meta-analysis which included an appraisal of four RCTs across three countries and which
demonstrated that the use of COPD discharge bundles reduced hospital readmissions by 20% showed
no demonstrable benefit in terms of LOS or mortality (Ospina 2017). Outpatient follow-up was found
to be a core element to reduce re-admissions.
A systematic literature review of 13 evidence based clinical pathways used in either primary care or
hospital settings across 10 countries has demonstrated a reduction in COPD re-admissions by 34%
(OR 0.66, 95% CI 0.49-0.88) [evidence level I], although with little reduction in length of stay. Studies
with longer follow ups appeared more likely to detect benefits (Plishka 2019).
156
Figure 8: Managing a COPD Exacerbation Checklist
157
X3.8 Support after discharge
Follow-up at home after discharge from hospital may extend the continuum-of-care process begun
within the acute environment and supported discharge programs are now well established. Such
programs are generally short term in nature and have clear criteria for which patients are suitable.
Compared to more traditional in-patient management, supported discharge programs are associated
with shorter length of stay and lower 90-day mortality, with little difference in readmission rate
(Kastelik 2012), confirming the safety of such an approach. Over the longer term, an integrated
approach involving a discharge plan shared with the primary care team together with access to a case
manager through a web-based call centre has been shown to reduce re-admissions for COPD
exacerbations compared to usual care (Casas 2006) [evidence level II]. Although a systematic review
of structured, planned, post-discharge support found evidence for a reduction in readmissions at 30
days, the study was unable to identify a single intervention ‘package’ that could be recommended
(Pedersen 2017). Notably, a study of supported self-management following discharge, which combined
home visits to empower participants to manage their COPD independently and case management to
facilitate prompt and appropriate access to care (not included in the above-mentioned systematic
review), did not find any significant benefit on COPD admissions or death when compared to usual
care (hazard ratio 1.05, 95% CI 0.08-1.38) (Bucknall 2012). Not only do many of these studies have
different outcomes, but many were conducted in Europe and their applicability to the Australasian
setting is not known. Telephone follow-up may be a way of systematically extending support to
patients and increasing their coping strategies at home, but the outcomes of this intervention have
not been studied systematically.
X3.9 Clinical review and follow-up
There are no randomised clinical trials that have addressed the best method for follow-up (Sin 2002).
It is recommended that the first review after a hospital admission should be by the GP and within
seven days of discharge (Box 15). Chronic cough and sputum production are associated with an
increased risk of further exacerbation (Burgel 2009) [evidence level III-2] and these patients may
warrant closer monitoring. A decision about the requirement for specialist review should be made at
the time of discharge. Follow-up care allows further discussion of self-management plans and future
monitoring (Sin 2002).
Box 15: Follow-up – initial and subsequent
Assessment of the patient’s coping ability and strategies

Measurement of FEV1 and performance status
Reassessment of medication adherence and techniques with inhalation devices
Review of immunisation status (influenza and pneumococcal)
Assessment for long-term oxygen therapy (may require reference to specialist facility)
Consideration of referral for pulmonary rehabilitation
Assessment of risk of osteoporosis and management
Smoking cessation — counsel and/or refer
Assess nutritional status (frequent small meals reduce dyspnoea)
158
X4. Uptake and impact of guidelines for exacerbations
Although there are many COPD guidelines around the world, there has been little evaluation of their
uptake into clinical practice, or their impact on clinical outcomes. A study of the compliance to COPD-
X (Gerber 2018) recommendations in 381 COPD patients attending the EDs of two hospitals within
one local Australian health service, has demonstrated moderately satisfactory results, with compliance
to individual recommendations of the order of 74 to 90%, and to the whole list of recommendations
of 49%, indicating some room for further improvement. Highest levels of compliance were seen in
the most severe COPD cases. This study did not show a reduction in LOS with greater compliance;
however this analysis did not adjust for severity.
A retrospective study of 134 patients admitted with an exacerbation of COPD at an Australian tertiary
hospital demonstrated poor adherence to COPD-X recommendations for managing exacerbations.
Controlled oxygen therapy to achieve SpO2 88-92% was provided in 42% of cases and referral to
pulmonary rehabilitation was made in only 17.9% of cases. Furthermore, smoking cessation
counselling was provided to 40% of patients and a review of immunisation status only occurred in 2%
of cases (Sha 2020).
A European study found that hospitalised COPD patients with an exacerbation received on average
only 41% of key diagnostic, pharmacological and non-pharmacological recommendations from clinical
guidelines, including low uptake of provision of smoking cessation advice (3%), inhaler technique
education (11%) and referral to pulmonary rehabilitation (29%) (Seys 2017).
An audit of COPD patients in the Outpatient respiratory clinics of 59 Spanish hospitals (Calle Rubio
2017) demonstrated that clinical practice, at least as recorded in the case notes, fell well short of
recommendations in GOLD and Spanish national guidelines for COPD.
A prospective cohort study of 415 patients with an exacerbation of COPD who presented at 46 EDs
in 5 Asia-Pacific countries, 65% of these arriving by ambulance, and 78% of those being admitted to
hospital, of which 7% to an ICU and median LOS 4 days highlights the public health and acute care
hospital burden of COPD exacerbations (Kelly 2018). Clinical management findings against COPD-X
benchmarks are to be interpreted with caution as they are based on case-note audit but were indicative
of excessive use of uncontrolled oxygen therapy and a suboptimal use of a combination of inhaled
corticosteroid/bronchodilator therapy, arterial blood gas measurement and also treatment with non-
invasive ventilation.
An audit of 801 patients with COPD who presented to 66 European and 46 Australasian participating
emergency departments (ED) with breathlessness demonstrated a low adherence to COPD-X and
GOLD guideline management recommendations with respect to the use of systemic corticosteroids and
antibiotics, especially in the European sites (Kelly 2019). Use of non-invasive ventilation when
indicated was equally low in both regions. The authors propose novel use of care bundles and
supportive clinical support systems in EDs to reduce the evidence–practice gap.
A tertiary hospital in Israel introduced an electronic clinical decision support tool for use in COPD
patient discharge and reported a very significant increase in adherence to guidelines with respect to
prescription of appropriate inhalers, recommendations regarding vaccination and smoking cessation
as well as follow up in outpatient clinics (Epstein 2019).
159
Appendices
Appendix 1. Use and doses of long-term inhaled bronchodilator and

corticosteroids determined in response trials
Response Drug Dose (mcg) Frequency Delivery
Improved airway function

Improved exercise capacity
Reduced breathlessness
Improved quality of life beta-agonist
Salbutamol 100-200mcg 4-6-hourly MDI/spacer
Salbutamol 200-400mcg 4-6 hourly DPI
Terbutaline 500-1500mcg 6-8-hourly DPI
Salmeterol 50mcg 12-hourly MDI/DPI
Formoterol 12mcg 12-hourly MDI/DPI
Indacaterol 150-300mcg 24-hourly DPI
Antimuscarinic (Anticholinergic)
Ipratropium 42-84mcg 6-8-hourly MDI/spacer
Tiotropium 18mcg 24-hourly DPI
Tiotropium 2.5mcg 24-hourly Respimat
Glycopyrronium 50mcg 24-hourly DPI
Corticosteroid Inhaled
Beclometasone (small particle) 50-200mcg/day 12-hourly MDI/spacer
Budesonide 400mcg 12-hourly DPI
Fluticasone propionate 250- 12-hourly MDI/DPI
500mcg/day
Fluticasone furoate 100mcg/day 12-hourly DPI
Ciclesonide 80-320mcg/day 24-hourly MDI/spacer
MDI=metered dose inhaler. DPI=dry powder inhaler.

Appendix 2. Explanation of inhaler devices
Delivery system Available products Considerations
Metered dose inhaler Ventolin, Asmol, Airomir, Epaq (salbutamol 100mcg); Atrovent • MDIs should be used with a spacer device, as some people have difficulty
(MDI) (ipratropium bromide 21mcg); Qvar (beclometasone 50mcg, coordinating the release of medication with inhalation.
100mcg); Alvesco (ciclesonide 80mcg, 160mcg); Flixotide
(fluticasone 50mcg, 125mcg, 250mcg); Serevent (salmeterol
25mcg); Seretide (salmeterol 25mcg and fluticasone 50mcg,
salmeterol 25mcg and fluticasone 125mcg, salmeterol 25mcg
and fluticasone 250mcg); Symbicort Rapihaler (budesonide 200
mcg and formoterol 6 mcg)
Spacers Aerochamber Breath-A-Tech Fisonair Nebuhaler Volumatic • The spacer chamber acts as a reservoir for the aerosol released from an MDI. The
patient can then inhale from this chamber without having to coordinate the release
of the medication.
• Use of spacers with inhaled corticosteroids reduces adverse effects of oral
candidiasis and hoarseness, as well as optimising medication delivery.
• MDI with spacer is as effective as a nebuliser if an equivalent dose is taken; 10-15
puffs of 100mcg salbutamol MDI via a spacer is therapeutically equivalent to a
5mg salbutamol nebule.
• Spacers are cost effective, portable, easily cleaned and maintained, do not require
electricity and are simple and quick to use.
• A small volume spacer is preferable when the vital capacity is less than 1.5 L.
Autohaler Airomir (salbutamol 100mcg); • Breath-activated MDI containing 200 doses of medication.
Qvar (beclometasone 50mcg, 100mcg) • Use can improve lung deposition in patients with poor MDI inhaler technique. As
the patient starts a slow, deep breath through the mouthpiece, a flap valve is
triggered, and the dose automatically releases.
Dry powder inhalers

(DPI)

Accuhaler Serevent (salmeterol 50mcg); Flixotide (fluticasone propionate • Breath-activated multi-dose DPI containing 60 individually sealed doses. A dose
100mcg, 250mcg, 500mcg); Seretide (salmeterol 50mcg and counter shows the number of doses remaining. It gives accurate and consistent
fluticasone propionate 100mcg, salmeterol 50mcg and drug delivery over a range of inspiratory flow rates (30-120 L/minute).
fluticasone propionate 250mcg, salmeterol 50mcg and • Lactose powder is combined with the active medication for patients to taste and
fluticasone propionate 500mcg) reassure them that they have inhaled a dose.
Aerolizer Foradile (formoterol 12mcg) • Breath-activated single-dose powder inhaler that comes with a sheet of 60
capsules in push-out foil sheet. One capsule is loaded into the inhaler and pierced
before inhaling.
• Gives consistent drug delivery over a range of inspiratory flow rates.
Turbuhaler Bricanyl (terbutaline 500mcg); Pulmicort (budesonide 100mcg, • Breath-activated multi-dose inhaler, containing 60 (Oxis, Symbicort) or 200
200mcg, 400mcg); Oxis (formoterol 6mcg, 12mcg); Symbicort (Pulmicort, Bricanyl) doses; ensures delivery without the need to coordinate
(formoterol 6mcg and budesonide 100mcg, formoterol 6mcg inspiration with drug release.
and budesonide 200mcg, formoterol 12mcg and budesonide • Dose delivery is halved if the patient cannot produce inspiratory flow above 30
400mcg) L/min. Very few patients with COPD cannot produce a rate of >60 L/min.
• Produces very fine powder, so patients often don’t taste anything.
• Dose indicator shows when there are 20 doses remaining, and then when the
inhaler is empty (it contains a drying agent that can be heard when the inhaler is
shaken, which can be misinterpreted as available medication).
HandiHaler Spiriva (tiotropium 18mcg) • Breath-activated dry powder inhaler. A capsule containing tiotropium is dropped
into the HandiHaler, and pierced by pressing a button. The patient then inhales
through the mouthpiece for effective drug delivery. Studies have shown that
patients with a wide range of disease severity are able to generate sufficient
inspiratory airflow (as low as 20 L/min) to evacuate the powder from the capsule.
Breezhaler Onbrez (indacaterol 150mcg, 300 mcg) • Breath-activated single-dose powder inhaler
Seebri (glycopyrronium 50mcg) • Capsules come in foil packs containing 30 capsules in a cardboard carton
Ultibro (indacaterol 110 mcg/glycopyrronium 50 mcg) • Breezhaler inhalation device allows oral inhalation of the content of the capsule
shell. One capsule is loaded into the inhaler and pierced before inhaling.
• Gives consistent drug delivery over a range of inspiratory flow rates.

Genuair Bretaris (aclidinium 322 mcg/ dose) • Breath activated multi-dose DPI (containing 30 or 60 doses) with an integral dose
Brimica (aclidinium 340 mcg/formoterol 12 mcg) indicator, a green dosage button and a coloured control window. Before inhaling
the dose, the green button should be pressed all the way down and then released.
The coloured control window changes to green suggesting the dose is ready for
inhalation. If the full dose is inhaled correctly, the control window turns red.
Genuair is equipped with a dose indicator, displaying intervals of 10 (60, 50, 40,
30, 20, 10, 0). When a red striped band appears in the dose indicator, only a few
doses are left in the device. Bretaris Genuair also contains lactose.
Ellipta Breo (fluticasone furoate 100 mcg and vilanterol trifenatate 25 • Breath activated multi-dose DPI containing 14 or 30 doses. The active substances
mcg) are in separate blisters in powder form inside the device. It has a dose counter;
when fewer than 10 doses are left, half of the dose counter shows red.
Soft mist inhaler Spiriva Respimat (tiotropium 2.5 mcg) • Push button activated solution for inhalation. The cartridge is inserted and
Spiolto Respimat (tiotropium 2.5 mcg/olodaterol 2.5 mcg) primed before first use of the Respimat. To deliver the inhalation, the clear
base is turned until it clicks, the cap is opened, and the patient closes their
lips around the mouthpiece. The dose-release button is pressed, and the mist
is inhaled with a slow, deep breath, then a breath hold. A dose indicator
shows a low number of doses left, and the inhaler locks when empty. May be
suitable for patients with poor inspiratory effort.
Nebulisers Most nebulisers are electric. Some ultrasonic nebulisers are • Corticosteroid or ipratropium bromide aerosol should not be allowed to enter
battery operated. These models are not heavy duty but are the eyes to avoid the risk of adverse effects such as glaucoma or urinary
ideal for travelling. There are also 12-volt pumps that plug into outlet obstruction. Patients should be advised to wipe their face dry after
a car cigarette lighter. Use of inhaled corticosteroids requires a using the nebuliser to remove medication from the skin.
high-flow, heavy- duty pump. • Ipratropium can be combined with beta-agonist, but not with corticosteroid.
The products listed may not all be subsidised under the Pharmaceutical Benefits Scheme for use in COPD.

Appendix 3. Long term oxygen therapy (McDonald 2016a)
Initiating oxygen therapy

● Before introducing oxygen therapy, ensure optimal treatment of the pulmonary disorder while
monitoring improvement with objective tests such as FEV1 and forced vital capacity (FVC).
Treatment may include maximum therapy for airway obstruction, attention to nutrition and
bodyweight, an exercise rehabilitation program, control of infection, and treatment of cor
pulmonale.
● In patients selected for oxygen therapy, assess the adequacy of relief of hypoxaemia (PaO2
> 60 mmHg, or 8 kPa; SpO2 > 90%) and/or improvement in exercise capacity or nocturnal
arterial oxygen saturation while using a practical oxygen delivery system.
What the patient needs to know

● Patients receiving oxygen therapy in the home, and their carers, should have the use clearly
explained. That is, hours of use and flow rate, and any need to vary flow rates at given times.
The equipment and its care, including how to obtain servicing or replacements, needs to be
explained. The dangers of open flames (especially cigarettes, gas heaters and cookers) need
to be emphasised.
● Flow should be set at the lowest rate needed to maintain a resting PaO2of 60 mmHg (8kPa) or
SpO2 > 88%. For patients with COPD, 0.5–2.0 L/min is usually sufficient. Flow rate should be
increased by 1 L/min during exercise.
● Humidifiers are generally not needed at oxygen flow rates below 4 L/min.
● Extra soft nasal prongs are recommended for continuous oxygen use, but may become
uncomfortable at flow rates over 2–3 L/min and in the long term. Facemasks may be preferred
for at least some of the time, although there are dangers of rebreathing exhaled CO2 at flow
rates below 4 L/min.
Review
● Reassess 4–8 weeks after starting continuous or nocturnal oxygen therapy, both clinically and
by measurement of PaO2 and PaCO2, with and without supplementary oxygen. A decision can
then be made as to whether the treatment has been properly applied and whether it should be
continued or abandoned.
● Patients on intermittent oxygen therapy should also be reassessed periodically. The review can
be undertaken by appropriately trained staff using a pulse oximeter to confirm hypoxaemia
(SpO2 < 88%) at rest or during daily activities. They should also check compliance with therapy
and smoking status.
● Review at least annually or more often according to the clinical situation.
Dangers
● Supplementary oxygen in patients with increased arterial PaCO2 may depress ventilation,
increase physiological dead space, and further increase arterial PaCO2. This is suggested by
the development of somnolence, headache and disorientation.
● In long-term oxygen therapy, the increase in arterial PaCO2 is usually small and well tolerated.
However, serious hypercapnia may occasionally develop, making continued oxygen therapy
impractical. Risk appears greater during exacerbations of disease or if the flow of oxygen is
increased inappropriately.
● Sedatives (particularly benzodiazepines), narcotics, alcohol and other drugs that impair the
central regulation of breathing should not be used in patients with hypercapnia receiving
oxygen therapy.
164
Choosing the right method (see Adult Domiciliary Oxygen therapy Clinical Practice Guideline
for further details)
Domiciliary oxygen therapy can be delivered via the following systems:
● Stationary oxygen concentrators: These floor-standing electrically driven devices work by

extracting the nitrogen from room air by means of molecular sieves and deliver a continuous
flow of oxygen at the outlet. The percentage of oxygen is around 90 to 95% depending on the
model used. A back-up standard D-size oxygen cylinder is often supplied in case of
concentrator breakdown or power failure. Users may claim a rebate on their electricity account.
● Portable oxygen concentrators: These are small, lightweight portable oxygen

concentrators (POC) that are powered by the household electrical supply or via a car battery
or rechargeable battery which makes them suitable for ambulatory use. Some models have
been approved by some of the commercial airlines. Two types are available, those that are
only capable of delivering pulsed oxygen (these are generally smaller and lighter in weight)
and those that can deliver both pulsed and continuous flow oxygen. The performance
specifications of the different models of POCs vary considerably and for patients with high
oxygen needs, some POCs may not achieve a sufficient concentration of inspired oxygen to
meet the patient’s needs during exercise.
● Cylinders: These contain compressed oxygen gas and deliver 100% oxygen at the outlet.
Portable lightweight cylinders are available. Electronic conservation devices are often supplied
to deliver oxygen predominantly during inspiration and therefore avoid wastage. Demand flow
devices are the most common and deliver a pre-set volume or bolus of oxygen in early
inspiration. Use of such devices results in up to a fourfold reduction in oxygen consumption.
Reservoir-style conservers (i.e. nasal cannulae with an integrated pendant shaped reservoir)
are a cost-effective alternative.
The prescription should always specify:
● the source of supplemental oxygen;

● method of delivery;
● duration of use; and
● flow rate at rest, during exercise and during sleep.
There is no significant difference in the quality of oxygen delivery among the above methods.
However:
● Concentrators are cheaper than cylinders if use is equivalent to or more than three E-size
cylinders per month.
● Concentrators can be wheeled around the home but are heavy (about 21–26 kg) and are
difficult to move up stairs and in and out of cars.
● Concentrators cannot be used for nebulisation, as the pressure delivered is too low (35–63 kPa,
compared with 140 kPa for nebuliser pumps).
● If the anticipated need is for longer than three years, it is cheaper to buy than to rent a unit.
The units usually have a five-year guarantee. However, public funding is available for
pensioners and Health Care Card holders, subject to means testing.
165
Appendix 4. Strategies that may assist in reminding people to reduce
sedentary time
TV viewing During each advertisement break, stand up and go for a short walk around your
house.
Reading At the end of each book chapter or after a few pages of the newspaper, stand up
and go for a short walk around your house.
Transport Stand up whilst waiting for a bus or train.
Daily tasks When ironing, put items away in multiple small trips rather than putting everything
away once you have finished.
Computer use Consider setting an alarm (e.g. on your phone) to remind you to stand up every
30 minutes.
Phone use Consider standing up to use your phone. Go for a short walk around your house
after you finish using your phone to call / text someone.
166
Appendix 5. Table of Minimum Clinically Important Differences (MCID) for
COPD (Cazzola 2015b)
Health Status measures

Patient Purpose Domains No. Reliability Validity MCID
Reported items
Outcome
Measure
(PROM)
St George’s Assess health status Symptoms, 50 ✔ ✔ 4 units
Respiratory impairment in activity, impacts
Questionnaire airways disease
(SGRQ) (COPD, Asthma,
Bronchiectasis)
St George’s Assess health status Symptoms, 40 ✔ ✔ 4 units

Respiratory in COPD – weakest activity, impacts
Questionnaire-COPD items removed
(SGRQ-C)
Chronic Respiratory health-related Mastery, fatigue, 20 ✔ ✔ 0.5 units
Questionnaire (CRQ) quality of life in emotional function
(short form also chronic respiratory and dyspnoea
available) disease
Clinical COPD Health status Symptoms, 10 ✔ ✔ 0.4 units

Questionnaire (CCQ) assessment in a functional state,
primary care setting mental state
COPD Assessment Quantifies symptom Energy, Sleep, 8 ✔ ✔ 2 units

Test burden of COPD, confidence,
(CAT) health status activities,
measurement breathlessness,
chest tightness,
phlegm, cough
Symptom measures
Patient Reported Purpose Domains No. Reliability Validity MCID
Outcome Measure items
(PROM)
Modified Medical Disability from COPD Uni-dimensional 1 - 5- ✔ ✔ ~ 1, but

Research Council related to point limited data
(MMRC) breathlessness scale
Baseline Dyspnoea Measurement of BDI: functional BDI 3 ✔ ✔ 1 unit in TDI
Index (BDI) dyspnoea based on impairment, TDI 3
Transitional Dyspnoea activities of daily magnitude of task,
Index (TDI) living magnitude of effort
The Breathlessness Tracks severity of Breathlessness, 3 Acceptable Acceptable >1

Cough and Sputum resp symptoms and cough, sputum substantial
Scale (BCSS) evaluate efficacy in .6 mod
clinical trials - COPD .3 small
Dyspnoea 12 Current level of Uni-dimensional 12 ✔ ✔ Not yet

breathlessness established
severity
167
Exacerbations
Patient Reported Purpose Domains No. Reliability Validity MCID
Outcome Measure items
(PROM)
The EXAcerbations Evaluates Breathlessness, 14 ✔ ✔ Not yet established

of Chronic Pulmonary frequency, severity cough and
Disease Tool (EXACT®) and duration of an sputum, chest
AE COPD symptoms
(Daily)
Evaluating Respiratory Derivative Breathlessness, 11 ✔ ✔ 3 point Δ(total score)

Symptom (E-RS®) instrument of the cough and 2 point
EXACT, designed to sputum, chest Δ(breathlessness)
address the need symptoms 1 point Δ(cough & sp)
for a standardized 1 point Δ(chest
daily diary to symptoms)
assess respiratory
symptoms in
patients with stable
COPD
168
Appendix 6: Table of Systematic Reviews Evaluating the Effect of Self
Management in COPD
Authors Design Studies Participants Aims Intervention
hospitalisations
hospitalisations
included n=
Medication use
presentations
Respiratory-
Respiratory-
depression
healthcare
Dyspnoea
Anxiety &
All-cause
mortality
Mortality
related
related
Urgent
HRQoL
6MWD
ED
Dickens RCT 32 3941 To examine the Multiple components and/or ☺
et al., studies, characteristics of professionals, individual, group,
2014 database complex phone or computer. Including
inception- interventions education, rehabilitation,
2013 intended to psychological therapy, social
reduce the use of intervention, organisational
urgent and intervention (e.g. collaborative
unscheduled care or case management),
healthcare among psychological drug trials. Simple
people with COPD interventions, e.g. new treatment
for underlying long-term
condition, compared to treatment
as usual excluded
Zwerink RCT, 29 3688 To assess the Structured interventions aimed at ☺ ☺ ☺ 😐 ☺ 😐
et al., CCT studies, efficacy of self- improvement of self-health
2014 1995- management behaviours and self-management
2014 interventions for skills. Interventions required at
individuals with least an iterative process of
COPD interaction between participant
and healthcare provider, and
ideally included formulation of
goals and provision of feedback.
Interventions with < 2 contact
moments were excluded.

Majothi RCT 9 studies, 1466 To evaluate the 1+ components commonly ☺ 😐 😐 😐
et al., Moderate- effect of COPD included in self-management
2015 severe self-management interventions, e.g. action plans,
COPD, following exercise, education, inhaler
database admission to technique, bronchial hygiene and
inception- hospital breathing techniques, stress
2012 management and relaxation,
nutritional programs, patient
empowerment, support groups
and telecare, provided in hospital
or community setting with a
usual care, control, sham
intervention or other self-
management intervention
comparator.
Cannon RCT 25 4082 To analyse the Self-management intervention ☺ 😐 😐 ☺
et al., studies, outcome of self- including at least 4 of the
2016 1990- management following: Exacerbation action
2016 RCTs and their plan, COPD education,
impact upon medication information,
COPD patients' management of exacerbations,
health outcomes management of stress and/or
using meta- anxiety, nutritional guidance,
analysis exercise program/information, or
managing a healthy lifestyle.
Howcroft RCT, 7 studies, 1550 Compare COPD Action plan with a single ☺ 😐 ☺ 😐 ☺
et al. quasi Database exacerbation educational component of short
2016 RCT inception action plans with duration allowing time for the
-2015 a single short clinician to personalise plan.
educational Ongoing support delivered by
component + phone or direct contact. Studies
ongoing support with broader self-management
directed at use of support interventions, e.g.
action plan education in multiple sessions
over a longer period or exercise
programmes, with or w/out an
action plan were excluded. Active
intervention was compared to
’usual care’.

Jolly et RCT 173 n/a To identify the Include 3+ components e.g. ☺ 😐
al., 2016 studies, most effective structured group-based PR
database components of programs (to teach self-
inception- interventions to management skills); educational
2012 facilitate self- self-management interventions
management of delivered in an outpatient setting
health care or at home, sometimes with
behaviours telephone follow-up; integrated
disease management with
multidisciplinary input and often
some element of monitoring by
health professionals; exercise-
only interventions (with some
dyspnoea management) and
respiratory muscle training using
threshold devices.
Jonkman RCT 14 3282 Determine if self- Interventions providing ☺ ☺ ☺ 😐
et al., studies, management information to patients and
2016 1985- programs were including 2+ of: stimulation of
2013 associated with sign/symptom monitoring;
better outcomes education in problem solving
and if any skills, i.e. self-treatment of acute
subgroups benefit exacerbations and
more stress/symptom management;
smoking cessation; and
stimulation of medical treatment
adherence; physical activity; or
improving dietary intake.
Components aimed at enhancing
the patient’s active role and
responsibility.
Lenferin RCT 22 3854 To evaluate the Must include a written action plan ☺ 😐 ☺ 😐 😐 😐 ☹
k et al., studies, efficacy of COPD- for AECOPD and an iterative
2017 1995- specific self- process between participant and
2017 management healthcare provider(s) in which
interventions that feedback was provided.
include an action
plan for
exacerbations
Table ☺= improved, 😐= no change, ☹= worsened., grey shading indicates outcome was not analysed. HRQoL=
health-related quality of life, 6MWD= 6-minute walk distance, RCT= randomised controlled trial, CCT= controlled

clinical trials, COPD= chronic obstructive pulmonary disease, ED= emergency department, PR = pulmonary
rehabilitation.

List of Figures
Figure 1: COPD Phenotypes .................................................................................................... 18
Figure 2: Time-course of chronic obstructive pulmonary disease (COPD) (Fletcher 1977) ................. 20
Figure 3: Risk of occupational exposure for COPD from selected studies ........................................ 21
Figure 4: Comparison of flow-volume curves for spirometry ........................................................ 27
Figure 5: Important considerations for inhaler device prescription ................................................ 59
Figure 6: Table of Systematic Reviews Evaluating the Effect of Self-Management in COPD ............. 130
Figure 7: The DECAF Score ................................................................................................... 138
Figure 8: Managing a COPD Exacerbation Checklist .................................................................. 157
List of Boxes
Box 1: Levels of evidence ....................................................................................................... 12
Box 2: Risk Factors for COPD .................................................................................................. 23
Box 3: Modified Medical Research Council (mMRC) Dyspnoea Scale for grading the severity of
breathlessness during daily activities ....................................................................................... 25
Box 4: Classification of severity of chronic obstructive pulmonary disease (COPD) .......................... 31
Box 5: Assessment of acute response to inhaled beta-agonist at diagnosis .................................... 32
Box 6:Indication for referral to specialist respiratory outpatient services ....................................... 32
Box 7: Eating strategies which may prevent dyspnoea ................................................................ 74
Box 8: Breathlessness management strategies ........................................................................ 100
Box 9: Comparison of outcomes for COPD management programs ............................................. 127
Box 10: Patient Support Groups ............................................................................................ 136
Box 11: Reducing hospital utilisation: current level I and II evidence from COPD-X ....................... 141
Box 12: Indications for hospitalisation of patients with chronic obstructive pulmonary disease ........ 149
Box 13: Indications for non-invasive or invasive ventilation ....................................................... 149
Box 14: Criteria for discharge ............................................................................................... 156
Box 15: Follow-up – initial and subsequent ............................................................................. 158
173
Glossary of Terms
6MWD 6-Minute Walk Distance
6MWT 6-Minute Walk Test
AAT Alpha-1 Antitrypsin
ABG Arterial Blood Gas
ACT Airway Clearance Techniques
ADO Age, Dyspnoea score and Obstruction
BODE Body mass index, degree of Obstruction as measured by FEV1, Dyspnoea score and
Exercise capacity
CAT COPD Assessment Test
CBT Cognitive Behaviour Therapy
CCQ Clinical COPD Questionnaire
CI Confidence Interval
CrI Credible Interval
CPAP Continuous Positive Airway Pressure
CRQ Chronic Respiratory Disease Questionnaire
CVD Cardiovascular Disease
DLCO Diffusing Capacity of Lung for Carbon Monoxide test
DPI Dry Powder Inhaler
EPC Extended Primary Care
ERV Expiratory Reserve Volume
FeNO Exhaled nitric oxide fraction
FEV1 Forced Expiratory Volume in 1 Second
FFM Fat Free Mass
FRC Functional Residual Capacity
FVC Forced Vital Capacity
HADS Hospital Anxiety and Depression Scale
HFNC High Flow Nasal Cannula
HR Hazard ratio
HRCT High Resolution Computed Tomography
HRQoL Health-related quality of life
IC Inspiratory Capacity
IPAP Inspiratory Positive Airway Pressure
ISWD Incremental Shuttle Walk Distance
LOS Length of Stay
LTOT Long Term Oxygen Therapy
MCID Minimum Clinically Important Difference
MDI Metered Dose Inhaler
mMRC Modified Medical Research Council Dyspnoea Scale
NHF Nasal High Flow
NIV Non-Invasive Ventilation
NNH Number Needed to Harm
NNT Number Needed to Treat
NNTB Number needed to treat for an additional beneficial outcome
OR Odds Ratio
OSA Obstructive Sleep Apnoea
PBS Pharmaceutical Benefits Scheme
PEP Positive Expiratory Pressure
PHT Pulmonary Hypertension
174
pMDI Pressurised Metered Dose Inhaler
RCT Randomised Controlled Trial
RR Relative Risk/ Rate Ratio
SD Standard Deviation
SES Socioeconomic Status
SGRQ St George’s Respiratory Questionnaire
SGRQ-C St George’s Respiratory Questionnaire-COPD
TB Tuberculosis
TLC Total Lung Capacity
WMD Weighted Mean Difference
175
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COPDX Plan 2023

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The COPD-X Plan:

Australian and New Zealand Guidelines

Lung Foundation Australia Staff

The COPD-X Plan – Version 2 71 (July 2023)

Past Committee Members

The COPD-X Plan – Version 2 71 (July 2023)

The COPD-X Plan – Version 2 71 (July 2023)

Current COPD Guidelines Committee ......................................................................................... 1

Lung Foundation Australia Staff ................................................................................................ 1

Past Committee Members ........................................................................................................ 2

Past Chairpersons ................................................................................................................ 2

Past Committee Members ..................................................................................................... 2

Other contributors - Past and Present ..................................................................................... 3

Table of Contents ................................................................................................................... 4

The origins of the COPD-X guidelines..................................................................................... 10

COPD-X Methodology .......................................................................................................... 11

Levels of evidence ................................................................................................................. 12

Key Recommendations of the COPD-X Guidelines ....................................................................... 13

C: Case finding and confirm diagnosis ...................................................................................... 17

C1. Aetiology and natural history .......................................................................................... 19

C3. Assessing the severity of COPD ....................................................................................... 30

C4. Assessing acute response to bronchodilators ..................................................................... 31

C5. Specialist referral .......................................................................................................... 32

O1. Inhaled bronchodilators ................................................................................................. 38

The COPD-X Plan – Version 2 71 (July 2023)

O2. Oral bronchodilators ...................................................................................................... 44

O3. Corticosteroids ............................................................................................................. 45

O4. Combination therapies and biologic therapies ................................................................... 47

O5. Inhaler technique and adherence .................................................................................... 57

O6. Non-pharmacological interventions .................................................................................. 60

O7. Comorbidities ............................................................................................................... 75

O8. Hypoxaemia and pulmonary hypertension ........................................................................ 91

O9. Surgery ....................................................................................................................... 93

O10. Palliative and supportive care ....................................................................................... 96

P: Prevent deterioration ....................................................................................................... 101

P1. Risk factor reduction .................................................................................................... 101

P2. Immunisations ............................................................................................................ 107

P3. Immunomodulatory agents ........................................................................................... 110

P4. Macrolides.................................................................................................................. 110

P5. Long-acting bronchodilators .......................................................................................... 110

P6. Corticosteroids............................................................................................................ 111

P7. Mucolytic agents ......................................................................................................... 111

P9. Regular review ........................................................................................................... 113

P10. Oxygen therapy ........................................................................................................... 114

P11 Long-term home non-invasive ventilation ...................................................................... 117

P12 Alpha1-antitrypsin deficiency ....................................................................................... 118

D: Develop a plan of care ..................................................................................................... 119

D1. Support team ............................................................................................................... 119

D2. Multidisciplinary care plans........................................................................................... 124

D3. Chronic Disease Self-management ................................................................................ 126

D4. Telehealth ................................................................................................................. 132

The COPD-X Plan – Version 2 71 (July 2023)

D6. Referral to a support group .......................................................................................... 136

X: Manage eXacerbations ..................................................................................................... 136

X1. Home management ..................................................................................................... 143

X2. COPD exacerbation management .................................................................................. 143

X3. Refer appropriately to prevent further deterioration (‘P’) ................................................... 149

X4. Uptake and impact of guidelines for exacerbations ........................................................... 159

Appendices ........................................................................................................................ 160