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Treatment of stable chronic obstructive pulmonary disease: a protocol for a systematic review and evidence map

Journal: BMJ Open ManuscriptFor ID peerbmjopen-2018-027935 review only Article Type: Protocol

Date Submitted by the 15-Nov-2018 Author:

Complete List of Authors: Dobler, Claudia; Mayo Clinic, Evidence-Based Practice Center, Robert D. and Patricia E. Kern Center for the Science of Health Care Delivery Farah, Magdoleen; Mayo Clinic, Evidence-Based Practice Center, Robert D. and Patricia E. Kern Center for the Science of Health Care Delivery Morrow, Allison; Mayo Clinic, Evidence-Based Practice Center, Robert D. and Patricia E. Kern Center for the Science of Health Care Delivery alsawas, mouaz; Mayo Clinic, Evidence-Based Practice Center, Robert D. and Patricia E. Kern Center for the Science of Health Care Delivery Benkhadra, Raed; Mayo Clinic, Evidence-Based Practice Center, Robert D. and Patricia E. Kern Center for the Science of Health Care Delivery Hasan, Bashar; Mayo Clinic, Evidence-Based Practice Center, Robert D. and Patricia E. Kern Center for the Science of Health Care Delivery

Prokop, Larry; Mayo Clinic, Library Public Services http://bmjopen.bmj.com/ Wang, Zhen; Mayo Clinic, Evidence-Based Practice Center, Robert D. and Patricia E. Kern Center for the Science of Health Care Delivery Murad, M. Hassan; Mayo Clinic, Evidence-Based Practice Center, Robert D. and Patricia E. Kern Center for the Science of Health Care Delivery

Chronic obstructive pulmonary disease, pharmacological interventions, Keywords: non-pharmacological interventions, umbrella review, evidence map, knowledge translation

on September 26, 2021 by guest. Protected copyright.

For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 1 of 43 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2018-027935 on 5 May 2019. Downloaded from 1 2 3 Treatment of stable chronic obstructive pulmonary disease: a protocol for a 4 5 6 systematic review and evidence map 7 8 9 1 1 1 1 1 10 Claudia C. Dobler, Magdoleen H Farah, Allison S. Morrow, Mouaz Alsawas, Raed Benkhadra Bashar 11 1 2 1 1 12 Hasan, Larry J Prokop, Zhen Wang, M. Hassan Murad 13 14 15 1) Evidence-Based Practice Center, Robert D. and Patricia E. Kern Center for the Science of Health 16 For peer review only 17 Care Delivery, Mayo Clinic, Rochester, Minnesota, USA 18 19 2) Library Public Services, Mayo Clinic, Rochester, Minnesota, USA. 20 21 22 23 24 25 26 27 28 29 Correspondence to 30 31 Dr. Claudia C Dobler

32 http://bmjopen.bmj.com/ 33 Evidence-based Practice Center 34 35 Mayo Clinic 36 Rochester MN 55905 37 38 USA 39 40 [email protected] on September 26, 2021 by guest. Protected copyright. 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 1 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 2 of 43 BMJ Open: first published as 10.1136/bmjopen-2018-027935 on 5 May 2019. Downloaded from 1 2 3 Abstract 4 5 Introduction: Chronic obstructive pulmonary (COPD) disease is a progressive lung disease, usually 6 7 caused by tobacco smoking, but other important risk factors include exposures to combustion products of 8 9 biomass fuels and environmental pollution. The introduction of several new (combination) inhaler 10 11 therapies, increasing uncertainty about the role of inhaled corticosteroids and a rapid proliferation of the 12 13 literature on management of stable COPD in general, call for novel ways of evidence synthesis in this 14 15 area. A systematic review and evidence map can provide the basis for shared decision-making tools and 16 For peer review only 17 help establish a future research agenda. 18 19 Methods and analysis: This systematic review will follow an umbrella systematic review design (also 20 21 called overview of reviews). We plan to conduct a comprehensive literature search of six databases. We 22 23 will include systematic reviews that assessed the effectiveness of any pharmacological or non- 24 25 pharmacological intervention on one or more patient-important outcomes and/or lung function in patients 26 with stable COPD. For every intervention/outcome pair one systematic review will be included. An a priori 27 28 protocol will guide which systematic reviews will be chosen, how their credibility will be evaluated, and 29 30 how the quality of the body of evidence will be rated. Data will be synthesized into an evidence map that 31 32 will present a matrix that depicts each available treatment for stable COPD with a quantitative estimate on http://bmjopen.bmj.com/ 33 34 symptoms/outcomes from the patient perspective, along with an indication of the size and certainty in the 35 36 evidence. 37 38 Ethics and dissemination: Approval by a research ethics committee is not required since the review will 39

40 only include published and publicly accessible data. The systematic review will be published in a peer- on September 26, 2021 by guest. Protected copyright. 41 42 reviewed journal and will provide various stakeholders with an evidence map. 43 44 Systematic review registration: PROSPERO registration number CRD42018095079 45 46 47 48 Keywords 49 Chronic obstructive pulmonary disease, pharmacological interventions, non-pharmacological 50 51 interventions, umbrella review, evidence map, knowledge translation, decision aid 52 53 54 55 56 57 58 2 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 3 of 43 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2018-027935 on 5 May 2019. Downloaded from 1 2 3 Article Summary 4 5 Strengths and limitations of this study 6 7  The planned evidence synthesis will summarise a very large body of literature on 8 9 pharmacological and non-pharmacological interventions thus making research evidence more 10 11 accessible for stakeholders 12 13  The systematic review will be the first to use an evidence map to identify evidence gaps and to 14 15 facilitate evidence communication in clinical encounters for COPD. 16 For peer review only 17  For patients and clinicians, the map will facilitate the production of decision aids. For 18 19 policymakers and researchers, the map helps in establishing a future research agenda. 20 21  The systematic review uses an a priori protocol to identify the most up-to-date systematic reviews 22 23 of the highest possible quality, and the level of evidence for many intervention/outcome pairs will 24 25 therefore likely be high 26 27  As we will only include one systematic review per intervention/outcome pair, it is possible that 28 29 some studies will not have been captured in included systematic reviews 30 31

32 http://bmjopen.bmj.com/ 33 34 35 36 37 38 39

40 on September 26, 2021 by guest. Protected copyright. 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 3 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 4 of 43 BMJ Open: first published as 10.1136/bmjopen-2018-027935 on 5 May 2019. Downloaded from 1 2 3 Introduction 4 5 6 Chronic obstructive pulmonary disease (COPD) is a progressive lung disease characterized by chronic 7 8 obstruction of airflow and permanent damage to the air sacs that leads to breathing problems. COPD is 9 10 mainly a consequence of tobacco smoking, but other important risk factors include exposures to 11 12 combustion products of biomass fuels and environmental pollution.1 COPD is the fourth most common 13 14 cause of death globally and is predicted to be the third by 2030.2 In 2010, the number of COPD cases 15 16 was estimated at 384For million, which peer corresponded review to a global prevalence only of 11.7% (95% confidence 17 18 interval [CI] 8.4%–15.0%).2 COPD was responsible for about 5% of global disability–adjusted life years 19 20 (76.7 million) and 5% of total deaths (2.9 million) based on data from the 2010 Global Burden of Disease 21 3 4 22 study. In some low- and middle income countries COPD has become a growing, but often neglected, 23 epidemic, with a recent study showing a prevalence of COPD of 13.7% (95% CI 12.1–15.5) in Chinese 24 25 people aged 40 years or older.5 Patients with COPD are frequent users of the health care system and 26 27 often need to be admitted to hospital repeatedly, often within short intervals.6 28 29 30 31 Recently, there has been a rapid increase in inhaler therapies available for the management of COPD. In 32 http://bmjopen.bmj.com/ 33 particular, several new inhalers including fixed-dose combinations (containing bronchodilator(s) with or 34 35 without inhaled corticosteroids) have been introduced. Concurrently, the literature on pharmacological 36 37 and non-pharmacological interventions for COPD has proliferated substantially. Multiple systematic 38 39 reviews have been conducted to synthesise the evidence on inhalation treatments in COPD.7-16

40 on September 26, 2021 by guest. Protected copyright. 41 42 43 The role of inhaled corticosteroids for the treatment of stable COPD is increasingly questioned, including 44 45 in patients with severe disease, driven by the growing evidence of an increased risk of pneumonia 46 associated with inhaled corticosteroids,17 18 and the introduction of combined dual long acting 47 48 bronchodilator inhalation therapy as a plausible treatment alternative.19 20 49 50 51 52 A search of the Cochrane Database of Systematic Reviews (Issue 5 of 12, May 2018) with the keyword 53 54 “chronic obstructive pulmonary disease” yielded 132 unique records, indicating that keeping track not just 55 56 57 58 4 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 5 of 43 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2018-027935 on 5 May 2019. Downloaded from 1 2 3 of original studies, but also evidence syntheses, has become a daunting task for decision makers in this 4 5 area. 6 7 8 9 The implementation of evidence-based practice in the management of patients with COPD is challenging 10 11 for medical practitioners due to the rapidly growing body of evidence. Additionally, non-adherence of 12 13 patients with COPD to prescribed treatments is an ongoing challenge, with many patients being 14 21-24 15 overburdened with the treatment work they need to do for their COPD care. Patients' beliefs and 16 For peer review only 17 concerns about the safety and benefits of their treatment and complex treatment regimens all impact on 18 adherence. Non-pharmacological interventions such as pulmonary rehabilitation are persistently 19 20 underutilised despite scientific evidence of their effectiveness.25 21 22 23 24 Faced with these challenges, novel tools of evidence synthesis and evidence communication in CODP for 25 26 the patient-clinician encounter are needed that will allow collaborative deliberation of treatment options 27 28 between patients and clinicians to make health care decisions together, taking into account the best 29 30 scientific evidence available, as well as the patient’s values and preferences.26-29 Further, given the 31

32 rapidly growing body of evidence on treatments for stable COPD, it is timely to identify current knowledge http://bmjopen.bmj.com/ 33 34 gaps to inform future research needs. 35 36 37 38 Consequently, the aim of our systematic review is 1) to synthesise the evidence on pharmacological and 39 non-pharmacological treatments for stable COPD, 2) produce an evidence map that identifies evidence 40 on September 26, 2021 by guest. Protected copyright. 41 gaps in order to inform future research, and that provides information that can be incorporated into a 42 43 decision/communication aid for use during clinical encounters between patients and clinicians. 44 45 46 47 Methods and analysis 48 49 This protocol adheres to the Preferred Reporting Items for Systematic Review and Meta-analysis 50 51 Protocols (PRISMA-P) (see “Additional file 1 PRISMA-P checklist.pdf”).30 52 53 54 55 Patient and Public Involvement 56 57 58 5 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 6 of 43 BMJ Open: first published as 10.1136/bmjopen-2018-027935 on 5 May 2019. Downloaded from 1 2 3 No patients or the public were involved in this systematic review of the literature. 4 5 6 7 Review question 8 9 What are the impacts of pharmacological and non-pharmacological interventions in patients with COPD 10 11 on patient-important outcomes (including dyspnea and other symptoms such as anxiety, 12 13 functional/exercise capacity, frequency of acute exacerbations, health-related quality of life, 14 15 hospitalizations, emergency department visits) and lung function parameters? 16 For peer review only 17 18 Eligibility criteria 19 20 Types of studies 21 22 We will include systematic reviews that assessed the effectiveness of any pharmacological or non- 23 24 pharmacological intervention on one or more relevant outcomes (see below) in patients with stable 25 26 COPD. For every intervention/outcome pair (e.g. effectiveness of pulmonary rehabilitation to improve 27 28 dyspnea) one systematic review will be included. The following a priori protocol will guide which 29 30 systematic reviews will be chosen, how their credibility will be evaluated, and how the quality of the body 31

32 of evidence will be rated. http://bmjopen.bmj.com/ 33 34 Systematic reviews will be excluded if: 35 36  they were not published in English (included studies, however, could have been in any language) 37 38  their pooled estimates were (partially) derived from studies that had not been published in the 39

40 peer-reviewed literature (e.g. abstracts, studies only published on pharmaceutical company on September 26, 2021 by guest. Protected copyright. 41 42 websites) 43 44  they only contained indirect or mixed indirect and direct comparisons (network meta-analysis) 45  they were umbrella reviews (reviews of reviews) 46 47  they included patient populations other than patients with COPD and did not report outcomes 48 49 separately for COPD patients 50 51 52 53 54 55 56 57 58 6 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 7 of 43 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2018-027935 on 5 May 2019. Downloaded from 1 2 3 We will derive a single pooled estimate per outcome per intervention. If multiple systematic reviews 4 5 provided multiple estimates for the same intervention and outcome, we will choose a systematic review 6 7 based on the following a priori defined scoring system: 8 9 10 11 a. Availability of one or more meta-analyses (as opposed to narrative data synthesis only) 12 13 b. Year of publication, date of literature search 14 15 c. Size based on a) Number of studies included, b) Number of participants included 16 For peer review only 17 d. Type of studies: randomized controlled trials (RCTs) generally provide stronger evidence than 18 observational studies 19 20 e. Synthesis of data from drug classes rather than specific drugs 21 22 23 24 If we encounter the scenario in which despite the above mentioned criteria we still have to choose 25 26 between two or more systematic reviews, we will make this choice based on these additional criteria: 27 28 a. Consensus among two practicing pulmonologists 29 30 b. Credibility of the systematic reviews as judged using the “A Measurement Tool to Assess 31

32 Systematic Reviews” (AMSTAR2) criteria.31 http://bmjopen.bmj.com/ 33 34 35 36 Types of participants 37 38 Studies that evaluated adults (aged 18 years and older) with stable COPD will be included. Studies 39 conducted in patients with an acute exacerbation of COPD will be excluded. 40 on September 26, 2021 by guest. Protected copyright. 41 42 43 Types of interventions 44 45 We will include any pharmacological or non-pharmacological intervention. Interventions that we are 46 47 expecting are the following: inhaled and other medications, smoking cessation, vaccinations, exercise 48 49 and pulmonary rehabilitation, airway clearance techniques, nutrition and dietary interventions, COPD 50 51 action plans, psychological interventions, home oxygen therapy, home mechanical ventilation, 52 53 interventional bronchoscopy, and surgery. Complex interventions with multiple components such as 54 55 56 57 58 7 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 8 of 43 BMJ Open: first published as 10.1136/bmjopen-2018-027935 on 5 May 2019. Downloaded from 1 2 3 exercise, smoking cessation advice, psychological support and home visits will be excluded. We will also 4 5 exclude interventions only relevant during an acute exacerbation of COPD. 6 7 8 9 Comparators will include placebo or usual care. Comparisons between different (combinations of) inhaler 10 11 treatments (focusing on different drug classes rather than different inhalation devices/ formulations) will 12 13 also be included. We will exclude indirect comparisons between interventions or mixed direct and indirect 14 15 comparisons (network meta-analyses). 16 For peer review only 17 18 Types of outcomes 19 20 The following outcomes will be included: 21 22 a. Dyspnea and other symptoms 23 24 b. Exercise capacity and functional capacity 25 26 c. COPD exacerbations 27 28 d. Health-related quality of life 29 30 e. Hospitalizations, emergency department visits 31

32 f. Mortality http://bmjopen.bmj.com/ 33 34 g. Lung function parameters 35 36 h. Adverse events 37 38 There will be no restrictions based on measurement methods. 39

40 on September 26, 2021 by guest. Protected copyright. 41 Information sources and search strategy 42 43 This systematic review will follow an umbrella systematic review design (also called overview of reviews). 44 45 We plan to conduct a comprehensive literature search of six databases, including Ovid MEDLINE Epub 46 47 Ahead of Print, Ovid MEDLINE In-Process and Other Non-Indexed Citations, Ovid MEDLINE, Ovid 48 49 EMBASE, Ovid Cochrane Database of Systematic Reviews, and Scopus from database inception to the 50 51 present. We have developed a preliminary database search strategy and found that these databases can 52 53 adequately identify the relevant literature. Reference mining of relevant publications will be conducted. 54 55 The search strategy will be designed and conducted by an experienced librarian with input from the 56 57 58 8 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 9 of 43 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2018-027935 on 5 May 2019. Downloaded from 1 2 3 study’s principle investigator. Controlled vocabulary supplemented with keywords will be used to search 4 5 for systematic reviews and meta-analyses of pharmacological and non-pharmacological treatments for 6 7 stable COPD. Search strategies are shown in Additional file 2. 8 9 10 11 All citations identified through the process will be imported to a reference management system 12 13 (EndNote® Version X7 and X8; Thomson Reuters, Philadelphia, PA). We will use a web-based 14 15 systematic review software, DistillerSR (Evidence Partners Incorporated, Ottawa, Canada), to facilitate 16 For peer review only 17 the study selection process. 18 19 20 Data extraction 21 22 For every intervention/outcome pair one systematic review will be chosen following the priori protocol 23 24 outlined above. At the beginning of data abstraction, we will develop a standardized data extraction form 25 26 to extract study characteristics (author, study design, inclusion and exclusion criteria, patient 27 28 characteristics, interventions, comparisons, outcomes, and related items for assessing study quality and 29 30 applicability). The standardized form will be pilot-tested by all study team members. We will iteratively 31

32 continue testing the form until no additional items or unresolved questions exist. All study details will be http://bmjopen.bmj.com/ 33 34 extracted by two independent reviewers. A third reviewer will review data extraction, and resolve conflicts. 35 36 37 38 Strategy for data synthesis 39 Data will be synthesized into an evidence map. An evidence map is defined as a systematic search of a 40 on September 26, 2021 by guest. Protected copyright. 41 broad field to identify gaps in knowledge and/or future research needs that presents results in a user- 42 43 friendly format, often a visual figure or graph, or a searchable database.32 The planned map will present a 44 45 matrix that depicts each available treatment for stable COPD with a quantitative estimate on 46 47 symptoms/outcomes from the patient perspective, along with an indication of the size and certainty in the 48 49 evidence. 50 51 52 53 54 55 56 57 58 9 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 10 of 43 BMJ Open: first published as 10.1136/bmjopen-2018-027935 on 5 May 2019. Downloaded from 1 2 3 We will also provide a narrative synthesis of the findings from the included systematic reviews, structured 4 5 around the type of intervention, target population characteristics (e.g. severity of COPD), type of outcome 6 7 and intervention content. 8 9 10 11 Analysis of subgroups or subsets 12 13 Pre-determined characteristics for subgroup analysis are: 14 15  Severity of COPD, e.g. based on GOLD (Global Initiative for Chronic Obstructive Lung Disease) 16 For peer review only 17 criteria,33 FEV1 (forced expiratory volume in one second) in % predicted 18 19  COPD phenotypes, e.g. patients with frequent exacerbations, eosinophilic inflammation 20 21  Duration of intervention 22 23  Different study types (e.g. randomized controlled trials versus observational studies) 24 25 26 27 Credibility (methodological quality) assessment 28 31 29 We will use AMSTAR2 to assess the credibility of the included systematic reviews. The AMSTAR2 tool 30 addresses the following 16 items: 31

32 http://bmjopen.bmj.com/  Use of the components of PICO (population, intervention, comparator, outcome) for research 33 34 questions and inclusion criteria 35 36  Protocol for the systematic review, justification of any significant protocol deviations 37 38  Study selection 39 40  Literature search strategy on September 26, 2021 by guest. Protected copyright. 41 42  Study selection by two independent reviewers 43 44  Data extraction by two independent reviewers 45 46  Excluded studies 47 48  Description of included studies 49 50  Risk of bias assessment in individual studies 51 52  Sources of funding 53 54  Methods for meta-analysis 55 56  Impact of risk of bias on the meta-analysis or other evidence synthesis 57 58 10 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 11 of 43 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2018-027935 on 5 May 2019. Downloaded from 1 2 3  Accounting for risk of bias in the interpretation/discussion of results 4 5  Explanation for heterogeneity in the results 6 7  Publication bias 8 9  Conflicts of interest 10 11 12 13 Ethics and dissemination 14 15 16 This systematic reviewFor is registered peer with PROSPERO review (registration onlynumber: CRD42018095079; 17 18 http://www.crd.york.ac.uk/PROSPERO). Approval by a research ethics committee is not required since 19 the review will only include published and publicly accessible data. The systematic review will be 20 21 published in a peer-reviewed journal and will provide various stakeholders with an evidence map. 22 23 24 25 Discussion 26 27 The aim of this systematic review is to systematically identify, summarize and assess a large body of 28 29 evidence on pharmacological and non-pharmacological interventions in stable COPD. The information will 30 31 be used to produce an evidence map to identify knowledge gaps and to inform a decision/communication 32 http://bmjopen.bmj.com/ 33 aid for the clinical encounter between patients and clinicians. 34 35 36 37 Strengths and limitations of this systematic review 38 39 We have not identified any systematic reviews that have provided an evidence map for the treatment of

40 on September 26, 2021 by guest. Protected copyright. 41 stable COPD, and this systematic review will therefore be the first to use an evidence map to identify 42 43 evidence gaps and to facilitate evidence communication in clinical encounters for COPD. The systematic 44 45 review uses an a priori protocol to identify the most up-to-date systematic reviews of the highest possible 46 47 quality, and the level of evidence for many intervention/outcome pairs will therefore likely be high. 48 49 As we will only include one systematic review per intervention/outcome pair, it is possible that some 50 studies will not have been captured in included systematic reviews. 51 52 53 54 Practical Implications 55 56 57 58 11 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 12 of 43 BMJ Open: first published as 10.1136/bmjopen-2018-027935 on 5 May 2019. Downloaded from 1 2 3 Evidence mapping is a relative novel method of evidence synthesis, which aims to identify gaps in 4 5 knowledge and/or future research needs based on a comprehensive literature search and present results 6 7 in an easy to understand format in a figure or graph.32 Evidence presented in such a user-friendly way 8 9 may facilitate knowledge dissemination and implementation among relevant stakeholder groups including 10 11 policy makers.34 35 In this proposed study, we are targeting two aims that address the needs of different 12 13 stakeholders. 14 15 16 For peer review only 17 The first type of stakeholders is patients and clinicians. In the context of a clinical encounter, they require 18 shared decision-making tools (decision aids) because the available treatments are numerous and the 19 20 impact on the different symptoms varies by intervention. Traditional systematic reviews usually 21 22 summarize evidence grouped around specific interventions. In clinical practice, however, discussions 23 24 between patients and clinicians often focus on a problem that demands a solution (e.g. shortness of 25 26 breath or limited functional capacity in patients with COPD). This requires that evidence is communicated 27 28 from an outcome rather than an intervention perspective (e.g. which interventions can improve shortness 29 30 of breath or functional capacity in patients with stable COPD?). We plan to present the results of our 31

32 systematic review structured by outcomes to facilitate knowledge translation into a http://bmjopen.bmj.com/ 33 34 decision/communication aid (the COPD CHOICE decision aid project). This will hopefully contribute to 35 36 patient-centred and transparent evidence communication in clinical encounters. 37 38 39 The second type of stakeholders is policymakers funding research and researchers. The presentation of 40 on September 26, 2021 by guest. Protected copyright. 41 results in the form of evidence map can quickly provide them with a snapshot of which symptoms (daily 42 43 dilemmas that patients face) or which interventions are only supported by low quality evidence (or no 44 45 evidence). Such areas are prime targets for future research. 46 47 48 49 The proposed approach (overview of reviews and evidence mapping) is ideal in the context of the very 50 51 large volume of literature available on pharmacological and non-pharmacological interventions in stable 52 53 COPD, and the need to synthesize and present summaries that cater to different stakeholders. 54 55 56 57 58 12 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 13 of 43 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2018-027935 on 5 May 2019. Downloaded from 1 2 3 List of abbreviations 4 5 95% CI: 95% confidence interval; AMSTAR2: A Measurement Tool to Assess Systematic Reviews 2; 6 7 COPD: Chronic obstructive pulmonary disease (COPD); FEV1: forced expiratory volume in one second; 8 9 GOLD: Global Initiative for Chronic Obstructive Lung Disease; PICO: population, intervention, 10 11 comparator, outcome; PRISMA-P: Preferred Reporting Items for Systematic Review and Meta-analysis 12 13 Protocols; RCT: randomized controlled trial 14 15 16 For peer review only 17 18 Authors’ contributions 19 20 CCD drafted the manuscript. MHM made substantial contributions to the conception and design. Working 21 22 with CCD, LJP designed the search strategy for the systematic review. All authors revised the manuscript 23 24 critically for important intellectual content. All authors read and approved the final manuscript. 25 26 27 28 Funding 29 30 This research received no specific grant from any funding agency in the public, 31

32 commercial or not-for-profit sectors. CCD was supported by a fellowship from the Australian National http://bmjopen.bmj.com/ 33 34 Health and Medical Research Council (NHMRC), grant number APP1123733. 35 36 37 38 Competing interests statement 39 No conflict of interest to declare. 40 on September 26, 2021 by guest. Protected copyright. 41 42 43 Word count 44 45 Abstract 283, Main text 2,328 46 47 48 49 50 51 52 53 54 55 56 57 58 13 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 14 of 43 BMJ Open: first published as 10.1136/bmjopen-2018-027935 on 5 May 2019. Downloaded from 1 2 3 References 4 5 1. Postma DS, Bush A, van den Berge M. Risk factors and early origins of chronic 6 7 obstructive pulmonary disease. Lancet (London, England) 2015;385(9971):899-909. doi: 8 9 10.1016/s0140-6736(14)60446-3 [published Online First: 2014/08/16] 10 11 2. Adeloye D, Chua S, Lee C, et al. Global and regional estimates of COPD prevalence: 12 13 Systematic review and meta-analysis. Journal of global health 2015;5(2):020415. doi: 14 15 10.7189/jogh.05-020415 [published Online First: 2016/01/13] 16 For peer review only 17 3. Murray CJ, Vos T, Lozano R, et al. Disability-adjusted life years (DALYs) for 291 18 diseases and injuries in 21 regions, 1990-2010: a systematic analysis for the Global 19 20 Burden of Disease Study 2010. Lancet (London, England) 2012;380(9859):2197-223. 21 22 doi: 10.1016/s0140-6736(12)61689-4 [published Online First: 2012/12/19] 23 24 4. Lozano R, Naghavi M, Foreman K, et al. Global and regional mortality from 235 causes 25 26 of death for 20 age groups in 1990 and 2010: a systematic analysis for the Global Burden 27 28 of Disease Study 2010. Lancet (London, England) 2012;380(9859):2095-128. doi: 29 30 10.1016/s0140-6736(12)61728-0 [published Online First: 2012/12/19] 31

32 5. Wang C, Xu J, Yang L, et al. Prevalence and risk factors of chronic obstructive http://bmjopen.bmj.com/ 33 34 pulmonary disease in China (the China Pulmonary Health [CPH] study): a national cross- 35 36 sectional study. Lancet (London, England) 2018;391(10131):1706-17. doi: 37 38 10.1016/s0140-6736(18)30841-9 [published Online First: 2018/04/14] 39 6. Hakim MA, Garden FL, Jennings MD, et al. Performance of the LACE index to predict 30- 40 on September 26, 2021 by guest. Protected copyright. 41 day hospital readmissions in patients with chronic obstructive pulmonary disease. Clinical 42 43 epidemiology 2018;10:51-59. doi: 10.2147/clep.s149574 [published Online First: 44 45 2018/01/19] 46 47 7. Horita N, Goto A, Shibata Y, et al. Long-acting muscarinic antagonist (LAMA) plus long- 48 49 acting beta-agonist (LABA) versus LABA plus inhaled corticosteroid (ICS) for stable 50 51 chronic obstructive pulmonary disease (COPD). Cochrane Database Syst Rev 52 53 2017;2:CD012066. doi: https://dx.doi.org/10.1002/14651858.CD012066.pub2 54 55 56 57 58 14 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 15 of 43 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2018-027935 on 5 May 2019. Downloaded from 1 2 3 8. Calzetta L, Ora J, Cavalli F, et al. Impact of LABA/LAMA combination on exercise 4 5 endurance and lung hyperinflation in COPD: A pair-wise and network meta-analysis. 6 7 Respir Med 2017;129:189-98. doi: https://dx.doi.org/10.1016/j.rmed.2017.06.020 8 9 9. Farne HA, Cates CJ. Long-acting beta2-agonist in addition to tiotropium versus either 10 11 tiotropium or long-acting beta2-agonist alone for chronic obstructive pulmonary disease. 12 13 Cochrane Database Syst Rev 2015(10):CD008989. doi: 14 15 https://dx.doi.org/10.1002/14651858.CD008989.pub3 16 For peer review only 17 10. Rodrigo GJ, Price D, Anzueto A, et al. LABA/LAMA combinations versus LAMA 18 monotherapy or LABA/ICS in COPD: a systematic review and meta-analysis. Int J Chron 19 20 Obstruct Pulmon Dis 2017;12:907-22. doi: https://dx.doi.org/10.2147/COPD.S130482 21 22 11. Karner C, Cates CJ. Combination inhaled steroid and long-acting beta(2)-agonist in 23 24 addition to tiotropium versus tiotropium or combination alone for chronic obstructive 25 26 pulmonary disease. Cochrane Database Syst Rev 2011(3):CD008532. doi: 27 28 https://dx.doi.org/10.1002/14651858.CD008532.pub2 29 30 12. Kwak M-S, Kim E, Jang EJ, et al. The efficacy and safety of triple inhaled treatment in 31

32 patients with chronic obstructive pulmonary disease: a systematic review and meta- http://bmjopen.bmj.com/ 33 34 analysis using Bayesian methods. Int J Chron Obstruct Pulmon Dis 2015;10:2365-76. 35 36 doi: https://dx.doi.org/10.2147/COPD.S93191 37 38 13. Nannini LJ, Lasserson TJ, Poole P. Combined corticosteroid and long-acting beta(2)- 39 agonist in one inhaler versus long-acting beta(2)-agonists for chronic obstructive 40 on September 26, 2021 by guest. Protected copyright. 41 pulmonary disease. Cochrane Database Syst Rev 2012(9):CD006829. doi: 42 43 https://dx.doi.org/10.1002/14651858.CD006829.pub2 44 45 14. Nannini LJ, Poole P, Milan SJ, et al. Combined corticosteroid and long-acting beta(2)- 46 47 agonist in one inhaler versus inhaled corticosteroids alone for chronic obstructive 48 49 pulmonary disease. Cochrane Database Syst Rev 2013(8):CD006826. doi: 50 51 https://dx.doi.org/10.1002/14651858.CD006826.pub2 52 53 15. Rojas-Reyes MX, Garcia Morales OM, Dennis RJ, et al. Combination inhaled steroid and 54 55 long-acting beta2-agonist in addition to tiotropium versus tiotropium or combination alone 56 57 58 15 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 16 of 43 BMJ Open: first published as 10.1136/bmjopen-2018-027935 on 5 May 2019. Downloaded from 1 2 3 for chronic obstructive pulmonary disease. Cochrane Database Syst Rev 4 5 2016(6):CD008532. doi: https://dx.doi.org/10.1002/14651858.CD008532.pub3 6 7 16. Welsh EJ, Cates CJ, Poole P. Combination inhaled steroid and long-acting beta2-agonist 8 9 versus tiotropium for chronic obstructive pulmonary disease. Cochrane Database Syst 10 11 Rev 2013(5) 12 13 17. Singh S, Amin AV, Loke YK. Long-term use of inhaled corticosteroids and the risk of 14 15 pneumonia in chronic obstructive pulmonary disease: a meta-analysis. Arch Intern Med 16 For peer review only 17 2009;169(3):219-29. doi: https://dx.doi.org/10.1001/archinternmed.2008.550 18 18. Kew KM, Seniukovich A. Inhaled steroids and risk of pneumonia for chronic obstructive 19 20 pulmonary disease. Cochrane Database Syst Rev 2014(3):CD010115. doi: 21 22 https://dx.doi.org/10.1002/14651858.CD010115.pub2 23 24 19. Wedzicha JA, Banerji D, Chapman KR, et al. Indacaterol-Glycopyrronium versus 25 26 Salmeterol-Fluticasone for COPD. The New England journal of medicine 27 28 2016;374(23):2222-34. doi: 10.1056/NEJMoa1516385 [published Online First: 29 30 2016/05/18] 31

32 20. Magnussen H, Disse B, Rodriguez-Roisin R, et al. Withdrawal of inhaled glucocorticoids http://bmjopen.bmj.com/ 33 34 and exacerbations of COPD. The New England journal of medicine 2014;371(14):1285- 35 36 94. doi: 10.1056/NEJMoa1407154 [published Online First: 2014/09/10] 37 38 21. Bourbeau J, Bartlett SJ. Patient adherence in COPD. Thorax 2008;63(9):831-8. doi: 39 10.1136/thx.2007.086041 [published Online First: 2008/08/30] 40 on September 26, 2021 by guest. Protected copyright. 41 22. Agh T, Inotai A, Meszaros A. Factors associated with medication adherence in patients 42 43 with chronic obstructive pulmonary disease. Respiration; international review of thoracic 44 45 diseases 2011;82(4):328-34. doi: 10.1159/000324453 [published Online First: 46 47 2011/04/02] 48 49 23. Harb N, Foster JM, Dobler CC. Patient-perceived treatment burden of chronic obstructive 50 51 pulmonary disease. Int J Chron Obstruct Pulmon Dis 2017;12:1641-52. doi: 52 53 10.2147/copd.s130353 [published Online First: 2017/06/16] 54 55 56 57 58 16 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 17 of 43 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2018-027935 on 5 May 2019. Downloaded from 1 2 3 24. Dobler CC, Harb N, Maguire CA, et al. Treatment burden should be included in clinical 4 5 practice guidelines. BMJ (Clinical research ed) 2018;363:k4065. doi: 10.1136/bmj.k4065 6 7 [published Online First: 2018/10/14] 8 9 25. Safka KA, McIvor RA. Non-pharmacological management of chronic obstructive 10 11 pulmonary disease. The Ulster medical journal 2015;84(1):13-21. [published Online First: 12 13 2015/05/13] 14 15 26. Stiggelbout AM, Van der Weijden T, De Wit MP, et al. Shared decision making: really 16 For peer review only 17 putting patients at the centre of healthcare. BMJ (Clinical research ed) 2012;344:e256. 18 doi: 10.1136/bmj.e256 [published Online First: 2012/01/31] 19 20 27. Elwyn G, Frosch D, Thomson R, et al. Shared decision making: a model for clinical 21 22 practice. Journal of general internal medicine 2012;27(10):1361-7. doi: 10.1007/s11606- 23 24 012-2077-6 [published Online First: 2012/05/24] 25 26 28. Dobler CC, Sanchez M, Gionfriddo MR, et al. Impact of decision aids used during clinical 27 28 encounters on clinician outcomes and consultation length: a systematic review. BMJ 29 30 quality & safety 2018 doi: 10.1136/bmjqs-2018-008022 [published Online First: 31

32 2018/10/12] http://bmjopen.bmj.com/ 33 34 29. Dobler CC, Midthun DE, Montori VM. Quality of Shared Decision Making in Lung Cancer 35 36 Screening: The Right Process, With the Right Partners, at the Right Time and Place. 37 38 Mayo Clinic proceedings 2017;92(11):1612-16. doi: 10.1016/j.mayocp.2017.08.010 39 [published Online First: 2017/11/06] 40 on September 26, 2021 by guest. Protected copyright. 41 30. Shamseer L, Moher D, Clarke M, et al. Preferred reporting items for systematic review 42 43 and meta-analysis protocols (PRISMA-P) 2015: elaboration and explanation. BMJ 44 45 (Clinical research ed) 2015;350:g7647. doi: 10.1136/bmj.g7647 [published Online First: 46 47 2015/01/04] 48 49 31. Shea BJ, Reeves BC, Wells G, et al. AMSTAR 2: a critical appraisal tool for systematic 50 51 reviews that include randomised or non-randomised studies of healthcare interventions, 52 53 or both. BMJ (Clinical research ed) 2017;358:j4008. doi: 10.1136/bmj.j4008 [published 54 55 Online First: 2017/09/25] 56 57 58 17 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 18 of 43 BMJ Open: first published as 10.1136/bmjopen-2018-027935 on 5 May 2019. Downloaded from 1 2 3 32. Miake-Lye IM, Hempel S, Shanman R, et al. What is an evidence map? A systematic 4 5 review of published evidence maps and their definitions, methods, and products. 6 7 Systematic reviews 2016;5:28. doi: 10.1186/s13643-016-0204-x [published Online First: 8 9 2016/02/13] 10 11 33. Global Strategy for Prevention, Diagnosis and Management of COPD, 2018 reprt. 12 13 Available at: http://goldcopd.org/wp-content/uploads/2017/11/GOLD-2018-v6.0-FINAL- 14 15 revised-20-Nov_WMS.pdf Accessed May 15, 2018. 16 For peer review only 17 34. Bangerter LR, Griffin JM, Langer S, et al. The Effect of Psychosocial Interventions on 18 Outcomes for Caregivers of Hematopoietic Cell Transplant Patients. Current hematologic 19 20 malignancy reports 2018 doi: 10.1007/s11899-018-0445-y [published Online First: 21 22 2018/05/01] 23 24 35. Farah WH, Alsawas M, Mainou M, et al. Non-pharmacological treatment of depression: a 25 26 systematic review and evidence map. Evidence-based medicine 2016;21(6):214-21. doi: 27 28 10.1136/ebmed-2016-110522 [published Online First: 2016/11/12] 29 30 31

32 http://bmjopen.bmj.com/ 33 34 35 36 37 38 39

40 on September 26, 2021 by guest. Protected copyright. 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 18 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open: first published as 10.1136/bmjopen-2018-027935 on 5 May 2019. Downloaded from

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1 2 3 PRISMA-P (Preferred Reporting Items for Systematic review and Meta-Analysis Protocols) 2015 checklist: recommended items to 4 address in a systematic review protocol* 5 6 Section and topic Item No Checklist item 7 8 ADMINISTRATIVE INFORMATION 9 Title: 10 Identification 1a Identify the report as a protocol of a systematic review 11 Update 1b If the protocol is for an update of a previous systematic review, identify as such 12 Registration 2For If registered, peer provide the name review of the registry (such as PROSPERO) only and registration number 13 14 Authors: 15 Contact 3a Provide name, institutional affiliation, e-mail address of all protocol authors; provide physical mailing address of 16 corresponding author http://bmjopen.bmj.com/ 17 Contributions 3b Describe contributions of protocol authors and identify the guarantor of the review 18 Amendments 4 If the protocol represents an amendment of a previously completed or published protocol, identify as such and list changes; 19 otherwise, state plan for documenting important protocol amendments 20 Support: 21 Sources 5a Indicate sources of financial or other support for the review 22 Sponsor 5b Provide name for the review funder and/or sponsor 23 24 Role of sponsor or funder 5c Describe roles of funder(s), sponsor(s), and/or institution(s), if any, in developing on September 26, 2021 by guest. Protected copyright. the protocol 25 INTRODUCTION 26 27 Rationale 6 Describe the rationale for the review in the context of what is already known 28 Objectives 7 Provide an explicit statement of the question(s) the review will address with reference to participants, interventions, 29 comparators, and outcomes (PICO) 30 METHODS 31 32 Eligibility criteria 8 Specify the study characteristics (such as PICO, study design, setting, time frame) and report characteristics (such as years 33 considered, language, publication status) to be used as criteria for eligibility for the review 34 Information sources 9 Describe all intended information sources (such as electronic databases, contact with study authors, trial registers or other 35 grey literature sources) with planned dates of coverage 36 Search strategy 10 Present draft of search strategy to be used for at least one electronic database, including planned limits, such that it could be 37 repeated 38 Study records: 39 Data management 11a Describe the mechanism(s) that will be used to manage records and data throughout the review 40 41 42 43 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2018-027935 on 5 May 2019. Downloaded from

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1 2 3 Selection process 11b State the process that will be used for selecting studies (such as two independent reviewers) through each phase of the 4 review (that is, screening, eligibility and inclusion in meta-analysis) 5 Data collection process 11c Describe planned method of extracting data from reports (such as piloting forms, done independently, in duplicate), any 6 processes for obtaining and confirming data from investigators 7 Data items 12 List and define all variables for which data will be sought (such as PICO items, funding sources), any pre-planned data 8 assumptions and simplifications 9 10 Outcomes and prioritization 13 List and define all outcomes for which data will be sought, including prioritization of main and additional outcomes, with rationale 11 12 Risk of bias in individual studies 14 Describe anticipated methods for assessing risk of bias of individual studies, including whether this will be done at the Foroutcome peer or study level, or both; review state how this information onlywill be used in data synthesis 13 14 Data synthesis 15a Describe criteria under which study data will be quantitatively synthesised 15 15b If data are appropriate for quantitative synthesis, describe planned summary measures, methods of handling data and 16 methods of combining data from studies, including any planned exploration of consistencyhttp://bmjopen.bmj.com/ (such as I2, Kendall’s τ) 17 15c Describe any proposed additional analyses (such as sensitivity or subgroup analyses, meta-regression) 18 15d If quantitative synthesis is not appropriate, describe the type of summary planned 19 Meta-bias(es) 16 Specify any planned assessment of meta-bias(es) (such as publication bias across studies, selective reporting within studies) 20 Confidence in cumulative evidence 17 Describe how the strength of the body of evidence will be assessed (such as GRADE) 21

22 * It is strongly recommended that this checklist be read in conjunction with the PRISMA-P Explanation and Elaboration (cite when available) for important 23 clarification on the items. Amendments to a review protocol should be tracked and dated. The copyright for PRISMA-P (including checklist) is held by the

on September 26, 2021 by guest. Protected copyright. 24 PRISMA-P Group and is distributed under a Creative Commons Attribution Licence 4.0. 25 26 From: Shamseer L, Moher D, Clarke M, Ghersi D, Liberati A, Petticrew M, Shekelle P, Stewart L, PRISMA-P Group. Preferred reporting items for systematic review and 27 meta-analysis protocols (PRISMA-P) 2015: elaboration and explanation. BMJ. 2015 Jan 2;349(jan02 1):g7647. 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 Page 21 of 43 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2018-027935 on 5 May 2019. Downloaded from 1 2 3 Literature search strategy for 4 5 Treatment of stable chronic obstructive pulmonary disease: a protocol for a systematic 6 7 review and evidence map 8 9

10 11 1 1 1 1 1 Claudia C. Dobler, Magdoleen H Farah, Allison S. Morrow, Mouaz Alsawas, Raed Benkhadra Bashar 12 13 Hasan,1 Larry J Prokop,2 Zhen Wang,1 M. Hassan Murad1 14 15 16 For peer review only 17 1) Evidence-Based Practice Center, Robert D. and Patricia E. Kern Center for the Science of Health 18 19 Care Delivery, Mayo Clinic, Rochester, Minnesota, USA 20 21 2) Library Public Services, Mayo Clinic, Rochester, Minnesota, USA. 22 23 24 25 26 27 Ovid 28 29 Part 1 30 31 Database(s): Embase 1988 to 2018 Week 16, EBM Reviews - Cochrane Database of Systematic

32 Reviews 2005 to April 11, 2018, Ovid MEDLINE(R) Epub Ahead of Print, In-Process & Other Non- http://bmjopen.bmj.com/ 33 Indexed Citations, Ovid MEDLINE(R) Daily and Ovid MEDLINE(R) 1946 to Present Search Strategy: 34 35 # Searches Results exp Pulmonary Disease, Chronic Obstructive/dh, dt, px, rh, su, th [Diet Therapy, Drug 36 1 18829 37 Therapy, Psychology, Rehabilitation, Surgery, Therapy] 38 exp chronic obstructive lung disease/dm, dt, rh, su, th [Disease Management, Drug Therapy, 2 27067 39 Rehabilitation, Surgery, Therapy] 40 3 1 or 2 45896 on September 26, 2021 by guest. Protected copyright. 41 ("chronic airflow disease*" or "chronic airflow disorder*" or "chronic airflow limitation*" or 42 "chronic airflow obstruction*" or "chronic airway disease*" or "chronic airway disorder*" or 43 "chronic airway limitation*" or "chronic airway obstruction*" or "chronic bronchitis" or "chronic 44 obstructive airflow disease*" or "chronic obstructive airflow disorder*" or "chronic obstructive 45 airway disease*" or "chronic obstructive airway disorder*" or "chronic obstructive bronchitis" 46 or "chronic obstructive bronchopulmonary disease*" or "chronic obstructive broncho- 47 pulmonary disease*" or "chronic obstructive bronchopulmonary disorder*" or "chronic 48 obstructive broncho-pulmonary disorder*" or "chronic obstructive lung disease*" or "chronic 4 248757 49 obstructive lung disorder*" or "chronic obstructive pulmonary disease*" or "chronic 50 obstructive pulmonary disorder*" or "chronic obstructive respiratory disease*" or "chronic 51 obstructive respiratory disorder*" or coad or copd or emphysema or "obstructive lung 52 disease" or "obstructive lung disorder*" or "obstructive pulmonary disease*" or "obstructive 53 pulmonary disorder*" or "obstructive pulmonary tract disease*" or "obstructive pulmonary 54 tract disorder*" or "obstructive respiratory disease*" or "obstructive respiratory disorder*" or 55 "obstructive respiratory tract disease*" or "obstructive respiratory tract 56 disorder*").ti,ab,hw,kw. 57 58 1 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 22 of 43 BMJ Open: first published as 10.1136/bmjopen-2018-027935 on 5 May 2019. Downloaded from 1 2 3 5 exp Bronchodilator Agents/ 383398 4 5 (abediterol or acefylline or "acefylline clofibrol" or "acefylline piperazine" or "aclidinium bromide" or "adrenalin hydrogen tartrate" or Adrenomedullin or Albuterol or ambuphylline or 6 Aminophylline or antibronchospastic or arformoterol or Atropine or bambuterol or bamifylline 7 or baralgin or batefenterol or bitolterol or "bitolterol mesilate" or "bronchial dilating" or 8 "bronchial-dilating" or bronchodilatant* or "broncho-dilatant*" or bronchodilatating or 9 "broncho-dilatating" or bronchodilatator* or "broncho-dilatator*" or bronchodilating or 10 "broncho-dilating" or bronchodilator* or "broncho-dilator*" or broncholytic* or broncholytica or 11 bronchospasmolytic or broxaterol or Budesonide or carbuterol or carmoterol or "choline 12 theophyllinate" or Clenbuterol or clorprenaline or Colforsin or Cromakalim or danirixin or 13 "darotropium bromide" or dilator* or diprophylline or ditec or doxofylline or Dyphylline or 14 elubrixin or enprofylline or ephedrine or "ephedrine sulfate" or Epinephrine or eprozinol or 15 espatropate or etafedrine or etamiphyllin or "etamiphyllin camsilate" or etanterol or etofylline 16 or Fenoterol or fenspirideFor or Fluticasonepeer or review"flutropium bromide" only or formoterol or "Formoterol 17 Fumarate" or furafylline or glycopyrronium or "gsk 159802" or "gsk 597901" or guaifylline or 6 860675 18 "gw 678007" or Hexoprenaline or Hyoscyamine or ibuterol or "ilmetropium iodide" or 19 imoxiterol or indacaterol or inhaler* or Ipratropium or "ipratropium bromide" or isbufylline or 20 isoetarine or "isoetarine mesylate" or Isoetharine or isoprenaline or Isoproterenol or Khellin 21 or laprafylline or levalbuterol or mabuterol or marax or Metaproterenol or methoxyphenamine 22 or milveterol or "n methylmequitazine" or naminterol or neobiphyllin or nestifylline or "Nitric 23 Oxide" or olodaterol or orciprenaline or "oxitropium bromide" or "oxyphenonium bromide" or 24 pibaxizine or pirbuterol or "pirbuterol acetate" or pneumodilator or Procaterol or protokylol or 25 proxyphylline or Pseudoephedrine or racephedrine or Racepinephrine or reproterol or 26 rimiterol or "ru 45703" or salbutamol or "salbutamol sulfate" or salmefamol or salmeterol or 27 "Salmeterol Xinafoate" or sibenadet or "S-Nitrosoglutathione" or "S-Nitrosothiols" or 28 soterenol or tazifylline or Terbutaline or Theobromine or Theophylline or "theophylline sodium glycinate" or thiazinamium or "thiazinamium metilsulfate" or Tiotropium or Tretoquinol 29 or "tretoquinol derivative" or trimetaquinol or tulobuterol or "uk 432097" or Umeclidinium or 30 vephylline or verofylline or vilanterol or "vilanterol trifenatate" or zindotrine).ti,ab,hw,kw. 31

32 7 exp Adrenergic beta-2 Receptor Agonists/ 82439 http://bmjopen.bmj.com/ 33 ("adrenergic beta 2 agonist*" or "adrenergic beta 2 receptor agonist*" or "adrenergic beta2 34 agonist*" or "adrenergic beta-2 agonist*" or "adrenergic beta-2 receptor agonist*" or 35 "adrenergic beta2-agonist*" or Albuterol or "beta 2 adrenergic agent*" or "beta 2 adrenergic 36 agonist*" or "beta 2 adrenergic receptor agonist*" or "beta 2 adrenergic receptor stimulant*" 37 or "beta 2 adrenergic receptor stimulat*" or "beta 2 adrenergic receptor stimulator*" or "beta 2 adrenergic stimulant*" or "beta 2 adrenergic stimulat*" or "beta 2 adrenergic stimulator*" or 38 8 83917 39 "beta 2 adrenoceptor agonist*" or "beta 2 adrenoceptor stimulant*" or "beta 2 adrenoceptor stimulat**" or "beta 2 adrenoceptor stimulator*" or "beta 2 agonist*" or "beta agonist*" or 40 on September 26, 2021 by guest. Protected copyright. "beta receptor agonist*" or "beta receptor stimulant*" or "beta stimulant" or "beta2 adrenergic 41 receptor stimulat*" or Fenoterol or formoterol or Hexoprenaline or indacaterol or Isoetharine 42 or LABA or LABAs or Metaproterenol or Procaterol or Ritodrine or SABA or SABAs or 43 salmeterol or "Salmeterol Xinafoate" or Terbutaline).ti,ab,hw,kw. 44 45 9 exp Cholinergic Antagonists/ 215195 46 ("acetylcholine antagonist*" or "acetylcholine receptor block*" or "acetylcholine receptor 47 inhibitor*" or "AChR inhibitor" or aclidinium or "aclidinium bromide" or acotiamide or 48 adiphenine or afacifenacin or Alcuronium or "alpha conotoxin MII" or alvameline or alverine 49 or "alverine citrate" or anisodamine or "anti cholinergics" or anticholinergic or anticholinergic* 50 or "anti-cholinergic*" or antimuscarinic* or aprofene or aspaminol or Atracurium or Atropine 51 10 or atropinic* or azaprophen or belladonna or bellergal or Benactyzine or benzetimide or 400683 52 benzilonium or "benzilylcholine mustard" or benzoquinonium or Benztropine or Biperiden or bornaprine or Butylscopolammonium or buzepide or catestatin or "central anticholinergic" or 53 Chlorisondamine or chlorphenoxamine or cholinolytic* or cimetropium or clidinium or Curare 54 or Cyclopentolate or cycrimine or darifenacin or darotropium or deptropine or 55 desfesoterodine or Dexetimide or dexmecamylamine or "dibutoline sulfate" or Dicyclomine or 56 57 58 2 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 23 of 43 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2018-027935 on 5 May 2019. Downloaded from 1 2 3 dicycloverine or diethazine or dimevamide or "diphemanil methylsulfate" or drofenine or 4 elantrine or Emepronium or espatropate or Ethidium or "ethylcholine mustard aziridinium" or 5 eucatropine or fenoverine or fenpipramide or fenpiverinium or fesoterodine or fluperlapine or 6 flutropium or furtramine or "Gallamine Triethiodide" or ganglefene or Glycopyrrolate or 7 glycopyrronium or "gsk 202405" or "h cholinoreactive cell*" or hemicholinium or 8 hexahydrodifenidol or hexahydroprocyclidine or hexahydrosiladifenidol or Hexamethonium or 9 hexbutinol or "hexbutinol methiodide" or "hexocyclium metilsulfate" or himbacine or 10 homatropine or "homatropine methyl" or "homatropine terephthalate" or Hyoscyamine or 11 imidafenacin or Ipratropium or isomylamine or "isopropamide iodide" or LAMA or LAMAs or 12 levetimide or lophotoxin or mazaticol or Mecamylamine or mefurtramine or mepenzolate or 13 meptazinol or "meta cholinoreactive cell*" or methantheline or methoctramine or 14 methylatropine or methyllycaconitine or methylscopolamine or metixene or muscarinic* or 15 muscarinolytic* or "nicotine tartrate" or nicotinic* or nuvenzepine or "octatropine 16 methylbromide" orFor Orphenadrine peer or otenzepad review or oxitropium or onlyoxybutynin or 17 oxyphencyclimine or Oxyphenonium or Pancuronium or "para fluorohexahydrosiladifenidol" 18 or "para fluorohexbutinol" or parapenzolate or "parasympathetic block*" or "parasympathetic 19 inhibitor*" or parasympathicolytic* or parasympatholytic* or parasympatolytic* or Pempidine 20 or penthienate or "Pentolinium Tartrate" or phenglutarimide or Pipecuronium or pipenzolate 21 or piperidolate or piperphenamine or pipethanate or Pirenzepine or piroheptine or "poldine 22 methylsulfate" or pridinol or "pridinol mesilate" or "prifinium bromide" or Procyclidine or profenamine or proglumide or Propantheline or propiverine or "propylbenziloylcholine 23 mustard" or "Propylbenzilylcholine Mustard" or pyrrinol or Quinidine or "Quinuclidinyl 24 Benzilate" or revatropate or revefenacin or rispenzepine or SAMA or SAMAs or Scopolamine 25 or secoverine or silahexocyclium or siltenzepine or sofpironium or solifenacin or "Solifenacin 26 Succinate" or stramonium or sydnofen or tarafenacin or telenzepine or tematropium or 27 temiverine or thiazinamium or "thiazinamium metilsulfate" or thihexinol or "tiemonium iodide" 28 or "tiemonium methylsulfate" or tifenamil or timepidium or Tiotropium or tofenacin or 29 tolterodine or "Tolterodine Tartrate" or tonopan or Toxiferine or tricyclamol or "tridihexethyl 30 chloride" or Trihexyphenidyl or Trimethaphan or triperidene or tripitramine or tropacin or 31 Tropicamide or tropine or "tropine benzoate" or "trospium chloride" or troventol or 32 Tubocurarine or umeclidinium or valethamate or vamicamide or Vecuronium or vedaclidine http://bmjopen.bmj.com/ 33 or zamifenacin or zolenzepine).ti,ab,hw,kw. 34 11 exp Phosphodiesterase 4 Inhibitors/ 10642 35 (apremilast or arofylline or atizoram or benzafentrine or catramilast or cilomilast or 36 cipamfylline or daxalipram or denbufylline or elbimilast or filaminast or ibudilast or indimilast 37 or lavamilast or nitraquazone or oglemilast or "PDE 4 inhibitor*" or "PDE IV inhibitor*" or 38 "PDE type 4 inhibitor*" or "PDE type IV inhibitor*" or "pde-4 inhibitor*" or "PDE4 inhibitor*" or 12 12671 39 "phosphodiesterase 4 inhibitor*" or "phosphodiesterase IV inhibitor*" or "phosphodiesterase 40 type 4 inhibitor*" or "phosphodiesterase type IV inhibitor*" or piclamilast or pumafentrine or on September 26, 2021 by guest. Protected copyright. 41 revamilast or roflumilast or Rolipram or tetomilast or tibenelast or tilivapram or tipelukast or 42 tofimilast or tolafentrine or zardaverine).ti,ab,hw,kw. 43 13 or/5-12 1192205 44 45 14 4 and 13 38943 46 15 3 or 14 67111 47 16 exp meta analysis/ 229890 48 17 exp "systematic review"/ 165306 49 18 ((meta adj analys*) or (systematic* adj3 review*)).ti,ab,hw,kw,pt. 589817 50 51 19 16 or 17 or 18 589821 52 20 15 and 19 2911 53 limit 20 to (editorial or erratum or letter or note or addresses or autobiography or bibliography 54 or biography or blogs or comment or dictionary or directory or interactive tutorial or interview 21 161 55 or lectures or legal cases or legislation or news or newspaper article or overall or patient 56 education handout or periodical index or portraits or published erratum or video-audio media 57 58 3 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 24 of 43 BMJ Open: first published as 10.1136/bmjopen-2018-027935 on 5 May 2019. Downloaded from 1 2 3 or webcasts) [Limit not valid in Embase,CDSR,Ovid MEDLINE(R),Ovid MEDLINE(R) Daily 4 Update,Ovid MEDLINE(R) In-Process,Ovid MEDLINE(R) Publisher; records were retained] 5 22 20 not 21 2750 6 7 23 from 15 keep 41670-41728 59 8 24 22 or 23 2809 9 25 remove duplicates from 24 2077 10 11 12 13 14 15 16 For peer review only 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31

32 http://bmjopen.bmj.com/ 33 34 35 36 37 38 39

40 on September 26, 2021 by guest. Protected copyright. 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 4 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 25 of 43 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2018-027935 on 5 May 2019. Downloaded from 1 2 3 Part 2 4 5 Database(s): Embase 1988 to 2018 Week 16, EBM Reviews - Cochrane Database of Systematic 6 Reviews 2005 to April 11, 2018, Ovid MEDLINE(R) Epub Ahead of Print, In-Process & Other Non- 7 Indexed Citations, Ovid MEDLINE(R) Daily and Ovid MEDLINE(R) 1946 to Present 8 Search Strategy: 9 # Searches Results 10 ("chronic airflow disease*" or "chronic airflow disorder*" or "chronic airflow limitation*" or 11 "chronic airflow obstruction*" or "chronic airway disease*" or "chronic airway disorder*" or 12 "chronic airway limitation*" or "chronic airway obstruction*" or "chronic bronchitis" or "chronic 13 obstructive airflow disease*" or "chronic obstructive airflow disorder*" or "chronic obstructive 14 airway disease*" or "chronic obstructive airway disorder*" or "chronic obstructive bronchitis" 15 or "chronic obstructive bronchopulmonary disease*" or "chronic obstructive broncho- 16 pulmonary disease*"For or "chronic peer obstructive review bronchopulmonary onlydisorder*" or "chronic 17 obstructive broncho-pulmonary disorder*" or "chronic obstructive lung disease*" or "chronic 1 248757 18 obstructive lung disorder*" or "chronic obstructive pulmonary disease*" or "chronic 19 obstructive pulmonary disorder*" or "chronic obstructive respiratory disease*" or "chronic 20 obstructive respiratory disorder*" or coad or copd or emphysema or "obstructive lung 21 disease" or "obstructive lung disorder*" or "obstructive pulmonary disease*" or "obstructive 22 pulmonary disorder*" or "obstructive pulmonary tract disease*" or "obstructive pulmonary 23 tract disorder*" or "obstructive respiratory disease*" or "obstructive respiratory disorder*" or 24 "obstructive respiratory tract disease*" or "obstructive respiratory tract 25 disorder*").ti,ab,hw,kw. 26 2 exp Antibiotic Prophylaxis/ 39823 27 3 exp Anti-Bacterial Agents/ 3061033 28 4 exp antibiotic agent/ 986815 29 30 ("1 methylmocimycin*" or "11 deoxydaunorubicin*" or "14 hydroxyclarithromycin*" or "19 31 deformyl 4 deoxydesmycosin*" or "19 deformyldesmycosin*" or "2 acetylerythromycin*" or "2 fluoroidarubicin*" or "2 n ethylnetilmicin*" or "2 pyrrolinodoxorubicin*" or "21 aminoepothilone 32 http://bmjopen.bmj.com/ B" or "3 3 cyanomorpholino 3 deaminodoxorubicin*" or "3 deamino 2 fluoro 3 33 hydroxydoxorubicin 14 pimelate" or "3 deamino 3 morpholinodoxorubicin*" or "3 deamino 3 34 morpholinooxaunomycin*" or "4 demethoxy 11 deoxydaunomycinone" or "4 35 demethoxydaunomycinone" or "4 demethoxydoxorubicin*" or "4 deoxydesmycosin*" or "4 36 iodoesorubicin*" or "5 iminodaunorubicin*" or "6 n ethylnetilmicin*" or "6beta iodopenicillanic 37 acid" or "9 deacetyl 9 methylidarubicin*" or "9 deoxydoxorubicin*" or "9 dihydroerythronolide 38 A" or "a 102395" or "a 10255" or "a 10947" or "a 130b" or "a 192411" or "a 63075" or 39 abkhazomycin* or abyssomicin* or acetomycin* or acetylspiramycin* or aclacinomycin* or 40 aclarubicin* or actagardin* or actaplanin* or actinorhodine or "aculeacin A" or aculeximycin* on September 26, 2021 by guest. Protected copyright. 41 or adicillin* or aditoprim or adriamycinone or agglomerin* or aklavinone or alafosfalin* or 42 Alamethicin* or albocycline or aldecalmycin* or aldoxorubicin* or alisamycin* or allicin* or 5 2430080 43 almecillin* or "alpha defensin*" or ambruticin* or Amdinocillin* or amfomycin* or Amikacin* or 44 aminoglycoside* or aminopenicillin* or "Aminosalicylic Acid" or Amoxicillin* or "Amphotericin 45 B" or Ampicillin* or amrubicin* or "angucycline derivative" or anhydrochlortetracycline or 46 anhydroepitetracycline or anhydrotetracycline or anidulafungin* or Anisomycin* or 47 annamycin* or ansamitocin* or "ansamycin derivative" or anthracycline* or anthracyclinone* 48 or antibacterial* or "anti-bacterial*" or antibiotic* or "anti-biotic*" or "antimicrobial cationic 49 peptide*" or Antimycin* or antimycobacterial* or "anti-mycobacterial*" or Antitreponemal* or 50 "Anti-treponemal*" or Antitubercular* or "Anti-tubercular*" or apalcillin* or aplasmomycin* or 51 "aplysianin E" or apramycin* or aristeromycin* or Arsphenamine or aspoxicillin* or 52 astromicin* or asukamycin* or "atpenin B" or auricularum or Aurodox or aurograb or 53 avibactam or avilamycin* or avoparcin* or azidamfenicol or azidocillin* or Azithromycin* or 54 Azlocillin* or Aztreonam or "aztreonam lysine" or azurocidin* or bacampicillin* or Bacitracin* or bacmecillinam or bactenecin* or bacteriocid* or Bacteriocin* or bafilomycin* or balhimycin* 55 or "baliz 2" or Bambermycin* or baquiloprim or "barminomycin I" or baycuten or beauvericin* 56 57 58 5 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 26 of 43 BMJ Open: first published as 10.1136/bmjopen-2018-027935 on 5 May 2019. Downloaded from 1 2 3 or beroline or berubicin* or berythromycin* or "beta defensin*" or betafectin* or "beta- 4 Lactam*" or "betaLactamase Inhibitor*" or "beta-Lactamase Inhibitor*" or betamipron or 5 bialaphos or biapenem or bicozamycin* or "biphenomycin A" or bluensomycin* or bombinin* 6 or "Bongkrekic Acid" or boromycin* or borrelidin* or "Brefeldin A" or brilacidin* or brobactam 7 or butalactin* or butirosin* or cadazolid or Calcimycin* or Candicidin* or Capreomycin* or 8 carbacephem or carbadox or carbapenem or "carbazomycin A" or Carbenicillin* or 9 carbomycin* or Carfecillin* or carindacillin* or carubicin* or carumonam or caspofungin* or 10 cathelicidin* or cecropin* or cefacetrile or Cefaclor or Cefadroxil or cefalexin* or cefaloglycin* 11 or cefaloram or cefaloridine or cefalotin* or Cefamandole or cefapirin* or Cefatrizine or 12 cefazaflur or cefazedone or Cefazolin* or cefbuperazone or cefcanel or cefcapene or 13 cefclidin* or cefdaloxime or cefdinir or cefditoren or cefepime or cefetamet or cefetecol or 14 cefilavancin* or Cefixime or cefluprenam or cefmatilen or Cefmenoxime or Cefmetazole or 15 cefminox or cefodizime or Cefonicid or Cefoperazone or ceforanide or cefoselis or 16 Cefotaxime or CefotetanFor or Cefotiampeer or cefovecin* review or Cefoxitin* only or cefozopran or cefpimizole 17 or cefpiramide or cefpirome or cefpodoxime or cefprozil or cefquinome or cefradine or 18 cefroxadine or Cefsulodin* or ceftaroline or Ceftazidime or cefteram or ceftezole or ceftibuten 19 or ceftiofur or Ceftizoxime or ceftobiprole or ceftolozane or Ceftriaxone or Cefuroxime or 20 cefuzonam or Cephacetrile or Cephalexin* or Cephaloglycin* or Cephaloridine or 21 cephalosporin* or Cephalothin* or cephamycin* or Cephapirin* or Cephradine or 22 chalcomycin* or Chloramphenicol* or chloroorienticin* or chloropolysporin* or chlorothricin* or chlorothricolide or Chlortetracycline or "chymotrypsin trypsin*" or ciadox or "cilastatin plus 23 imipenem" or "cinerubin A" or "cinerubin B" or cinoquidox or Ciprofloxacin* or cirramycin* or 24 Citrinin* or Clarithromycin* or "clavulanate potassium" or "Clavulanic Acid*" or Clindamycin* 25 or clomocycline or Cloxacillin* or colicin* or colistimethate or Colistin* or "concanamycin A" or 26 coumamidine or coumamycin* or "cp 63956" or cryptosporin* or Cyclacillin* or cycloheximide 27 or Cycloserine or cystargin* or "cytarabine plus daunorubicin*" or cytovaricin* or dactimicin* 28 or Dactinomycin* or dalbaheptide or dalbavancin* or dalfopristin* or "damavaricin Fc pentyl 29 ether" or Daptomycin* or daunomycinone or daunorubicin* or daunorubicinol or 30 "deacetoxycephalosporin C" or deacetylcefotaxime or "deacetylcephalosporin C" or 31 dealanylalahopcin* or decaplanin* or dechloroeremomycin* or decilorubicin* or defensin* or 32 Demeclocycline or dermaseptin* or dermcidin* or dermostatin* or desmycosin* or http://bmjopen.bmj.com/ 33 detorubicin* or Diarylquinoline* or Dibekacin* or Dicloxacillin* or dihydrostreptomycin* or 34 Diketopiperazines or dimethylchlortetracycline or dioxidine or dirithromycin* or Distamycin* or 35 "ditrisarubicin B" or doripenem or doxorubicin* or doxorubicinol or Doxycycline or drosocin* 36 or echinocandin* or Echinomycin* or Edeine or efepristin* or efrotomycin* or emimycin* or 37 endusamycin* or enniatin* or Enoxacin* or Enviomycin* or eperezolid or epetraborole or 38 epicillin* or epidermin* or epiderstatin* or epiroprim or epirubicin* or epirubicinol or 39 epitetracycline or epothilone* or "epsilon rhodomycinone" or eravacycline or eremomycin* or

40 ertapenem or Erythromycin* or erythromycylamine or erythronolide* or esorubicin* or on September 26, 2021 by guest. Protected copyright. 41 Ethambutol or Ethionamide or ethylhydrocupreine or etimicin* or evernimicin* or 42 everninomicin* or faeriefungin* or fidaxomicin* or Filipin* or "fleroxacin deacetylcefotaxime 43 ester" or flomoxef or flopristin* or florfenicol or Floxacillin* or flucloxacillin* or flumoxil or 44 Fluoroquinolone* or flurithromycin* or fomidacillin* or fortimicin* or Fosfomycin* or 45 fosmidomycin* or Framycetin* or fropenem or fungichromin* or furaquinocin* or furazidin* or "furazolium chloride" or furbenicillin* or fusafungine or "fusidate sodium" or "Fusidic Acid" or 46 fuzlocillin* or galarubicin* or gallidermin* or gamithromycin* or ganefromycin* or "ge 2270a" 47 or gentamicin* or gepotidacin* or globomycin* or gloximonam or "glycylcycline derivative" or 48 "gonadorelin6 dextro lysine 2 pyrrolinodoxorubicin*" or "goniodomin A" or Gramicidin* or 49 granulysin* or grisein* or guamecycline or habekacin* or hamycin* or hatomamicin* or 50 hedamycin* or heliomycin* or hepcidin* or hetacillin* or hexacycline or hidamicin* or "histatin 51 5" or histatin* or hygromycin* or hymeglusin* or hypothemycin* or iclaprim or idarubicin* or 52 idarubicinol or ikarugamycin* or "imidacloprid plus moxidectin*" or Imipenem or indolicidin* or 53 inostamycin* or iseganan or isepamicin* or Isoniazid or "isopenicillin N" or "isoswinholide A" 54 or istamycin* or "iturin A" or ixabepilone or Josamycin* or "k 252a" or kalafungin* or 55 Kanamycin* or kanendomycin* or kasugamycin* or kelfiprim or ketolide or kidamycin* or 56 kinamycin* or Kitasamycin* or "l 156602" or "l 733560" or "l 786392" or lactacystin* or 57 58 6 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 27 of 43 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2018-027935 on 5 May 2019. Downloaded from 1 2 3 Lactams or lactivicin* or "lactocin S" or lactococcin* or lactoferricin* or ladirubicin* or 4 laidlomycin* or lancovutide or lankamycin* or lanopepden or lanthiopeptin* or lantibiotic or 5 Lasalocid or latamoxef or lavanducyanin* or lefamulin* or lenampicillin* or lenapenem or 6 lenoremycin* or Leprostatic* or "leucinostatin A" or "leucinostatin B" or Leucomycin* or 7 leurubicin* or Levofloxacin* or lexithromycin* or "lff 571" or Lincomycin* or lincosamide* or 8 Linezolid or linopristin* or lividomycin* or "lonomycin A" or loracarbef or lotilibcin* or 9 Lucensomycin* or lydicamycin* or Lymecycline or lysobactin* or lysocellin* or lysostaphin* or 10 macrolide or magainin* or malyngolide or manumycin* or maridomycin* or "mdl 62208" or 11 "mdl 62211" or mecillinam or meclocycline or megacin* or megalomicin* or Mepartricin* or 12 meropenem or mersacidin* or metacycline or metampicillin* or Methacycline or Methicillin* or 13 "methylenomycin A" or "methylenomycin B" or methymycin* or methynolide or meticillin* or 14 Mezlocillin* or "microcin b17" or "microcin J25" or micronomicin* or midecamycin* or 15 mideplanin* or "mikamycin B" or Mikamycin* or "milbemycin oxime" or milbemycin* or 16 Minocycline or Miocamycin*For orpeer miokamycin* review or miporamicin* or onlymiraxid or mocimycin* or 17 "moenomycin A" or monensin* or "monobactam derivative" or Moxalactam or moxidectin* or 18 "ms 8209" or Mupirocin* or mureidomycin* or murepavadin* or mycinamicin* or Mycobacillin* 19 or mycolog or mycoticin* or myxothiazol or "n benzyldoxorubicin 14 valerate" or "n 20 trifluoroacetyldoxorubicin*" or Nafcillin* or "Nalidixic Acid" or narasin* or Natamycin* or 21 neamine or nebacetin* or Nebramycin* or negamycin* or nemadectin* or nemorubicin* or 22 Neomycin* or neosporin* or Netilmicin* or Netropsin* or niddamycin* or Nigericin* or Nisin* or nitrocefin* or nitrosochloramphenicol or "nocardicin A" or "nocardicin E" or "nocardicinic acid 23 derivative*" or Norfloxacin* or nosiheptide or nourseothricin* or Novobiocin* or "nvb 302" or 24 nybomycin* or Nystatin* or "oasomycin A" or obelmycin* or Ofloxacin* or olaquindox or 25 oleandolide or Oleandomycin* or oligomycin* or omadacycline or omiganan or optocillin* or 26 "orienticin A" or orientiparcin* or oritavancin* or oropivalone or Oxacillin* or oxaunomycin* or 27 "Oxolinic Acid" or Oxytetracycline or paldimycin* or panipenem or pardaxin* or 28 Paromomycin* or patulin* or pediazole or pediocin* or Pefloxacin* or penamecillin* or 29 penethamate or "Penicillanic Acid" or "Penicillic Acid" or penicillin* or "penicilloic acid" or 30 pentalenolactone or pentisomicin* or peptaibol or pexiganan or "pf 708093" or 31 phenelfamycin* or pheneticillin* or phleomycin* or pikromycin* or "Pipemidic Acid" or 32 Piperacillin* or pirarubicin* or pirazmonam or pirlimycin* or Pivampicillin* or pivmecillinam or http://bmjopen.bmj.com/ 33 platensimycin* or plazomicin* or plectasin* or pleuromutilin* or pluramycin* or 34 pneumocandin* or "polyactin A" or polyfungin* or polymyxin* or "polyoxin B" or "polyoxin D" 35 or polysporin* or polytrim or posizolid or "pr 39" or Pristinamycin* or Prodigiosin* or 36 prohepcidin* or propicillin* or protegrin* or Prothionamide or prothracarcin* or "pseudomonic 37 acid" or Pyrazinamide or pyrromycinone or pyrroxamycin* or quinacillin* or quinomycin* or 38 quinupristin* or radezolid or radicicol or ramoplanin* or ranalexin* or ranbezolid or 39 razupenem or retacillin* or retapamulin* or "rhodomycin A" or Ribostamycin* or Rifabutin* or

40 Rifampin* or Rifamycin* or rimocidin* or Ristocetin* or ritipenem or "ritipenem acoxil" or on September 26, 2021 by guest. Protected copyright. 41 rodorubicin* or roflamycoin* or rokitamycin* or Rolitetracycline or rosaramicin* or Roxarsone 42 or Roxithromycin* or ruboxyl or Rutamycin* or sabarubicin* or sagopilone or sanfetrinem or 43 sarecycline or "simaomicin alpha" or "simocyclinone D8" or Sirolimus or "sisomicin sulfate" or 44 Sisomicin* or "skf 104662" or sofradex or Spectinomycin* or "spinosyn A" or Spiramycin* or 45 squalamine or stigmatellin* or streptoduocin* or Streptogramin* or streptolydigin* or Streptomycin* or streptothricin* or streptotriad or Streptovaricin* or streptovirudin* or 46 "streptovitacin A" or stubomycin* or subtilin* or Sulbactam or Sulbenicillin* or Sulfamerazine 47 or Sulfamethoxypyridazine or sulfazecin* or sulopenem or sultamicillin* or surfactin* or 48 surotomycin* or "swinholide A" or "swinholide B" or tachyplesin* or Talampicillin* or 49 tameticillin* or tazobactam or tebipenem or tedizolid or Teicoplanin* or teixobactin* or 50 telavancin* or temocillin* or terdecamycin* or tetracyclin* or Tetracycline or tetramycin* or 51 tetronasin* or tetronomycin* or tetroxoprim or Thiamphenicol or Thienamycin* or 52 Thioacetazone or thiolactomycin* or "thionin peptide" or thiopeptin* or thiophenoxycefalotin* 53 or Thiostrepton or tiamulin* or "tibezonium iodide" or Ticarcillin* or tigecycline or tigemonam 54 or tildipirosin* or tilmicosin* or timentin* or tirandamycin* or tizoxanide or tobicillin* or 55 Tobramycin* or tolramycin* or tomopenem or toyocamycin* or tresaderm or tribactam or 56 trichomycin* or "trichostatic acid" or "trichostatin A" or trimethoprim* or "trinem derivative" or 57 58 7 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 28 of 43 BMJ Open: first published as 10.1136/bmjopen-2018-027935 on 5 May 2019. Downloaded from 1 2 3 "triostin A" or triplopen or trisep or Troleandomycin* or trospectomycin* or tuftsin* or 4 tulathromycin* or Tunicamycin* or tutofusin* or Tylosin* or tylvalosin* or Tyrocidine or 5 Tyrothricin* or "u 78608" or "uk 69753" or unphenelfamycin* or "urdamycin C" or "urdamycin 6 D" or "urdamycin H" or ureidopenicillin* or urobiotic or "vacidin A" or validamycin* or 7 Valinomycin* or valnemulin* or valrubicin* or Vancomycin* or venturicidin* or vernamycin* or 8 "violamycin B1" or Viomycin* or "virginiae butanolide A" or "virginiae butanolide C" or 9 "virginiamycin M" or "virginiamycin S" or Virginiamycin* or "viriplanin A" or viscosin* or 10 volpristin* or "ws 9659 b" or "zibrofusidic acid" or zineryt or "zoptarelin doxorubicin*" or 11 zorbamycin* or zorubicin*).mp. 12 6 or/2-5 3703559 13 7 1 and 6 28719 14 15 8 exp meta analysis/ 229890 16 9 exp "systematic review"/For peer review only 165306 17 10 ((meta adj analys*) or (systematic* adj3 review*)).ti,ab,hw,kw,pt. 589817 18 11 8 or 9 or 10 589821 19 12 7 and 11 879 20 21 limit 12 to (editorial or erratum or letter or note or addresses or autobiography or bibliography 22 or biography or blogs or comment or dictionary or directory or interactive tutorial or interview or lectures or legal cases or legislation or news or newspaper article or overall or patient 23 13 64 24 education handout or periodical index or portraits or published erratum or video-audio media or webcasts) [Limit not valid in Embase,CDSR,Ovid MEDLINE(R),Ovid MEDLINE(R) Daily 25 Update,Ovid MEDLINE(R) In-Process,Ovid MEDLINE(R) Publisher; records were retained] 26 27 14 12 not 13 815 28 15 from 7 keep 23035-23104 70 29 16 14 or 15 885 30 17 remove duplicates from 16 767 31

32 http://bmjopen.bmj.com/ 33 34 35 36 37 38 39

40 on September 26, 2021 by guest. Protected copyright. 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 8 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 29 of 43 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2018-027935 on 5 May 2019. Downloaded from 1 2 3 Part 3 4 5 Database(s): Embase 1988 to 2018 Week 16, EBM Reviews - Cochrane Database of Systematic 6 Reviews 2005 to April 11, 2018, Ovid MEDLINE(R) Epub Ahead of Print, In-Process & Other Non- 7 Indexed Citations, Ovid MEDLINE(R) Daily and Ovid MEDLINE(R) 1946 to Present 8 Search Strategy: 9 # Searches Results 10 ("chronic airflow disease*" or "chronic airflow disorder*" or "chronic airflow limitation*" or 11 "chronic airflow obstruction*" or "chronic airway disease*" or "chronic airway disorder*" or 12 "chronic airway limitation*" or "chronic airway obstruction*" or "chronic bronchitis" or "chronic 13 obstructive airflow disease*" or "chronic obstructive airflow disorder*" or "chronic obstructive 14 airway disease*" or "chronic obstructive airway disorder*" or "chronic obstructive bronchitis" 15 or "chronic obstructive bronchopulmonary disease*" or "chronic obstructive broncho- 16 pulmonary disease*"For or "chronic peer obstructive review bronchopulmonary onlydisorder*" or "chronic 17 1 obstructive broncho-pulmonary disorder*" or "chronic obstructive lung disease*" or "chronic 248757 18 obstructive lung disorder*" or "chronic obstructive pulmonary disease*" or "chronic obstructive 19 pulmonary disorder*" or "chronic obstructive respiratory disease*" or "chronic obstructive 20 respiratory disorder*" or coad or copd or emphysema or "obstructive lung disease" or 21 "obstructive lung disorder*" or "obstructive pulmonary disease*" or "obstructive pulmonary 22 disorder*" or "obstructive pulmonary tract disease*" or "obstructive pulmonary tract disorder*" 23 or "obstructive respiratory disease*" or "obstructive respiratory disorder*" or "obstructive 24 respiratory tract disease*" or "obstructive respiratory tract disorder*").ti,ab,hw,kw. 25 2 exp Benzodiazepines/ 223779 26 (Alprazolam or arfendazam or benzodiazepin or benzodiazepine* or Benzodiazepinone* or 27 bromazepam or camazepam or Chlordiazepoxide or cinolazepam or clobazam or 28 clonazepam or clorazepate or "Clorazepate Dipotassium" or "clorazepate potassium" or 29 dealkylflurazepam or delorazepam or demoxepam or devazepide or diazepam or 30 doxefazepam or Estazolam or fludiazepam or flunitrazepam or flurazepam or flutoprazepam 31 or fosazepam or gidazepam or girisopam or halazepam or loflazepate or lorazepam or

32 3 lormetazepam or lotrafiban or meclonazepam or Medazepam or metaclazepam or Midazolam 271678 http://bmjopen.bmj.com/ 33 or nastorazepide or nerisopam or netazepide or nimetazepam or nitrazepam or 34 nitrosochlordiazepoxide or norchlordiazepoxide or norclobazam or nordazepam or 35 norfludiazepam or norflunitrazepam or oxazepam or phenazepam or pinazepam or prazepam 36 or quazepam or "ro 7 0213" or talampanel or tampramine or tarazepide or temazepam or 37 tetrazepam or tibezonium or tifluadom or tofisopam or tomaymycin or Triazolam or 38 tuclazepam or uxepam).ti,ab,hw,kw. 39 4 exp Home Care Services/ 101515

40 (((domestic or home or domiciliary) adj3 (residence or residences or setting or settings or on September 26, 2021 by guest. Protected copyright. 41 care or nurs* or help or service* or treatment* or therap* or "respiratory care" or "respiratory 5 209664 42 treatment*" or "respiratory therap*" or "respiratory service*" or "respiratory assist*" or 43 ventilat*)) or "assisted living" or homecare).ti,ab,hw,kw. 44 6 "nursing home*".ti,ab,hw,kw. 90908 45 7 (4 or 5) not 6 151038 46 47 8 exp Respiration, Artificial/ 225415 48 (((((respiration* or respiratory or breathing) adj3 (assist* or controlled or mechanical)) or 49 (facial or face or nasal)) adj3 mask*) or "artificial respiration*" or BiPAP or CPAP or "Fluidic Breathing Assister" or HMV or IPPB or IPPV or NIAV or NIV or NPPV or "Oxygen Regulator*" 50 9 529399 51 or PAP or PAV or "Portable Oxygen" or "Positive Airway Pressure*" or "positive end- 52 expiratory pressure*" or "positive pressure*" or respirator or respirators or "Respiratory 53 insufficiency" or Tracheostom* or ventilation or ventilator*).ti,ab,hw,kw. 54 10 8 or 9 549586 55 11 7 and 10 6909 56 57 58 9 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 30 of 43 BMJ Open: first published as 10.1136/bmjopen-2018-027935 on 5 May 2019. Downloaded from 1 2 3 12 2 or 3 or 11 280786 4 5 13 1 and 12 3036 6 14 exp meta analysis/ 229890 7 15 exp "systematic review"/ 165306 8 16 ((meta adj analys*) or (systematic* adj3 review*)).ti,ab,hw,kw,pt. 589817 9 17 14 or 15 or 16 589821 10 11 18 13 and 17 119 12 limit 18 to (editorial or erratum or letter or note or addresses or autobiography or bibliography 13 or biography or blogs or comment or dictionary or directory or interactive tutorial or interview or lectures or legal cases or legislation or news or newspaper article or overall or patient 14 19 3 15 education handout or periodical index or portraits or published erratum or video-audio media 16 or webcasts) [LimitFor not valid inpeer Embase,CDSR,Ovid review MEDLINE(R),Ovid only MEDLINE(R) Daily 17 Update,Ovid MEDLINE(R) In-Process,Ovid MEDLINE(R) Publisher; records were retained] 18 20 18 not 19 116 19 21 from 13 keep 2384 1 20 22 20 or 21 117 21 23 remove duplicates from 22 97 22 23 24

25 26 27 28 29 30 31

32 http://bmjopen.bmj.com/ 33 34 35 36 37 38 39

40 on September 26, 2021 by guest. Protected copyright. 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 10 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 31 of 43 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2018-027935 on 5 May 2019. Downloaded from 1 2 3 Part 4 4 5 6 7 Database(s): Embase 1988 to 2018 Week 16, EBM Reviews - Cochrane Database of Systematic 8 Reviews 2005 to April 11, 2018, Ovid MEDLINE(R) Epub Ahead of Print, In-Process & Other Non- 9 Indexed Citations, Ovid MEDLINE(R) Daily and Ovid MEDLINE(R) 1946 to Present 10 Search Strategy: 11 # Searches Results 12 ("chronic airflow disease*" or "chronic airflow disorder*" or "chronic airflow limitation*" or 13 "chronic airflow obstruction*" or "chronic airway disease*" or "chronic airway disorder*" or 14 "chronic airway limitation*" or "chronic airway obstruction*" or "chronic bronchitis" or 15 "chronic obstructive airflow disease*" or "chronic obstructive airflow disorder*" or "chronic 16 obstructive airway Fordisease*" peeror "chronic obstructive review airway disorder*" only or "chronic obstructive 17 bronchitis" or "chronic obstructive bronchopulmonary disease*" or "chronic obstructive 18 broncho-pulmonary disease*" or "chronic obstructive bronchopulmonary disorder*" or 19 "chronic obstructive broncho-pulmonary disorder*" or "chronic obstructive lung disease*" or 1 248757 20 "chronic obstructive lung disorder*" or "chronic obstructive pulmonary disease*" or "chronic 21 obstructive pulmonary disorder*" or "chronic obstructive respiratory disease*" or "chronic 22 obstructive respiratory disorder*" or coad or copd or emphysema or "obstructive lung 23 disease" or "obstructive lung disorder*" or "obstructive pulmonary disease*" or "obstructive 24 pulmonary disorder*" or "obstructive pulmonary tract disease*" or "obstructive pulmonary 25 tract disorder*" or "obstructive respiratory disease*" or "obstructive respiratory disorder*" or 26 "obstructive respiratory tract disease*" or "obstructive respiratory tract 27 disorder*").ti,ab,hw,kw. 28 2 exp Adrenal Cortex Hormones/ 1085572 29 3 exp corticosteroid/ 710384 30 4 exp corticosteroid therapy/ 41274 31 ("adrenal cortex hormone*" or "adrenal cortex steroid*" or "adrenal cortical hormone*" or 32 http://bmjopen.bmj.com/ "adrenal cortical steroid*" or "adrenal steroid*" or "adreno cortical steroid*" or "adreno 33 corticosteroid*" or "adrenocortical hormone*" or "adrenocortical steroid*" or 34 adrenocorticosteroid* or adreson or alclometasone or aldosterone or algestone or 35 "algestone acetonide" or amcinonide or amelometasone or beclometasone or budesonide 36 or butixocort or chloroprednisone or ciclesonide or ciprocinonide or clioquinol or clobetasol 37 or clobetasone or clocortolone or cloprednol or "cortical steroid*" or corticalsteroid* or 38 "cortico steroid*" or corticoid* or corticosteroid* or corticosterone or corticotherap* or 39 cortifair or cortisol or cortisone or cortivazol or cortril or deflazacort or dehydrocorticosterone 40 or dehydrocortisone or deoxycorticosterone or dermocorticosteroid* or dexamethasone or on September 26, 2021 by guest. Protected copyright. 41 diflorasone or diflucortolone or difluprednate or domoprednate or drocinonide or dutimelan 42 or epicortisol or "etiprednol dicloacetate" or fluclorolone or fludrocortisone or fludroxycortide 43 or flumetasone or flumoxonide or flunisolide or fluocinolone or fluocinonide or fluocortin or 5 1707747 44 fluocortolone or fluorometholone or fluprednidene or fluprednisolone or fluticasone or 45 formocortal or "formoterol fumarate" or Glucocorticoid* or glucocorticoidsteroid* or 46 glucocorticosteroid* or glucocortoid* or glycocorticoid* or glycocorticosteroid* or halcinonide 47 or halometasone or halopredone or hydrocortisone or "hydroxy norcorticosterone" or 48 hydroxycorticoid* or hydroxycorticosteroid* or hydroxycorticosterone or 49 hydroxydeoxycorticosterone or hydroxyhydrocortisone or "icometasone enbutate" or 50 isoflupredone or itrocinonide or "locicortolone dicibate" or "lorinden a" or "lorinden t" or 51 loteprednol or mazipredone or medrysone or meprednisone or mineralcorticosteroid* or 52 mineralocorticosteroid* or minerocorticoid* or mometasone or nicocortonide or nivacortol or 53 nordeoxycorticosterone or oropivalone or oxohydrocortisone or oxycorticosteroid* or 54 paramethasone or prednisolone or prednisone or pregnenolone or procinonide or promestriene or resocortol or rimexolone or rofleponide or steroid* or 55 tetrahydrodeoxycorticosterone or ticabesone or timobesone or tipredane or tixocortol or 56 57 58 11 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 32 of 43 BMJ Open: first published as 10.1136/bmjopen-2018-027935 on 5 May 2019. Downloaded from 1 2 3 triamcinolone or "ulobetasol propionate" or uniderm or zoticasone).ti,ab,hw,kw. 4 5 6 exp Expectorants/ 30553 6 (Acetylcysteine or Ambroxol or aminophylline or Bromhexine or bron or cafedrine or 7 Carbocysteine or diprophylline or etofylline or eucalyptus or expectorant* or fudosteine or 8 7 guaiacol or "guaiacol carbonate" or guaietolin or Guaifenesin or guaifylline or "iodinated 91107 9 glycerol" or ipecac or mucolytic* or "Potassium Citrate" or "primula flower" or stepronin or 10 "stepronin lysine" or sulfoguaiacol or tipepidine or ulogesic).ti,ab,hw,kw. 11 8 exp narcotic analgesic agent/ 243598 12 9 exp Analgesics, Opioid/ 347494 13 (acetorphine or acetylcodeine or acetylmethadol or Alfentanil or Alphaprodine or anileridine 14 or apadoline or azidomorphine or benzhydrocodone or bezitramide or bremazocine or 15 "Brompton mixture" or Buprenorphine or Butorphanol or ciramadol or cocodamol or 16 Codeine or codydramolFor or conorfone peer or cyclazocine review or Dextromoramide only or 17 Dextropropoxyphene or dextrorphan or dezocine or diamorphine or diconal or 18 dihydrocodeine or dihydroetorphine or Dihydromorphine or dimethylthiambutene or 19 Diphenoxylate or dipipanone or enadoline or eptazocine or ethylketazocine or 20 Ethylketocyclazocine or Ethylmorphine or etonitazene or Etorphine or etoxeridine or 21 faxeladol or Fentanyl or furethidine or gelonida or Heroin or Hydrocodone or isalmadol or 22 isomethadone or ketazocine or ketobemidone or ketogan or kyotorphin or lefetamine or 23 10 levacetylmethadol or levomethadone or Levorphanol or Meperidine or Meptazinol or 525567 24 metazocine or Methadone or "Methadyl Acetate" or methylsamidorphan or Morphine or 25 "morphinomimetic agent*" or "morphinomimetic drug*" or morphinone or Nalbuphine or 26 narcotic* or nicocodine or nicomorphine or noracymethadol or norbuprenorphine or 27 nordextropropoxyphene or normorphine or norpethidine or norpropoxyphene or "o 28 nortramadol" or oliceridine or opiate or Opiate* or opioid* or Opium or oripavine or 29 Oxycodone or Oxymorphone or pentamorphone or Pentazocine or pethidine or phenadoxone or phenaridine or Phenazocine or phencyclidine or Phenoperidine or 30 picenadol or piminodine or Pirinitramide or piritramide or profadol or Promedol or propiram 31 or sameridine or samidorphan or semorphone or Sufentanil or tapentadol or thebaine or 32 http://bmjopen.bmj.com/ tifluadom or Tilidine or tonazocine or Tramadol or trimeperidine).ti,ab,hw,kw. 33 34 11 exp Bronchoscopy/ 68088 35 12 exp lung/su 8000 36 13 exp Pneumonectomy/ 49308 37 ("airflow clearance" or "airway clearance" or BLVR or bronchoscop* or ELVR or "lung 38 clearance" or "lung denervation" or LVRS or pneumectom* or pneumonectom* or 14 143837 39 pneumoresection* or "pulmonary clearance" or "volume reducing" or "volume 40 reduction*").ti,ab,hw,kw. on September 26, 2021 by guest. Protected copyright. 41 15 exp Smoking Cessation/ 76463 42 ((smoking* or tobacco* or cigar* or cigarette* or cigaret*) and (quit* or discontinu* or ceas* 43 16 110813 or cessation*)).ti,ab,hw,kw. 44 45 17 exp Respiratory Therapy/ 107010 46 18 exp exercise/ 423706 47 19 exp Exercise Therapy/ 102223 48 20 exp Breathing Exercises/ 8723 49 21 exp Exercise Movement Techniques/ 66908 50 51 (aerobics or anaerobics or "artificial respiration*" or bicycling or biking or "Chest Wall 52 Oscillation*" or dance or dancing or "endurance training" or exercis* or "Extracorporeal Membrane Oxygen*" or "fitness training" or "inhalation therap*" or isometrics or oxygen or 53 22 2620447 54 "physical activit*" or "physical exertion" or "postural drain*" or rehab* or "resistance training" 55 or "respiration care*" or "respiration therap*" or "respiratory care*" or "respiratory therap*" or running or "strength training" or swimming or "Tai Chi" or "Tai Ji" or walking or weightlifting 56 57 58 12 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 33 of 43 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2018-027935 on 5 May 2019. Downloaded from 1 2 3 or yoga).ti,ab,hw,kw. 4 5 23 exp Nutrition Therapy/ 384447 6 24 (diet or dietary or diets or nutrition* or supplementation or supplements).ti,ab,hw,kw. 1856949 7 25 exp Influenza Vaccines/ 50514 8 26 exp Pneumococcal Vaccines/ 22742 9 27 exp vaccination/ 204458 10 11 (moniarix or "pcv 13" or pcv13 or "pneu immune" or "pneumo 23" or pneumopur or pneumovax or "pnu immune" or "pnu imune" or "polysaccharide vaccine pneumococcal" or 12 28 702951 prevenar or prevnar or "streptococcus pneumoniae vaccine" or streptopur or streptorix or 13 synflorix or vaccin*).ti,ab,hw,kw. 14 15 29 exp Psychotherapy/ 367662 16 30 exp Cognitive Therapy/For peer review only 66331 17 31 exp Cognitive Behavior Therapy/ 28661 18 32 exp Mindfulness/ 6317 19 33 exp Mind-Body Therapies/ 90152 20 21 34 exp Mentoring/ 1557 22 35 exp Health Promotion/ 153501 23 (CBT or coach* or "Cognitive behavioral therap*" or "Cognitive therap*" or "health 24 36 promotion*" or meditat* or mentor* or "mind body" or mindfulness or psychological or 1535477 25 psychosocial or psychotherap*).ti,ab,hw,kw. 26 37 exp Self Care/ 113331 27 38 exp Telemedicine/ 53304 28 29 39 exp Therapy, Computer-Assisted/ 67118 30 40 exp Mobile Applications/ 8595 31 ("action plan*" or android or app or apps or ehealth or "e-health" or internet or ipad* or 32 iphone* or mhealth or "m-health" or "mobile app*" or "mobile health" or "mobile technolog*" http://bmjopen.bmj.com/ 33 or "portable computer*" or "portable electronic app*" or "portable software app*" or "remote 34 41 consultation*" or "self care" or "self help" or "self management" or "self treatment" or "smart 603033 35 phone*" or smartphone* or "tablet computer*" or teleconsultation* or "tele-consultation*" or 36 telehealth or "tele-health" or telemedicine or "tele-medicine" or teletherap* or "tele-therap*" 37 or web).ti,ab,hw,kw. 38 42 exp "Delivery of Health Care, Integrated"/ 20570 39 43 exp Acupuncture/ 38261 40 on September 26, 2021 by guest. Protected copyright. 44 exp Complementary Therapies/ 250389 41 42 45 exp Electric Stimulation Therapy/ 260840 43 (acupuncture or agent* or "alternative medicine" or "care package*" or chemotherap* or 44 "complementary medicine" or drug* or "electric stimulation*" or holistic or "integrated care" 45 46 or "integrated health care" or "integrated healthcare" or intervention* or manag* or 26377389 46 medication* or "muscle stimulation*" or operat* or pharmacotherap* or procedure* or 47 reconstruction* or repair* or resect* or surg* or therap* or treat* or wellness).ti,ab,hw,kw. 48 47 or/2-46 30049403 49 48 1 and 47 182842 50 49 exp meta analysis/ 229890 51 52 50 exp "systematic review"/ 165306 53 51 ((meta adj analys*) or (systematic* adj3 review*)).ti,ab,hw,kw,pt. 589817 54 52 49 or 50 or 51 589821 55 53 48 and 52 5613 56 57 58 13 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 34 of 43 BMJ Open: first published as 10.1136/bmjopen-2018-027935 on 5 May 2019. Downloaded from 1 2 3 limit 53 to (editorial or erratum or letter or note or addresses or autobiography or 4 bibliography or biography or blogs or comment or dictionary or directory or interactive 5 tutorial or interview or lectures or legal cases or legislation or news or newspaper article or 6 54 overall or patient education handout or periodical index or portraits or published erratum or 261 7 video-audio media or webcasts) [Limit not valid in Embase,CDSR,Ovid MEDLINE(R),Ovid 8 MEDLINE(R) Daily Update,Ovid MEDLINE(R) In-Process,Ovid MEDLINE(R) Publisher; 9 records were retained] 10 55 53 not 54 5352 11 56 from 48 keep 121215-121366 152 12 13 57 55 or 56 5504 14 58 remove duplicates from 57 3991 15 16 For peer review only 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31

32 http://bmjopen.bmj.com/ 33 34 35 36 37 38 39

40 on September 26, 2021 by guest. Protected copyright. 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 14 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 35 of 43 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2018-027935 on 5 May 2019. Downloaded from 1 2 3 4 5 Scopus 6 7 Part 1 8 9 1 TITLE-ABS-KEY("chronic airflow disease*" OR "chronic airflow disorder*" OR "chronic airflow 10 limitation*" OR "chronic airflow obstruction*" OR "chronic airway disease*" OR "chronic airway 11 disorder*" OR "chronic airway limitation*" OR "chronic airway obstruction*" OR "chronic 12 bronchitis" OR "chronic obstructive airflow disease*" OR "chronic obstructive airflow disorder*" 13 OR "chronic obstructive airway disease*" OR "chronic obstructive airway disorder*" OR "chronic 14 obstructive bronchitis" OR "chronic obstructive bronchopulmonary disease*" OR "chronic 15 obstructive broncho-pulmonary disease*" OR "chronic obstructive bronchopulmonary disorder*" 16 OR "chronic obstructiveFor peerbroncho-pulmonary review disorder*" OR only"chronic obstructive lung disease*" OR 17 "chronic obstructive lung disorder*" OR "chronic obstructive pulmonary disease*" OR "chronic 18 obstructive pulmonary disorder*" OR "chronic obstructive respiratory disease*" OR "chronic 19 obstructive respiratory disorder*" OR coad OR copd OR emphysema OR "obstructive lung 20 disease" OR "obstructive lung disorder*" OR "obstructive pulmonary disease*" OR "obstructive pulmonary disorder*" OR "obstructive pulmonary tract disease*" OR "obstructive pulmonary tract 21 disorder*" OR "obstructive respiratory disease*" OR "obstructive respiratory disorder*" OR 22 "obstructive respiratory tract disease*" OR "obstructive respiratory tract disorder*") 23 2 TITLE-ABS-KEY(abediterol OR acefylline OR "acefylline clofibrol" OR "acefylline piperazine" OR 24 "aclidinium bromide" OR "adrenalin hydrogen tartrate" OR Adrenomedullin OR Albuterol OR 25 ambuphylline OR Aminophylline OR antibronchospastic OR arformoterol OR Atropine OR 26 bambuterol OR bamifylline OR baralgin OR batefenterol OR bitolterol OR "bitolterol mesilate" OR 27 "bronchial dilating" OR "bronchial-dilating" OR bronchodilatant* OR "broncho-dilatant*" OR 28 bronchodilatating OR "broncho-dilatating" OR bronchodilatator* OR "broncho-dilatator*" OR 29 bronchodilating OR "broncho-dilating" OR bronchodilator* OR "broncho-dilator*" OR broncholytic* 30 OR broncholytica OR bronchospasmolytic OR broxaterol OR Budesonide OR carbuterol OR 31 carmoterol OR "choline theophyllinate" OR Clenbuterol OR clorprenaline OR Colforsin OR

32 Cromakalim OR danirixin OR "darotropium bromide" OR dilator* OR diprophylline OR ditec OR http://bmjopen.bmj.com/ 33 doxofylline OR Dyphylline OR elubrixin OR enprofylline OR ephedrine OR "ephedrine sulfate" OR 34 Epinephrine OR eprozinol OR espatropate OR etafedrine OR etamiphyllin OR "etamiphyllin 35 camsilate" OR etanterol OR etofylline OR Fenoterol OR fenspiride OR Fluticasone OR "flutropium 36 bromide" OR formoterol OR "Formoterol Fumarate" OR furafylline OR glycopyrronium OR "gsk 37 159802" OR "gsk 597901" OR guaifylline OR "gw 678007" OR Hexoprenaline OR Hyoscyamine 38 OR ibuterol OR "ilmetropium iodide" OR imoxiterol OR indacaterol OR inhaler* OR Ipratropium 39 OR "ipratropium bromide" OR isbufylline OR isoetarine OR "isoetarine mesylate" OR Isoetharine

40 OR isoprenaline OR Isoproterenol OR Khellin OR laprafylline OR levalbuterol OR mabuterol OR on September 26, 2021 by guest. Protected copyright. 41 marax OR Metaproterenol OR methoxyphenamine OR milveterol OR "n methylmequitazine" OR 42 naminterol OR neobiphyllin OR nestifylline OR "Nitric Oxide" OR olodaterol OR orciprenaline OR 43 "oxitropium bromide" OR "oxyphenonium bromide" OR pibaxizine OR pirbuterol OR "pirbuterol acetate" OR pneumodilator OR Procaterol OR protokylol OR proxyphylline OR Pseudoephedrine 44 OR racephedrine OR Racepinephrine OR reproterol OR rimiterol OR "ru 45703" OR salbutamol 45 OR "salbutamol sulfate" OR salmefamol OR salmeterol OR "Salmeterol Xinafoate" OR sibenadet 46 OR "S-Nitrosoglutathione" OR "S-Nitrosothiols" OR soterenol OR tazifylline OR Terbutaline OR 47 Theobromine OR Theophylline OR "theophylline sodium glycinate" OR thiazinamium OR 48 "thiazinamium metilsulfate" OR Tiotropium OR Tretoquinol OR "tretoquinol derivative" OR 49 trimetaquinol OR tulobuterol OR "uk 432097" OR Umeclidinium OR vephylline OR verofylline OR 50 vilanterol OR "vilanterol trifenatate" OR zindotrine) 51 3 TITLE-ABS-KEY("adrenergic beta 2 agonist*" OR "adrenergic beta 2 receptor agonist*" OR 52 "adrenergic beta2 agonist*" OR "adrenergic beta-2 agonist*" OR "adrenergic beta-2 receptor 53 agonist*" OR "adrenergic beta2-agonist*" OR Albuterol OR "beta 2 adrenergic agent*" OR "beta 2 54 adrenergic agonist*" OR "beta 2 adrenergic receptor agonist*" OR "beta 2 adrenergic receptor 55 stimulant*" OR "beta 2 adrenergic receptor stimulat*" OR "beta 2 adrenergic receptor stimulator*" 56 OR "beta 2 adrenergic stimulant*" OR "beta 2 adrenergic stimulat*" OR "beta 2 adrenergic 57 58 15 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 36 of 43 BMJ Open: first published as 10.1136/bmjopen-2018-027935 on 5 May 2019. Downloaded from 1 2 3 stimulator*" OR "beta 2 adrenoceptor agonist*" OR "beta 2 adrenoceptor stimulant*" OR "beta 2 4 adrenoceptor stimulat**" OR "beta 2 adrenoceptor stimulator*" OR "beta 2 agonist*" OR "beta 5 agonist*" OR "beta receptor agonist*" OR "beta receptor stimulant*" OR "beta stimulant" OR 6 "beta2 adrenergic receptor stimulat*" OR Fenoterol OR formoterol OR Hexoprenaline OR 7 indacaterol OR Isoetharine OR LABA OR LABAs OR Metaproterenol OR Procaterol OR Ritodrine 8 OR SABA OR SABAs OR salmeterol OR "Salmeterol Xinafoate" OR Terbutaline) 9 4 TITLE-ABS-KEY("acetylcholine antagonist*" OR "acetylcholine receptor block*" OR "acetylcholine 10 receptor inhibitor*" OR "AChR inhibitor" OR aclidinium OR "aclidinium bromide" OR acotiamide 11 OR adiphenine OR afacifenacin OR Alcuronium OR "alpha conotoxin MII" OR alvameline OR 12 alverine OR "alverine citrate" OR anisodamine OR "anti cholinergics" OR anticholinergic OR 13 anticholinergic* OR "anti-cholinergic*" OR antimuscarinic* OR aprofene OR aspaminol OR 14 Atracurium OR Atropine OR atropinic* OR azaprophen OR belladonna OR bellergal OR 15 Benactyzine OR benzetimide OR benzilonium OR "benzilylcholine mustard" OR benzoquinonium 16 OR BenztropineFor OR Biperiden peer OR bornaprine review OR Butylscopolammonium only OR buzepide OR 17 catestatin OR "central anticholinergic" OR Chlorisondamine OR chlorphenoxamine OR 18 cholinolytic* OR cimetropium OR clidinium OR Curare OR Cyclopentolate OR cycrimine OR 19 darifenacin OR darotropium OR deptropine OR desfesoterodine OR Dexetimide OR dexmecamylamine OR "dibutoline sulfate" OR Dicyclomine OR dicycloverine OR diethazine OR 20 dimevamide OR "diphemanil methylsulfate" OR drofenine OR elantrine OR Emepronium OR 21 espatropate OR Ethidium OR "ethylcholine mustard aziridinium" OR eucatropine OR fenoverine 22 OR fenpipramide OR fenpiverinium OR fesoterodine OR fluperlapine OR flutropium OR 23 furtramine OR "Gallamine Triethiodide" OR ganglefene OR Glycopyrrolate OR glycopyrronium 24 OR "gsk 202405" OR "h cholinoreactive cell*" OR hemicholinium OR hexahydrodifenidol OR 25 hexahydroprocyclidine OR hexahydrosiladifenidol OR Hexamethonium OR hexbutinol OR 26 "hexbutinol methiodide" OR "hexocyclium metilsulfate" OR himbacine OR homatropine OR 27 "homatropine methyl" OR "homatropine terephthalate" OR Hyoscyamine OR imidafenacin OR 28 Ipratropium OR isomylamine OR "isopropamide iodide" OR LAMA OR LAMAs OR levetimide OR 29 lophotoxin OR mazaticol OR Mecamylamine OR mefurtramine OR mepenzolate OR meptazinol 30 OR "meta cholinoreactive cell*" OR methantheline OR methoctramine OR methylatropine OR 31 methyllycaconitine OR methylscopolamine OR metixene OR muscarinic* OR muscarinolytic* OR

32 "nicotine tartrate" OR nicotinic* OR nuvenzepine OR "octatropine methylbromide" OR http://bmjopen.bmj.com/ 33 Orphenadrine OR otenzepad OR oxitropium OR oxybutynin OR oxyphencyclimine OR 34 Oxyphenonium OR Pancuronium OR "para fluorohexahydrosiladifenidol" OR "para 35 fluorohexbutinol" OR parapenzolate OR "parasympathetic block*" OR "parasympathetic inhibitor*" 36 OR parasympathicolytic* OR parasympatholytic* OR parasympatolytic* OR Pempidine OR 37 penthienate OR "Pentolinium Tartrate" OR phenglutarimide OR Pipecuronium OR pipenzolate 38 OR piperidolate OR piperphenamine OR pipethanate OR Pirenzepine OR piroheptine OR 39 "poldine methylsulfate" OR pridinol OR "pridinol mesilate" OR "prifinium bromide" OR

40 Procyclidine OR profenamine OR proglumide OR Propantheline OR propiverine OR on September 26, 2021 by guest. Protected copyright. 41 "propylbenziloylcholine mustard" OR "Propylbenzilylcholine Mustard" OR pyrrinol OR Quinidine 42 OR "Quinuclidinyl Benzilate" OR revatropate OR revefenacin OR rispenzepine OR SAMA OR SAMAs OR Scopolamine OR secoverine OR silahexocyclium OR siltenzepine OR sofpironium 43 OR solifenacin OR "Solifenacin Succinate" OR stramonium OR sydnofen OR tarafenacin OR 44 telenzepine OR tematropium OR temiverine OR thiazinamium OR "thiazinamium metilsulfate" OR 45 thihexinol OR "tiemonium iodide" OR "tiemonium methylsulfate" OR tifenamil OR timepidium OR 46 Tiotropium OR tofenacin OR tolterodine OR "Tolterodine Tartrate" OR tonopan OR Toxiferine OR 47 tricyclamol OR "tridihexethyl chloride" OR Trihexyphenidyl OR Trimethaphan OR triperidene OR 48 tripitramine OR tropacin OR Tropicamide OR tropine OR "tropine benzoate" OR "trospium 49 chloride" OR troventol OR Tubocurarine OR umeclidinium OR valethamate OR vamicamide OR 50 Vecuronium OR vedaclidine OR zamifenacin OR zolenzepine) 51 5 TITLE-ABS-KEY("adrenal cortex hormone*" OR "adrenal cortex steroid*" OR "adrenal cortical 52 hormone*" OR "adrenal cortical steroid*" OR "adrenal steroid*" OR "adreno cortical steroid*" OR 53 "adreno corticosteroid*" OR "adrenocortical hormone*" OR "adrenocortical steroid*" OR 54 adrenocorticosteroid* OR adreson OR alclometasone OR aldosterone OR algestone OR 55 "algestone acetonide" OR amcinonide OR amelometasone OR beclometasone OR budesonide 56 OR butixocort OR chloroprednisone OR ciclesonide OR ciprocinonide OR clioquinol OR 57 58 16 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 37 of 43 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2018-027935 on 5 May 2019. Downloaded from 1 2 3 clobetasol OR clobetasone OR clocortolone OR cloprednol OR "cortical steroid*" OR 4 corticalsteroid* OR "cortico steroid*" OR corticoid* OR corticosteroid* OR corticosterone OR 5 corticotherap* OR cortifair OR cortisol OR cortisone OR cortivazol OR cortril OR deflazacort OR 6 dehydrocorticosterone OR dehydrocortisone OR deoxycorticosterone OR dermocorticosteroid* 7 OR dexamethasone OR diflorasone OR diflucortolone OR difluprednate OR domoprednate OR 8 drocinonide OR dutimelan OR epicortisol OR "etiprednol dicloacetate" OR fluclorolone OR 9 fludrocortisone OR fludroxycortide OR flumetasone OR flumoxonide OR flunisolide OR 10 fluocinolone OR fluocinonide OR fluocortin OR fluocortolone OR fluorometholone OR 11 fluprednidene OR fluprednisolone OR fluticasone OR formocortal OR "formoterol fumarate" OR 12 Glucocorticoid* OR glucocorticoidsteroid* OR glucocorticosteroid* OR glucocortoid* OR 13 glycocorticoid* OR glycocorticosteroid* OR halcinonide OR halometasone OR halopredone OR 14 hydrocortisone OR "hydroxy norcorticosterone" OR hydroxycorticoid* OR hydroxycorticosteroid* 15 OR hydroxycorticosterone OR hydroxydeoxycorticosterone OR hydroxyhydrocortisone OR 16 "icometasoneFor enbutate" peerOR isoflupredone review OR itrocinonide onlyOR "locicortolone dicibate" OR 17 "lorinden a" OR "lorinden t" OR loteprednol OR mazipredone OR medrysone OR meprednisone 18 OR mineralcorticosteroid* OR mineralocorticosteroid* OR minerocorticoid* OR mometasone OR 19 nicocortonide OR nivacortol OR nordeoxycorticosterone OR oropivalone OR oxohydrocortisone OR oxycorticosteroid* OR paramethasone OR prednisolone OR prednisone OR pregnenolone 20 OR procinonide OR promestriene OR resocortol OR rimexolone OR rofleponide OR steroid* OR 21 tetrahydrodeoxycorticosterone OR ticabesone OR timobesone OR tipredane OR tixocortol OR 22 triamcinolone OR "ulobetasol propionate" OR uniderm OR zoticasone) 23 6 TITLE-ABS-KEY(apremilast OR arofylline OR atizoram OR benzafentrine OR catramilast OR 24 cilomilast OR cipamfylline OR daxalipram OR denbufylline OR elbimilast OR filaminast OR 25 ibudilast OR indimilast OR lavamilast OR nitraquazone OR oglemilast OR "PDE 4 inhibitor*" OR 26 "PDE IV inhibitor*" OR "PDE type 4 inhibitor*" OR "PDE type IV inhibitor*" OR "pde-4 inhibitor*" 27 OR "PDE4 inhibitor*" OR "phosphodiesterase 4 inhibitor*" OR "phosphodiesterase IV inhibitor*" 28 OR "phosphodiesterase type 4 inhibitor*" OR "phosphodiesterase type IV inhibitor*" OR 29 piclamilast OR pumafentrine OR revamilast OR roflumilast OR Rolipram OR tetomilast OR 30 tibenelast OR tilivapram OR tipelukast OR tofimilast OR tolafentrine OR zardaverine) 31 7 1 and (2 or 3 or 4 or 5 or 6)

32 8 TITLE-ABS-KEY((meta W/1 analys*) OR (systematic* W/3 review*)) http://bmjopen.bmj.com/ 33 9 7 and 8 34 10 DOCTYPE(le) OR DOCTYPE(ed) OR DOCTYPE(bk) OR DOCTYPE(er) OR DOCTYPE(no) OR 35 DOCTYPE(sh) 36 11 9 and not 10 37 12 PMID(0*) OR PMID(1*) OR PMID(2*) OR PMID(3*) OR PMID(4*) OR PMID(5*) OR PMID(6*) OR 38 PMID(7*) OR PMID(8*) OR PMID(9*) 39 13 11 and not 12

40 on September 26, 2021 by guest. Protected copyright. 41 Part 2 42 1 TITLE-ABS-KEY("chronic airflow disease*" OR "chronic airflow disorder*" OR "chronic airflow 43 limitation*" OR "chronic airflow obstruction*" OR "chronic airway disease*" OR "chronic airway 44 disorder*" OR "chronic airway limitation*" OR "chronic airway obstruction*" OR "chronic 45 bronchitis" OR "chronic obstructive airflow disease*" OR "chronic obstructive airflow disorder*" 46 OR "chronic obstructive airway disease*" OR "chronic obstructive airway disorder*" OR "chronic 47 obstructive bronchitis" OR "chronic obstructive bronchopulmonary disease*" OR "chronic 48 obstructive broncho-pulmonary disease*" OR "chronic obstructive bronchopulmonary disorder*" 49 OR "chronic obstructive broncho-pulmonary disorder*" OR "chronic obstructive lung disease*" OR 50 "chronic obstructive lung disorder*" OR "chronic obstructive pulmonary disease*" OR "chronic 51 obstructive pulmonary disorder*" OR "chronic obstructive respiratory disease*" OR "chronic 52 obstructive respiratory disorder*" OR coad OR copd OR emphysema OR "obstructive lung 53 disease" OR "obstructive lung disorder*" OR "obstructive pulmonary disease*" OR "obstructive 54 pulmonary disorder*" OR "obstructive pulmonary tract disease*" OR "obstructive pulmonary tract 55 disorder*" OR "obstructive respiratory disease*" OR "obstructive respiratory disorder*" OR 56 "obstructive respiratory tract disease*" OR "obstructive respiratory tract disorder*") 57 58 17 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 38 of 43 BMJ Open: first published as 10.1136/bmjopen-2018-027935 on 5 May 2019. Downloaded from 1 2 3 2 TITLE-ABS-KEY(Acetylcysteine OR Ambroxol OR aminophylline OR Bromhexine OR bron OR 4 cafedrine OR Carbocysteine OR diprophylline OR etofylline OR eucalyptus OR expectorant* OR 5 fudosteine OR guaiacol OR "guaiacol carbonate" OR guaietolin OR Guaifenesin OR guaifylline 6 OR "iodinated glycerol" OR ipecac OR mucolytic* OR "Potassium Citrate" OR "primula flower" 7 OR stepronin OR "stepronin lysine" OR sulfoguaiacol OR tipepidine OR ulogesic) 8 3 TITLE-ABS-KEY("1 methylmocimycin*" OR "11 deoxydaunorubicin*" OR "14 9 hydroxyclarithromycin*" OR "19 deformyl 4 deoxydesmycosin*" OR "19 deformyldesmycosin*" 10 OR "2 acetylerythromycin*" OR "2 fluoroidarubicin*" OR "2 n ethylnetilmicin*" OR "2 11 pyrrolinodoxorubicin*" OR "21 aminoepothilone B" OR "3 3 cyanomorpholino 3 12 deaminodoxorubicin*" OR "3 deamino 2 fluoro 3 hydroxydoxorubicin 14 pimelate" OR "3 deamino 13 3 morpholinodoxorubicin*" OR "3 deamino 3 morpholinooxaunomycin*" OR "4 demethoxy 11 14 deoxydaunomycinone" OR "4 demethoxydaunomycinone" OR "4 demethoxydoxorubicin*" OR "4 15 deoxydesmycosin*" OR "4 iodoesorubicin*" OR "5 iminodaunorubicin*" OR "6 n ethylnetilmicin*" 16 OR "6beta iodopenicillanicFor peer acid" OR "9 review deacetyl 9 methylidarubicin*" only OR "9 deoxydoxorubicin*" 17 OR "9 dihydroerythronolide A" OR "a 102395" OR "a 10255" OR "a 10947" OR "a 130b" OR "a 18 192411" OR "a 63075" OR abkhazomycin* OR abyssomicin* OR acetomycin* OR 19 acetylspiramycin* OR aclacinomycin* OR aclarubicin* OR actagardin* OR actaplanin* OR actinorhodine OR "aculeacin A" OR aculeximycin* OR adicillin* OR aditoprim OR adriamycinone 20 OR agglomerin* OR aklavinone OR alafosfalin* OR Alamethicin* OR albocycline OR 21 aldecalmycin* OR aldoxorubicin* OR alisamycin* OR allicin* OR almecillin* OR "alpha defensin*" 22 OR ambruticin* OR Amdinocillin* OR amfomycin* OR Amikacin* OR aminoglycoside* OR 23 aminopenicillin* OR "Aminosalicylic Acid" OR Amoxicillin* OR "Amphotericin B" OR Ampicillin* 24 OR amrubicin* OR "angucycline derivative" OR anhydrochlortetracycline OR 25 anhydroepitetracycline OR anhydrotetracycline OR anidulafungin* OR Anisomycin* OR 26 annamycin* OR ansamitocin* OR "ansamycin derivative" OR anthracycline* OR anthracyclinone* 27 OR antibacterial* OR "anti-bacterial*" OR antibiotic* OR "anti-biotic*" OR "antimicrobial cationic 28 peptide*" OR Antimycin* OR antimycobacterial* OR "anti-mycobacterial*" OR Antitreponemal* 29 OR "Anti-treponemal*" OR Antitubercular* OR "Anti-tubercular*" OR apalcillin* OR 30 aplasmomycin* OR "aplysianin E" OR apramycin* OR aristeromycin* OR Arsphenamine OR 31 aspoxicillin* OR astromicin* OR asukamycin* OR "atpenin B" OR auricularum OR Aurodox OR

32 aurograb OR avibactam OR avilamycin* OR avoparcin* OR azidamfenicol OR azidocillin* OR http://bmjopen.bmj.com/ 33 Azithromycin* OR Azlocillin* OR Aztreonam OR "aztreonam lysine" OR azurocidin* OR 34 bacampicillin* OR Bacitracin* OR bacmecillinam OR bactenecin* OR bacteriocid* OR 35 Bacteriocin* OR bafilomycin* OR balhimycin* OR "baliz 2" OR Bambermycin* OR baquiloprim OR 36 "barminomycin I" OR baycuten OR beauvericin* OR beroline OR berubicin* OR berythromycin* 37 OR "beta defensin*" OR betafectin* OR "beta-Lactam*" OR "betaLactamase Inhibitor*" OR "beta- 38 Lactamase Inhibitor*" OR betamipron OR bialaphos OR biapenem OR bicozamycin* OR 39 "biphenomycin A" OR bluensomycin* OR bombinin* OR "Bongkrekic Acid" OR boromycin* OR

40 borrelidin* OR "Brefeldin A" OR brilacidin* OR brobactam OR butalactin* OR butirosin* OR on September 26, 2021 by guest. Protected copyright. 41 cadazolid OR Calcimycin* OR Candicidin* OR Capreomycin* OR carbacephem OR carbadox OR 42 carbapenem OR "carbazomycin A" OR Carbenicillin* OR carbomycin* OR Carfecillin* OR carindacillin* OR carubicin* OR carumonam OR caspofungin* OR cathelicidin* OR cecropin* OR 43 cefacetrile OR Cefaclor OR Cefadroxil OR cefalexin* OR cefaloglycin* OR cefaloram OR 44 cefaloridine OR cefalotin* OR Cefamandole OR cefapirin* OR Cefatrizine OR cefazaflur OR 45 cefazedone OR Cefazolin* OR cefbuperazone OR cefcanel OR cefcapene OR cefclidin* OR 46 cefdaloxime OR cefdinir OR cefditoren OR cefepime OR cefetamet OR cefetecol OR 47 cefilavancin* OR Cefixime OR cefluprenam OR cefmatilen OR Cefmenoxime OR Cefmetazole 48 OR cefminox OR cefodizime OR Cefonicid OR Cefoperazone OR ceforanide OR cefoselis OR 49 Cefotaxime OR Cefotetan OR Cefotiam OR cefovecin* OR Cefoxitin* OR cefozopran OR 50 cefpimizole OR cefpiramide OR cefpirome OR cefpodoxime OR cefprozil OR cefquinome OR 51 cefradine OR cefroxadine OR Cefsulodin* OR ceftaroline OR Ceftazidime OR cefteram OR 52 ceftezole OR ceftibuten OR ceftiofur OR Ceftizoxime OR ceftobiprole OR ceftolozane OR 53 Ceftriaxone OR Cefuroxime OR cefuzonam OR Cephacetrile OR Cephalexin* OR Cephaloglycin* 54 OR Cephaloridine OR cephalosporin* OR Cephalothin* OR cephamycin* OR Cephapirin* OR 55 Cephradine OR chalcomycin* OR Chloramphenicol* OR chloroorienticin* OR chloropolysporin* 56 OR chlorothricin* OR chlorothricolide OR Chlortetracycline OR "chymotrypsin trypsin*" OR ciadox 57 58 18 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 39 of 43 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2018-027935 on 5 May 2019. Downloaded from 1 2 3 OR "cilastatin plus imipenem" OR "cinerubin A" OR "cinerubin B" OR cinoquidox OR 4 Ciprofloxacin* OR cirramycin* OR Citrinin* OR Clarithromycin* OR "clavulanate potassium" OR 5 "Clavulanic Acid*" OR Clindamycin* OR clomocycline OR Cloxacillin* OR colicin* OR 6 colistimethate OR Colistin* OR "concanamycin A" OR coumamidine OR coumamycin* OR "cp 7 63956" OR cryptosporin* OR Cyclacillin* OR cycloheximide OR Cycloserine OR cystargin* OR 8 "cytarabine plus daunorubicin*" OR cytovaricin* OR dactimicin* OR Dactinomycin* OR 9 dalbaheptide OR dalbavancin* OR dalfopristin* OR "damavaricin Fc pentyl ether" OR 10 Daptomycin* OR daunomycinone OR daunorubicin* OR daunorubicinol OR 11 "deacetoxycephalosporin C" OR deacetylcefotaxime OR "deacetylcephalosporin C" OR 12 dealanylalahopcin* OR decaplanin* OR dechloroeremomycin* OR decilorubicin* OR defensin* 13 OR Demeclocycline OR dermaseptin* OR dermcidin* OR dermostatin* OR desmycosin* OR 14 detorubicin* OR Diarylquinoline* OR Dibekacin* OR Dicloxacillin* OR dihydrostreptomycin* OR 15 Diketopiperazines OR dimethylchlortetracycline OR dioxidine OR dirithromycin* OR Distamycin* 16 OR "ditrisarubicinFor B" OR peer doripenem OR review doxorubicin* OR doxorubicinolonly OR Doxycycline OR 17 drosocin* OR echinocandin* OR Echinomycin* OR Edeine OR efepristin* OR efrotomycin* OR 18 emimycin* OR endusamycin* OR enniatin* OR Enoxacin* OR Enviomycin* OR eperezolid OR 19 epetraborole OR epicillin* OR epidermin* OR epiderstatin* OR epiroprim OR epirubicin* OR epirubicinol OR epitetracycline OR epothilone* OR "epsilon rhodomycinone" OR eravacycline OR 20 eremomycin* OR ertapenem OR Erythromycin* OR erythromycylamine OR erythronolide* OR 21 esorubicin* OR Ethambutol OR Ethionamide OR ethylhydrocupreine OR etimicin* OR 22 evernimicin* OR everninomicin* OR faeriefungin* OR fidaxomicin* OR Filipin* OR "fleroxacin 23 deacetylcefotaxime ester" OR flomoxef OR flopristin* OR florfenicol OR Floxacillin* OR 24 flucloxacillin* OR flumoxil OR Fluoroquinolone* OR flurithromycin* OR fomidacillin* OR fortimicin* 25 OR Fosfomycin* OR fosmidomycin* OR Framycetin* OR fropenem OR fungichromin* OR 26 furaquinocin* OR furazidin* OR "furazolium chloride" OR furbenicillin* OR fusafungine OR 27 "fusidate sodium" OR "Fusidic Acid" OR fuzlocillin* OR galarubicin* OR gallidermin* OR 28 gamithromycin* OR ganefromycin* OR "ge 2270a" OR gentamicin* OR gepotidacin* OR 29 globomycin* OR gloximonam OR "glycylcycline derivative" OR "gonadorelin6 dextro lysine 2 30 pyrrolinodoxorubicin*" OR "goniodomin A" OR Gramicidin* OR granulysin* OR grisein* OR 31 guamecycline OR habekacin* OR hamycin* OR hatomamicin* OR hedamycin* OR heliomycin*

32 OR hepcidin* OR hetacillin* OR hexacycline OR hidamicin* OR "histatin 5" OR histatin* OR http://bmjopen.bmj.com/ 33 hygromycin* OR hymeglusin* OR hypothemycin* OR iclaprim OR idarubicin* OR idarubicinol OR 34 ikarugamycin* OR "imidacloprid plus moxidectin*" OR Imipenem OR indolicidin* OR inostamycin* 35 OR iseganan OR isepamicin* OR Isoniazid OR "isopenicillin N" OR "isoswinholide A" OR 36 istamycin* OR "iturin A" OR ixabepilone OR Josamycin* OR "k 252a" OR kalafungin* OR 37 Kanamycin* OR kanendomycin* OR kasugamycin* OR kelfiprim OR ketolide OR kidamycin* OR 38 kinamycin* OR Kitasamycin* OR "l 156602" OR "l 733560" OR "l 786392" OR lactacystin* OR 39 Lactams OR lactivicin* OR "lactocin S" OR lactococcin* OR lactoferricin* OR ladirubicin* OR

40 laidlomycin* OR lancovutide OR lankamycin* OR lanopepden OR lanthiopeptin* OR lantibiotic on September 26, 2021 by guest. Protected copyright. 41 OR Lasalocid OR latamoxef OR lavanducyanin* OR lefamulin* OR lenampicillin* OR lenapenem 42 OR lenoremycin* OR Leprostatic* OR "leucinostatin A" OR "leucinostatin B" OR Leucomycin* OR leurubicin* OR Levofloxacin* OR lexithromycin* OR "lff 571" OR Lincomycin* OR lincosamide* 43 OR Linezolid OR linopristin* OR lividomycin* OR "lonomycin A" OR loracarbef OR lotilibcin* OR 44 Lucensomycin* OR lydicamycin* OR Lymecycline OR lysobactin* OR lysocellin* OR lysostaphin* 45 OR macrolide OR magainin* OR malyngolide OR manumycin* OR maridomycin* OR "mdl 62208" 46 OR "mdl 62211" OR mecillinam OR meclocycline OR megacin* OR megalomicin* OR 47 Mepartricin* OR meropenem OR mersacidin* OR metacycline OR metampicillin* OR 48 Methacycline OR Methicillin* OR "methylenomycin A" OR "methylenomycin B" OR methymycin* 49 OR methynolide OR meticillin* OR Mezlocillin* OR "microcin b17" OR "microcin J25" OR 50 micronomicin* OR midecamycin* OR mideplanin* OR "mikamycin B" OR Mikamycin* OR 51 "milbemycin oxime" OR milbemycin* OR Minocycline OR Miocamycin* OR miokamycin* OR 52 miporamicin* OR miraxid OR mocimycin* OR "moenomycin A" OR monensin* OR "monobactam 53 derivative" OR Moxalactam OR moxidectin* OR "ms 8209" OR Mupirocin* OR mureidomycin* OR 54 murepavadin* OR mycinamicin* OR Mycobacillin* OR mycolog OR mycoticin* OR myxothiazol 55 OR "n benzyldoxorubicin 14 valerate" OR "n trifluoroacetyldoxorubicin*" OR Nafcillin* OR 56 "Nalidixic Acid" OR narasin* OR Natamycin* OR neamine OR nebacetin* OR Nebramycin* OR 57 58 19 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 40 of 43 BMJ Open: first published as 10.1136/bmjopen-2018-027935 on 5 May 2019. Downloaded from 1 2 3 negamycin* OR nemadectin* OR nemorubicin* OR Neomycin* OR neosporin* OR Netilmicin* OR 4 Netropsin* OR niddamycin* OR Nigericin* OR Nisin* OR nitrocefin* OR nitrosochloramphenicol 5 OR "nocardicin A" OR "nocardicin E" OR "nocardicinic acid derivative*" OR Norfloxacin* OR 6 nosiheptide OR nourseothricin* OR Novobiocin* OR "nvb 302" OR nybomycin* OR Nystatin* OR 7 "oasomycin A" OR obelmycin* OR Ofloxacin* OR olaquindox OR oleandolide OR Oleandomycin* 8 OR oligomycin* OR omadacycline OR omiganan OR optocillin* OR "orienticin A" OR 9 orientiparcin* OR oritavancin* OR oropivalone OR Oxacillin* OR oxaunomycin* OR "Oxolinic 10 Acid" OR Oxytetracycline OR paldimycin* OR panipenem OR pardaxin* OR Paromomycin* OR 11 patulin* OR pediazole OR pediocin* OR Pefloxacin* OR penamecillin* OR penethamate OR 12 "Penicillanic Acid" OR "Penicillic Acid" OR penicillin* OR "penicilloic acid" OR pentalenolactone 13 OR pentisomicin* OR peptaibol OR pexiganan OR "pf 708093" OR phenelfamycin* OR 14 pheneticillin* OR phleomycin* OR pikromycin* OR "Pipemidic Acid" OR Piperacillin* OR 15 pirarubicin* OR pirazmonam OR pirlimycin* OR Pivampicillin* OR pivmecillinam OR 16 platensimycin*For OR plazomicin* peer OR plectasin* review OR pleuromutilin* only OR pluramycin* OR 17 pneumocandin* OR "polyactin A" OR polyfungin* OR polymyxin* OR "polyoxin B" OR "polyoxin 18 D" OR polysporin* OR polytrim OR posizolid OR "pr 39" OR Pristinamycin* OR Prodigiosin* OR 19 prohepcidin* OR propicillin* OR protegrin* OR Prothionamide OR prothracarcin* OR "pseudomonic acid" OR Pyrazinamide OR pyrromycinone OR pyrroxamycin* OR quinacillin* OR 20 quinomycin* OR quinupristin* OR radezolid OR radicicol OR ramoplanin* OR ranalexin* OR 21 ranbezolid OR razupenem OR retacillin* OR retapamulin* OR "rhodomycin A" OR Ribostamycin* 22 OR Rifabutin* OR Rifampin* OR Rifamycin* OR rimocidin* OR Ristocetin* OR ritipenem OR 23 "ritipenem acoxil" OR rodorubicin* OR roflamycoin* OR rokitamycin* OR Rolitetracycline OR 24 rosaramicin* OR Roxarsone OR Roxithromycin* OR ruboxyl OR Rutamycin* OR sabarubicin* OR 25 sagopilone OR sanfetrinem OR sarecycline OR "simaomicin alpha" OR "simocyclinone D8" OR 26 Sirolimus OR "sisomicin sulfate" OR Sisomicin* OR "skf 104662" OR sofradex OR 27 Spectinomycin* OR "spinosyn A" OR Spiramycin* OR squalamine OR stigmatellin* OR 28 streptoduocin* OR Streptogramin* OR streptolydigin* OR Streptomycin* OR streptothricin* OR 29 streptotriad OR Streptovaricin* OR streptovirudin* OR "streptovitacin A" OR stubomycin* OR 30 subtilin* OR Sulbactam OR Sulbenicillin* OR Sulfamerazine OR Sulfamethoxypyridazine OR 31 sulfazecin* OR sulopenem OR sultamicillin* OR surfactin* OR surotomycin* OR "swinholide A"

32 OR "swinholide B" OR tachyplesin* OR Talampicillin* OR tameticillin* OR tazobactam OR http://bmjopen.bmj.com/ 33 tebipenem OR tedizolid OR Teicoplanin* OR teixobactin* OR telavancin* OR temocillin* OR 34 terdecamycin* OR tetracyclin* OR Tetracycline OR tetramycin* OR tetronasin* OR tetronomycin* 35 OR tetroxoprim OR Thiamphenicol OR Thienamycin* OR Thioacetazone OR thiolactomycin* OR 36 "thionin peptide" OR thiopeptin* OR thiophenoxycefalotin* OR Thiostrepton OR tiamulin* OR 37 "tibezonium iodide" OR Ticarcillin* OR tigecycline OR tigemonam OR tildipirosin* OR tilmicosin* 38 OR timentin* OR tirandamycin* OR tizoxanide OR tobicillin* OR Tobramycin* OR tolramycin* OR 39 tomopenem OR toyocamycin* OR tresaderm OR tribactam OR trichomycin* OR "trichostatic acid"

40 OR "trichostatin A" OR trimethoprim* OR "trinem derivative" OR "triostin A" OR triplopen OR on September 26, 2021 by guest. Protected copyright. 41 trisep OR Troleandomycin* OR trospectomycin* OR tuftsin* OR tulathromycin* OR Tunicamycin* 42 OR tutofusin* OR Tylosin* OR tylvalosin* OR Tyrocidine OR Tyrothricin* OR "u 78608" OR "uk 69753" OR unphenelfamycin* OR "urdamycin C" OR "urdamycin D" OR "urdamycin H" OR 43 ureidopenicillin* OR urobiotic OR "vacidin A" OR validamycin* OR Valinomycin* OR valnemulin* 44 OR valrubicin* OR Vancomycin* OR venturicidin* OR vernamycin* OR "violamycin B1" OR 45 Viomycin* OR "virginiae butanolide A" OR "virginiae butanolide C" OR "virginiamycin M" OR 46 "virginiamycin S" OR Virginiamycin* OR "viriplanin A" OR viscosin* OR volpristin* OR "ws 9659 b" 47 OR "zibrofusidic acid" OR zineryt OR "zoptarelin doxorubicin*" OR zorbamycin* OR zorubicin*) 48 4 TITLE-ABS-KEY(Alprazolam OR arfendazam OR benzodiazepin OR benzodiazepine* OR 49 Benzodiazepinone* OR bromazepam OR camazepam OR Chlordiazepoxide OR cinolazepam 50 OR clobazam OR clonazepam OR clorazepate OR "Clorazepate Dipotassium" OR "clorazepate 51 potassium" OR dealkylflurazepam OR delorazepam OR demoxepam OR devazepide OR 52 diazepam OR doxefazepam OR Estazolam OR fludiazepam OR flunitrazepam OR flurazepam 53 OR flutoprazepam OR fosazepam OR gidazepam OR girisopam OR halazepam OR loflazepate 54 OR lorazepam OR lormetazepam OR lotrafiban OR meclonazepam OR Medazepam OR 55 metaclazepam OR Midazolam OR nastorazepide OR nerisopam OR netazepide OR 56 nimetazepam OR nitrazepam OR nitrosochlordiazepoxide OR norchlordiazepoxide OR 57 58 20 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 41 of 43 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2018-027935 on 5 May 2019. Downloaded from 1 2 3 norclobazam OR nordazepam OR norfludiazepam OR norflunitrazepam OR oxazepam OR 4 phenazepam OR pinazepam OR prazepam OR quazepam OR "ro 7 0213" OR talampanel OR 5 tampramine OR tarazepide OR temazepam OR tetrazepam OR tibezonium OR tifluadom OR 6 tofisopam OR tomaymycin OR Triazolam OR tuclazepam OR uxepam) 7 5 TITLE-ABS-KEY(acetorphine OR acetylcodeine OR acetylmethadol OR Alfentanil OR 8 Alphaprodine OR anileridine OR apadoline OR azidomorphine OR benzhydrocodone OR 9 bezitramide OR bremazocine OR "Brompton mixture" OR Buprenorphine OR Butorphanol OR 10 ciramadol OR cocodamol OR Codeine OR codydramol OR conorfone OR cyclazocine OR 11 Dextromoramide OR Dextropropoxyphene OR dextrorphan OR dezocine OR diamorphine OR 12 diconal OR dihydrocodeine OR dihydroetorphine OR Dihydromorphine OR dimethylthiambutene 13 OR Diphenoxylate OR dipipanone OR enadoline OR eptazocine OR ethylketazocine OR 14 Ethylketocyclazocine OR Ethylmorphine OR etonitazene OR Etorphine OR etoxeridine OR 15 faxeladol OR Fentanyl OR furethidine OR gelonida OR Heroin OR Hydrocodone OR isalmadol 16 OR isomethadoneFor OR ketazocinepeer OR reviewketobemidone OR ketoganonly OR kyotorphin OR lefetamine 17 OR levacetylmethadol OR levomethadone OR Levorphanol OR Meperidine OR Meptazinol OR 18 metazocine OR Methadone OR "Methadyl Acetate" OR methylsamidorphan OR Morphine OR 19 "morphinomimetic agent*" OR "morphinomimetic drug*" OR morphinone OR Nalbuphine OR narcotic* OR nicocodine OR nicomorphine OR noracymethadol OR norbuprenorphine OR 20 nordextropropoxyphene OR normorphine OR norpethidine OR norpropoxyphene OR "o 21 nortramadol" OR oliceridine OR opiate OR Opiate* OR opioid* OR Opium OR oripavine OR 22 Oxycodone OR Oxymorphone OR pentamorphone OR Pentazocine OR pethidine OR 23 phenadoxone OR phenaridine OR Phenazocine OR phencyclidine OR Phenoperidine OR 24 picenadol OR piminodine OR Pirinitramide OR piritramide OR profadol OR Promedol OR 25 propiram OR sameridine OR samidorphan OR semorphone OR Sufentanil OR tapentadol OR 26 thebaine OR tifluadom OR Tilidine OR tonazocine OR Tramadol OR trimeperidine) 27 6 TITLE-ABS-KEY("airflow clearance" OR "airway clearance" OR BLVR OR bronchoscop* OR 28 ELVR OR "lung clearance" OR "lung denervation" OR LVRS OR pneumectom* OR 29 pneumonectom* OR pneumoresection* OR "pulmonary clearance" OR "volume reducing" OR 30 "volume reduction*") 31 7 1 and (2 or 3 or 4 or 5 or 6)

32 8 TITLE-ABS-KEY((meta W/1 analys*) OR (systematic* W/3 review*)) http://bmjopen.bmj.com/ 33 9 7 and 8 34 10 DOCTYPE(le) OR DOCTYPE(ed) OR DOCTYPE(bk) OR DOCTYPE(er) OR DOCTYPE(no) OR 35 DOCTYPE(sh) 36 11 9 and not 10 37 12 PMID(0*) OR PMID(1*) OR PMID(2*) OR PMID(3*) OR PMID(4*) OR PMID(5*) OR PMID(6*) OR 38 PMID(7*) OR PMID(8*) OR PMID(9*) 39 13 11 and not 12

40 on September 26, 2021 by guest. Protected copyright. 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 21 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 42 of 43 BMJ Open: first published as 10.1136/bmjopen-2018-027935 on 5 May 2019. Downloaded from 1 2 3 Part 3 4 5 1 TITLE-ABS-KEY("chronic airflow disease*" OR "chronic airflow disorder*" OR "chronic airflow 6 limitation*" OR "chronic airflow obstruction*" OR "chronic airway disease*" OR "chronic airway 7 disorder*" OR "chronic airway limitation*" OR "chronic airway obstruction*" OR "chronic 8 bronchitis" OR "chronic obstructive airflow disease*" OR "chronic obstructive airflow disorder*" 9 OR "chronic obstructive airway disease*" OR "chronic obstructive airway disorder*" OR "chronic 10 obstructive bronchitis" OR "chronic obstructive bronchopulmonary disease*" OR "chronic 11 obstructive broncho-pulmonary disease*" OR "chronic obstructive bronchopulmonary disorder*" 12 OR "chronic obstructive broncho-pulmonary disorder*" OR "chronic obstructive lung disease*" OR 13 "chronic obstructive lung disorder*" OR "chronic obstructive pulmonary disease*" OR "chronic 14 obstructive pulmonary disorder*" OR "chronic obstructive respiratory disease*" OR "chronic 15 obstructive respiratory disorder*" OR coad OR copd OR emphysema OR "obstructive lung 16 disease" OR For"obstructive peer lung disorder*" review OR "obstructive pulmonaryonly disease*" OR "obstructive 17 pulmonary disorder*" OR "obstructive pulmonary tract disease*" OR "obstructive pulmonary tract 18 disorder*" OR "obstructive respiratory disease*" OR "obstructive respiratory disorder*" OR 19 "obstructive respiratory tract disease*" OR "obstructive respiratory tract disorder*") 2 TITLE-ABS-KEY((smoking* or tobacco* or cigar* or cigarette* or cigaret*) and (quit* or 20 discontinu* or ceas* or cessation*)) 21 3 TITLE-ABS-KEY(aerobics OR anaerobics OR "artificial respiration*" OR bicycling OR biking OR 22 "Chest Wall Oscillation*" OR dance OR dancing OR "endurance training" OR exercis* OR 23 "Extracorporeal Membrane Oxygen*" OR "fitness training" OR "inhalation therap*" OR isometrics 24 OR oxygen OR "physical activit*" OR "physical exertion" OR "postural drain*" OR rehab* OR 25 "resistance training" OR "respiration care*" OR "respiration therap*" OR "respiratory care*" OR 26 "respiratory therap*" OR running OR "strength training" OR swimming OR "Tai Chi" OR "Tai Ji" 27 OR walking OR weightlifting OR yoga) 28 4 TITLE-ABS-KEY(diet OR dietary OR diets OR nutrition* OR supplementation OR supplements) 29 5 TITLE-ABS-KEY(immuniz* OR innoculat* OR moniarix OR "pcv 13" OR pcv13 OR "pneu 30 immune" OR "pneumo 23" OR pneumopur OR pneumovax OR "pnu immune" OR "pnu imune" 31 OR "polysaccharide vaccine pneumococcal" OR prevenar OR prevnar OR "streptococcus

32 pneumoniae vaccine" OR streptopur OR streptorix OR synflorix OR vaccin*) http://bmjopen.bmj.com/ 33 6 ((TITLE-ABS-KEY(((domestic or home or domiciliary) and (residence or residences or setting or 34 settings or care or nurs* or help or service* or treatment* or therap* or "respiratory care" or 35 "respiratory treatment*" or "respiratory therap*" or "respiratory service*" or "respiratory assist*" or 36 ventilat*)) or "assisted living" or homecare)) and (TITLE-ABS-KEY(((((respiration* or respiratory or 37 breathing) and (assist* or controlled or mechanical)) or (facial or face or nasal)) and mask*) or 38 "artificial respiration*" or BiPAP or CPAP or "Fluidic Breathing Assister" or HMV or IPPB or IPPV 39 or NIAV or NIV or NPPV or "Oxygen Regulator*" or PAP or PAV or "Portable Oxygen" or "Positive

40 Airway Pressure*" or "positive end-expiratory pressure*" or "positive pressure*" or respirator or on September 26, 2021 by guest. Protected copyright. 41 respirators or "Respiratory insufficiency" or Tracheostom* or ventilation or ventilator*))) 42 7 1 and (2 or 3 or 4 or 5 or 6) 8 TITLE-ABS-KEY((meta W/1 analys*) OR (systematic* W/3 review*)) 43 9 7 and 8 44 10 DOCTYPE(le) OR DOCTYPE(ed) OR DOCTYPE(bk) OR DOCTYPE(er) OR DOCTYPE(no) OR 45 DOCTYPE(sh) 46 11 9 and not 10 47 12 PMID(0*) OR PMID(1*) OR PMID(2*) OR PMID(3*) OR PMID(4*) OR PMID(5*) OR PMID(6*) OR 48 PMID(7*) OR PMID(8*) OR PMID(9*) 49 13 11 and not 12 50 51 Part 4 52 1 TITLE-ABS-KEY("chronic airflow disease*" OR "chronic airflow disorder*" OR "chronic airflow 53 limitation*" OR "chronic airflow obstruction*" OR "chronic airway disease*" OR "chronic airway 54 disorder*" OR "chronic airway limitation*" OR "chronic airway obstruction*" OR "chronic 55 bronchitis" OR "chronic obstructive airflow disease*" OR "chronic obstructive airflow disorder*" 56 OR "chronic obstructive airway disease*" OR "chronic obstructive airway disorder*" OR "chronic 57 58 22 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 43 of 43 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2018-027935 on 5 May 2019. Downloaded from 1 2 3 obstructive bronchitis" OR "chronic obstructive bronchopulmonary disease*" OR "chronic 4 obstructive broncho-pulmonary disease*" OR "chronic obstructive bronchopulmonary disorder*" 5 OR "chronic obstructive broncho-pulmonary disorder*" OR "chronic obstructive lung disease*" OR 6 "chronic obstructive lung disorder*" OR "chronic obstructive pulmonary disease*" OR "chronic 7 obstructive pulmonary disorder*" OR "chronic obstructive respiratory disease*" OR "chronic 8 obstructive respiratory disorder*" OR coad OR copd OR emphysema OR "obstructive lung 9 disease" OR "obstructive lung disorder*" OR "obstructive pulmonary disease*" OR "obstructive 10 pulmonary disorder*" OR "obstructive pulmonary tract disease*" OR "obstructive pulmonary tract 11 disorder*" OR "obstructive respiratory disease*" OR "obstructive respiratory disorder*" OR 12 "obstructive respiratory tract disease*" OR "obstructive respiratory tract disorder*") 13 2 TITLE-ABS-KEY(CBT OR coach* OR "Cognitive behavioral therap*" OR "Cognitive therap*" OR 14 "health promotion*" OR meditat* OR mentor* OR "mind body" OR mindfulness OR psychological 15 OR psychosocial OR psychotherap*) 16 3 TITLE-ABS-KEY("actionFor peer plan*" OR android review OR app OR apps only OR ehealth OR "e-health" OR 17 internet OR ipad* OR iphone* OR mhealth OR "m-health" OR "mobile app*" OR "mobile health" 18 OR "mobile technolog*" OR "portable computer*" OR "portable electronic app*" OR "portable 19 software app*" OR "remote consultation*" OR "self care" OR "self help" OR "self management" OR "self treatment" OR "smart phone*" OR smartphone* OR "tablet computer*" OR 20 teleconsultation* OR "tele-consultation*" OR telehealth OR "tele-health" OR telemedicine OR 21 "tele-medicine" OR teletherap* OR "tele-therap*" OR web) 22 4 TITLE-ABS-KEY(acupuncture OR agent* OR "alternative medicine" OR "care package*" OR 23 chemotherap* OR "complementary medicine" OR drug* OR "electric stimulation*" OR holistic OR 24 "integrated care" OR "integrated health care" OR "integrated healthcare" OR intervention* OR 25 manag* OR medication* OR "muscle stimulation*" OR operat* OR pharmacotherap* OR 26 procedure* OR reconstruction* OR repair* OR resect* OR surg* OR therap* OR treat* OR 27 wellness) 28 5 1 and (2 or 3 or 4) 29 6 TITLE-ABS-KEY((meta W/1 analys*) OR (systematic* W/3 review*)) 30 7 5 and 6 31 8 DOCTYPE(le) OR DOCTYPE(ed) OR DOCTYPE(bk) OR DOCTYPE(er) OR DOCTYPE(no) OR

32 DOCTYPE(sh) http://bmjopen.bmj.com/ 33 9 7 and not 8 34 10 PMID(0*) OR PMID(1*) OR PMID(2*) OR PMID(3*) OR PMID(4*) OR PMID(5*) OR PMID(6*) OR 35 PMID(7*) OR PMID(8*) OR PMID(9*) 36 11 9 and not 10 37 38 39

40 on September 26, 2021 by guest. Protected copyright. 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 23 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open BMJ Open: first published as 10.1136/bmjopen-2018-027935 on 5 May 2019. Downloaded from

Treatment of stable chronic obstructive pulmonary disease: a protocol for a systematic review and evidence map

Journal: BMJ Open ManuscriptFor ID peerbmjopen-2018-027935.R1 review only Article Type: Protocol

Date Submitted by the 29-Jan-2019 Author:

Complete List of Authors: Dobler, Claudia; Mayo Clinic, Evidence-Based Practice Center, Robert D. and Patricia E. Kern Center for the Science of Health Care Delivery Farah, Magdoleen; Mayo Clinic, Evidence-Based Practice Center, Robert D. and Patricia E. Kern Center for the Science of Health Care Delivery Morrow, Allison; Mayo Clinic, Evidence-Based Practice Center, Robert D. and Patricia E. Kern Center for the Science of Health Care Delivery alsawas, mouaz; Mayo Clinic, Evidence-Based Practice Center, Robert D. and Patricia E. Kern Center for the Science of Health Care Delivery Benkhadra, Raed; Mayo Clinic, Evidence-Based Practice Center, Robert D. and Patricia E. Kern Center for the Science of Health Care Delivery Hasan, Bashar; Mayo Clinic, Evidence-Based Practice Center, Robert D. and Patricia E. Kern Center for the Science of Health Care Delivery

Prokop, Larry; Mayo Clinic, Library Public Services http://bmjopen.bmj.com/ Wang, Zhen; Mayo Clinic, Evidence-Based Practice Center, Robert D. and Patricia E. Kern Center for the Science of Health Care Delivery Murad, M. Hassan; Mayo Clinic, Evidence-Based Practice Center, Robert D. and Patricia E. Kern Center for the Science of Health Care Delivery

Primary Subject Respiratory medicine Heading:

Secondary Subject Heading: Evidence based practice on September 26, 2021 by guest. Protected copyright. Chronic obstructive pulmonary disease, pharmacological interventions, Keywords: non-pharmacological interventions, umbrella review, evidence map, knowledge translation

For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 1 of 44 BMJ Open

1 2 3 Treatment of stable chronic obstructive pulmonary disease: a protocol for a

4 BMJ Open: first published as 10.1136/bmjopen-2018-027935 on 5 May 2019. Downloaded from 5 6 systematic review and evidence map 7 8 9 1 1 1 1 1 10 Claudia C. Dobler, Magdoleen H. Farah, Allison S. Morrow, Mouaz Alsawas, Raed Benkhadra 11 1 2 1 1 12 Bashar Hasan, Larry J. Prokop, Zhen Wang, M. Hassan Murad 13 14 15 1) Evidence-Based Practice Center, Robert D. and Patricia E. Kern Center for the Science of 16 17 Health Care Delivery, Mayo Clinic, Rochester, Minnesota, USA 18 For peer review only 19 2) Library Public Services, Mayo Clinic, Rochester, Minnesota, USA. 20 21 22 23 24 25 26 27 28 29 Correspondence to 30 31 Dr. Claudia C Dobler 32 33 Evidence-based Practice Center 34 35 Mayo Clinic

36 http://bmjopen.bmj.com/ Rochester MN 55905 37 38 USA 39 40 [email protected] 41 42 43

44 on September 26, 2021 by guest. Protected copyright. 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

1 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 2 of 44 BMJ Open: first published as 10.1136/bmjopen-2018-027935 on 5 May 2019. Downloaded from 1 2 3 Abstract 4 5 Introduction: Chronic obstructive pulmonary (COPD) disease is a progressive lung disease, usually 6 7 caused by tobacco smoking, but other important risk factors include exposures to combustion products of 8 9 biomass fuels and environmental pollution. The introduction of several new (combination) inhaler 10 11 therapies, increasing uncertainty about the role of inhaled corticosteroids and a rapid proliferation of the 12 13 literature on management of stable COPD in general, call for novel ways of evidence synthesis in this 14 15 area. A systematic review and evidence map can provide the basis for shared decision-making tools and 16 For peer review only 17 help establish a future research agenda. 18 19 Methods and analysis: This systematic review will follow an umbrella systematic review design (also 20 21 called overview of reviews). We plan to conduct a comprehensive literature search of Ovid MEDLINE 22 23 (including Epub Ahead of Print, In-Process and Other Non-Indexed Citations), Ovid EMBASE, Ovid 24 25 Cochrane Database of Systematic Reviews, and Scopus from database inception to the present. We will 26 include systematic reviews that assessed the effectiveness of any pharmacological or non- 27 28 pharmacological intervention on one or more patient-important outcomes and/or lung function in patients 29 30 with stable COPD. For every intervention/outcome pair one systematic review will be included. An a priori 31 32 protocol will guide which systematic reviews will be chosen, how their credibility will be evaluated, and http://bmjopen.bmj.com/ 33 34 how the quality of the body of evidence will be rated. Data will be synthesized into an evidence map that 35 36 will present a matrix that depicts each available treatment for stable COPD with a quantitative estimate on 37 38 symptoms/outcomes from the patient perspective, along with an indication of the size and certainty in the 39

40 evidence. on September 26, 2021 by guest. Protected copyright. 41 42 Ethics and dissemination: Approval by a research ethics committee is not required since the review will 43 44 only include published data. The systematic review will be published in a peer-reviewed journal. 45 46 Systematic review registration: PROSPERO registration number CRD42018095079 47 48 49 Keywords 50 51 Chronic obstructive pulmonary disease, pharmacological interventions, non-pharmacological 52 53 interventions, umbrella review, evidence map, knowledge translation, decision aid 54 55 56 57 58 2 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 3 of 44 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2018-027935 on 5 May 2019. Downloaded from 1 2 3 Article Summary 4 5 Strengths and limitations of this study 6 7  The planned evidence synthesis will summarise a very large body of literature on 8 9 pharmacological and non-pharmacological interventions thus making research evidence more 10 11 accessible for stakeholders 12 13  The systematic review will be the first to use an evidence map to identify evidence gaps and to 14 15 facilitate evidence communication in clinical encounters for COPD. 16 For peer review only 17  For patients and clinicians, the map will facilitate the production of decision aids. For 18 19 policymakers and researchers, the map helps in establishing a future research agenda. 20 21  The systematic review uses an a priori protocol to identify the most up-to-date systematic reviews 22 23 of the highest possible quality, and the level of evidence for many intervention/outcome pairs will 24 25 therefore likely be high 26 27  As we will only include one systematic review per intervention/outcome pair, it is possible that 28 29 some studies will not have been captured in included systematic reviews 30 31

32 http://bmjopen.bmj.com/ 33 34 35 36 37 38 39

40 on September 26, 2021 by guest. Protected copyright. 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 3 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 4 of 44 BMJ Open: first published as 10.1136/bmjopen-2018-027935 on 5 May 2019. Downloaded from 1 2 3 Introduction 4 5 6 Chronic obstructive pulmonary disease (COPD) is a progressive lung disease characterized by chronic 7 8 obstruction of airflow and permanent damage to the air sacs that leads to breathing problems. COPD is 9 10 mainly a consequence of tobacco smoking, but other important risk factors include exposures to 11 12 combustion products of biomass fuels and environmental pollution.1 COPD is the fourth most common 13 14 cause of death globally and is predicted to be the third by 2030.2 In 2010, the number of COPD cases 15 16 was estimated at 384For million, which peer corresponded review to a global prevalence only of 11.7% (95% confidence 17 18 interval [CI] 8.4%–15.0%).2 COPD was responsible for about 5% of global disability–adjusted life years 19 20 (76.7 million) and 5% of total deaths (2.9 million) based on data from the 2010 Global Burden of Disease 21 3 4 22 study. In some low- and middle income countries COPD has become a growing, but often neglected, 23 epidemic, with a recent study showing a prevalence of COPD of 13.7% (95% CI 12.1–15.5) in Chinese 24 25 people aged 40 years or older.5 Patients with COPD are frequent users of the health care system and 26 27 often need to be admitted to hospital repeatedly, often within short intervals.6 28 29 30 31 Recently, there has been a rapid increase in inhaler therapies available for the management of COPD. In 32 http://bmjopen.bmj.com/ 33 particular, several new inhalers including fixed-dose combinations (containing bronchodilator(s) with or 34 35 without inhaled corticosteroids) have been introduced. Concurrently, the literature on pharmacological 36 37 and non-pharmacological interventions for COPD has proliferated substantially. Multiple systematic 38 39 reviews have been conducted to synthesise the evidence on inhalation treatments in COPD.7-16

40 on September 26, 2021 by guest. Protected copyright. 41 42 43 The role of inhaled corticosteroids for the treatment of stable COPD is increasingly questioned, including 44 45 in patients with severe disease, driven by the growing evidence of an increased risk of pneumonia 46 associated with inhaled corticosteroids,17 18 and the introduction of combined dual long acting 47 48 bronchodilator inhalation therapy as a plausible treatment alternative.19 20 49 50 51 52 A search of the Cochrane Database of Systematic Reviews (Issue 5 of 12, May 2018) with the keyword 53 54 “chronic obstructive pulmonary disease” yielded 132 unique records, indicating that keeping track not just 55 56 57 58 4 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 5 of 44 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2018-027935 on 5 May 2019. Downloaded from 1 2 3 of original studies, but also evidence syntheses, has become a daunting task for decision makers in this 4 5 area. 6 7 8 9 The implementation of evidence-based practice in the management of patients with COPD is challenging 10 11 for medical practitioners due to the rapidly growing body of evidence. Additionally, non-adherence of 12 13 patients with COPD to prescribed treatments is an ongoing challenge, with many patients being 14 21-24 15 overburdened with the treatment work they need to do for their COPD care. Patients' beliefs and 16 For peer review only 17 concerns about the safety and benefits of their treatment and complex treatment regimens all impact on 18 adherence. Non-pharmacological interventions such as pulmonary rehabilitation are persistently 19 20 underutilised despite scientific evidence of their effectiveness.25 21 22 23 24 Faced with these challenges, novel tools of evidence synthesis and evidence communication in CODP for 25 26 the patient-clinician encounter are needed that will allow collaborative deliberation of treatment options 27 28 between patients and clinicians to make health care decisions together, taking into account the best 29 30 scientific evidence available, as well as the patient’s values and preferences.26-29 Further, given the 31

32 rapidly growing body of evidence on treatments for stable COPD, it is timely to identify current knowledge http://bmjopen.bmj.com/ 33 34 gaps to inform future research needs. 35 36 37 38 Consequently, the aim of our systematic review is 1) to synthesise the evidence on pharmacological and 39 non-pharmacological treatments in patients with stable COPD, 2) produce an evidence map that identifies 40 on September 26, 2021 by guest. Protected copyright. 41 evidence gaps in order to inform future research, and that provides information that can be incorporated 42 43 into a decision/communication aid for use during clinical encounters between patients and clinicians. 44 45 46 47 Methods and analysis 48 49 This protocol adheres to the Preferred Reporting Items for Systematic Review and Meta-analysis 50 51 Protocols (PRISMA-P) (see “Additional file 1 PRISMA-P checklist.pdf”).30 52 53 54 55 Patient and Public Involvement 56 57 58 5 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 6 of 44 BMJ Open: first published as 10.1136/bmjopen-2018-027935 on 5 May 2019. Downloaded from 1 2 3 No patients or the public were involved in this systematic review of the literature. 4 5 6 7 Review question 8 9 What are the impacts of pharmacological and non-pharmacological interventions in patients with stable 10 11 COPD on patient-important outcomes (including dyspnea and other symptoms such as anxiety, 12 13 functional/exercise capacity, frequency of acute exacerbations, health-related quality of life, 14 15 hospitalizations, emergency department visits) and lung function parameters? 16 For peer review only 17 18 Eligibility criteria 19 20 Types of studies 21 22 We will include systematic reviews that assessed the effectiveness of any pharmacological or non- 23 24 pharmacological intervention on one or more relevant outcomes (see below) in patients with stable 25 26 COPD. For every intervention/outcome pair (e.g. effectiveness of pulmonary rehabilitation to improve 27 28 dyspnea) one systematic review will be included. The rationale for including only one systematic review 29 30 per intervention/outcome pair is to avoid duplication in included original studies. Alternatively, an umbrella 31

32 review could be conducted at the level of the original studies included in different systematic reviews, http://bmjopen.bmj.com/ 33 34 which would require a new meta-analysis. The latter approach is significantly more resource-intensive 35 36 and time consuming and would not necessarily result in a more accurate pooled estimate compared with 37 38 the result from a single systematic review, provided that the chosen review is a recent comprehensive 39 high quality systematic review. 40 on September 26, 2021 by guest. Protected copyright. 41 42 43 The following a priori protocol will guide which systematic reviews will be chosen, how their credibility will 44 45 be evaluated, and how the quality of the body of evidence will be rated. 46 47 Systematic reviews will be excluded if: 48 49  their pooled estimates were (partially) derived from studies that had not been published in the 50 51 peer-reviewed literature (e.g. abstracts, studies only published on pharmaceutical company 52 53 websites) 54 55  they only contained indirect or mixed indirect and direct comparisons (network meta-analysis) 56 57 58 6 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 7 of 44 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2018-027935 on 5 May 2019. Downloaded from 1 2 3  they were umbrella reviews (reviews of reviews) 4 5  they included patient populations other than patients with COPD and did not report outcomes 6 7 separately for patients with COPD 8 9 10 11 We will derive a single pooled estimate per outcome per intervention. If multiple systematic reviews 12 13 provided multiple estimates for the same intervention and outcome, we will choose a systematic review 14 15 based on the following a priori defined scoring system: 16 For peer review only 17 18 19 a. Availability of one or more meta-analyses, as opposed to narrative data synthesis only (number of 20 available meta-analyses positively correlated with scores) 21 22 b. Year of publication, date of literature search (higher scores for more recent systematic reviews) 23 24 c. Size based on a) Number of studies included, b) Number of participants included (higher scores 25 26 for greater number of studies and participants) 27 28 d. Type of studies: randomized controlled trials (RCTs) generally provide stronger evidence than 29 30 observational studies (highest score for RCTs, followed by prospective cohort studies, 31

32 retrospective cohort studies, and case-control studies) http://bmjopen.bmj.com/ 33 34 e. Synthesis of data from drug classes rather than specific drugs (higher scores if pooled estimates 35 36 are available for drug classes compared to specific drugs only) 37 38 39

40 If we encounter the scenario in which despite the above mentioned criteria we still have to choose on September 26, 2021 by guest. Protected copyright. 41 42 between two or more systematic reviews, we will make this choice based on these additional criteria: 43 a. Consensus among two practicing pulmonologists 44 45 b. Credibility of the systematic reviews as judged using the “A Measurement Tool to Assess 46 47 Systematic Reviews” (AMSTAR2) criteria.31 48 49 50 51 Types of participants 52 53 Studies that evaluated patients aged 40 years and older with stable COPD defined as “persistent 54 55 respiratory symptoms and airflow limitations that are due to airway and/or alveolar abnormalities usually 56 57 58 7 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 8 of 44 BMJ Open: first published as 10.1136/bmjopen-2018-027935 on 5 May 2019. Downloaded from 1 2 3 caused by significant exposure to noxious particles or gases” 32 will be included. Studies conducted in 4 5 patients with an acute exacerbation of COPD will be excluded. 6 7 8 9 Types of interventions 10 11 We will include any pharmacological or non-pharmacological intervention. Interventions that we are 12 13 expecting are the following: inhaled and other medications, smoking cessation, vaccinations, exercise 14 15 and pulmonary rehabilitation, airway clearance techniques, nutrition and dietary interventions, COPD 16 For peer review only 17 action plans, psychological interventions, home oxygen therapy, home mechanical ventilation, 18 interventional bronchoscopy, and surgery. Complex interventions with multiple components such as 19 20 exercise, smoking cessation advice, psychological support and home visits will be excluded. We will also 21 22 exclude interventions only relevant during an acute exacerbation of COPD. 23 24 25 26 Comparators will include placebo or usual/standard care as well as active interventions.. We will exclude 27 28 indirect comparisons between interventions or mixed direct and indirect comparisons (network meta- 29 30 analyses). 31

32 http://bmjopen.bmj.com/ 33 34 Types of outcomes 35 36 The following outcomes will be included: 37 38 a. Dyspnea and other symptoms (e.g. cough, sputum production, and fatigue) 39 b. Exercise capacity and functional capacity 40 on September 26, 2021 by guest. Protected copyright. 41 c. COPD exacerbations 42 43 d. Health-related quality of life 44 45 e. Hospitalizations, emergency department visits 46 47 f. Mortality 48 49 g. Lung function parameters 50 51 h. Adverse events 52 53 There will be no restrictions based on measurement methods. 54 55 56 57 58 8 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 9 of 44 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2018-027935 on 5 May 2019. Downloaded from 1 2 3 Information sources and search strategy 4 5 This systematic review will follow an umbrella systematic review design (also called overview of reviews). 6 7 We plan to conduct a comprehensive literature search of six databases, including Ovid MEDLINE Epub 8 9 Ahead of Print, Ovid MEDLINE In-Process and Other Non-Indexed Citations, Ovid MEDLINE, Ovid 10 11 EMBASE, Ovid Cochrane Database of Systematic Reviews, and Scopus from database inception to the 12 13 present. We have developed a preliminary database search strategy and found that these databases can 14 15 adequately identify the relevant literature. Reference mining of relevant publications will be conducted. 16 For peer review only 17 The search strategy will be designed and conducted by an experienced librarian with input from the 18 study’s principle investigator. Controlled vocabulary supplemented with keywords will be used to search 19 20 for systematic reviews and meta-analyses of pharmacological and non-pharmacological treatments for 21 22 stable COPD. Search strategies are shown in Additional file 2. 23 24 25 26 All citations identified through the process will be imported to a reference management system 27 28 (EndNote® Version X7 and X8; Thomson Reuters, Philadelphia, PA). We will use a web-based 29 30 systematic review software, DistillerSR (Evidence Partners Incorporated, Ottawa, Canada), to facilitate 31

32 the study selection process. http://bmjopen.bmj.com/ 33 34 35 36 Data extraction 37 38 For every intervention/outcome pair one systematic review will be chosen following the priori protocol 39 outlined above. At the beginning of data abstraction, we will develop a standardized data extraction form 40 on September 26, 2021 by guest. Protected copyright. 41 to extract study characteristics (author, study design, inclusion and exclusion criteria, patient 42 43 characteristics, interventions, comparisons, outcomes, and related items for assessing study quality and 44 45 applicability). The standardized form will be pilot-tested by all study team members. We will iteratively 46 47 continue testing the form until no additional items or unresolved questions exist. All study details will be 48 49 extracted by two independent reviewers. A third reviewer will review data extraction, and resolve conflicts. 50 51 52 53 Strategy for data synthesis 54 55 56 57 58 9 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 10 of 44 BMJ Open: first published as 10.1136/bmjopen-2018-027935 on 5 May 2019. Downloaded from 1 2 3 Data will be synthesized into an evidence map. An evidence map is defined as a systematic search of a 4 5 broad field to identify gaps in knowledge and/or future research needs that presents results in a user- 6 7 friendly format, often a visual figure or graph, or a searchable database.33 The planned map will present a 8 9 matrix that depicts each available treatment for stable COPD with a quantitative estimate on 10 11 symptoms/outcomes from the patient perspective, along with an indication of the size and certainty in the 12 13 evidence. 14 15 16 For peer review only 17 We will also provide a narrative synthesis of the findings from the included systematic reviews, structured 18 around the type of intervention, target population characteristics (e.g. severity of COPD), type of outcome 19 20 and intervention content. 21 22 23 24 Analysis of subgroups or subsets 25 26 Pre-determined characteristics for subgroup analysis are: 27 28  Severity of COPD, e.g. based on GOLD (Global Initiative for Chronic Obstructive Lung Disease) 29 30 criteria,34 FEV1 (forced expiratory volume in one second) in % predicted 31 32  COPD phenotypes, e.g. patients with frequent exacerbations, eosinophilic inflammation, http://bmjopen.bmj.com/ 33 34 emphysema-hyperinflation35 35 36  Duration of intervention 37 38  Different study types (e.g. randomized controlled trials versus observational studies) 39

40 on September 26, 2021 by guest. Protected copyright. 41 42 Credibility (methodological quality) assessment 43 44 We will use AMSTAR231 to assess the credibility of the included systematic reviews. The AMSTAR2 tool 45 46 addresses the following 16 items: 47 48  Use of the components of PICO (population, intervention, comparator, outcome) for research 49 50 questions and inclusion criteria 51 52  Protocol for the systematic review, justification of any significant protocol deviations 53 54  Study selection 55 56  Literature search strategy 57 58 10 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 11 of 44 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2018-027935 on 5 May 2019. Downloaded from 1 2 3  Study selection by two independent reviewers 4 5  Data extraction by two independent reviewers 6 7  Excluded studies 8 9  Description of included studies 10 11  Risk of bias assessment in individual studies 12 13  Sources of funding 14 15  Methods for meta-analysis 16 For peer review only 17  Impact of risk of bias on the meta-analysis or other evidence synthesis 18 19  Accounting for risk of bias in the interpretation/discussion of results 20 21  Explanation for heterogeneity in the results 22 23  Publication bias 24 25  Conflicts of interest 26 27 28 29 Ethics and dissemination 30 31 This systematic review is registered with PROSPERO (registration number: CRD42018095079; 32 http://bmjopen.bmj.com/ 33 http://www.crd.york.ac.uk/PROSPERO). Important protocol amendments will be documented in 34 35 PROSPERO. Approval by a research ethics committee is not required since the review will only include 36 37 published and publicly accessible data. The systematic review will be published in a peer-reviewed 38 39 journal and will provide various stakeholders with an evidence map.

40 on September 26, 2021 by guest. Protected copyright. 41 42 43 Discussion 44 45 The aim of this systematic review is to systematically identify, summarize and assess a large body of 46 47 evidence on pharmacological and non-pharmacological interventions in stable COPD. The information will 48 49 be used to produce an evidence map to identify knowledge gaps and to inform a decision/communication 50 51 aid for the clinical encounter between patients and clinicians. 52 53 54 55 Strengths and limitations of this systematic review 56 57 58 11 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 12 of 44 BMJ Open: first published as 10.1136/bmjopen-2018-027935 on 5 May 2019. Downloaded from 1 2 3 We have not identified any systematic reviews that have provided an evidence map for the treatment of 4 5 stable COPD, and this systematic review will therefore be the first to use an evidence map to identify 6 7 evidence gaps and to facilitate evidence communication in clinical encounters for COPD. The systematic 8 9 review uses an a priori protocol to identify the most up-to-date systematic reviews of the highest possible 10 11 quality, and the level of evidence for many intervention/outcome pairs will therefore likely be high. 12 13 As we will only include one systematic review per intervention/outcome pair, it is possible that some 14 15 studies will not have been captured in included systematic reviews. 16 For peer review only 17 18 Practical Implications 19 20 Evidence mapping is a relative novel method of evidence synthesis, which aims to identify gaps in 21 22 knowledge and/or future research needs based on a comprehensive literature search and present results 23 24 in an easy to understand format in a figure or graph.33 Evidence presented in such a user-friendly way 25 26 may facilitate knowledge dissemination and implementation among relevant stakeholder groups including 27 28 policy makers.36 37 In this proposed study, we are targeting two aims that address the needs of different 29 30 stakeholders. 31

32 http://bmjopen.bmj.com/ 33 34 The first type of stakeholders is patients and clinicians. In the context of a clinical encounter, they require 35 36 shared decision-making tools (decision aids) because the available treatments are numerous and the 37 38 impact on the different symptoms varies by intervention. Traditional systematic reviews usually 39 summarize evidence grouped around specific interventions. In clinical practice, however, discussions 40 on September 26, 2021 by guest. Protected copyright. 41 between patients and clinicians often focus on a problem that demands a solution (e.g. shortness of 42 43 breath or limited functional capacity in patients with COPD). This requires that evidence is communicated 44 45 from an outcome rather than an intervention perspective (e.g. which interventions can improve shortness 46 47 of breath or functional capacity in patients with stable COPD?). We plan to present the results of our 48 49 systematic review structured by outcomes to facilitate knowledge translation into a 50 51 decision/communication aid (the COPD CHOICE decision aid project). This will hopefully contribute to 52 53 patient-centred and transparent evidence communication in clinical encounters. 54 55 56 57 58 12 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 13 of 44 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2018-027935 on 5 May 2019. Downloaded from 1 2 3 The second type of stakeholders is policymakers funding research and researchers. The presentation of 4 5 results in the form of evidence map can quickly provide them with a snapshot of which symptoms (daily 6 7 dilemmas that patients face) or which interventions are only supported by low quality evidence (or no 8 9 evidence). Such areas are prime targets for future research. 10 11 12 13 The proposed approach (overview of reviews and evidence mapping) is ideal in the context of the very 14 15 large volume of literature available on pharmacological and non-pharmacological interventions in stable 16 For peer review only 17 COPD, and the need to synthesize and present summaries that cater to different stakeholders. 18 19 20 List of abbreviations 21 22 95% CI: 95% confidence interval; AMSTAR2: A Measurement Tool to Assess Systematic Reviews 2; 23 24 COPD: Chronic obstructive pulmonary disease (COPD); FEV1: forced expiratory volume in one second; 25 26 GOLD: Global Initiative for Chronic Obstructive Lung Disease; PICO: population, intervention, 27 28 comparator, outcome; PRISMA-P: Preferred Reporting Items for Systematic Review and Meta-analysis 29 30 Protocols; RCT: randomized controlled trial 31

32 http://bmjopen.bmj.com/ 33 34 35 36 Authors’ contributions 37 38 Claudia C. Dobler drafted the manuscript. M. Hassan Murad made substantial contributions to the 39 conception and design. Working with Claudia C. Dobler, Larry J. Prokop designed the search strategy for 40 on September 26, 2021 by guest. Protected copyright. 41 the systematic review. Claudia C. Dobler, Magdoleen H. Farah, Allison S. Morrow, Mouaz Alsawas, Raed 42 43 Benkhadra, Bashar Hasan, Larry J. Prokop, Zhen Wang, and M. Hassan Murad revised the manuscript 44 45 critically for important intellectual content and approved the final manuscript. 46 47 48 49 Funding 50 51 This research received no specific grant from any funding agency in the public, 52 53 commercial or not-for-profit sectors. Claudia C. Dobler was supported by a fellowship from the Australian 54 55 National Health and Medical Research Council (NHMRC), grant number APP1123733. 56 57 58 13 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 14 of 44 BMJ Open: first published as 10.1136/bmjopen-2018-027935 on 5 May 2019. Downloaded from 1 2 3 4 5 Competing interests statement 6 7 No conflict of interest to declare. 8 9 10 11 Word count 12 13 Abstract 297, Main text 2,494 14 15 16 For peer review only 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31

32 http://bmjopen.bmj.com/ 33 34 35 36 37 38 39

40 on September 26, 2021 by guest. Protected copyright. 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 14 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 15 of 44 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2018-027935 on 5 May 2019. Downloaded from 1 2 3 References 4 5 1. Postma DS, Bush A, van den Berge M. Risk factors and early origins of chronic obstructive 6 7 pulmonary disease. Lancet (London, England) 2015;385(9971):899-909. doi: 10.1016/s0140- 8 9 6736(14)60446-3 [published Online First: 2014/08/16] 10 11 2. Adeloye D, Chua S, Lee C, et al. Global and regional estimates of COPD prevalence: Systematic 12 13 review and meta-analysis. Journal of global health 2015;5(2):020415. doi: 10.7189/jogh.05- 14 15 020415 [published Online First: 2016/01/13] 16 For peer review only 17 3. Murray CJ,os T, Lozano R, et al. Disability-adjusted life years (DALYs) for 291 diseases and 18 injuries in 21 regions, 1990-2010: a systematic analysis for the Global Burden of Disease Study 19 20 2010. Lancet (London, England) 2012;380(9859):2197-223. doi: 10.1016/s0140-6736(12)61689- 21 22 4 [published Online First: 2012/12/19] 23 24 4. Lano R, Naghavi M, Foreman K, et al. Global and regional mortality from 235 causes of death for 25 26 20 age groups in 1990 and 2010: a systematic analysis for the Global Burden of Disease Study 27 28 2010. Lancet (London, England) 2012;380(9859):2095-128. doi: 10.1016/s0140-6736(12)61728- 29 30 0 [published Online First: 2012/12/19] 31

32 5. Wang C, Xu J, Yang L, et al. Prevalence and risk factors of chronic obstructive pulmonary http://bmjopen.bmj.com/ 33 34 disease in China (the China Pulmonary Health [CPH] study): a national cross-sectional study. 35 36 Lancet (London, England) 2018;391(10131):1706-17. doi: 10.1016/s0140-6736(18)30841-9 37 38 [published Online First: 2018/04/14] 39 6. Hakim MA, Garden FL, Jennings MD, et al. Performance of the LACE index to predict 30-day 40 on September 26, 2021 by guest. Protected copyright. 41 hospital readmissions in patients with chronic obstructive pulmonary disease. Clinical 42 43 epidemiology 2018;10:51-59. doi: 10.2147/clep.s149574 [published Online First: 2018/01/19] 44 45 7. Horita N, Goto A, Shibata Y, et al. Long-acting muscarinic antagonist (LAMA) plus long-acting 46 47 beta-agonist (LABA) versus LABA plus inhaled corticosteroid (ICS) for stable chronic obstructive 48 49 pulmonary disease (COPD). Cochrane Database Syst Rev 2017;2:CD012066. doi: 50 51 https://dx.doi.org/10.1002/14651858.CD012066.pub2 52 53 54 55 56 57 58 15 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 16 of 44 BMJ Open: first published as 10.1136/bmjopen-2018-027935 on 5 May 2019. Downloaded from 1 2 3 8. Calzetta L, Ora J, Cavalli F, et al. Impact of LABA/LAMA combination on exercise endurance and 4 5 lung hyperinflation in COPD: A pair-wise and network meta-analysis. Respir Med 2017;129:189- 6 7 98. doi: https://dx.doi.org/10.1016/j.rmed.2017.06.020 8 9 9. Farne HA, Cates CJ. Long-acting beta2-agonist in addition to tiotropium versus either tiotropium 10 11 or long-acting beta2-agonist alone for chronic obstructive pulmonary disease. Cochrane 12 13 Database Syst Rev 2015(10):CD008989. doi: 14 15 https://dx.doi.org/10.1002/14651858.CD008989.pub3 16 For peer review only 17 10. Rodrigo GJ, Price D, Anzueto A, et al. LABA/LAMA combinations versus LAMA monotherapy or 18 LABA/ICS in COPD: a systematic review and meta-analysis. Int J Chron Obstruct Pulmon Dis 19 20 2017;12:907-22. doi: https://dx.doi.org/10.2147/COPD.S130482 21 22 11. Karner C, Cates CJ. Combination inhaled steroid and long-acting beta(2)-agonist in addition to 23 24 tiotropium versus tiotropium or combination alone for chronic obstructive pulmonary disease. 25 26 Cochrane Database Syst Rev 2011(3):CD008532. doi: 27 28 https://dx.doi.org/10.1002/14651858.CD008532.pub2 29 30 12. Kwak M-S, Kim E, Jang EJ, et al. The efficacy and safety of triple inhaled treatment in patients 31

32 with chronic obstructive pulmonary disease: a systematic review and meta-analysis using http://bmjopen.bmj.com/ 33 34 Bayesian methods. Int J Chron Obstruct Pulmon Dis 2015;10:2365-76. doi: 35 36 https://dx.doi.org/10.2147/COPD.S93191 37 38 13. Nannini LJ, Lasserson TJ, Poole P. Combined corticosteroid and long-acting beta(2)-agonist in 39 one inhaler versus long-acting beta(2)-agonists for chronic obstructive pulmonary disease. 40 on September 26, 2021 by guest. Protected copyright. 41 Cochrane Database Syst Rev 2012(9):CD006829. doi: 42 43 https://dx.doi.org/10.1002/14651858.CD006829.pub2 44 45 14. Nannini LJ, Poole P, Milan SJ, et al. Combined corticosteroid and long-acting beta(2)-agonist in 46 47 one inhaler versus inhaled corticosteroids alone for chronic obstructive pulmonary disease. 48 49 Cochrane Database Syst Rev 2013(8):CD006826. doi: 50 51 https://dx.doi.org/10.1002/14651858.CD006826.pub2 52 53 15. Rojas-Reyes MX, Garcia Morales OM, Dennis RJ, et al. Combination inhaled steroid and long- 54 55 acting beta2-agonist in addition to tiotropium versus tiotropium or combination alone for chronic 56 57 58 16 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 17 of 44 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2018-027935 on 5 May 2019. Downloaded from 1 2 3 obstructive pulmonary disease. Cochrane Database Syst Rev 2016(6):CD008532. doi: 4 5 https://dx.doi.org/10.1002/14651858.CD008532.pub3 6 7 16. Welsh EJ, Cates CJ, Poole P. Combination inhaled steroid and long-acting beta2-agonist versus 8 9 tiotropium for chronic obstructive pulmonary disease. Cochrane Database Syst Rev 2013(5) 10 11 17. Singh S, Amin AV, Loke YK. Long-term use of inhaled corticosteroids and the risk of pneumonia 12 13 in chronic obstructive pulmonary disease: a meta-analysis. Arch Intern Med 2009;169(3):219-29. 14 15 doi: https://dx.doi.org/10.1001/archinternmed.2008.550 16 For peer review only 17 18. Kew KM, Seniukovich A. Inhaled steroids and risk of pneumonia for chronic obstructive 18 pulmonary disease. Cochrane Database Syst Rev 2014(3):CD010115. doi: 19 20 https://dx.doi.org/10.1002/14651858.CD010115.pub2 21 22 19. Wedzicha JA, Banerji D, Chapman KR, et al. Indacaterol-Glycopyrronium versus Salmeterol- 23 24 Fluticasone for COPD. The New England journal of medicine 2016;374(23):2222-34. doi: 25 26 10.1056/NEJMoa1516385 [published Online First: 2016/05/18] 27 28 20. Magnussen H, Disse B, Rodriguez-Roisin R, et al. Withdrawal of inhaled glucocorticoids and 29 30 exacerbations of COPD. The New England journal of medicine 2014;371(14):1285-94. doi: 31

32 10.1056/NEJMoa1407154 [published Online First: 2014/09/10] http://bmjopen.bmj.com/ 33 34 21. Bourbeau J, Bartlett SJ. Patient adherence in COPD. Thorax 2008;63(9):831-8. doi: 35 36 10.1136/thx.2007.086041 [published Online First: 2008/08/30] 37 38 22. Agh T, Inotai A, Meszaros A. Factors associated with medication adherence in patients with 39 chronic obstructive pulmonary disease. Respiration; international review of thoracic diseases 40 on September 26, 2021 by guest. Protected copyright. 41 2011;82(4):328-34. doi: 10.1159/000324453 [published Online First: 2011/04/02] 42 43 23. Harb N, Foster JM, Dobler CC. Patient-perceived treatment burden of chronic obstructive 44 45 pulmonary disease. Int J Chron Obstruct Pulmon Dis 2017;12:1641-52. doi: 46 47 10.2147/copd.s130353 [published Online First: 2017/06/16] 48 49 24. Dobler CC, Harb N, Maguire CA, et al. Treatment burden should be included in clinical practice 50 51 guidelines. BMJ (Clinical research ed) 2018;363:k4065. doi: 10.1136/bmj.k4065 [published Online 52 53 First: 2018/10/14] 54 55 56 57 58 17 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 18 of 44 BMJ Open: first published as 10.1136/bmjopen-2018-027935 on 5 May 2019. Downloaded from 1 2 3 25. Safka KA, McIvor RA. Non-pharmacological management of chronic obstructive pulmonary 4 5 disease. The Ulster medical journal 2015;84(1):13-21. [published Online First: 2015/05/13] 6 7 26. Stiggelbout AM, Van der Weijden T, De Wit MP, et al. Shared decision making: really putting 8 9 patients at the centre of healthcare. BMJ (Clinical research ed) 2012;344:e256. doi: 10 11 10.1136/bmj.e256 [published Online First: 2012/01/31] 12 13 27. Elwyn G, Frosch D, Thomson R, et al. Shared decision making: a model for clinical practice. 14 15 Journal of general internal medicine 2012;27(10):1361-7. doi: 10.1007/s11606-012-2077-6 16 For peer review only 17 [published Online First: 2012/05/24] 18 28. Dobler CC, Sanchez M, Gionfriddo MR, et al. Impact of decision aids used during clinical 19 20 encounters on clinician outcomes and consultation length: a systematic review. BMJ quality & 21 22 safety 2018 doi: 10.1136/bmjqs-2018-008022 [published Online First: 2018/10/12] 23 24 29. Dobler CC, Midthun DE, Montori VM. Quality of Shared Decision Making in Lung Cancer 25 26 Screening: The Right Process, With the Right Partners, at the Right Time and Place. Mayo Clinic 27 28 proceedings 2017;92(11):1612-16. doi: 10.1016/j.mayocp.2017.08.010 [published Online First: 29 30 2017/11/06] 31

32 30. Shamseer L, Moher D, Clarke M, et al. Preferred reporting items for systematic review and meta- http://bmjopen.bmj.com/ 33 34 analysis protocols (PRISMA-P) 2015: elaboration and explanation. BMJ (Clinical research ed) 35 36 2015;350:g7647. doi: 10.1136/bmj.g7647 [published Online First: 2015/01/04] 37 38 31. Shea BJ, Reeves BC, Wells G, et al. AMSTAR 2: a critical appraisal tool for systematic reviews 39 that include randomised or non-randomised studies of healthcare interventions, or both. BMJ 40 on September 26, 2021 by guest. Protected copyright. 41 (Clinical research ed) 2017;358:j4008. doi: 10.1136/bmj.j4008 [published Online First: 42 43 2017/09/25] 44 45 32. Global Initiative for Chronic Obstructive Lung Disease. Global strategy for the diagnosis, 46 47 management, and prevention of chronic obstructive pulmonary disease (2019 report) [Available 48 49 from: https://goldcopd.org/gold-reports/ accessed January 28, 2019. 50 51 33. Miake-Lye IM, Hempel S, Shanman R, et al. What is an evidence map? A systematic review of 52 53 published evidence maps and their definitions, methods, and products. Systematic reviews 54 55 2016;5:28. doi: 10.1186/s13643-016-0204-x [published Online First: 2016/02/13] 56 57 58 18 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 19 of 44 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2018-027935 on 5 May 2019. Downloaded from 1 2 3 34. Global Strategy for Prevention, Diagnosis and Management of COPD, 2018 reprt. Available at: 4 5 http://goldcopd.org/wp-content/uploads/2017/11/GOLD-2018-v6.0-FINAL-revised-20- 6 7 Nov_WMS.pdf Accessed May 15, 2018. 8 9 35. Miravitlles M, Calle M, Soler-Cataluna JJ. Clinical phenotypes of COPD: identification, definition 10 11 and implications for guidelines. Archivos de bronconeumologia 2012;48(3):86-98. doi: 12 13 10.1016/j.arbres.2011.10.007 [published Online First: 2011/12/27] 14 15 36. Bangerter LR, Griffin JM, Langer S, et al. The Effect of Psychosocial Interventions on Outcomes 16 For peer review only 17 for Caregivers of Hematopoietic Cell Transplant Patients. Current hematologic malignancy 18 reports 2018 doi: 10.1007/s11899-018-0445-y [published Online First: 2018/05/01] 19 20 37. Farah WH, Alsawas M, Mainou M, et al. Non-pharmacological treatment of depression: a 21 22 systematic review and evidence map. Evidence-based medicine 2016;21(6):214-21. doi: 23 24 10.1136/ebmed-2016-110522 [published Online First: 2016/11/12] 25 26 27 28 29 30 31

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40 on September 26, 2021 by guest. Protected copyright. 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 19 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open: first published as 10.1136/bmjopen-2018-027935 on 5 May 2019. Downloaded from

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1 2 3 PRISMA-P (Preferred Reporting Items for Systematic review and Meta-Analysis Protocols) 2015 checklist: recommended items to 4 address in a systematic review protocol* 5 6 Section and topic Item No Checklist item 7 8 ADMINISTRATIVE INFORMATION 9 Title: 10 Identification 1a Identify the report as a protocol of a systematic review 11 Update 1b If the protocol is for an update of a previous systematic review, identify as such 12 Registration 2For If registered, peer provide the name review of the registry (such as PROSPERO) only and registration number 13 14 Authors: 15 Contact 3a Provide name, institutional affiliation, e-mail address of all protocol authors; provide physical mailing address of 16 corresponding author http://bmjopen.bmj.com/ 17 Contributions 3b Describe contributions of protocol authors and identify the guarantor of the review 18 Amendments 4 If the protocol represents an amendment of a previously completed or published protocol, identify as such and list changes; 19 otherwise, state plan for documenting important protocol amendments 20 Support: 21 Sources 5a Indicate sources of financial or other support for the review 22 Sponsor 5b Provide name for the review funder and/or sponsor 23 24 Role of sponsor or funder 5c Describe roles of funder(s), sponsor(s), and/or institution(s), if any, in developing on September 26, 2021 by guest. Protected copyright. the protocol 25 INTRODUCTION 26 27 Rationale 6 Describe the rationale for the review in the context of what is already known 28 Objectives 7 Provide an explicit statement of the question(s) the review will address with reference to participants, interventions, 29 comparators, and outcomes (PICO) 30 METHODS 31 32 Eligibility criteria 8 Specify the study characteristics (such as PICO, study design, setting, time frame) and report characteristics (such as years 33 considered, language, publication status) to be used as criteria for eligibility for the review 34 Information sources 9 Describe all intended information sources (such as electronic databases, contact with study authors, trial registers or other 35 grey literature sources) with planned dates of coverage 36 Search strategy 10 Present draft of search strategy to be used for at least one electronic database, including planned limits, such that it could be 37 repeated 38 Study records: 39 Data management 11a Describe the mechanism(s) that will be used to manage records and data throughout the review 40 41 42 43 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2018-027935 on 5 May 2019. Downloaded from

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1 2 3 Selection process 11b State the process that will be used for selecting studies (such as two independent reviewers) through each phase of the 4 review (that is, screening, eligibility and inclusion in meta-analysis) 5 Data collection process 11c Describe planned method of extracting data from reports (such as piloting forms, done independently, in duplicate), any 6 processes for obtaining and confirming data from investigators 7 Data items 12 List and define all variables for which data will be sought (such as PICO items, funding sources), any pre-planned data 8 assumptions and simplifications 9 10 Outcomes and prioritization 13 List and define all outcomes for which data will be sought, including prioritization of main and additional outcomes, with rationale 11 12 Risk of bias in individual studies 14 Describe anticipated methods for assessing risk of bias of individual studies, including whether this will be done at the Foroutcome peer or study level, or both; review state how this information onlywill be used in data synthesis 13 14 Data synthesis 15a Describe criteria under which study data will be quantitatively synthesised 15 15b If data are appropriate for quantitative synthesis, describe planned summary measures, methods of handling data and 16 methods of combining data from studies, including any planned exploration of consistencyhttp://bmjopen.bmj.com/ (such as I2, Kendall’s τ) 17 15c Describe any proposed additional analyses (such as sensitivity or subgroup analyses, meta-regression) 18 15d If quantitative synthesis is not appropriate, describe the type of summary planned 19 Meta-bias(es) 16 Specify any planned assessment of meta-bias(es) (such as publication bias across studies, selective reporting within studies) 20 Confidence in cumulative evidence 17 Describe how the strength of the body of evidence will be assessed (such as GRADE) 21

22 * It is strongly recommended that this checklist be read in conjunction with the PRISMA-P Explanation and Elaboration (cite when available) for important 23 clarification on the items. Amendments to a review protocol should be tracked and dated. The copyright for PRISMA-P (including checklist) is held by the

on September 26, 2021 by guest. Protected copyright. 24 PRISMA-P Group and is distributed under a Creative Commons Attribution Licence 4.0. 25 26 From: Shamseer L, Moher D, Clarke M, Ghersi D, Liberati A, Petticrew M, Shekelle P, Stewart L, PRISMA-P Group. Preferred reporting items for systematic review and 27 meta-analysis protocols (PRISMA-P) 2015: elaboration and explanation. BMJ. 2015 Jan 2;349(jan02 1):g7647. 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open Page 22 of 44 BMJ Open: first published as 10.1136/bmjopen-2018-027935 on 5 May 2019. Downloaded from 1 2 3 Literature search strategy for 4 5 Treatment of stable chronic obstructive pulmonary disease: a protocol for a systematic 6 7 review and evidence map 8 9

10 11 1 1 1 1 1 Claudia C. Dobler, Magdoleen H Farah, Allison S. Morrow, Mouaz Alsawas, Raed Benkhadra Bashar 12 13 Hasan,1 Larry J Prokop,2 Zhen Wang,1 M. Hassan Murad1 14 15 16 For peer review only 17 1) Evidence-Based Practice Center, Robert D. and Patricia E. Kern Center for the Science of Health 18 19 Care Delivery, Mayo Clinic, Rochester, Minnesota, USA 20 21 2) Library Public Services, Mayo Clinic, Rochester, Minnesota, USA. 22 23 24 25 26 27 Ovid 28 29 Part 1 30 31 Database(s): Embase 1988 to 2018 Week 16, EBM Reviews - Cochrane Database of Systematic

32 Reviews 2005 to April 11, 2018, Ovid MEDLINE(R) Epub Ahead of Print, In-Process & Other Non- http://bmjopen.bmj.com/ 33 Indexed Citations, Ovid MEDLINE(R) Daily and Ovid MEDLINE(R) 1946 to Present Search Strategy: 34 35 # Searches Results exp Pulmonary Disease, Chronic Obstructive/dh, dt, px, rh, su, th [Diet Therapy, Drug 36 1 18829 37 Therapy, Psychology, Rehabilitation, Surgery, Therapy] 38 exp chronic obstructive lung disease/dm, dt, rh, su, th [Disease Management, Drug Therapy, 2 27067 39 Rehabilitation, Surgery, Therapy] 40 3 1 or 2 45896 on September 26, 2021 by guest. Protected copyright. 41 ("chronic airflow disease*" or "chronic airflow disorder*" or "chronic airflow limitation*" or 42 "chronic airflow obstruction*" or "chronic airway disease*" or "chronic airway disorder*" or 43 "chronic airway limitation*" or "chronic airway obstruction*" or "chronic bronchitis" or "chronic 44 obstructive airflow disease*" or "chronic obstructive airflow disorder*" or "chronic obstructive 45 airway disease*" or "chronic obstructive airway disorder*" or "chronic obstructive bronchitis" 46 or "chronic obstructive bronchopulmonary disease*" or "chronic obstructive broncho- 47 pulmonary disease*" or "chronic obstructive bronchopulmonary disorder*" or "chronic 48 obstructive broncho-pulmonary disorder*" or "chronic obstructive lung disease*" or "chronic 4 248757 49 obstructive lung disorder*" or "chronic obstructive pulmonary disease*" or "chronic 50 obstructive pulmonary disorder*" or "chronic obstructive respiratory disease*" or "chronic 51 obstructive respiratory disorder*" or coad or copd or emphysema or "obstructive lung 52 disease" or "obstructive lung disorder*" or "obstructive pulmonary disease*" or "obstructive 53 pulmonary disorder*" or "obstructive pulmonary tract disease*" or "obstructive pulmonary 54 tract disorder*" or "obstructive respiratory disease*" or "obstructive respiratory disorder*" or 55 "obstructive respiratory tract disease*" or "obstructive respiratory tract 56 disorder*").ti,ab,hw,kw. 57 58 1 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 23 of 44 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2018-027935 on 5 May 2019. Downloaded from 1 2 3 5 exp Bronchodilator Agents/ 383398 4 5 (abediterol or acefylline or "acefylline clofibrol" or "acefylline piperazine" or "aclidinium bromide" or "adrenalin hydrogen tartrate" or Adrenomedullin or Albuterol or ambuphylline or 6 Aminophylline or antibronchospastic or arformoterol or Atropine or bambuterol or bamifylline 7 or baralgin or batefenterol or bitolterol or "bitolterol mesilate" or "bronchial dilating" or 8 "bronchial-dilating" or bronchodilatant* or "broncho-dilatant*" or bronchodilatating or 9 "broncho-dilatating" or bronchodilatator* or "broncho-dilatator*" or bronchodilating or 10 "broncho-dilating" or bronchodilator* or "broncho-dilator*" or broncholytic* or broncholytica or 11 bronchospasmolytic or broxaterol or Budesonide or carbuterol or carmoterol or "choline 12 theophyllinate" or Clenbuterol or clorprenaline or Colforsin or Cromakalim or danirixin or 13 "darotropium bromide" or dilator* or diprophylline or ditec or doxofylline or Dyphylline or 14 elubrixin or enprofylline or ephedrine or "ephedrine sulfate" or Epinephrine or eprozinol or 15 espatropate or etafedrine or etamiphyllin or "etamiphyllin camsilate" or etanterol or etofylline 16 or Fenoterol or fenspirideFor or Fluticasonepeer or review"flutropium bromide" only or formoterol or "Formoterol 17 Fumarate" or furafylline or glycopyrronium or "gsk 159802" or "gsk 597901" or guaifylline or 6 860675 18 "gw 678007" or Hexoprenaline or Hyoscyamine or ibuterol or "ilmetropium iodide" or 19 imoxiterol or indacaterol or inhaler* or Ipratropium or "ipratropium bromide" or isbufylline or 20 isoetarine or "isoetarine mesylate" or Isoetharine or isoprenaline or Isoproterenol or Khellin 21 or laprafylline or levalbuterol or mabuterol or marax or Metaproterenol or methoxyphenamine 22 or milveterol or "n methylmequitazine" or naminterol or neobiphyllin or nestifylline or "Nitric 23 Oxide" or olodaterol or orciprenaline or "oxitropium bromide" or "oxyphenonium bromide" or 24 pibaxizine or pirbuterol or "pirbuterol acetate" or pneumodilator or Procaterol or protokylol or 25 proxyphylline or Pseudoephedrine or racephedrine or Racepinephrine or reproterol or 26 rimiterol or "ru 45703" or salbutamol or "salbutamol sulfate" or salmefamol or salmeterol or 27 "Salmeterol Xinafoate" or sibenadet or "S-Nitrosoglutathione" or "S-Nitrosothiols" or 28 soterenol or tazifylline or Terbutaline or Theobromine or Theophylline or "theophylline sodium glycinate" or thiazinamium or "thiazinamium metilsulfate" or Tiotropium or Tretoquinol 29 or "tretoquinol derivative" or trimetaquinol or tulobuterol or "uk 432097" or Umeclidinium or 30 vephylline or verofylline or vilanterol or "vilanterol trifenatate" or zindotrine).ti,ab,hw,kw. 31

32 7 exp Adrenergic beta-2 Receptor Agonists/ 82439 http://bmjopen.bmj.com/ 33 ("adrenergic beta 2 agonist*" or "adrenergic beta 2 receptor agonist*" or "adrenergic beta2 34 agonist*" or "adrenergic beta-2 agonist*" or "adrenergic beta-2 receptor agonist*" or 35 "adrenergic beta2-agonist*" or Albuterol or "beta 2 adrenergic agent*" or "beta 2 adrenergic 36 agonist*" or "beta 2 adrenergic receptor agonist*" or "beta 2 adrenergic receptor stimulant*" 37 or "beta 2 adrenergic receptor stimulat*" or "beta 2 adrenergic receptor stimulator*" or "beta 2 adrenergic stimulant*" or "beta 2 adrenergic stimulat*" or "beta 2 adrenergic stimulator*" or 38 8 83917 39 "beta 2 adrenoceptor agonist*" or "beta 2 adrenoceptor stimulant*" or "beta 2 adrenoceptor stimulat**" or "beta 2 adrenoceptor stimulator*" or "beta 2 agonist*" or "beta agonist*" or 40 on September 26, 2021 by guest. Protected copyright. "beta receptor agonist*" or "beta receptor stimulant*" or "beta stimulant" or "beta2 adrenergic 41 receptor stimulat*" or Fenoterol or formoterol or Hexoprenaline or indacaterol or Isoetharine 42 or LABA or LABAs or Metaproterenol or Procaterol or Ritodrine or SABA or SABAs or 43 salmeterol or "Salmeterol Xinafoate" or Terbutaline).ti,ab,hw,kw. 44 45 9 exp Cholinergic Antagonists/ 215195 46 ("acetylcholine antagonist*" or "acetylcholine receptor block*" or "acetylcholine receptor 47 inhibitor*" or "AChR inhibitor" or aclidinium or "aclidinium bromide" or acotiamide or 48 adiphenine or afacifenacin or Alcuronium or "alpha conotoxin MII" or alvameline or alverine 49 or "alverine citrate" or anisodamine or "anti cholinergics" or anticholinergic or anticholinergic* 50 or "anti-cholinergic*" or antimuscarinic* or aprofene or aspaminol or Atracurium or Atropine 51 10 or atropinic* or azaprophen or belladonna or bellergal or Benactyzine or benzetimide or 400683 52 benzilonium or "benzilylcholine mustard" or benzoquinonium or Benztropine or Biperiden or bornaprine or Butylscopolammonium or buzepide or catestatin or "central anticholinergic" or 53 Chlorisondamine or chlorphenoxamine or cholinolytic* or cimetropium or clidinium or Curare 54 or Cyclopentolate or cycrimine or darifenacin or darotropium or deptropine or 55 desfesoterodine or Dexetimide or dexmecamylamine or "dibutoline sulfate" or Dicyclomine or 56 57 58 2 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 24 of 44 BMJ Open: first published as 10.1136/bmjopen-2018-027935 on 5 May 2019. Downloaded from 1 2 3 dicycloverine or diethazine or dimevamide or "diphemanil methylsulfate" or drofenine or 4 elantrine or Emepronium or espatropate or Ethidium or "ethylcholine mustard aziridinium" or 5 eucatropine or fenoverine or fenpipramide or fenpiverinium or fesoterodine or fluperlapine or 6 flutropium or furtramine or "Gallamine Triethiodide" or ganglefene or Glycopyrrolate or 7 glycopyrronium or "gsk 202405" or "h cholinoreactive cell*" or hemicholinium or 8 hexahydrodifenidol or hexahydroprocyclidine or hexahydrosiladifenidol or Hexamethonium or 9 hexbutinol or "hexbutinol methiodide" or "hexocyclium metilsulfate" or himbacine or 10 homatropine or "homatropine methyl" or "homatropine terephthalate" or Hyoscyamine or 11 imidafenacin or Ipratropium or isomylamine or "isopropamide iodide" or LAMA or LAMAs or 12 levetimide or lophotoxin or mazaticol or Mecamylamine or mefurtramine or mepenzolate or 13 meptazinol or "meta cholinoreactive cell*" or methantheline or methoctramine or 14 methylatropine or methyllycaconitine or methylscopolamine or metixene or muscarinic* or 15 muscarinolytic* or "nicotine tartrate" or nicotinic* or nuvenzepine or "octatropine 16 methylbromide" orFor Orphenadrine peer or otenzepad review or oxitropium or onlyoxybutynin or 17 oxyphencyclimine or Oxyphenonium or Pancuronium or "para fluorohexahydrosiladifenidol" 18 or "para fluorohexbutinol" or parapenzolate or "parasympathetic block*" or "parasympathetic 19 inhibitor*" or parasympathicolytic* or parasympatholytic* or parasympatolytic* or Pempidine 20 or penthienate or "Pentolinium Tartrate" or phenglutarimide or Pipecuronium or pipenzolate 21 or piperidolate or piperphenamine or pipethanate or Pirenzepine or piroheptine or "poldine 22 methylsulfate" or pridinol or "pridinol mesilate" or "prifinium bromide" or Procyclidine or profenamine or proglumide or Propantheline or propiverine or "propylbenziloylcholine 23 mustard" or "Propylbenzilylcholine Mustard" or pyrrinol or Quinidine or "Quinuclidinyl 24 Benzilate" or revatropate or revefenacin or rispenzepine or SAMA or SAMAs or Scopolamine 25 or secoverine or silahexocyclium or siltenzepine or sofpironium or solifenacin or "Solifenacin 26 Succinate" or stramonium or sydnofen or tarafenacin or telenzepine or tematropium or 27 temiverine or thiazinamium or "thiazinamium metilsulfate" or thihexinol or "tiemonium iodide" 28 or "tiemonium methylsulfate" or tifenamil or timepidium or Tiotropium or tofenacin or 29 tolterodine or "Tolterodine Tartrate" or tonopan or Toxiferine or tricyclamol or "tridihexethyl 30 chloride" or Trihexyphenidyl or Trimethaphan or triperidene or tripitramine or tropacin or 31 Tropicamide or tropine or "tropine benzoate" or "trospium chloride" or troventol or 32 Tubocurarine or umeclidinium or valethamate or vamicamide or Vecuronium or vedaclidine http://bmjopen.bmj.com/ 33 or zamifenacin or zolenzepine).ti,ab,hw,kw. 34 11 exp Phosphodiesterase 4 Inhibitors/ 10642 35 (apremilast or arofylline or atizoram or benzafentrine or catramilast or cilomilast or 36 cipamfylline or daxalipram or denbufylline or elbimilast or filaminast or ibudilast or indimilast 37 or lavamilast or nitraquazone or oglemilast or "PDE 4 inhibitor*" or "PDE IV inhibitor*" or 38 "PDE type 4 inhibitor*" or "PDE type IV inhibitor*" or "pde-4 inhibitor*" or "PDE4 inhibitor*" or 12 12671 39 "phosphodiesterase 4 inhibitor*" or "phosphodiesterase IV inhibitor*" or "phosphodiesterase 40 type 4 inhibitor*" or "phosphodiesterase type IV inhibitor*" or piclamilast or pumafentrine or on September 26, 2021 by guest. Protected copyright. 41 revamilast or roflumilast or Rolipram or tetomilast or tibenelast or tilivapram or tipelukast or 42 tofimilast or tolafentrine or zardaverine).ti,ab,hw,kw. 43 13 or/5-12 1192205 44 45 14 4 and 13 38943 46 15 3 or 14 67111 47 16 exp meta analysis/ 229890 48 17 exp "systematic review"/ 165306 49 18 ((meta adj analys*) or (systematic* adj3 review*)).ti,ab,hw,kw,pt. 589817 50 51 19 16 or 17 or 18 589821 52 20 15 and 19 2911 53 limit 20 to (editorial or erratum or letter or note or addresses or autobiography or bibliography 54 or biography or blogs or comment or dictionary or directory or interactive tutorial or interview 21 161 55 or lectures or legal cases or legislation or news or newspaper article or overall or patient 56 education handout or periodical index or portraits or published erratum or video-audio media 57 58 3 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 25 of 44 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2018-027935 on 5 May 2019. Downloaded from 1 2 3 or webcasts) [Limit not valid in Embase,CDSR,Ovid MEDLINE(R),Ovid MEDLINE(R) Daily 4 Update,Ovid MEDLINE(R) In-Process,Ovid MEDLINE(R) Publisher; records were retained] 5 22 20 not 21 2750 6 7 23 from 15 keep 41670-41728 59 8 24 22 or 23 2809 9 25 remove duplicates from 24 2077 10 11 12 13 14 15 16 For peer review only 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31

32 http://bmjopen.bmj.com/ 33 34 35 36 37 38 39

40 on September 26, 2021 by guest. Protected copyright. 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 4 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 26 of 44 BMJ Open: first published as 10.1136/bmjopen-2018-027935 on 5 May 2019. Downloaded from 1 2 3 Part 2 4 5 Database(s): Embase 1988 to 2018 Week 16, EBM Reviews - Cochrane Database of Systematic 6 Reviews 2005 to April 11, 2018, Ovid MEDLINE(R) Epub Ahead of Print, In-Process & Other Non- 7 Indexed Citations, Ovid MEDLINE(R) Daily and Ovid MEDLINE(R) 1946 to Present 8 Search Strategy: 9 # Searches Results 10 ("chronic airflow disease*" or "chronic airflow disorder*" or "chronic airflow limitation*" or 11 "chronic airflow obstruction*" or "chronic airway disease*" or "chronic airway disorder*" or 12 "chronic airway limitation*" or "chronic airway obstruction*" or "chronic bronchitis" or "chronic 13 obstructive airflow disease*" or "chronic obstructive airflow disorder*" or "chronic obstructive 14 airway disease*" or "chronic obstructive airway disorder*" or "chronic obstructive bronchitis" 15 or "chronic obstructive bronchopulmonary disease*" or "chronic obstructive broncho- 16 pulmonary disease*"For or "chronic peer obstructive review bronchopulmonary onlydisorder*" or "chronic 17 obstructive broncho-pulmonary disorder*" or "chronic obstructive lung disease*" or "chronic 1 248757 18 obstructive lung disorder*" or "chronic obstructive pulmonary disease*" or "chronic 19 obstructive pulmonary disorder*" or "chronic obstructive respiratory disease*" or "chronic 20 obstructive respiratory disorder*" or coad or copd or emphysema or "obstructive lung 21 disease" or "obstructive lung disorder*" or "obstructive pulmonary disease*" or "obstructive 22 pulmonary disorder*" or "obstructive pulmonary tract disease*" or "obstructive pulmonary 23 tract disorder*" or "obstructive respiratory disease*" or "obstructive respiratory disorder*" or 24 "obstructive respiratory tract disease*" or "obstructive respiratory tract 25 disorder*").ti,ab,hw,kw. 26 2 exp Antibiotic Prophylaxis/ 39823 27 3 exp Anti-Bacterial Agents/ 3061033 28 4 exp antibiotic agent/ 986815 29 30 ("1 methylmocimycin*" or "11 deoxydaunorubicin*" or "14 hydroxyclarithromycin*" or "19 31 deformyl 4 deoxydesmycosin*" or "19 deformyldesmycosin*" or "2 acetylerythromycin*" or "2 fluoroidarubicin*" or "2 n ethylnetilmicin*" or "2 pyrrolinodoxorubicin*" or "21 aminoepothilone 32 http://bmjopen.bmj.com/ B" or "3 3 cyanomorpholino 3 deaminodoxorubicin*" or "3 deamino 2 fluoro 3 33 hydroxydoxorubicin 14 pimelate" or "3 deamino 3 morpholinodoxorubicin*" or "3 deamino 3 34 morpholinooxaunomycin*" or "4 demethoxy 11 deoxydaunomycinone" or "4 35 demethoxydaunomycinone" or "4 demethoxydoxorubicin*" or "4 deoxydesmycosin*" or "4 36 iodoesorubicin*" or "5 iminodaunorubicin*" or "6 n ethylnetilmicin*" or "6beta iodopenicillanic 37 acid" or "9 deacetyl 9 methylidarubicin*" or "9 deoxydoxorubicin*" or "9 dihydroerythronolide 38 A" or "a 102395" or "a 10255" or "a 10947" or "a 130b" or "a 192411" or "a 63075" or 39 abkhazomycin* or abyssomicin* or acetomycin* or acetylspiramycin* or aclacinomycin* or 40 aclarubicin* or actagardin* or actaplanin* or actinorhodine or "aculeacin A" or aculeximycin* on September 26, 2021 by guest. Protected copyright. 41 or adicillin* or aditoprim or adriamycinone or agglomerin* or aklavinone or alafosfalin* or 42 Alamethicin* or albocycline or aldecalmycin* or aldoxorubicin* or alisamycin* or allicin* or 5 2430080 43 almecillin* or "alpha defensin*" or ambruticin* or Amdinocillin* or amfomycin* or Amikacin* or 44 aminoglycoside* or aminopenicillin* or "Aminosalicylic Acid" or Amoxicillin* or "Amphotericin 45 B" or Ampicillin* or amrubicin* or "angucycline derivative" or anhydrochlortetracycline or 46 anhydroepitetracycline or anhydrotetracycline or anidulafungin* or Anisomycin* or 47 annamycin* or ansamitocin* or "ansamycin derivative" or anthracycline* or anthracyclinone* 48 or antibacterial* or "anti-bacterial*" or antibiotic* or "anti-biotic*" or "antimicrobial cationic 49 peptide*" or Antimycin* or antimycobacterial* or "anti-mycobacterial*" or Antitreponemal* or 50 "Anti-treponemal*" or Antitubercular* or "Anti-tubercular*" or apalcillin* or aplasmomycin* or 51 "aplysianin E" or apramycin* or aristeromycin* or Arsphenamine or aspoxicillin* or 52 astromicin* or asukamycin* or "atpenin B" or auricularum or Aurodox or aurograb or 53 avibactam or avilamycin* or avoparcin* or azidamfenicol or azidocillin* or Azithromycin* or 54 Azlocillin* or Aztreonam or "aztreonam lysine" or azurocidin* or bacampicillin* or Bacitracin* or bacmecillinam or bactenecin* or bacteriocid* or Bacteriocin* or bafilomycin* or balhimycin* 55 or "baliz 2" or Bambermycin* or baquiloprim or "barminomycin I" or baycuten or beauvericin* 56 57 58 5 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 27 of 44 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2018-027935 on 5 May 2019. Downloaded from 1 2 3 or beroline or berubicin* or berythromycin* or "beta defensin*" or betafectin* or "beta- 4 Lactam*" or "betaLactamase Inhibitor*" or "beta-Lactamase Inhibitor*" or betamipron or 5 bialaphos or biapenem or bicozamycin* or "biphenomycin A" or bluensomycin* or bombinin* 6 or "Bongkrekic Acid" or boromycin* or borrelidin* or "Brefeldin A" or brilacidin* or brobactam 7 or butalactin* or butirosin* or cadazolid or Calcimycin* or Candicidin* or Capreomycin* or 8 carbacephem or carbadox or carbapenem or "carbazomycin A" or Carbenicillin* or 9 carbomycin* or Carfecillin* or carindacillin* or carubicin* or carumonam or caspofungin* or 10 cathelicidin* or cecropin* or cefacetrile or Cefaclor or Cefadroxil or cefalexin* or cefaloglycin* 11 or cefaloram or cefaloridine or cefalotin* or Cefamandole or cefapirin* or Cefatrizine or 12 cefazaflur or cefazedone or Cefazolin* or cefbuperazone or cefcanel or cefcapene or 13 cefclidin* or cefdaloxime or cefdinir or cefditoren or cefepime or cefetamet or cefetecol or 14 cefilavancin* or Cefixime or cefluprenam or cefmatilen or Cefmenoxime or Cefmetazole or 15 cefminox or cefodizime or Cefonicid or Cefoperazone or ceforanide or cefoselis or 16 Cefotaxime or CefotetanFor or Cefotiampeer or cefovecin* review or Cefoxitin* only or cefozopran or cefpimizole 17 or cefpiramide or cefpirome or cefpodoxime or cefprozil or cefquinome or cefradine or 18 cefroxadine or Cefsulodin* or ceftaroline or Ceftazidime or cefteram or ceftezole or ceftibuten 19 or ceftiofur or Ceftizoxime or ceftobiprole or ceftolozane or Ceftriaxone or Cefuroxime or 20 cefuzonam or Cephacetrile or Cephalexin* or Cephaloglycin* or Cephaloridine or 21 cephalosporin* or Cephalothin* or cephamycin* or Cephapirin* or Cephradine or 22 chalcomycin* or Chloramphenicol* or chloroorienticin* or chloropolysporin* or chlorothricin* or chlorothricolide or Chlortetracycline or "chymotrypsin trypsin*" or ciadox or "cilastatin plus 23 imipenem" or "cinerubin A" or "cinerubin B" or cinoquidox or Ciprofloxacin* or cirramycin* or 24 Citrinin* or Clarithromycin* or "clavulanate potassium" or "Clavulanic Acid*" or Clindamycin* 25 or clomocycline or Cloxacillin* or colicin* or colistimethate or Colistin* or "concanamycin A" or 26 coumamidine or coumamycin* or "cp 63956" or cryptosporin* or Cyclacillin* or cycloheximide 27 or Cycloserine or cystargin* or "cytarabine plus daunorubicin*" or cytovaricin* or dactimicin* 28 or Dactinomycin* or dalbaheptide or dalbavancin* or dalfopristin* or "damavaricin Fc pentyl 29 ether" or Daptomycin* or daunomycinone or daunorubicin* or daunorubicinol or 30 "deacetoxycephalosporin C" or deacetylcefotaxime or "deacetylcephalosporin C" or 31 dealanylalahopcin* or decaplanin* or dechloroeremomycin* or decilorubicin* or defensin* or 32 Demeclocycline or dermaseptin* or dermcidin* or dermostatin* or desmycosin* or http://bmjopen.bmj.com/ 33 detorubicin* or Diarylquinoline* or Dibekacin* or Dicloxacillin* or dihydrostreptomycin* or 34 Diketopiperazines or dimethylchlortetracycline or dioxidine or dirithromycin* or Distamycin* or 35 "ditrisarubicin B" or doripenem or doxorubicin* or doxorubicinol or Doxycycline or drosocin* 36 or echinocandin* or Echinomycin* or Edeine or efepristin* or efrotomycin* or emimycin* or 37 endusamycin* or enniatin* or Enoxacin* or Enviomycin* or eperezolid or epetraborole or 38 epicillin* or epidermin* or epiderstatin* or epiroprim or epirubicin* or epirubicinol or 39 epitetracycline or epothilone* or "epsilon rhodomycinone" or eravacycline or eremomycin* or

40 ertapenem or Erythromycin* or erythromycylamine or erythronolide* or esorubicin* or on September 26, 2021 by guest. Protected copyright. 41 Ethambutol or Ethionamide or ethylhydrocupreine or etimicin* or evernimicin* or 42 everninomicin* or faeriefungin* or fidaxomicin* or Filipin* or "fleroxacin deacetylcefotaxime 43 ester" or flomoxef or flopristin* or florfenicol or Floxacillin* or flucloxacillin* or flumoxil or 44 Fluoroquinolone* or flurithromycin* or fomidacillin* or fortimicin* or Fosfomycin* or 45 fosmidomycin* or Framycetin* or fropenem or fungichromin* or furaquinocin* or furazidin* or "furazolium chloride" or furbenicillin* or fusafungine or "fusidate sodium" or "Fusidic Acid" or 46 fuzlocillin* or galarubicin* or gallidermin* or gamithromycin* or ganefromycin* or "ge 2270a" 47 or gentamicin* or gepotidacin* or globomycin* or gloximonam or "glycylcycline derivative" or 48 "gonadorelin6 dextro lysine 2 pyrrolinodoxorubicin*" or "goniodomin A" or Gramicidin* or 49 granulysin* or grisein* or guamecycline or habekacin* or hamycin* or hatomamicin* or 50 hedamycin* or heliomycin* or hepcidin* or hetacillin* or hexacycline or hidamicin* or "histatin 51 5" or histatin* or hygromycin* or hymeglusin* or hypothemycin* or iclaprim or idarubicin* or 52 idarubicinol or ikarugamycin* or "imidacloprid plus moxidectin*" or Imipenem or indolicidin* or 53 inostamycin* or iseganan or isepamicin* or Isoniazid or "isopenicillin N" or "isoswinholide A" 54 or istamycin* or "iturin A" or ixabepilone or Josamycin* or "k 252a" or kalafungin* or 55 Kanamycin* or kanendomycin* or kasugamycin* or kelfiprim or ketolide or kidamycin* or 56 kinamycin* or Kitasamycin* or "l 156602" or "l 733560" or "l 786392" or lactacystin* or 57 58 6 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 28 of 44 BMJ Open: first published as 10.1136/bmjopen-2018-027935 on 5 May 2019. Downloaded from 1 2 3 Lactams or lactivicin* or "lactocin S" or lactococcin* or lactoferricin* or ladirubicin* or 4 laidlomycin* or lancovutide or lankamycin* or lanopepden or lanthiopeptin* or lantibiotic or 5 Lasalocid or latamoxef or lavanducyanin* or lefamulin* or lenampicillin* or lenapenem or 6 lenoremycin* or Leprostatic* or "leucinostatin A" or "leucinostatin B" or Leucomycin* or 7 leurubicin* or Levofloxacin* or lexithromycin* or "lff 571" or Lincomycin* or lincosamide* or 8 Linezolid or linopristin* or lividomycin* or "lonomycin A" or loracarbef or lotilibcin* or 9 Lucensomycin* or lydicamycin* or Lymecycline or lysobactin* or lysocellin* or lysostaphin* or 10 macrolide or magainin* or malyngolide or manumycin* or maridomycin* or "mdl 62208" or 11 "mdl 62211" or mecillinam or meclocycline or megacin* or megalomicin* or Mepartricin* or 12 meropenem or mersacidin* or metacycline or metampicillin* or Methacycline or Methicillin* or 13 "methylenomycin A" or "methylenomycin B" or methymycin* or methynolide or meticillin* or 14 Mezlocillin* or "microcin b17" or "microcin J25" or micronomicin* or midecamycin* or 15 mideplanin* or "mikamycin B" or Mikamycin* or "milbemycin oxime" or milbemycin* or 16 Minocycline or Miocamycin*For orpeer miokamycin* review or miporamicin* or onlymiraxid or mocimycin* or 17 "moenomycin A" or monensin* or "monobactam derivative" or Moxalactam or moxidectin* or 18 "ms 8209" or Mupirocin* or mureidomycin* or murepavadin* or mycinamicin* or Mycobacillin* 19 or mycolog or mycoticin* or myxothiazol or "n benzyldoxorubicin 14 valerate" or "n 20 trifluoroacetyldoxorubicin*" or Nafcillin* or "Nalidixic Acid" or narasin* or Natamycin* or 21 neamine or nebacetin* or Nebramycin* or negamycin* or nemadectin* or nemorubicin* or 22 Neomycin* or neosporin* or Netilmicin* or Netropsin* or niddamycin* or Nigericin* or Nisin* or nitrocefin* or nitrosochloramphenicol or "nocardicin A" or "nocardicin E" or "nocardicinic acid 23 derivative*" or Norfloxacin* or nosiheptide or nourseothricin* or Novobiocin* or "nvb 302" or 24 nybomycin* or Nystatin* or "oasomycin A" or obelmycin* or Ofloxacin* or olaquindox or 25 oleandolide or Oleandomycin* or oligomycin* or omadacycline or omiganan or optocillin* or 26 "orienticin A" or orientiparcin* or oritavancin* or oropivalone or Oxacillin* or oxaunomycin* or 27 "Oxolinic Acid" or Oxytetracycline or paldimycin* or panipenem or pardaxin* or 28 Paromomycin* or patulin* or pediazole or pediocin* or Pefloxacin* or penamecillin* or 29 penethamate or "Penicillanic Acid" or "Penicillic Acid" or penicillin* or "penicilloic acid" or 30 pentalenolactone or pentisomicin* or peptaibol or pexiganan or "pf 708093" or 31 phenelfamycin* or pheneticillin* or phleomycin* or pikromycin* or "Pipemidic Acid" or 32 Piperacillin* or pirarubicin* or pirazmonam or pirlimycin* or Pivampicillin* or pivmecillinam or http://bmjopen.bmj.com/ 33 platensimycin* or plazomicin* or plectasin* or pleuromutilin* or pluramycin* or 34 pneumocandin* or "polyactin A" or polyfungin* or polymyxin* or "polyoxin B" or "polyoxin D" 35 or polysporin* or polytrim or posizolid or "pr 39" or Pristinamycin* or Prodigiosin* or 36 prohepcidin* or propicillin* or protegrin* or Prothionamide or prothracarcin* or "pseudomonic 37 acid" or Pyrazinamide or pyrromycinone or pyrroxamycin* or quinacillin* or quinomycin* or 38 quinupristin* or radezolid or radicicol or ramoplanin* or ranalexin* or ranbezolid or 39 razupenem or retacillin* or retapamulin* or "rhodomycin A" or Ribostamycin* or Rifabutin* or

40 Rifampin* or Rifamycin* or rimocidin* or Ristocetin* or ritipenem or "ritipenem acoxil" or on September 26, 2021 by guest. Protected copyright. 41 rodorubicin* or roflamycoin* or rokitamycin* or Rolitetracycline or rosaramicin* or Roxarsone 42 or Roxithromycin* or ruboxyl or Rutamycin* or sabarubicin* or sagopilone or sanfetrinem or 43 sarecycline or "simaomicin alpha" or "simocyclinone D8" or Sirolimus or "sisomicin sulfate" or 44 Sisomicin* or "skf 104662" or sofradex or Spectinomycin* or "spinosyn A" or Spiramycin* or 45 squalamine or stigmatellin* or streptoduocin* or Streptogramin* or streptolydigin* or Streptomycin* or streptothricin* or streptotriad or Streptovaricin* or streptovirudin* or 46 "streptovitacin A" or stubomycin* or subtilin* or Sulbactam or Sulbenicillin* or Sulfamerazine 47 or Sulfamethoxypyridazine or sulfazecin* or sulopenem or sultamicillin* or surfactin* or 48 surotomycin* or "swinholide A" or "swinholide B" or tachyplesin* or Talampicillin* or 49 tameticillin* or tazobactam or tebipenem or tedizolid or Teicoplanin* or teixobactin* or 50 telavancin* or temocillin* or terdecamycin* or tetracyclin* or Tetracycline or tetramycin* or 51 tetronasin* or tetronomycin* or tetroxoprim or Thiamphenicol or Thienamycin* or 52 Thioacetazone or thiolactomycin* or "thionin peptide" or thiopeptin* or thiophenoxycefalotin* 53 or Thiostrepton or tiamulin* or "tibezonium iodide" or Ticarcillin* or tigecycline or tigemonam 54 or tildipirosin* or tilmicosin* or timentin* or tirandamycin* or tizoxanide or tobicillin* or 55 Tobramycin* or tolramycin* or tomopenem or toyocamycin* or tresaderm or tribactam or 56 trichomycin* or "trichostatic acid" or "trichostatin A" or trimethoprim* or "trinem derivative" or 57 58 7 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 29 of 44 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2018-027935 on 5 May 2019. Downloaded from 1 2 3 "triostin A" or triplopen or trisep or Troleandomycin* or trospectomycin* or tuftsin* or 4 tulathromycin* or Tunicamycin* or tutofusin* or Tylosin* or tylvalosin* or Tyrocidine or 5 Tyrothricin* or "u 78608" or "uk 69753" or unphenelfamycin* or "urdamycin C" or "urdamycin 6 D" or "urdamycin H" or ureidopenicillin* or urobiotic or "vacidin A" or validamycin* or 7 Valinomycin* or valnemulin* or valrubicin* or Vancomycin* or venturicidin* or vernamycin* or 8 "violamycin B1" or Viomycin* or "virginiae butanolide A" or "virginiae butanolide C" or 9 "virginiamycin M" or "virginiamycin S" or Virginiamycin* or "viriplanin A" or viscosin* or 10 volpristin* or "ws 9659 b" or "zibrofusidic acid" or zineryt or "zoptarelin doxorubicin*" or 11 zorbamycin* or zorubicin*).mp. 12 6 or/2-5 3703559 13 7 1 and 6 28719 14 15 8 exp meta analysis/ 229890 16 9 exp "systematic review"/For peer review only 165306 17 10 ((meta adj analys*) or (systematic* adj3 review*)).ti,ab,hw,kw,pt. 589817 18 11 8 or 9 or 10 589821 19 12 7 and 11 879 20 21 limit 12 to (editorial or erratum or letter or note or addresses or autobiography or bibliography 22 or biography or blogs or comment or dictionary or directory or interactive tutorial or interview or lectures or legal cases or legislation or news or newspaper article or overall or patient 23 13 64 24 education handout or periodical index or portraits or published erratum or video-audio media or webcasts) [Limit not valid in Embase,CDSR,Ovid MEDLINE(R),Ovid MEDLINE(R) Daily 25 Update,Ovid MEDLINE(R) In-Process,Ovid MEDLINE(R) Publisher; records were retained] 26 27 14 12 not 13 815 28 15 from 7 keep 23035-23104 70 29 16 14 or 15 885 30 17 remove duplicates from 16 767 31

32 http://bmjopen.bmj.com/ 33 34 35 36 37 38 39

40 on September 26, 2021 by guest. Protected copyright. 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 8 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 30 of 44 BMJ Open: first published as 10.1136/bmjopen-2018-027935 on 5 May 2019. Downloaded from 1 2 3 Part 3 4 5 Database(s): Embase 1988 to 2018 Week 16, EBM Reviews - Cochrane Database of Systematic 6 Reviews 2005 to April 11, 2018, Ovid MEDLINE(R) Epub Ahead of Print, In-Process & Other Non- 7 Indexed Citations, Ovid MEDLINE(R) Daily and Ovid MEDLINE(R) 1946 to Present 8 Search Strategy: 9 # Searches Results 10 ("chronic airflow disease*" or "chronic airflow disorder*" or "chronic airflow limitation*" or 11 "chronic airflow obstruction*" or "chronic airway disease*" or "chronic airway disorder*" or 12 "chronic airway limitation*" or "chronic airway obstruction*" or "chronic bronchitis" or "chronic 13 obstructive airflow disease*" or "chronic obstructive airflow disorder*" or "chronic obstructive 14 airway disease*" or "chronic obstructive airway disorder*" or "chronic obstructive bronchitis" 15 or "chronic obstructive bronchopulmonary disease*" or "chronic obstructive broncho- 16 pulmonary disease*"For or "chronic peer obstructive review bronchopulmonary onlydisorder*" or "chronic 17 1 obstructive broncho-pulmonary disorder*" or "chronic obstructive lung disease*" or "chronic 248757 18 obstructive lung disorder*" or "chronic obstructive pulmonary disease*" or "chronic obstructive 19 pulmonary disorder*" or "chronic obstructive respiratory disease*" or "chronic obstructive 20 respiratory disorder*" or coad or copd or emphysema or "obstructive lung disease" or 21 "obstructive lung disorder*" or "obstructive pulmonary disease*" or "obstructive pulmonary 22 disorder*" or "obstructive pulmonary tract disease*" or "obstructive pulmonary tract disorder*" 23 or "obstructive respiratory disease*" or "obstructive respiratory disorder*" or "obstructive 24 respiratory tract disease*" or "obstructive respiratory tract disorder*").ti,ab,hw,kw. 25 2 exp Benzodiazepines/ 223779 26 (Alprazolam or arfendazam or benzodiazepin or benzodiazepine* or Benzodiazepinone* or 27 bromazepam or camazepam or Chlordiazepoxide or cinolazepam or clobazam or 28 clonazepam or clorazepate or "Clorazepate Dipotassium" or "clorazepate potassium" or 29 dealkylflurazepam or delorazepam or demoxepam or devazepide or diazepam or 30 doxefazepam or Estazolam or fludiazepam or flunitrazepam or flurazepam or flutoprazepam 31 or fosazepam or gidazepam or girisopam or halazepam or loflazepate or lorazepam or

32 3 lormetazepam or lotrafiban or meclonazepam or Medazepam or metaclazepam or Midazolam 271678 http://bmjopen.bmj.com/ 33 or nastorazepide or nerisopam or netazepide or nimetazepam or nitrazepam or 34 nitrosochlordiazepoxide or norchlordiazepoxide or norclobazam or nordazepam or 35 norfludiazepam or norflunitrazepam or oxazepam or phenazepam or pinazepam or prazepam 36 or quazepam or "ro 7 0213" or talampanel or tampramine or tarazepide or temazepam or 37 tetrazepam or tibezonium or tifluadom or tofisopam or tomaymycin or Triazolam or 38 tuclazepam or uxepam).ti,ab,hw,kw. 39 4 exp Home Care Services/ 101515

40 (((domestic or home or domiciliary) adj3 (residence or residences or setting or settings or on September 26, 2021 by guest. Protected copyright. 41 care or nurs* or help or service* or treatment* or therap* or "respiratory care" or "respiratory 5 209664 42 treatment*" or "respiratory therap*" or "respiratory service*" or "respiratory assist*" or 43 ventilat*)) or "assisted living" or homecare).ti,ab,hw,kw. 44 6 "nursing home*".ti,ab,hw,kw. 90908 45 7 (4 or 5) not 6 151038 46 47 8 exp Respiration, Artificial/ 225415 48 (((((respiration* or respiratory or breathing) adj3 (assist* or controlled or mechanical)) or 49 (facial or face or nasal)) adj3 mask*) or "artificial respiration*" or BiPAP or CPAP or "Fluidic Breathing Assister" or HMV or IPPB or IPPV or NIAV or NIV or NPPV or "Oxygen Regulator*" 50 9 529399 51 or PAP or PAV or "Portable Oxygen" or "Positive Airway Pressure*" or "positive end- 52 expiratory pressure*" or "positive pressure*" or respirator or respirators or "Respiratory 53 insufficiency" or Tracheostom* or ventilation or ventilator*).ti,ab,hw,kw. 54 10 8 or 9 549586 55 11 7 and 10 6909 56 57 58 9 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 31 of 44 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2018-027935 on 5 May 2019. Downloaded from 1 2 3 12 2 or 3 or 11 280786 4 5 13 1 and 12 3036 6 14 exp meta analysis/ 229890 7 15 exp "systematic review"/ 165306 8 16 ((meta adj analys*) or (systematic* adj3 review*)).ti,ab,hw,kw,pt. 589817 9 17 14 or 15 or 16 589821 10 11 18 13 and 17 119 12 limit 18 to (editorial or erratum or letter or note or addresses or autobiography or bibliography 13 or biography or blogs or comment or dictionary or directory or interactive tutorial or interview or lectures or legal cases or legislation or news or newspaper article or overall or patient 14 19 3 15 education handout or periodical index or portraits or published erratum or video-audio media 16 or webcasts) [LimitFor not valid inpeer Embase,CDSR,Ovid review MEDLINE(R),Ovid only MEDLINE(R) Daily 17 Update,Ovid MEDLINE(R) In-Process,Ovid MEDLINE(R) Publisher; records were retained] 18 20 18 not 19 116 19 21 from 13 keep 2384 1 20 22 20 or 21 117 21 23 remove duplicates from 22 97 22 23 24

25 26 27 28 29 30 31

32 http://bmjopen.bmj.com/ 33 34 35 36 37 38 39

40 on September 26, 2021 by guest. Protected copyright. 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 10 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 32 of 44 BMJ Open: first published as 10.1136/bmjopen-2018-027935 on 5 May 2019. Downloaded from 1 2 3 Part 4 4 5 6 7 Database(s): Embase 1988 to 2018 Week 16, EBM Reviews - Cochrane Database of Systematic 8 Reviews 2005 to April 11, 2018, Ovid MEDLINE(R) Epub Ahead of Print, In-Process & Other Non- 9 Indexed Citations, Ovid MEDLINE(R) Daily and Ovid MEDLINE(R) 1946 to Present 10 Search Strategy: 11 # Searches Results 12 ("chronic airflow disease*" or "chronic airflow disorder*" or "chronic airflow limitation*" or 13 "chronic airflow obstruction*" or "chronic airway disease*" or "chronic airway disorder*" or 14 "chronic airway limitation*" or "chronic airway obstruction*" or "chronic bronchitis" or 15 "chronic obstructive airflow disease*" or "chronic obstructive airflow disorder*" or "chronic 16 obstructive airway Fordisease*" peeror "chronic obstructive review airway disorder*" only or "chronic obstructive 17 bronchitis" or "chronic obstructive bronchopulmonary disease*" or "chronic obstructive 18 broncho-pulmonary disease*" or "chronic obstructive bronchopulmonary disorder*" or 19 "chronic obstructive broncho-pulmonary disorder*" or "chronic obstructive lung disease*" or 1 248757 20 "chronic obstructive lung disorder*" or "chronic obstructive pulmonary disease*" or "chronic 21 obstructive pulmonary disorder*" or "chronic obstructive respiratory disease*" or "chronic 22 obstructive respiratory disorder*" or coad or copd or emphysema or "obstructive lung 23 disease" or "obstructive lung disorder*" or "obstructive pulmonary disease*" or "obstructive 24 pulmonary disorder*" or "obstructive pulmonary tract disease*" or "obstructive pulmonary 25 tract disorder*" or "obstructive respiratory disease*" or "obstructive respiratory disorder*" or 26 "obstructive respiratory tract disease*" or "obstructive respiratory tract 27 disorder*").ti,ab,hw,kw. 28 2 exp Adrenal Cortex Hormones/ 1085572 29 3 exp corticosteroid/ 710384 30 4 exp corticosteroid therapy/ 41274 31 ("adrenal cortex hormone*" or "adrenal cortex steroid*" or "adrenal cortical hormone*" or 32 http://bmjopen.bmj.com/ "adrenal cortical steroid*" or "adrenal steroid*" or "adreno cortical steroid*" or "adreno 33 corticosteroid*" or "adrenocortical hormone*" or "adrenocortical steroid*" or 34 adrenocorticosteroid* or adreson or alclometasone or aldosterone or algestone or 35 "algestone acetonide" or amcinonide or amelometasone or beclometasone or budesonide 36 or butixocort or chloroprednisone or ciclesonide or ciprocinonide or clioquinol or clobetasol 37 or clobetasone or clocortolone or cloprednol or "cortical steroid*" or corticalsteroid* or 38 "cortico steroid*" or corticoid* or corticosteroid* or corticosterone or corticotherap* or 39 cortifair or cortisol or cortisone or cortivazol or cortril or deflazacort or dehydrocorticosterone 40 or dehydrocortisone or deoxycorticosterone or dermocorticosteroid* or dexamethasone or on September 26, 2021 by guest. Protected copyright. 41 diflorasone or diflucortolone or difluprednate or domoprednate or drocinonide or dutimelan 42 or epicortisol or "etiprednol dicloacetate" or fluclorolone or fludrocortisone or fludroxycortide 43 or flumetasone or flumoxonide or flunisolide or fluocinolone or fluocinonide or fluocortin or 5 1707747 44 fluocortolone or fluorometholone or fluprednidene or fluprednisolone or fluticasone or 45 formocortal or "formoterol fumarate" or Glucocorticoid* or glucocorticoidsteroid* or 46 glucocorticosteroid* or glucocortoid* or glycocorticoid* or glycocorticosteroid* or halcinonide 47 or halometasone or halopredone or hydrocortisone or "hydroxy norcorticosterone" or 48 hydroxycorticoid* or hydroxycorticosteroid* or hydroxycorticosterone or 49 hydroxydeoxycorticosterone or hydroxyhydrocortisone or "icometasone enbutate" or 50 isoflupredone or itrocinonide or "locicortolone dicibate" or "lorinden a" or "lorinden t" or 51 loteprednol or mazipredone or medrysone or meprednisone or mineralcorticosteroid* or 52 mineralocorticosteroid* or minerocorticoid* or mometasone or nicocortonide or nivacortol or 53 nordeoxycorticosterone or oropivalone or oxohydrocortisone or oxycorticosteroid* or 54 paramethasone or prednisolone or prednisone or pregnenolone or procinonide or promestriene or resocortol or rimexolone or rofleponide or steroid* or 55 tetrahydrodeoxycorticosterone or ticabesone or timobesone or tipredane or tixocortol or 56 57 58 11 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 33 of 44 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2018-027935 on 5 May 2019. Downloaded from 1 2 3 triamcinolone or "ulobetasol propionate" or uniderm or zoticasone).ti,ab,hw,kw. 4 5 6 exp Expectorants/ 30553 6 (Acetylcysteine or Ambroxol or aminophylline or Bromhexine or bron or cafedrine or 7 Carbocysteine or diprophylline or etofylline or eucalyptus or expectorant* or fudosteine or 8 7 guaiacol or "guaiacol carbonate" or guaietolin or Guaifenesin or guaifylline or "iodinated 91107 9 glycerol" or ipecac or mucolytic* or "Potassium Citrate" or "primula flower" or stepronin or 10 "stepronin lysine" or sulfoguaiacol or tipepidine or ulogesic).ti,ab,hw,kw. 11 8 exp narcotic analgesic agent/ 243598 12 9 exp Analgesics, Opioid/ 347494 13 (acetorphine or acetylcodeine or acetylmethadol or Alfentanil or Alphaprodine or anileridine 14 or apadoline or azidomorphine or benzhydrocodone or bezitramide or bremazocine or 15 "Brompton mixture" or Buprenorphine or Butorphanol or ciramadol or cocodamol or 16 Codeine or codydramolFor or conorfone peer or cyclazocine review or Dextromoramide only or 17 Dextropropoxyphene or dextrorphan or dezocine or diamorphine or diconal or 18 dihydrocodeine or dihydroetorphine or Dihydromorphine or dimethylthiambutene or 19 Diphenoxylate or dipipanone or enadoline or eptazocine or ethylketazocine or 20 Ethylketocyclazocine or Ethylmorphine or etonitazene or Etorphine or etoxeridine or 21 faxeladol or Fentanyl or furethidine or gelonida or Heroin or Hydrocodone or isalmadol or 22 isomethadone or ketazocine or ketobemidone or ketogan or kyotorphin or lefetamine or 23 10 levacetylmethadol or levomethadone or Levorphanol or Meperidine or Meptazinol or 525567 24 metazocine or Methadone or "Methadyl Acetate" or methylsamidorphan or Morphine or 25 "morphinomimetic agent*" or "morphinomimetic drug*" or morphinone or Nalbuphine or 26 narcotic* or nicocodine or nicomorphine or noracymethadol or norbuprenorphine or 27 nordextropropoxyphene or normorphine or norpethidine or norpropoxyphene or "o 28 nortramadol" or oliceridine or opiate or Opiate* or opioid* or Opium or oripavine or 29 Oxycodone or Oxymorphone or pentamorphone or Pentazocine or pethidine or phenadoxone or phenaridine or Phenazocine or phencyclidine or Phenoperidine or 30 picenadol or piminodine or Pirinitramide or piritramide or profadol or Promedol or propiram 31 or sameridine or samidorphan or semorphone or Sufentanil or tapentadol or thebaine or 32 http://bmjopen.bmj.com/ tifluadom or Tilidine or tonazocine or Tramadol or trimeperidine).ti,ab,hw,kw. 33 34 11 exp Bronchoscopy/ 68088 35 12 exp lung/su 8000 36 13 exp Pneumonectomy/ 49308 37 ("airflow clearance" or "airway clearance" or BLVR or bronchoscop* or ELVR or "lung 38 clearance" or "lung denervation" or LVRS or pneumectom* or pneumonectom* or 14 143837 39 pneumoresection* or "pulmonary clearance" or "volume reducing" or "volume 40 reduction*").ti,ab,hw,kw. on September 26, 2021 by guest. Protected copyright. 41 15 exp Smoking Cessation/ 76463 42 ((smoking* or tobacco* or cigar* or cigarette* or cigaret*) and (quit* or discontinu* or ceas* 43 16 110813 or cessation*)).ti,ab,hw,kw. 44 45 17 exp Respiratory Therapy/ 107010 46 18 exp exercise/ 423706 47 19 exp Exercise Therapy/ 102223 48 20 exp Breathing Exercises/ 8723 49 21 exp Exercise Movement Techniques/ 66908 50 51 (aerobics or anaerobics or "artificial respiration*" or bicycling or biking or "Chest Wall 52 Oscillation*" or dance or dancing or "endurance training" or exercis* or "Extracorporeal Membrane Oxygen*" or "fitness training" or "inhalation therap*" or isometrics or oxygen or 53 22 2620447 54 "physical activit*" or "physical exertion" or "postural drain*" or rehab* or "resistance training" 55 or "respiration care*" or "respiration therap*" or "respiratory care*" or "respiratory therap*" or running or "strength training" or swimming or "Tai Chi" or "Tai Ji" or walking or weightlifting 56 57 58 12 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 34 of 44 BMJ Open: first published as 10.1136/bmjopen-2018-027935 on 5 May 2019. Downloaded from 1 2 3 or yoga).ti,ab,hw,kw. 4 5 23 exp Nutrition Therapy/ 384447 6 24 (diet or dietary or diets or nutrition* or supplementation or supplements).ti,ab,hw,kw. 1856949 7 25 exp Influenza Vaccines/ 50514 8 26 exp Pneumococcal Vaccines/ 22742 9 27 exp vaccination/ 204458 10 11 (moniarix or "pcv 13" or pcv13 or "pneu immune" or "pneumo 23" or pneumopur or pneumovax or "pnu immune" or "pnu imune" or "polysaccharide vaccine pneumococcal" or 12 28 702951 prevenar or prevnar or "streptococcus pneumoniae vaccine" or streptopur or streptorix or 13 synflorix or vaccin*).ti,ab,hw,kw. 14 15 29 exp Psychotherapy/ 367662 16 30 exp Cognitive Therapy/For peer review only 66331 17 31 exp Cognitive Behavior Therapy/ 28661 18 32 exp Mindfulness/ 6317 19 33 exp Mind-Body Therapies/ 90152 20 21 34 exp Mentoring/ 1557 22 35 exp Health Promotion/ 153501 23 (CBT or coach* or "Cognitive behavioral therap*" or "Cognitive therap*" or "health 24 36 promotion*" or meditat* or mentor* or "mind body" or mindfulness or psychological or 1535477 25 psychosocial or psychotherap*).ti,ab,hw,kw. 26 37 exp Self Care/ 113331 27 38 exp Telemedicine/ 53304 28 29 39 exp Therapy, Computer-Assisted/ 67118 30 40 exp Mobile Applications/ 8595 31 ("action plan*" or android or app or apps or ehealth or "e-health" or internet or ipad* or 32 iphone* or mhealth or "m-health" or "mobile app*" or "mobile health" or "mobile technolog*" http://bmjopen.bmj.com/ 33 or "portable computer*" or "portable electronic app*" or "portable software app*" or "remote 34 41 consultation*" or "self care" or "self help" or "self management" or "self treatment" or "smart 603033 35 phone*" or smartphone* or "tablet computer*" or teleconsultation* or "tele-consultation*" or 36 telehealth or "tele-health" or telemedicine or "tele-medicine" or teletherap* or "tele-therap*" 37 or web).ti,ab,hw,kw. 38 42 exp "Delivery of Health Care, Integrated"/ 20570 39 43 exp Acupuncture/ 38261 40 on September 26, 2021 by guest. Protected copyright. 44 exp Complementary Therapies/ 250389 41 42 45 exp Electric Stimulation Therapy/ 260840 43 (acupuncture or agent* or "alternative medicine" or "care package*" or chemotherap* or 44 "complementary medicine" or drug* or "electric stimulation*" or holistic or "integrated care" 45 46 or "integrated health care" or "integrated healthcare" or intervention* or manag* or 26377389 46 medication* or "muscle stimulation*" or operat* or pharmacotherap* or procedure* or 47 reconstruction* or repair* or resect* or surg* or therap* or treat* or wellness).ti,ab,hw,kw. 48 47 or/2-46 30049403 49 48 1 and 47 182842 50 49 exp meta analysis/ 229890 51 52 50 exp "systematic review"/ 165306 53 51 ((meta adj analys*) or (systematic* adj3 review*)).ti,ab,hw,kw,pt. 589817 54 52 49 or 50 or 51 589821 55 53 48 and 52 5613 56 57 58 13 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 35 of 44 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2018-027935 on 5 May 2019. Downloaded from 1 2 3 limit 53 to (editorial or erratum or letter or note or addresses or autobiography or 4 bibliography or biography or blogs or comment or dictionary or directory or interactive 5 tutorial or interview or lectures or legal cases or legislation or news or newspaper article or 6 54 overall or patient education handout or periodical index or portraits or published erratum or 261 7 video-audio media or webcasts) [Limit not valid in Embase,CDSR,Ovid MEDLINE(R),Ovid 8 MEDLINE(R) Daily Update,Ovid MEDLINE(R) In-Process,Ovid MEDLINE(R) Publisher; 9 records were retained] 10 55 53 not 54 5352 11 56 from 48 keep 121215-121366 152 12 13 57 55 or 56 5504 14 58 remove duplicates from 57 3991 15 16 For peer review only 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31

32 http://bmjopen.bmj.com/ 33 34 35 36 37 38 39

40 on September 26, 2021 by guest. Protected copyright. 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 14 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 36 of 44 BMJ Open: first published as 10.1136/bmjopen-2018-027935 on 5 May 2019. Downloaded from 1 2 3 4 5 Scopus 6 7 Part 1 8 9 1 TITLE-ABS-KEY("chronic airflow disease*" OR "chronic airflow disorder*" OR "chronic airflow 10 limitation*" OR "chronic airflow obstruction*" OR "chronic airway disease*" OR "chronic airway 11 disorder*" OR "chronic airway limitation*" OR "chronic airway obstruction*" OR "chronic 12 bronchitis" OR "chronic obstructive airflow disease*" OR "chronic obstructive airflow disorder*" 13 OR "chronic obstructive airway disease*" OR "chronic obstructive airway disorder*" OR "chronic 14 obstructive bronchitis" OR "chronic obstructive bronchopulmonary disease*" OR "chronic 15 obstructive broncho-pulmonary disease*" OR "chronic obstructive bronchopulmonary disorder*" 16 OR "chronic obstructiveFor peerbroncho-pulmonary review disorder*" OR only"chronic obstructive lung disease*" OR 17 "chronic obstructive lung disorder*" OR "chronic obstructive pulmonary disease*" OR "chronic 18 obstructive pulmonary disorder*" OR "chronic obstructive respiratory disease*" OR "chronic 19 obstructive respiratory disorder*" OR coad OR copd OR emphysema OR "obstructive lung 20 disease" OR "obstructive lung disorder*" OR "obstructive pulmonary disease*" OR "obstructive pulmonary disorder*" OR "obstructive pulmonary tract disease*" OR "obstructive pulmonary tract 21 disorder*" OR "obstructive respiratory disease*" OR "obstructive respiratory disorder*" OR 22 "obstructive respiratory tract disease*" OR "obstructive respiratory tract disorder*") 23 2 TITLE-ABS-KEY(abediterol OR acefylline OR "acefylline clofibrol" OR "acefylline piperazine" OR 24 "aclidinium bromide" OR "adrenalin hydrogen tartrate" OR Adrenomedullin OR Albuterol OR 25 ambuphylline OR Aminophylline OR antibronchospastic OR arformoterol OR Atropine OR 26 bambuterol OR bamifylline OR baralgin OR batefenterol OR bitolterol OR "bitolterol mesilate" OR 27 "bronchial dilating" OR "bronchial-dilating" OR bronchodilatant* OR "broncho-dilatant*" OR 28 bronchodilatating OR "broncho-dilatating" OR bronchodilatator* OR "broncho-dilatator*" OR 29 bronchodilating OR "broncho-dilating" OR bronchodilator* OR "broncho-dilator*" OR broncholytic* 30 OR broncholytica OR bronchospasmolytic OR broxaterol OR Budesonide OR carbuterol OR 31 carmoterol OR "choline theophyllinate" OR Clenbuterol OR clorprenaline OR Colforsin OR

32 Cromakalim OR danirixin OR "darotropium bromide" OR dilator* OR diprophylline OR ditec OR http://bmjopen.bmj.com/ 33 doxofylline OR Dyphylline OR elubrixin OR enprofylline OR ephedrine OR "ephedrine sulfate" OR 34 Epinephrine OR eprozinol OR espatropate OR etafedrine OR etamiphyllin OR "etamiphyllin 35 camsilate" OR etanterol OR etofylline OR Fenoterol OR fenspiride OR Fluticasone OR "flutropium 36 bromide" OR formoterol OR "Formoterol Fumarate" OR furafylline OR glycopyrronium OR "gsk 37 159802" OR "gsk 597901" OR guaifylline OR "gw 678007" OR Hexoprenaline OR Hyoscyamine 38 OR ibuterol OR "ilmetropium iodide" OR imoxiterol OR indacaterol OR inhaler* OR Ipratropium 39 OR "ipratropium bromide" OR isbufylline OR isoetarine OR "isoetarine mesylate" OR Isoetharine

40 OR isoprenaline OR Isoproterenol OR Khellin OR laprafylline OR levalbuterol OR mabuterol OR on September 26, 2021 by guest. Protected copyright. 41 marax OR Metaproterenol OR methoxyphenamine OR milveterol OR "n methylmequitazine" OR 42 naminterol OR neobiphyllin OR nestifylline OR "Nitric Oxide" OR olodaterol OR orciprenaline OR 43 "oxitropium bromide" OR "oxyphenonium bromide" OR pibaxizine OR pirbuterol OR "pirbuterol acetate" OR pneumodilator OR Procaterol OR protokylol OR proxyphylline OR Pseudoephedrine 44 OR racephedrine OR Racepinephrine OR reproterol OR rimiterol OR "ru 45703" OR salbutamol 45 OR "salbutamol sulfate" OR salmefamol OR salmeterol OR "Salmeterol Xinafoate" OR sibenadet 46 OR "S-Nitrosoglutathione" OR "S-Nitrosothiols" OR soterenol OR tazifylline OR Terbutaline OR 47 Theobromine OR Theophylline OR "theophylline sodium glycinate" OR thiazinamium OR 48 "thiazinamium metilsulfate" OR Tiotropium OR Tretoquinol OR "tretoquinol derivative" OR 49 trimetaquinol OR tulobuterol OR "uk 432097" OR Umeclidinium OR vephylline OR verofylline OR 50 vilanterol OR "vilanterol trifenatate" OR zindotrine) 51 3 TITLE-ABS-KEY("adrenergic beta 2 agonist*" OR "adrenergic beta 2 receptor agonist*" OR 52 "adrenergic beta2 agonist*" OR "adrenergic beta-2 agonist*" OR "adrenergic beta-2 receptor 53 agonist*" OR "adrenergic beta2-agonist*" OR Albuterol OR "beta 2 adrenergic agent*" OR "beta 2 54 adrenergic agonist*" OR "beta 2 adrenergic receptor agonist*" OR "beta 2 adrenergic receptor 55 stimulant*" OR "beta 2 adrenergic receptor stimulat*" OR "beta 2 adrenergic receptor stimulator*" 56 OR "beta 2 adrenergic stimulant*" OR "beta 2 adrenergic stimulat*" OR "beta 2 adrenergic 57 58 15 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 37 of 44 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2018-027935 on 5 May 2019. Downloaded from 1 2 3 stimulator*" OR "beta 2 adrenoceptor agonist*" OR "beta 2 adrenoceptor stimulant*" OR "beta 2 4 adrenoceptor stimulat**" OR "beta 2 adrenoceptor stimulator*" OR "beta 2 agonist*" OR "beta 5 agonist*" OR "beta receptor agonist*" OR "beta receptor stimulant*" OR "beta stimulant" OR 6 "beta2 adrenergic receptor stimulat*" OR Fenoterol OR formoterol OR Hexoprenaline OR 7 indacaterol OR Isoetharine OR LABA OR LABAs OR Metaproterenol OR Procaterol OR Ritodrine 8 OR SABA OR SABAs OR salmeterol OR "Salmeterol Xinafoate" OR Terbutaline) 9 4 TITLE-ABS-KEY("acetylcholine antagonist*" OR "acetylcholine receptor block*" OR "acetylcholine 10 receptor inhibitor*" OR "AChR inhibitor" OR aclidinium OR "aclidinium bromide" OR acotiamide 11 OR adiphenine OR afacifenacin OR Alcuronium OR "alpha conotoxin MII" OR alvameline OR 12 alverine OR "alverine citrate" OR anisodamine OR "anti cholinergics" OR anticholinergic OR 13 anticholinergic* OR "anti-cholinergic*" OR antimuscarinic* OR aprofene OR aspaminol OR 14 Atracurium OR Atropine OR atropinic* OR azaprophen OR belladonna OR bellergal OR 15 Benactyzine OR benzetimide OR benzilonium OR "benzilylcholine mustard" OR benzoquinonium 16 OR BenztropineFor OR Biperiden peer OR bornaprine review OR Butylscopolammonium only OR buzepide OR 17 catestatin OR "central anticholinergic" OR Chlorisondamine OR chlorphenoxamine OR 18 cholinolytic* OR cimetropium OR clidinium OR Curare OR Cyclopentolate OR cycrimine OR 19 darifenacin OR darotropium OR deptropine OR desfesoterodine OR Dexetimide OR dexmecamylamine OR "dibutoline sulfate" OR Dicyclomine OR dicycloverine OR diethazine OR 20 dimevamide OR "diphemanil methylsulfate" OR drofenine OR elantrine OR Emepronium OR 21 espatropate OR Ethidium OR "ethylcholine mustard aziridinium" OR eucatropine OR fenoverine 22 OR fenpipramide OR fenpiverinium OR fesoterodine OR fluperlapine OR flutropium OR 23 furtramine OR "Gallamine Triethiodide" OR ganglefene OR Glycopyrrolate OR glycopyrronium 24 OR "gsk 202405" OR "h cholinoreactive cell*" OR hemicholinium OR hexahydrodifenidol OR 25 hexahydroprocyclidine OR hexahydrosiladifenidol OR Hexamethonium OR hexbutinol OR 26 "hexbutinol methiodide" OR "hexocyclium metilsulfate" OR himbacine OR homatropine OR 27 "homatropine methyl" OR "homatropine terephthalate" OR Hyoscyamine OR imidafenacin OR 28 Ipratropium OR isomylamine OR "isopropamide iodide" OR LAMA OR LAMAs OR levetimide OR 29 lophotoxin OR mazaticol OR Mecamylamine OR mefurtramine OR mepenzolate OR meptazinol 30 OR "meta cholinoreactive cell*" OR methantheline OR methoctramine OR methylatropine OR 31 methyllycaconitine OR methylscopolamine OR metixene OR muscarinic* OR muscarinolytic* OR

32 "nicotine tartrate" OR nicotinic* OR nuvenzepine OR "octatropine methylbromide" OR http://bmjopen.bmj.com/ 33 Orphenadrine OR otenzepad OR oxitropium OR oxybutynin OR oxyphencyclimine OR 34 Oxyphenonium OR Pancuronium OR "para fluorohexahydrosiladifenidol" OR "para 35 fluorohexbutinol" OR parapenzolate OR "parasympathetic block*" OR "parasympathetic inhibitor*" 36 OR parasympathicolytic* OR parasympatholytic* OR parasympatolytic* OR Pempidine OR 37 penthienate OR "Pentolinium Tartrate" OR phenglutarimide OR Pipecuronium OR pipenzolate 38 OR piperidolate OR piperphenamine OR pipethanate OR Pirenzepine OR piroheptine OR 39 "poldine methylsulfate" OR pridinol OR "pridinol mesilate" OR "prifinium bromide" OR

40 Procyclidine OR profenamine OR proglumide OR Propantheline OR propiverine OR on September 26, 2021 by guest. Protected copyright. 41 "propylbenziloylcholine mustard" OR "Propylbenzilylcholine Mustard" OR pyrrinol OR Quinidine 42 OR "Quinuclidinyl Benzilate" OR revatropate OR revefenacin OR rispenzepine OR SAMA OR SAMAs OR Scopolamine OR secoverine OR silahexocyclium OR siltenzepine OR sofpironium 43 OR solifenacin OR "Solifenacin Succinate" OR stramonium OR sydnofen OR tarafenacin OR 44 telenzepine OR tematropium OR temiverine OR thiazinamium OR "thiazinamium metilsulfate" OR 45 thihexinol OR "tiemonium iodide" OR "tiemonium methylsulfate" OR tifenamil OR timepidium OR 46 Tiotropium OR tofenacin OR tolterodine OR "Tolterodine Tartrate" OR tonopan OR Toxiferine OR 47 tricyclamol OR "tridihexethyl chloride" OR Trihexyphenidyl OR Trimethaphan OR triperidene OR 48 tripitramine OR tropacin OR Tropicamide OR tropine OR "tropine benzoate" OR "trospium 49 chloride" OR troventol OR Tubocurarine OR umeclidinium OR valethamate OR vamicamide OR 50 Vecuronium OR vedaclidine OR zamifenacin OR zolenzepine) 51 5 TITLE-ABS-KEY("adrenal cortex hormone*" OR "adrenal cortex steroid*" OR "adrenal cortical 52 hormone*" OR "adrenal cortical steroid*" OR "adrenal steroid*" OR "adreno cortical steroid*" OR 53 "adreno corticosteroid*" OR "adrenocortical hormone*" OR "adrenocortical steroid*" OR 54 adrenocorticosteroid* OR adreson OR alclometasone OR aldosterone OR algestone OR 55 "algestone acetonide" OR amcinonide OR amelometasone OR beclometasone OR budesonide 56 OR butixocort OR chloroprednisone OR ciclesonide OR ciprocinonide OR clioquinol OR 57 58 16 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 38 of 44 BMJ Open: first published as 10.1136/bmjopen-2018-027935 on 5 May 2019. Downloaded from 1 2 3 clobetasol OR clobetasone OR clocortolone OR cloprednol OR "cortical steroid*" OR 4 corticalsteroid* OR "cortico steroid*" OR corticoid* OR corticosteroid* OR corticosterone OR 5 corticotherap* OR cortifair OR cortisol OR cortisone OR cortivazol OR cortril OR deflazacort OR 6 dehydrocorticosterone OR dehydrocortisone OR deoxycorticosterone OR dermocorticosteroid* 7 OR dexamethasone OR diflorasone OR diflucortolone OR difluprednate OR domoprednate OR 8 drocinonide OR dutimelan OR epicortisol OR "etiprednol dicloacetate" OR fluclorolone OR 9 fludrocortisone OR fludroxycortide OR flumetasone OR flumoxonide OR flunisolide OR 10 fluocinolone OR fluocinonide OR fluocortin OR fluocortolone OR fluorometholone OR 11 fluprednidene OR fluprednisolone OR fluticasone OR formocortal OR "formoterol fumarate" OR 12 Glucocorticoid* OR glucocorticoidsteroid* OR glucocorticosteroid* OR glucocortoid* OR 13 glycocorticoid* OR glycocorticosteroid* OR halcinonide OR halometasone OR halopredone OR 14 hydrocortisone OR "hydroxy norcorticosterone" OR hydroxycorticoid* OR hydroxycorticosteroid* 15 OR hydroxycorticosterone OR hydroxydeoxycorticosterone OR hydroxyhydrocortisone OR 16 "icometasoneFor enbutate" peerOR isoflupredone review OR itrocinonide onlyOR "locicortolone dicibate" OR 17 "lorinden a" OR "lorinden t" OR loteprednol OR mazipredone OR medrysone OR meprednisone 18 OR mineralcorticosteroid* OR mineralocorticosteroid* OR minerocorticoid* OR mometasone OR 19 nicocortonide OR nivacortol OR nordeoxycorticosterone OR oropivalone OR oxohydrocortisone OR oxycorticosteroid* OR paramethasone OR prednisolone OR prednisone OR pregnenolone 20 OR procinonide OR promestriene OR resocortol OR rimexolone OR rofleponide OR steroid* OR 21 tetrahydrodeoxycorticosterone OR ticabesone OR timobesone OR tipredane OR tixocortol OR 22 triamcinolone OR "ulobetasol propionate" OR uniderm OR zoticasone) 23 6 TITLE-ABS-KEY(apremilast OR arofylline OR atizoram OR benzafentrine OR catramilast OR 24 cilomilast OR cipamfylline OR daxalipram OR denbufylline OR elbimilast OR filaminast OR 25 ibudilast OR indimilast OR lavamilast OR nitraquazone OR oglemilast OR "PDE 4 inhibitor*" OR 26 "PDE IV inhibitor*" OR "PDE type 4 inhibitor*" OR "PDE type IV inhibitor*" OR "pde-4 inhibitor*" 27 OR "PDE4 inhibitor*" OR "phosphodiesterase 4 inhibitor*" OR "phosphodiesterase IV inhibitor*" 28 OR "phosphodiesterase type 4 inhibitor*" OR "phosphodiesterase type IV inhibitor*" OR 29 piclamilast OR pumafentrine OR revamilast OR roflumilast OR Rolipram OR tetomilast OR 30 tibenelast OR tilivapram OR tipelukast OR tofimilast OR tolafentrine OR zardaverine) 31 7 1 and (2 or 3 or 4 or 5 or 6)

32 8 TITLE-ABS-KEY((meta W/1 analys*) OR (systematic* W/3 review*)) http://bmjopen.bmj.com/ 33 9 7 and 8 34 10 DOCTYPE(le) OR DOCTYPE(ed) OR DOCTYPE(bk) OR DOCTYPE(er) OR DOCTYPE(no) OR 35 DOCTYPE(sh) 36 11 9 and not 10 37 12 PMID(0*) OR PMID(1*) OR PMID(2*) OR PMID(3*) OR PMID(4*) OR PMID(5*) OR PMID(6*) OR 38 PMID(7*) OR PMID(8*) OR PMID(9*) 39 13 11 and not 12

40 on September 26, 2021 by guest. Protected copyright. 41 Part 2 42 1 TITLE-ABS-KEY("chronic airflow disease*" OR "chronic airflow disorder*" OR "chronic airflow 43 limitation*" OR "chronic airflow obstruction*" OR "chronic airway disease*" OR "chronic airway 44 disorder*" OR "chronic airway limitation*" OR "chronic airway obstruction*" OR "chronic 45 bronchitis" OR "chronic obstructive airflow disease*" OR "chronic obstructive airflow disorder*" 46 OR "chronic obstructive airway disease*" OR "chronic obstructive airway disorder*" OR "chronic 47 obstructive bronchitis" OR "chronic obstructive bronchopulmonary disease*" OR "chronic 48 obstructive broncho-pulmonary disease*" OR "chronic obstructive bronchopulmonary disorder*" 49 OR "chronic obstructive broncho-pulmonary disorder*" OR "chronic obstructive lung disease*" OR 50 "chronic obstructive lung disorder*" OR "chronic obstructive pulmonary disease*" OR "chronic 51 obstructive pulmonary disorder*" OR "chronic obstructive respiratory disease*" OR "chronic 52 obstructive respiratory disorder*" OR coad OR copd OR emphysema OR "obstructive lung 53 disease" OR "obstructive lung disorder*" OR "obstructive pulmonary disease*" OR "obstructive 54 pulmonary disorder*" OR "obstructive pulmonary tract disease*" OR "obstructive pulmonary tract 55 disorder*" OR "obstructive respiratory disease*" OR "obstructive respiratory disorder*" OR 56 "obstructive respiratory tract disease*" OR "obstructive respiratory tract disorder*") 57 58 17 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 39 of 44 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2018-027935 on 5 May 2019. Downloaded from 1 2 3 2 TITLE-ABS-KEY(Acetylcysteine OR Ambroxol OR aminophylline OR Bromhexine OR bron OR 4 cafedrine OR Carbocysteine OR diprophylline OR etofylline OR eucalyptus OR expectorant* OR 5 fudosteine OR guaiacol OR "guaiacol carbonate" OR guaietolin OR Guaifenesin OR guaifylline 6 OR "iodinated glycerol" OR ipecac OR mucolytic* OR "Potassium Citrate" OR "primula flower" 7 OR stepronin OR "stepronin lysine" OR sulfoguaiacol OR tipepidine OR ulogesic) 8 3 TITLE-ABS-KEY("1 methylmocimycin*" OR "11 deoxydaunorubicin*" OR "14 9 hydroxyclarithromycin*" OR "19 deformyl 4 deoxydesmycosin*" OR "19 deformyldesmycosin*" 10 OR "2 acetylerythromycin*" OR "2 fluoroidarubicin*" OR "2 n ethylnetilmicin*" OR "2 11 pyrrolinodoxorubicin*" OR "21 aminoepothilone B" OR "3 3 cyanomorpholino 3 12 deaminodoxorubicin*" OR "3 deamino 2 fluoro 3 hydroxydoxorubicin 14 pimelate" OR "3 deamino 13 3 morpholinodoxorubicin*" OR "3 deamino 3 morpholinooxaunomycin*" OR "4 demethoxy 11 14 deoxydaunomycinone" OR "4 demethoxydaunomycinone" OR "4 demethoxydoxorubicin*" OR "4 15 deoxydesmycosin*" OR "4 iodoesorubicin*" OR "5 iminodaunorubicin*" OR "6 n ethylnetilmicin*" 16 OR "6beta iodopenicillanicFor peer acid" OR "9 review deacetyl 9 methylidarubicin*" only OR "9 deoxydoxorubicin*" 17 OR "9 dihydroerythronolide A" OR "a 102395" OR "a 10255" OR "a 10947" OR "a 130b" OR "a 18 192411" OR "a 63075" OR abkhazomycin* OR abyssomicin* OR acetomycin* OR 19 acetylspiramycin* OR aclacinomycin* OR aclarubicin* OR actagardin* OR actaplanin* OR actinorhodine OR "aculeacin A" OR aculeximycin* OR adicillin* OR aditoprim OR adriamycinone 20 OR agglomerin* OR aklavinone OR alafosfalin* OR Alamethicin* OR albocycline OR 21 aldecalmycin* OR aldoxorubicin* OR alisamycin* OR allicin* OR almecillin* OR "alpha defensin*" 22 OR ambruticin* OR Amdinocillin* OR amfomycin* OR Amikacin* OR aminoglycoside* OR 23 aminopenicillin* OR "Aminosalicylic Acid" OR Amoxicillin* OR "Amphotericin B" OR Ampicillin* 24 OR amrubicin* OR "angucycline derivative" OR anhydrochlortetracycline OR 25 anhydroepitetracycline OR anhydrotetracycline OR anidulafungin* OR Anisomycin* OR 26 annamycin* OR ansamitocin* OR "ansamycin derivative" OR anthracycline* OR anthracyclinone* 27 OR antibacterial* OR "anti-bacterial*" OR antibiotic* OR "anti-biotic*" OR "antimicrobial cationic 28 peptide*" OR Antimycin* OR antimycobacterial* OR "anti-mycobacterial*" OR Antitreponemal* 29 OR "Anti-treponemal*" OR Antitubercular* OR "Anti-tubercular*" OR apalcillin* OR 30 aplasmomycin* OR "aplysianin E" OR apramycin* OR aristeromycin* OR Arsphenamine OR 31 aspoxicillin* OR astromicin* OR asukamycin* OR "atpenin B" OR auricularum OR Aurodox OR

32 aurograb OR avibactam OR avilamycin* OR avoparcin* OR azidamfenicol OR azidocillin* OR http://bmjopen.bmj.com/ 33 Azithromycin* OR Azlocillin* OR Aztreonam OR "aztreonam lysine" OR azurocidin* OR 34 bacampicillin* OR Bacitracin* OR bacmecillinam OR bactenecin* OR bacteriocid* OR 35 Bacteriocin* OR bafilomycin* OR balhimycin* OR "baliz 2" OR Bambermycin* OR baquiloprim OR 36 "barminomycin I" OR baycuten OR beauvericin* OR beroline OR berubicin* OR berythromycin* 37 OR "beta defensin*" OR betafectin* OR "beta-Lactam*" OR "betaLactamase Inhibitor*" OR "beta- 38 Lactamase Inhibitor*" OR betamipron OR bialaphos OR biapenem OR bicozamycin* OR 39 "biphenomycin A" OR bluensomycin* OR bombinin* OR "Bongkrekic Acid" OR boromycin* OR

40 borrelidin* OR "Brefeldin A" OR brilacidin* OR brobactam OR butalactin* OR butirosin* OR on September 26, 2021 by guest. Protected copyright. 41 cadazolid OR Calcimycin* OR Candicidin* OR Capreomycin* OR carbacephem OR carbadox OR 42 carbapenem OR "carbazomycin A" OR Carbenicillin* OR carbomycin* OR Carfecillin* OR carindacillin* OR carubicin* OR carumonam OR caspofungin* OR cathelicidin* OR cecropin* OR 43 cefacetrile OR Cefaclor OR Cefadroxil OR cefalexin* OR cefaloglycin* OR cefaloram OR 44 cefaloridine OR cefalotin* OR Cefamandole OR cefapirin* OR Cefatrizine OR cefazaflur OR 45 cefazedone OR Cefazolin* OR cefbuperazone OR cefcanel OR cefcapene OR cefclidin* OR 46 cefdaloxime OR cefdinir OR cefditoren OR cefepime OR cefetamet OR cefetecol OR 47 cefilavancin* OR Cefixime OR cefluprenam OR cefmatilen OR Cefmenoxime OR Cefmetazole 48 OR cefminox OR cefodizime OR Cefonicid OR Cefoperazone OR ceforanide OR cefoselis OR 49 Cefotaxime OR Cefotetan OR Cefotiam OR cefovecin* OR Cefoxitin* OR cefozopran OR 50 cefpimizole OR cefpiramide OR cefpirome OR cefpodoxime OR cefprozil OR cefquinome OR 51 cefradine OR cefroxadine OR Cefsulodin* OR ceftaroline OR Ceftazidime OR cefteram OR 52 ceftezole OR ceftibuten OR ceftiofur OR Ceftizoxime OR ceftobiprole OR ceftolozane OR 53 Ceftriaxone OR Cefuroxime OR cefuzonam OR Cephacetrile OR Cephalexin* OR Cephaloglycin* 54 OR Cephaloridine OR cephalosporin* OR Cephalothin* OR cephamycin* OR Cephapirin* OR 55 Cephradine OR chalcomycin* OR Chloramphenicol* OR chloroorienticin* OR chloropolysporin* 56 OR chlorothricin* OR chlorothricolide OR Chlortetracycline OR "chymotrypsin trypsin*" OR ciadox 57 58 18 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 40 of 44 BMJ Open: first published as 10.1136/bmjopen-2018-027935 on 5 May 2019. Downloaded from 1 2 3 OR "cilastatin plus imipenem" OR "cinerubin A" OR "cinerubin B" OR cinoquidox OR 4 Ciprofloxacin* OR cirramycin* OR Citrinin* OR Clarithromycin* OR "clavulanate potassium" OR 5 "Clavulanic Acid*" OR Clindamycin* OR clomocycline OR Cloxacillin* OR colicin* OR 6 colistimethate OR Colistin* OR "concanamycin A" OR coumamidine OR coumamycin* OR "cp 7 63956" OR cryptosporin* OR Cyclacillin* OR cycloheximide OR Cycloserine OR cystargin* OR 8 "cytarabine plus daunorubicin*" OR cytovaricin* OR dactimicin* OR Dactinomycin* OR 9 dalbaheptide OR dalbavancin* OR dalfopristin* OR "damavaricin Fc pentyl ether" OR 10 Daptomycin* OR daunomycinone OR daunorubicin* OR daunorubicinol OR 11 "deacetoxycephalosporin C" OR deacetylcefotaxime OR "deacetylcephalosporin C" OR 12 dealanylalahopcin* OR decaplanin* OR dechloroeremomycin* OR decilorubicin* OR defensin* 13 OR Demeclocycline OR dermaseptin* OR dermcidin* OR dermostatin* OR desmycosin* OR 14 detorubicin* OR Diarylquinoline* OR Dibekacin* OR Dicloxacillin* OR dihydrostreptomycin* OR 15 Diketopiperazines OR dimethylchlortetracycline OR dioxidine OR dirithromycin* OR Distamycin* 16 OR "ditrisarubicinFor B" OR peer doripenem OR review doxorubicin* OR doxorubicinolonly OR Doxycycline OR 17 drosocin* OR echinocandin* OR Echinomycin* OR Edeine OR efepristin* OR efrotomycin* OR 18 emimycin* OR endusamycin* OR enniatin* OR Enoxacin* OR Enviomycin* OR eperezolid OR 19 epetraborole OR epicillin* OR epidermin* OR epiderstatin* OR epiroprim OR epirubicin* OR epirubicinol OR epitetracycline OR epothilone* OR "epsilon rhodomycinone" OR eravacycline OR 20 eremomycin* OR ertapenem OR Erythromycin* OR erythromycylamine OR erythronolide* OR 21 esorubicin* OR Ethambutol OR Ethionamide OR ethylhydrocupreine OR etimicin* OR 22 evernimicin* OR everninomicin* OR faeriefungin* OR fidaxomicin* OR Filipin* OR "fleroxacin 23 deacetylcefotaxime ester" OR flomoxef OR flopristin* OR florfenicol OR Floxacillin* OR 24 flucloxacillin* OR flumoxil OR Fluoroquinolone* OR flurithromycin* OR fomidacillin* OR fortimicin* 25 OR Fosfomycin* OR fosmidomycin* OR Framycetin* OR fropenem OR fungichromin* OR 26 furaquinocin* OR furazidin* OR "furazolium chloride" OR furbenicillin* OR fusafungine OR 27 "fusidate sodium" OR "Fusidic Acid" OR fuzlocillin* OR galarubicin* OR gallidermin* OR 28 gamithromycin* OR ganefromycin* OR "ge 2270a" OR gentamicin* OR gepotidacin* OR 29 globomycin* OR gloximonam OR "glycylcycline derivative" OR "gonadorelin6 dextro lysine 2 30 pyrrolinodoxorubicin*" OR "goniodomin A" OR Gramicidin* OR granulysin* OR grisein* OR 31 guamecycline OR habekacin* OR hamycin* OR hatomamicin* OR hedamycin* OR heliomycin*

32 OR hepcidin* OR hetacillin* OR hexacycline OR hidamicin* OR "histatin 5" OR histatin* OR http://bmjopen.bmj.com/ 33 hygromycin* OR hymeglusin* OR hypothemycin* OR iclaprim OR idarubicin* OR idarubicinol OR 34 ikarugamycin* OR "imidacloprid plus moxidectin*" OR Imipenem OR indolicidin* OR inostamycin* 35 OR iseganan OR isepamicin* OR Isoniazid OR "isopenicillin N" OR "isoswinholide A" OR 36 istamycin* OR "iturin A" OR ixabepilone OR Josamycin* OR "k 252a" OR kalafungin* OR 37 Kanamycin* OR kanendomycin* OR kasugamycin* OR kelfiprim OR ketolide OR kidamycin* OR 38 kinamycin* OR Kitasamycin* OR "l 156602" OR "l 733560" OR "l 786392" OR lactacystin* OR 39 Lactams OR lactivicin* OR "lactocin S" OR lactococcin* OR lactoferricin* OR ladirubicin* OR

40 laidlomycin* OR lancovutide OR lankamycin* OR lanopepden OR lanthiopeptin* OR lantibiotic on September 26, 2021 by guest. Protected copyright. 41 OR Lasalocid OR latamoxef OR lavanducyanin* OR lefamulin* OR lenampicillin* OR lenapenem 42 OR lenoremycin* OR Leprostatic* OR "leucinostatin A" OR "leucinostatin B" OR Leucomycin* OR leurubicin* OR Levofloxacin* OR lexithromycin* OR "lff 571" OR Lincomycin* OR lincosamide* 43 OR Linezolid OR linopristin* OR lividomycin* OR "lonomycin A" OR loracarbef OR lotilibcin* OR 44 Lucensomycin* OR lydicamycin* OR Lymecycline OR lysobactin* OR lysocellin* OR lysostaphin* 45 OR macrolide OR magainin* OR malyngolide OR manumycin* OR maridomycin* OR "mdl 62208" 46 OR "mdl 62211" OR mecillinam OR meclocycline OR megacin* OR megalomicin* OR 47 Mepartricin* OR meropenem OR mersacidin* OR metacycline OR metampicillin* OR 48 Methacycline OR Methicillin* OR "methylenomycin A" OR "methylenomycin B" OR methymycin* 49 OR methynolide OR meticillin* OR Mezlocillin* OR "microcin b17" OR "microcin J25" OR 50 micronomicin* OR midecamycin* OR mideplanin* OR "mikamycin B" OR Mikamycin* OR 51 "milbemycin oxime" OR milbemycin* OR Minocycline OR Miocamycin* OR miokamycin* OR 52 miporamicin* OR miraxid OR mocimycin* OR "moenomycin A" OR monensin* OR "monobactam 53 derivative" OR Moxalactam OR moxidectin* OR "ms 8209" OR Mupirocin* OR mureidomycin* OR 54 murepavadin* OR mycinamicin* OR Mycobacillin* OR mycolog OR mycoticin* OR myxothiazol 55 OR "n benzyldoxorubicin 14 valerate" OR "n trifluoroacetyldoxorubicin*" OR Nafcillin* OR 56 "Nalidixic Acid" OR narasin* OR Natamycin* OR neamine OR nebacetin* OR Nebramycin* OR 57 58 19 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 41 of 44 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2018-027935 on 5 May 2019. Downloaded from 1 2 3 negamycin* OR nemadectin* OR nemorubicin* OR Neomycin* OR neosporin* OR Netilmicin* OR 4 Netropsin* OR niddamycin* OR Nigericin* OR Nisin* OR nitrocefin* OR nitrosochloramphenicol 5 OR "nocardicin A" OR "nocardicin E" OR "nocardicinic acid derivative*" OR Norfloxacin* OR 6 nosiheptide OR nourseothricin* OR Novobiocin* OR "nvb 302" OR nybomycin* OR Nystatin* OR 7 "oasomycin A" OR obelmycin* OR Ofloxacin* OR olaquindox OR oleandolide OR Oleandomycin* 8 OR oligomycin* OR omadacycline OR omiganan OR optocillin* OR "orienticin A" OR 9 orientiparcin* OR oritavancin* OR oropivalone OR Oxacillin* OR oxaunomycin* OR "Oxolinic 10 Acid" OR Oxytetracycline OR paldimycin* OR panipenem OR pardaxin* OR Paromomycin* OR 11 patulin* OR pediazole OR pediocin* OR Pefloxacin* OR penamecillin* OR penethamate OR 12 "Penicillanic Acid" OR "Penicillic Acid" OR penicillin* OR "penicilloic acid" OR pentalenolactone 13 OR pentisomicin* OR peptaibol OR pexiganan OR "pf 708093" OR phenelfamycin* OR 14 pheneticillin* OR phleomycin* OR pikromycin* OR "Pipemidic Acid" OR Piperacillin* OR 15 pirarubicin* OR pirazmonam OR pirlimycin* OR Pivampicillin* OR pivmecillinam OR 16 platensimycin*For OR plazomicin* peer OR plectasin* review OR pleuromutilin* only OR pluramycin* OR 17 pneumocandin* OR "polyactin A" OR polyfungin* OR polymyxin* OR "polyoxin B" OR "polyoxin 18 D" OR polysporin* OR polytrim OR posizolid OR "pr 39" OR Pristinamycin* OR Prodigiosin* OR 19 prohepcidin* OR propicillin* OR protegrin* OR Prothionamide OR prothracarcin* OR "pseudomonic acid" OR Pyrazinamide OR pyrromycinone OR pyrroxamycin* OR quinacillin* OR 20 quinomycin* OR quinupristin* OR radezolid OR radicicol OR ramoplanin* OR ranalexin* OR 21 ranbezolid OR razupenem OR retacillin* OR retapamulin* OR "rhodomycin A" OR Ribostamycin* 22 OR Rifabutin* OR Rifampin* OR Rifamycin* OR rimocidin* OR Ristocetin* OR ritipenem OR 23 "ritipenem acoxil" OR rodorubicin* OR roflamycoin* OR rokitamycin* OR Rolitetracycline OR 24 rosaramicin* OR Roxarsone OR Roxithromycin* OR ruboxyl OR Rutamycin* OR sabarubicin* OR 25 sagopilone OR sanfetrinem OR sarecycline OR "simaomicin alpha" OR "simocyclinone D8" OR 26 Sirolimus OR "sisomicin sulfate" OR Sisomicin* OR "skf 104662" OR sofradex OR 27 Spectinomycin* OR "spinosyn A" OR Spiramycin* OR squalamine OR stigmatellin* OR 28 streptoduocin* OR Streptogramin* OR streptolydigin* OR Streptomycin* OR streptothricin* OR 29 streptotriad OR Streptovaricin* OR streptovirudin* OR "streptovitacin A" OR stubomycin* OR 30 subtilin* OR Sulbactam OR Sulbenicillin* OR Sulfamerazine OR Sulfamethoxypyridazine OR 31 sulfazecin* OR sulopenem OR sultamicillin* OR surfactin* OR surotomycin* OR "swinholide A"

32 OR "swinholide B" OR tachyplesin* OR Talampicillin* OR tameticillin* OR tazobactam OR http://bmjopen.bmj.com/ 33 tebipenem OR tedizolid OR Teicoplanin* OR teixobactin* OR telavancin* OR temocillin* OR 34 terdecamycin* OR tetracyclin* OR Tetracycline OR tetramycin* OR tetronasin* OR tetronomycin* 35 OR tetroxoprim OR Thiamphenicol OR Thienamycin* OR Thioacetazone OR thiolactomycin* OR 36 "thionin peptide" OR thiopeptin* OR thiophenoxycefalotin* OR Thiostrepton OR tiamulin* OR 37 "tibezonium iodide" OR Ticarcillin* OR tigecycline OR tigemonam OR tildipirosin* OR tilmicosin* 38 OR timentin* OR tirandamycin* OR tizoxanide OR tobicillin* OR Tobramycin* OR tolramycin* OR 39 tomopenem OR toyocamycin* OR tresaderm OR tribactam OR trichomycin* OR "trichostatic acid"

40 OR "trichostatin A" OR trimethoprim* OR "trinem derivative" OR "triostin A" OR triplopen OR on September 26, 2021 by guest. Protected copyright. 41 trisep OR Troleandomycin* OR trospectomycin* OR tuftsin* OR tulathromycin* OR Tunicamycin* 42 OR tutofusin* OR Tylosin* OR tylvalosin* OR Tyrocidine OR Tyrothricin* OR "u 78608" OR "uk 69753" OR unphenelfamycin* OR "urdamycin C" OR "urdamycin D" OR "urdamycin H" OR 43 ureidopenicillin* OR urobiotic OR "vacidin A" OR validamycin* OR Valinomycin* OR valnemulin* 44 OR valrubicin* OR Vancomycin* OR venturicidin* OR vernamycin* OR "violamycin B1" OR 45 Viomycin* OR "virginiae butanolide A" OR "virginiae butanolide C" OR "virginiamycin M" OR 46 "virginiamycin S" OR Virginiamycin* OR "viriplanin A" OR viscosin* OR volpristin* OR "ws 9659 b" 47 OR "zibrofusidic acid" OR zineryt OR "zoptarelin doxorubicin*" OR zorbamycin* OR zorubicin*) 48 4 TITLE-ABS-KEY(Alprazolam OR arfendazam OR benzodiazepin OR benzodiazepine* OR 49 Benzodiazepinone* OR bromazepam OR camazepam OR Chlordiazepoxide OR cinolazepam 50 OR clobazam OR clonazepam OR clorazepate OR "Clorazepate Dipotassium" OR "clorazepate 51 potassium" OR dealkylflurazepam OR delorazepam OR demoxepam OR devazepide OR 52 diazepam OR doxefazepam OR Estazolam OR fludiazepam OR flunitrazepam OR flurazepam 53 OR flutoprazepam OR fosazepam OR gidazepam OR girisopam OR halazepam OR loflazepate 54 OR lorazepam OR lormetazepam OR lotrafiban OR meclonazepam OR Medazepam OR 55 metaclazepam OR Midazolam OR nastorazepide OR nerisopam OR netazepide OR 56 nimetazepam OR nitrazepam OR nitrosochlordiazepoxide OR norchlordiazepoxide OR 57 58 20 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 42 of 44 BMJ Open: first published as 10.1136/bmjopen-2018-027935 on 5 May 2019. Downloaded from 1 2 3 norclobazam OR nordazepam OR norfludiazepam OR norflunitrazepam OR oxazepam OR 4 phenazepam OR pinazepam OR prazepam OR quazepam OR "ro 7 0213" OR talampanel OR 5 tampramine OR tarazepide OR temazepam OR tetrazepam OR tibezonium OR tifluadom OR 6 tofisopam OR tomaymycin OR Triazolam OR tuclazepam OR uxepam) 7 5 TITLE-ABS-KEY(acetorphine OR acetylcodeine OR acetylmethadol OR Alfentanil OR 8 Alphaprodine OR anileridine OR apadoline OR azidomorphine OR benzhydrocodone OR 9 bezitramide OR bremazocine OR "Brompton mixture" OR Buprenorphine OR Butorphanol OR 10 ciramadol OR cocodamol OR Codeine OR codydramol OR conorfone OR cyclazocine OR 11 Dextromoramide OR Dextropropoxyphene OR dextrorphan OR dezocine OR diamorphine OR 12 diconal OR dihydrocodeine OR dihydroetorphine OR Dihydromorphine OR dimethylthiambutene 13 OR Diphenoxylate OR dipipanone OR enadoline OR eptazocine OR ethylketazocine OR 14 Ethylketocyclazocine OR Ethylmorphine OR etonitazene OR Etorphine OR etoxeridine OR 15 faxeladol OR Fentanyl OR furethidine OR gelonida OR Heroin OR Hydrocodone OR isalmadol 16 OR isomethadoneFor OR ketazocinepeer OR reviewketobemidone OR ketoganonly OR kyotorphin OR lefetamine 17 OR levacetylmethadol OR levomethadone OR Levorphanol OR Meperidine OR Meptazinol OR 18 metazocine OR Methadone OR "Methadyl Acetate" OR methylsamidorphan OR Morphine OR 19 "morphinomimetic agent*" OR "morphinomimetic drug*" OR morphinone OR Nalbuphine OR narcotic* OR nicocodine OR nicomorphine OR noracymethadol OR norbuprenorphine OR 20 nordextropropoxyphene OR normorphine OR norpethidine OR norpropoxyphene OR "o 21 nortramadol" OR oliceridine OR opiate OR Opiate* OR opioid* OR Opium OR oripavine OR 22 Oxycodone OR Oxymorphone OR pentamorphone OR Pentazocine OR pethidine OR 23 phenadoxone OR phenaridine OR Phenazocine OR phencyclidine OR Phenoperidine OR 24 picenadol OR piminodine OR Pirinitramide OR piritramide OR profadol OR Promedol OR 25 propiram OR sameridine OR samidorphan OR semorphone OR Sufentanil OR tapentadol OR 26 thebaine OR tifluadom OR Tilidine OR tonazocine OR Tramadol OR trimeperidine) 27 6 TITLE-ABS-KEY("airflow clearance" OR "airway clearance" OR BLVR OR bronchoscop* OR 28 ELVR OR "lung clearance" OR "lung denervation" OR LVRS OR pneumectom* OR 29 pneumonectom* OR pneumoresection* OR "pulmonary clearance" OR "volume reducing" OR 30 "volume reduction*") 31 7 1 and (2 or 3 or 4 or 5 or 6)

32 8 TITLE-ABS-KEY((meta W/1 analys*) OR (systematic* W/3 review*)) http://bmjopen.bmj.com/ 33 9 7 and 8 34 10 DOCTYPE(le) OR DOCTYPE(ed) OR DOCTYPE(bk) OR DOCTYPE(er) OR DOCTYPE(no) OR 35 DOCTYPE(sh) 36 11 9 and not 10 37 12 PMID(0*) OR PMID(1*) OR PMID(2*) OR PMID(3*) OR PMID(4*) OR PMID(5*) OR PMID(6*) OR 38 PMID(7*) OR PMID(8*) OR PMID(9*) 39 13 11 and not 12

40 on September 26, 2021 by guest. Protected copyright. 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 21 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 43 of 44 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2018-027935 on 5 May 2019. Downloaded from 1 2 3 Part 3 4 5 1 TITLE-ABS-KEY("chronic airflow disease*" OR "chronic airflow disorder*" OR "chronic airflow 6 limitation*" OR "chronic airflow obstruction*" OR "chronic airway disease*" OR "chronic airway 7 disorder*" OR "chronic airway limitation*" OR "chronic airway obstruction*" OR "chronic 8 bronchitis" OR "chronic obstructive airflow disease*" OR "chronic obstructive airflow disorder*" 9 OR "chronic obstructive airway disease*" OR "chronic obstructive airway disorder*" OR "chronic 10 obstructive bronchitis" OR "chronic obstructive bronchopulmonary disease*" OR "chronic 11 obstructive broncho-pulmonary disease*" OR "chronic obstructive bronchopulmonary disorder*" 12 OR "chronic obstructive broncho-pulmonary disorder*" OR "chronic obstructive lung disease*" OR 13 "chronic obstructive lung disorder*" OR "chronic obstructive pulmonary disease*" OR "chronic 14 obstructive pulmonary disorder*" OR "chronic obstructive respiratory disease*" OR "chronic 15 obstructive respiratory disorder*" OR coad OR copd OR emphysema OR "obstructive lung 16 disease" OR For"obstructive peer lung disorder*" review OR "obstructive pulmonaryonly disease*" OR "obstructive 17 pulmonary disorder*" OR "obstructive pulmonary tract disease*" OR "obstructive pulmonary tract 18 disorder*" OR "obstructive respiratory disease*" OR "obstructive respiratory disorder*" OR 19 "obstructive respiratory tract disease*" OR "obstructive respiratory tract disorder*") 2 TITLE-ABS-KEY((smoking* or tobacco* or cigar* or cigarette* or cigaret*) and (quit* or 20 discontinu* or ceas* or cessation*)) 21 3 TITLE-ABS-KEY(aerobics OR anaerobics OR "artificial respiration*" OR bicycling OR biking OR 22 "Chest Wall Oscillation*" OR dance OR dancing OR "endurance training" OR exercis* OR 23 "Extracorporeal Membrane Oxygen*" OR "fitness training" OR "inhalation therap*" OR isometrics 24 OR oxygen OR "physical activit*" OR "physical exertion" OR "postural drain*" OR rehab* OR 25 "resistance training" OR "respiration care*" OR "respiration therap*" OR "respiratory care*" OR 26 "respiratory therap*" OR running OR "strength training" OR swimming OR "Tai Chi" OR "Tai Ji" 27 OR walking OR weightlifting OR yoga) 28 4 TITLE-ABS-KEY(diet OR dietary OR diets OR nutrition* OR supplementation OR supplements) 29 5 TITLE-ABS-KEY(immuniz* OR innoculat* OR moniarix OR "pcv 13" OR pcv13 OR "pneu 30 immune" OR "pneumo 23" OR pneumopur OR pneumovax OR "pnu immune" OR "pnu imune" 31 OR "polysaccharide vaccine pneumococcal" OR prevenar OR prevnar OR "streptococcus

32 pneumoniae vaccine" OR streptopur OR streptorix OR synflorix OR vaccin*) http://bmjopen.bmj.com/ 33 6 ((TITLE-ABS-KEY(((domestic or home or domiciliary) and (residence or residences or setting or 34 settings or care or nurs* or help or service* or treatment* or therap* or "respiratory care" or 35 "respiratory treatment*" or "respiratory therap*" or "respiratory service*" or "respiratory assist*" or 36 ventilat*)) or "assisted living" or homecare)) and (TITLE-ABS-KEY(((((respiration* or respiratory or 37 breathing) and (assist* or controlled or mechanical)) or (facial or face or nasal)) and mask*) or 38 "artificial respiration*" or BiPAP or CPAP or "Fluidic Breathing Assister" or HMV or IPPB or IPPV 39 or NIAV or NIV or NPPV or "Oxygen Regulator*" or PAP or PAV or "Portable Oxygen" or "Positive

40 Airway Pressure*" or "positive end-expiratory pressure*" or "positive pressure*" or respirator or on September 26, 2021 by guest. Protected copyright. 41 respirators or "Respiratory insufficiency" or Tracheostom* or ventilation or ventilator*))) 42 7 1 and (2 or 3 or 4 or 5 or 6) 8 TITLE-ABS-KEY((meta W/1 analys*) OR (systematic* W/3 review*)) 43 9 7 and 8 44 10 DOCTYPE(le) OR DOCTYPE(ed) OR DOCTYPE(bk) OR DOCTYPE(er) OR DOCTYPE(no) OR 45 DOCTYPE(sh) 46 11 9 and not 10 47 12 PMID(0*) OR PMID(1*) OR PMID(2*) OR PMID(3*) OR PMID(4*) OR PMID(5*) OR PMID(6*) OR 48 PMID(7*) OR PMID(8*) OR PMID(9*) 49 13 11 and not 12 50 51 Part 4 52 1 TITLE-ABS-KEY("chronic airflow disease*" OR "chronic airflow disorder*" OR "chronic airflow 53 limitation*" OR "chronic airflow obstruction*" OR "chronic airway disease*" OR "chronic airway 54 disorder*" OR "chronic airway limitation*" OR "chronic airway obstruction*" OR "chronic 55 bronchitis" OR "chronic obstructive airflow disease*" OR "chronic obstructive airflow disorder*" 56 OR "chronic obstructive airway disease*" OR "chronic obstructive airway disorder*" OR "chronic 57 58 22 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 44 of 44 BMJ Open: first published as 10.1136/bmjopen-2018-027935 on 5 May 2019. Downloaded from 1 2 3 obstructive bronchitis" OR "chronic obstructive bronchopulmonary disease*" OR "chronic 4 obstructive broncho-pulmonary disease*" OR "chronic obstructive bronchopulmonary disorder*" 5 OR "chronic obstructive broncho-pulmonary disorder*" OR "chronic obstructive lung disease*" OR 6 "chronic obstructive lung disorder*" OR "chronic obstructive pulmonary disease*" OR "chronic 7 obstructive pulmonary disorder*" OR "chronic obstructive respiratory disease*" OR "chronic 8 obstructive respiratory disorder*" OR coad OR copd OR emphysema OR "obstructive lung 9 disease" OR "obstructive lung disorder*" OR "obstructive pulmonary disease*" OR "obstructive 10 pulmonary disorder*" OR "obstructive pulmonary tract disease*" OR "obstructive pulmonary tract 11 disorder*" OR "obstructive respiratory disease*" OR "obstructive respiratory disorder*" OR 12 "obstructive respiratory tract disease*" OR "obstructive respiratory tract disorder*") 13 2 TITLE-ABS-KEY(CBT OR coach* OR "Cognitive behavioral therap*" OR "Cognitive therap*" OR 14 "health promotion*" OR meditat* OR mentor* OR "mind body" OR mindfulness OR psychological 15 OR psychosocial OR psychotherap*) 16 3 TITLE-ABS-KEY("actionFor peer plan*" OR android review OR app OR apps only OR ehealth OR "e-health" OR 17 internet OR ipad* OR iphone* OR mhealth OR "m-health" OR "mobile app*" OR "mobile health" 18 OR "mobile technolog*" OR "portable computer*" OR "portable electronic app*" OR "portable 19 software app*" OR "remote consultation*" OR "self care" OR "self help" OR "self management" OR "self treatment" OR "smart phone*" OR smartphone* OR "tablet computer*" OR 20 teleconsultation* OR "tele-consultation*" OR telehealth OR "tele-health" OR telemedicine OR 21 "tele-medicine" OR teletherap* OR "tele-therap*" OR web) 22 4 TITLE-ABS-KEY(acupuncture OR agent* OR "alternative medicine" OR "care package*" OR 23 chemotherap* OR "complementary medicine" OR drug* OR "electric stimulation*" OR holistic OR 24 "integrated care" OR "integrated health care" OR "integrated healthcare" OR intervention* OR 25 manag* OR medication* OR "muscle stimulation*" OR operat* OR pharmacotherap* OR 26 procedure* OR reconstruction* OR repair* OR resect* OR surg* OR therap* OR treat* OR 27 wellness) 28 5 1 and (2 or 3 or 4) 29 6 TITLE-ABS-KEY((meta W/1 analys*) OR (systematic* W/3 review*)) 30 7 5 and 6 31 8 DOCTYPE(le) OR DOCTYPE(ed) OR DOCTYPE(bk) OR DOCTYPE(er) OR DOCTYPE(no) OR

32 DOCTYPE(sh) http://bmjopen.bmj.com/ 33 9 7 and not 8 34 10 PMID(0*) OR PMID(1*) OR PMID(2*) OR PMID(3*) OR PMID(4*) OR PMID(5*) OR PMID(6*) OR 35 PMID(7*) OR PMID(8*) OR PMID(9*) 36 11 9 and not 10 37 38 39

40 on September 26, 2021 by guest. Protected copyright. 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 23 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml