- Email: [email protected]
Pulmonary Rehabilitation in Individuals With Non–Cystic Fibrosis Bronchiectasis: A Systematic Review
Accepted Manuscript Pulmonary rehabilitation in individuals with non-cystic fibrosis bronchiectasis - a systematic review Annemarie L. Lee, PhD, Catherine J. Hill, PhD, Christine F. McDonald, PhD, Anne E. Holland, PhD PII:
S0003-9993(16)30246-5
DOI:
10.1016/j.apmr.2016.05.017
Reference:
YAPMR 56577
To appear in:
ARCHIVES OF PHYSICAL MEDICINE AND REHABILITATION
Received Date: 15 March 2016 Revised Date:
27 April 2016
Accepted Date: 17 May 2016
Please cite this article as: Lee AL, Hill CJ, McDonald CF, Holland AE, Pulmonary rehabilitation in individuals with non-cystic fibrosis bronchiectasis - a systematic review, ARCHIVES OF PHYSICAL MEDICINE AND REHABILITATION (2016), doi: 10.1016/j.apmr.2016.05.017. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Running title: Rehabilitation in bronchiectasis
Pulmonary rehabilitation in individuals with non-cystic fibrosis bronchiectasis - a
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Annemarie L Lee, PhD
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Catherine J Hill, PhD
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Christine F McDonald, PhD Anne E Holland, PhD
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systematic review
West Park Healthcare Centre, Toronto, Ontario, Canada
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Department of Physical Therapy, University of Toronto, Ontario, Canada
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Institute for Breathing and Sleep, Austin Health,
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Department of Physiotherapy, Austin Health
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Department of Respiratory and Sleep Medicine, Austin Health
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Department of Physiotherapy, Alfred Health
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Physiotherapy, La Trobe University
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Corresponding author:
Annemarie Lee, Department of Respiratory Medicine, West Park Healthcare Centre, 82 Buttonwood Ave, Toronto M6M 2J5. Email: [email protected] Phone: 011 416 243 2653, Fax: 011 416 243 3747
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Pulmonary rehabilitation in individuals with non-cystic fibrosis bronchiectasis - a
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systematic review
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The authors have no conflict of interest to declare.
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Abstract
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Objective: To examine the effect of pulmonary rehabilitation (PR) (exercise and education) or
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exercise training (ET) on exercise capacity, health-related quality of life (HRQOL), symptoms,
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frequency of exacerbations and mortality compared to no treatment in adults with bronchiectasis.
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Data sources: Computer-based databases were searched from their inception to February 2016.
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Study selection: Randomized controlled trials of PR or ET versus no treatment in adults with
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bronchiectasis were included.
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Data Extraction: Two reviewers independently extracted data and assessed methodological
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quality using the Cochrane Risk of Bias tool.
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Data synthesis: Four trials with 164 participants were included, with variable study quality.
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Supervised outpatient PR or ET of eight weeks improved incremental shuttle walk distance
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(weighted mean difference (WMD): 67m; 95% CI 52 to 82m) and disease-specific HRQOL
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(WMD -4.65, 95% CI -6.7 to -2.6 units) immediately following intervention, but these benefits
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were not sustained at six months. There was no effect on cough-related QOL (WMD 1.3, 95% CI
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-0.9 to 3.4 units) or psychological symptoms. PR commenced during an acute exacerbation and
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continued beyond discharge had no effect on exercise capacity or HRQOL. The frequency of
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exacerbations over 12 months reduced with outpatient ET (median 2 versus 1, p=0.013), but PR
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initiated during an exacerbation had no impact on exacerbation frequency or mortality.
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Conclusion: Short term improvements in exercise capacity and HRQOL were achieved with
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supervised PR and ET programs, but sustaining these benefits is challenging in people with
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bronchiectasis. The frequency of exacerbations over 12 months was reduced with ET only.
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Key words: bronchiectasis, rehabilitation, exercise, exercise tolerance, quality of life, disease
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exacerbation
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Abbreviations:
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CF – cystic fibrosis
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ET – exercise training
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PR – pulmonary rehabilitation
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HRQOL – health-related quality of life
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PRISMA - Preferred Reporting Items for Systematic Reviews and Meta-Analyses
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PEDro – Physiotherapy Evidence Database
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WMD – weighted mean difference
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SMD – standardized mean difference
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IMT – inspiratory muscle training
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ISWT – incremental shuttle walk test
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ISWD – incremental shuttle walk distance
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6MWT – 6-minute walk test
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6MWD – 6-minute walk distance
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SGRQ – St George’s Respiratory Questionnaire
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LCQ – Leicester Cough Questionnaire
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RR – Relative Risk
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MID – minimal important difference
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COPD – chronic obstructive pulmonary disease
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QOL – quality of life
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Introduction
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Non-cystic fibrosis (CF) bronchiectasis is characterized by bronchial dilatation with impaired
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mucociliary clearance and accumulation of secretions.1 Common symptoms include chronic
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cough and sputum production, dyspnoea and fatigue.1,2 The disease trajectory is commonly
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punctuated by acute exacerbations, associated with chronic bacterial colonization and
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inflammation, which lead to worsening lung damage and accelerated disease progression.3-5
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Other features include reduced peripheral muscle strength, reduced exercise capacity6,7 and low
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levels of physical activity.8
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International guidelines for the treatment of bronchiectasis recommend incorporating exercise
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training (ET) or pulmonary rehabilitation (PR), which involves a combination of exercise
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training and education.9,10 Retrospective studies of ET programs and PR have demonstrated
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improvements in submaximal and maximal exercise capacity and specific measures of
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HRQOL.11-14 An earlier systematic review of physical training in non-CF bronchiectasis was
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undertaken in 2002 and supported the treatment approach, with improvements in endurance
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exercise capacity and HRQOL with the combination of inspiratory muscle training (IMT) and
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ET.15 Since that review, further prospective studies have been undertaken using a mix of
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different approaches to ET and PR16-18 and exploring the short and long term effects on outcomes
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such as cough-related quality of life19 and incidence of acute exacerbations of bronchiectasis.20
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The effects of PR or ET on these outcomes have not been systematically reviewed.
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The aim of this study was to systematically review the effects of PR or ET in non-CF
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bronchiectasis on 1) measures of exercise capacity and muscle strength, 2) HRQOL; 3)
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symptoms and 4) frequency of exacerbations and mortality. This review was undertaken
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according to PRISMA recommendations21 and is registered with PROSPERO
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(CRD42015019684).
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Methods
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Search strategy
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The primary search strategy utilized electronic databases of Medline, CINAHL, EMBASE,
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PubMed, Cochrane Database of systematic reviews and Physiotherapy Evidence Database
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(PEDro) from inception to May 2015. The search was updated in February 2016. The key terms
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were ‘bronchiectasis/non-cystic fibrosis bronchiectasis/non-CF bronchiectasis/ciliary motility
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disease /Kartagener’s syndrome’, ‘rehabilitation/respiratory therapy/exercise/exercise movement
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techniques/exercise therapy/physical fitness’,
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‘dyspnea/dyspnoea/breathlessness/fatigue/perceived exertion/cough’, ‘exercise capacity/exercise
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tolerance’, ‘quality of life/health-related quality of life’, ‘anxiety/depression’, ‘healthcare
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utilisation/mortality/survival’. The search strategy used for Medline is shown in Supplementary
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Table S1 and was adapted for use in the other databases. Secondary searches involved hand
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searching of reference lists from identified articles, citation tracking of included articles and use
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of the PubMed ‘related articles’ option.
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Inclusion criteria
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Two investigators (AL and CH) reviewed titles and abstracts independently and potentially
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relevant articles were identified and retrieved in full text for independent assessment using the
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inclusion criteria. Any disagreements were resolved by consensus or in consultation with a third
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reviewer (AH) when necessary. Abstracts were included if sufficient data could be obtained. The
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inclusion criteria are outlined on Table 1.
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Data Extraction and Quality Assessment
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Two investigators (AL and AH) independently assessed the quality of the randomized
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(controlled and cross-over) studies using the Cochrane risk of bias tool22 and included items
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relating to the randomization process, blinding, and selective outcome reporting. Assessment was
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completed independently with discrepancies resolved to ensure complete agreement. Authors
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were contacted when necessary to obtain further information. Two reviewers independently
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extracted the data (AL and AH) which were clarified by consensus discussion.23
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Data Analysis
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Meta-analysis was planned for two or more studies which were considered clinically
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homogenous.23 Data were entered using Review Manager 5.3 (Cochrane Collaboration’s
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Information Management system), with outcomes treated as continuous variables. Where studies
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included two intervention groups, intervention groups were combined to enable a single
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comparison.24 Weighted mean difference (WMD: same metric scale) or standardised mean
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differences (SMD: different metric scale) using either a fixed-effects or random-effects model25
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were selected when estimating the total effect of pooled data at a given follow up period. Forest
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plots were generated to depict results, and heterogeneity was tested according to the overlap in
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confidence intervals, interpreting the chi-squared test, and the I2 statistic, with substantial
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heterogeneity represented by an I2 > 50%.25 When study findings could not be combined, a
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narrative format was used to report results. Additional information was retrieved from two
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studies following direct author correspondence.18,26
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Results
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A total of 119 studies were originally retrieved in the search. Following removal of duplicates, a
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total of 82 articles were retrieved. Of these trials, a total of four studies were included (Figure
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1),16-18,26 with reasons for study exclusion outlined in Figure 1 and strong agreement (k=0.82)
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achieved between reviewers for study selection. A total of 164 participants were included with
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the underlying cause of bronchiectasis reported in one study,16 which included idiopathic
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bronchiectasis and childhood illness (pneumonia and whooping cough).
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Three studies included hospital-based outpatient, supervised ET of eight weeks16-18 with
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education sessions also incorporated in two studies16,17 (Table 2). One study incorporated
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supervised ET within 48 hours of admission for an acute exacerbation to hospital, with
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instructions for daily walking (unsupervised) upon discharge over 12 months.26 Telephone
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consultation at 48 hours, two and four weeks post discharge was provided to measure adherence
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and for exercise progression.26 Long term follow up during which home exercise training was
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recommended ranged from three months,16,17 to 12 months.18,26 One study compared ET only to
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no intervention,18 one compared ET (which included IMT or sham IMT) and education to no
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intervention,16 one compared ET, education with airway clearance therapy to education and
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airway clearance therapy alone17 and the inpatient study compared ET plus self-management
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commenced during an acute admission and continuing upon discharge, to usual care.26 Three
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studies included a combination of endurance and upper and lower limb strength training,17,18,26
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while one study examined endurance training and IMT.18 The duration of endurance training
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ranged from 30 to 45 minutes in outpatient ET or PR,16-18 while strength training duration was
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unspecified. Participant compliance with ET was reported in one study, with 90% of participants
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achieving this target (defined as attending 12 out of 16 sessions).18 The remaining three studies
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did not report patient adherence.
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There was consistent agreement between reviewers for study quality (Table 3). Most studies
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reported random allocation16-18 but only one reported randomization sequence concealment.18
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While assessor blinding was applied in two studies,18,26 this was not consistently applied.16,17 An
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unclear or high level of bias for participant blinding was evident in all studies. We acknowledge
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such blinding is difficult to achieve with this type of intervention. All studies included complete
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reporting for outcomes with adequate follow-up.
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Exercise capacity
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The findings between groups for all studies are outlined on Table 2. Exercise capacity was
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measured using the incremental shuttle walk test (ISWT) in four studies.16-18,26 and the endurance
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shuttle walk test in two studies.17,26 Following two months of supervised outpatient PR or ET, the
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WMD for the incremental shuttle walk distance (ISWD) was 67m (95% CI 52 to 82m) in favour
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of the intervention (Figure 2). Although peak oxygen uptake did not change, endurance exercise
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capacity (incremental treadmill test at 85% of peak oxygen uptake or endurance shuttle walking
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test) improved with outpatient supervised PR compared to no treatment,16 or when compared to
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oscillating positive expiratory pressure therapy alone17 (Table 2). In one study of two months of
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ET alone significant improvement in the 6-minute walk distance (6MWD) by 32m (95% CI 18 to
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42m) was achieved at the end of training.18 However, th improvements in ISWD or 6MWD were
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not sustained at six or 12 months post intervention.18 The combination of in-and outpatient PR
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did not change ISWD or endurance shuttle walk distance at hospital discharge, six weeks, three
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months or 12 months (Table 2).26
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Muscle strength
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The combined approach of inpatient and outpatient PR did not alter quadriceps muscle strength
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immediately post-discharge or over the follow up period.26
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HRQOL and symptoms
Disease-specific
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Three studies evaluated HRQOL using the SGRQ with data pooled from two studies,17,18 with
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information obtained following author correspondence from one study;18 further details were
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also requested for an additional study but were unable to be procured.16 Outpatient supervised PR
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or ET were associated with improvement in the St George’s Respiratory questionnaire (SGRQ)
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total score (WMD -4.65 (95% CI -6.70 to -2.60 units) (Figure 3). At three months post PR, this
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improvement was still evident,17 although it was absent at six months post ET alone.18 The
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combination of in- and outpatient PR did not change the SGRQ total score at hospital discharge
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or over longer term follow up (Table 2).26 Lee et al18found less dyspnea and fatigue on the
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Chronic Respiratory Disease Questionnaire with ET only, however these improvements were
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not sustained at six months (Table 2) and there were no effects on emotional function or
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mastery.18
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Cough related QOL
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Of the two studies examining the effects on Leicester Cough Questionnaire (LCQ),17,18 no
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significant change was evident in the total LCQ score (WMD 1.27 (95% CI -0.89 to 3.42 units)
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immediately following supervised outpatient PR or ET (Figure 4).
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Psychological Symptoms
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One study explored the effects of ET on psychological symptoms,18 with no change in anxiety or
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depression levels post intervention, or over the longer term follow up based on the Hospital
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Anxiety and Depression Scale.
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Exacerbations and mortality
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The frequency of acute exacerbations was reduced with ET only (median 2 versus 1, p=0.013),
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with a longer time to first exacerbation (median of eight months versus six months, p=0.047)
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compared to no treatment.18 In contrast, a combined in- and outpatient PR did not lower the
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hospital admission rate (RR 1.5 (95% CI 0.75 to 3.0), nor the mortality rate between groups (RR
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3.0 (95% CI 0.74 to 12.7).26
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Discussion
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This systematic review included recent studies of PR or ET in individuals with non-CF
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bronchiectasis. Short term benefits in endurance and functional exercise capacity, cough-related
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symptoms and disease-specific HRQOL, with reductions in dyspnea and fatigue levels were
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evident with supervised outpatient programs in stable patients, but improvements were not
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sustained beyond three months. This intervention did not alter anxiety or depression. For PR
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initiated during an exacerbation requiring hospitalization and continued beyond discharge, there
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were no benefits for exercise capacity, muscle strength or HRQOL. The effect on exacerbation
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frequency was variable, with a reduction in frequency of acute exacerbations over 12 months
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following ET training in stable patients, but no difference with a combined in- and outpatient
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program approach in patients post exacerbation over the same time period.
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The magnitude of improvement in functional exercise capacity was consistent with previous
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retrospective studies of PR, in which the benefit ranged from 25 to 91m.11-14,27 The minimal
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important difference (MID) of the incremental shuttle walk test (ISWT) and the 6-minute walk
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test (6MWT) for COPD and bronchiectasis has been reported to be 35 to 48m28,29 and between
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22 and 33m respectively.29,30 The pooled improvement of 67m in the ISWD and change of 32m
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in the 6MWD in favour of ET suggests that the degree of improvement is clinically significant.
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All studies applied principles of exercise prescription based on those applied for COPD.31 These
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outcomes are promising, but the lack of change in peak exercise capacity suggests that the
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duration, frequency of exercise sessions and the model of ET which enable optimal benefits in
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bronchiectasis have not yet been identified. An additional relevant factor is patient compliance to
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the exercise protocol. Low levels of adherence to treatment, including respiratory medications,
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antibiotic therapy and airway clearance therapy have been reported in individuals with
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bronchiectasis.32 In this review, only one study outlined patient rates of completion and inferred
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compliance with an exercise protocol.18 In the absence of further details of adherence to PR, it is
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difficult to determine the influence of this factor. However, adherence to the exercise protocols
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was likely to affect outcomes related to exercise capacity. Further exploration of the effect of
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adherence to exercise training on outcomes of ET or PR in bronchiectasis is required.
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The lack of sustained improvement in exercise capacity with outpatient PR or ET only is
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consistent with the effects of such programs in COPD,31 implying that a model of maintenance
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PR or ET may be necessary to sustain beneficial effects in this population. The lack of a positive
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impact of PR on physical activity in individuals with COPD,33 together with the reduced levels of
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physical activity in bronchiectasis recently reported8 indicates that achieving long term changes
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in exercise capacity is a current challenge in management of bronchiectasis and may require
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broader approaches to PR and ET, including behavioural change.
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The clinically significant improvement in SGRQ following both ET and PR suggests that
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supervised, outpatient ET is a key component in improving HRQOL in these patients. The added
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benefit of education, which included instruction in self-management, the importance of airway
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clearance techniques and nutritional advice, may account for the greater magnitude of benefit in
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HRQOL in one study17 and the lack of change in mastery or emotional function with ET only.18
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However, the ideal approach to education as part of PR in this patient population is unclear. The
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recent development of a disease-specific HRQOL questionnaire, designed specifically for
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bronchiectasis,34 may capture more detailed insights into the effects of PR or ET on HRQOL. It
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may also provide direction as to relevant educational topics within PR which could be studied
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prospectively.
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High levels of anxiety and depression are evident in individuals with bronchiectasis35 and are
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linked to poorer HRQOL.36 Although amenable to change following PR in COPD,37 such change
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was not evident in the one study which examined this question in bronchiectasis, although it is
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noted low levels of anxiety and depression were present at baseline.18 Although the results of this
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review should be interpreted with caution for this reason and only examined in one study, there
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is a need for further prospective studies in individuals with higher baseline levels of
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psychological distress.
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The absence of improvement in cough-related QOL with PR or ET may relate to the fact that
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both studies which included this outcome actively incorporated instruction and/or review of
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airway clearance therapy for all participants, irrespective of group assignment.17,18 This may
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account for the non-significant change following this intervention.
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This review included the only study to date which has examined the effects of applying PR
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during an acute exacerbation of bronchiectasis.26 While supervised for exercise training during
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the inpatient stay, only three telephone calls were provided during the first four weeks post
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discharge, with no further supervision or contact over the remaining 11 months of the study.26
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Motivational interviewing techniques were used during the calls to discuss participant concerns,
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give advice for ongoing management, monitor adherence and progress exercise. This model
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differs from the standard PR approach.31 The lack of benefit with a combined in- and outpatient
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PR program suggests that a longer duration of supervision in the recovery phase may be critical
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to gain and maintain improvements if participants commence training when acutely unwell.
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However, this is derived from one study only, which may be insufficiently powered to determine
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this effect. Future studies of this approach to PR in this subgroup of individuals with
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bronchiectasis with adequate sample size are required.
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The positive impact of ET on exacerbation frequency for stable patients is likely to be clinically
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important. Although the precise mechanism behind this effect over 12 months and longer time to
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first exacerbation is unknown, these findings are encouraging. From the one study which
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examined this outcome, they are unlikely to be related to maintenance of exercise benefits, a
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theory supported by the lack of long term improvement in exercise capacity at 12 months.18,26
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With exacerbations negatively impacting on HRQOL,20 the means by which ET achieves a
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reduction in exacerbations is a focus of further exploration.
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This review offers some insight into the baseline functional capacity, extent of dyspnea and
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severity of lung disease of individuals with non-CF bronchiectasis who may benefit from ET or
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PR. Exercise capacity prior to training ranged from an ISWD of 288m to 474m (77% predicted
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normal value).17,18 Although the magnitude of change in ISWD was greater in those with more
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impairment16 compared to those with more preserved capacity,18 results suggests that individuals
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with both high and low baseline exercise capacity can benefit and should be considered for these
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interventions. Although dyspnea is not the primary symptom of bronchiectasis,38 clinical
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improvements in dyspnea were achieved in one study.18 Together with other common symptoms
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of this condition, this may partially contribute to the improvement in HRQOL.
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Study limitations
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This review is limited by the small number of trials, the heterogeneity in PR or ET programs
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included and the influence of this on outcomes. The lack of concealed allocation and lack of
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clarity in the blinding of therapists or assessors has the potential to introduce bias, particularly
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for outcomes which are dependent on patient reporting. While all authors of included studies
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were contacted when necessary for further information, some details were not provided and this
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limited the data included in specific meta-analyses.
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Conclusions
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Programs of PR or ET initiated during the stable state have clinically significant benefits, but
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there appears to be no benefits if initiated during an acute exacerbation and continued beyond
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discharge. The improvements in exercise capacity and HRQOL are of a short duration. Further
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exploration to identify the effects of these interventions on disease severity and optimal
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approaches to maintain positive outcomes are needed.
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I. Pulmonary rehabilitation in patients with bronchiectasis: pulmonary function, arterial
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11. van Zeller M, Mota PC, Amorim A, Viana P, Martins P, Gaspar L, Hespanhol V, Gomes
blood gases and the 6-minute walk test. J Cardiopulm Rehabil Prev 2012;32:278-83. 12. Foster S, Thomas III HM. Pulmonary rehabilitation in lung disease other than chronic obstructive pulmonary disease. Am Rev Respir Dis 1990;141:601-4. 13. Ferreira G, Feuerman M, Spiegler P. Results of an 8-week, outpatient pulmonary
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rehabilitation program on patients with and without chronic obstructive pulmonary
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disease. J Cardiopulm Rehabil Prev 2006;26:54-60.
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14. Ong HK, Lee AL, Hill CJ, Holland AE, Denehy L. Effects of pulmonary rehabilitation in bronchiectasis: a retrospective study. Chron Respir Dis 2011;8:21-30. 15. Bradley J, Moran F, Greenstone M. Physical training for bronchiectasis. Cochrane
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Database System Rev 2002;Issue 1:CD002166.
16. Newall C, Stockley RA, Hill SL. Exercise training and inspiratory muscle training in patients with bronchiectasis. Thorax 2005;60:943-48.
17. Mandal P, Sidhu MK, Kope L, Pollock W, Stevenson LM, Pentland JL, Turnbull K, MacQuarrie S, Hill AT. A pilot study of pulmonary rehabilitation and chest
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physiotherapy versus chest physiotherapy alone in bronchiectasis. Respir Med
2
2012;106:1647-54.
3
18. Lee AL, Hill CJ, Cecins N, Jenkins S, McDonald CF, Burge AT, Rautela L, Stirling RG, Thompson PJ, Holland AE. The short and long term effects of exercise training in non-
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cystic fibrosis bronchiectasis – a randomised controlled trial. Respir Res 2014:15;44.
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19. Murray MP, Turnbull K, MacQuarrie S, Pentland JL, Hill AT. Validation of the Leicester
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Cough Questionnaire in non-cystic fibrosis bronchiectasis. Eur Respir J 2009;34:125–31.
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20. Elborn JS, Bell SC. Pulmonary exacerbations in cystic fibrosis and bronchiectasis. Thorax 2007;62:288-90.
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21. Moher D, Libertati A, Tetzlaff J, Altman DG, PRISMA Group. Preferred reporting items
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for systematic reviews and metaanalyses: the PRISMA statement. PloS Med
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2009;6:e1000097.
22. Higgins J, Green S. Cochrane Handbook for Systematic Reviews of Interventions 2011;
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Version 5.1.0. General methods for Cochrane reviews, Chapter 8. Assessing risk of bias
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in included studies. Available at http://handbook.cochrane.org/.
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23. Ryan R Cochrane Consumers and Communication Review Group. Data extraction
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template for Cochrane reviews: meta-analysis, 2013. Cochrane Consumers and
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Communication Review Group website.
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org/sites/chmg.cochrane.org/files/uploads/Template-Data%20Extraction-CHMG.pdf . Accessed June 1, 2015.
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24. Higgins J, Green S. Cochrane Handbook for Systematic Reviews of Interventions 2011;
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Version 5.1.0. General methods for Cochrane reviews, Chapter 16. Special Topics in
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Statistics. Available at http://handbook.cochrane.org/.
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25. Higgins J, Green S. Cochrane Handbook for Systematic Reviews of Interventions 2011;
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Version 5.1.0. General methods for Cochrane reviews, Chapter 9. Analysing data and
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undertaking meta-analyses. Available at http://handbook.cochrane.org/. 26. Greening NJ, Williams JEA, Hussain SF, Harvey-Dunstan TC, Bankart MJ, Chaplin EJ,
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Vincent EE, Chimera R, Morgan MD, Singh SJ, Steiner MC. An early rehabilitation
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intervention to enhance recovery during hospital admission for an exacerbation of
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chronic respiratory disease: randomised controlled trial. BMJ 2014;349:g4315.
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27. Zanini A, Aiello M, Adamo D, Cherubino F, Zampogna E, Sotgui G, Chetta A,
SC
Spanevello A. Effects of pulmonary rehabilitation in patients with non-cystic fibrosis
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bronchiectasis: a retrospective analysis of clinical and functional predictors of efficacy.
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Respiration 2015;89:525-33.
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28. Singh SJ, Jones PW, Evans R, Morgan MD. Minimum clinically important improvement for the incremental shuttle walking test. Thorax. 2008;63:775-7.
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29. Lee AL, Hill CJ, Cecins N, Jenkins S, McDonald CF, Burge AT, Rautela L, Stirling RG, Thompson PJ, Holland AE. Minimal important difference in field walking tests in non-
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cystic fibrosis bronchiectasis following exercise training. Respir Med. 2014;108:1303-9.
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30. Singh SJ, Puhan MA, Andrianopoulos V, Hernandes NA, Mitchell KE, Hill CJ, Lee AL,
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Camillo CA, Troosters T, Spruit MA, Carlin BW, Wanger J, Pepin V, Saey D, Pitta F,
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Kaminsky DA, McCormack MC, MacIntyre N, Culver BH, Sciurba FC, Revill SM, Delafosse V, Holland AE. An official systematic review of the European Respiratory Society/American Thoracic Society: measurement properties of field walking tests in chronic respiratory disease. Eur Respir J 2014;44:1447-78.
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31. Spruit MA, Singh SJ, Garvey C, ZuWallack R, Nici L, Rochester C, Hill K, Holland AE, Lareau SC, Man WD, Pitta F, Sewell L, Raskin J, Bourbeau J, Crouch R, Franssen FM,
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Casaburi R, Vercoulen JH, Vogiatzis I, Gosselink R, Clini EM, Effing TW, Maltais F,
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van der Palen J, Troosters T, Janssen DJ, Collins E, Garcia-Aymerich J, Brooks D, Fahy
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BF, Puhan MA, Hoogendoorn M, Garrod R, Schols AM, Carlin B, Benzo R, Meek P,
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Morgan M, Rutten-van Mölken MP, Ries AL, Make B, Goldstein RS, Dowson CA,
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Brozek JL, Donner CF, Wouters EF; ATS/ERS Task Force on Pulmonary Rehabilitation.
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An official American Thoracic Society/European Respiratory Society statement: key
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concepts and advances in pulmonary rehabilitation. Am J Respir Crit Care Med
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2013;188:e13-64.
32. McCullough AR, Tunney MM, Quittner AL, Elborn JS, Bradley JM, Hughes CM. Treatment adherence and health outcomes in patients with bronchiectasis. BMC Pulm
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Med 2014;14:107.
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33. Troosters T, van der Molen T, Polkey M, Rabinovich RA, Vogiatzis I, Weisman I, Kulich K. Improving physical activity in COPD: towards a new paradigm. Respir Res
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2013;14:115.
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34. Quittner AL, Marciel KK, Salathe MA, O'Donnell AE, Gotfried MH, Ilowite JS, Metersky ML, Flume PA, Lewis SA, McKevitt M, Montgomery AB, O'Riordan TG,
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Barker AF. A preliminary quality of life questionnaire-bronchiectasis: a patient-reported outcome measure for bronchiectasis. Chest. 2014;146:437-48.
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35. Giron Moreno RM, Fernandes Vasconcelos G, Cisneros C, Gomez-Punter RM, Segrelles
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Calvo G, Ancochea J. Presence of anxiety and depression in patients with bronchiectasis
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unrelated to cystic fibrosis. Arch Bronconeumol 2013;49:415-20.
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36. Olveira C, Olveira G, Gaspar I, Dorado A, Cruz I, Soriguer F, Quittner AL, Espildora F.
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Depression and anxiety symptoms in bronchiectasis: association with health-related
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quality of life. Qual Life Res 2013;22:597-605.
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37. Coventry PA. Does pulmonary rehabilitation reduce anxiety and depression in chronic
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obstructive pulmonary disease. Curr Opin Pulm Med 2009:15:143-9.
38. King PT, Holdsworth SR, Freezer NJ, Villanueva E, Holmes PW. Characterisation of the
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onset and presenting clinical features of adult bronchiectasis. Respir Med 2006;100:2183-
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Figure 1. Study flow from identification to inclusion
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Figure 2. The effect of PR or ET vs no treatment on incremental shuttle walk distance
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immediately following 8 weeks of intervention.
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Figure 3. The effect of PR or ET vs no treatment on St George’s Respiratory Questionnaire
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(Total score) immediately following 8 weeks of intervention.
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Figure 4. The effect of PR or ET vs no treatment on Leicester Cough Questionnaire (Total score)
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Table 1. Inclusion criteria for studies Participants
Individuals diagnosed with non-cystic fibrosis (CF) bronchiectasis according to physician diagnosis or clinical evidence or high
Studies of randomized controlled or cross-over trials of: •
Exercise training only
•
Exercise training and education
•
Exercise training combined with another treatment (eg.
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Intervention
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resolution computed tomography
airway clearance therapy, medication, inhaled therapy)
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Exercise could be supervised or unsupervised, but included endurance/aerobic exercise and/or resistance exercise. Comparison
Control condition (no exercise training) or another type of intervention not involving exercise (usual care) (eg. Airway clearance therapy)
Outcomes
Exercise capacity (Field walking tests [6MWT, ISWT, ESWT],
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maximal exercise testing (CPET))* Symptoms (dyspnea, fatigue using self-reported or specific questionnaires)*
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Health-related quality of life (HRQOL using generic and disease specific questionnaires or self-reported measures)* Functional performance or activity (self-reported and generic and
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disease-specific measures of functional performance [measuring extent of engagement in daily activities to meet basic needs, fulfill usual roles and maintain health and well-being], measures of physical activity (objective or self-reported measures)* Upper and lower limb strength Psychological symptoms of anxiety or depression (questionnaires, self-reported)*
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Exacerbations (frequency, rate of, incidence of hospitalization) Mortality *Outcomes measures included instruments or formal tests which may or may not have
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established reliability and validity in the bronchiectasis population. CF – cystic fibrosis; 6MWT – 6-minute walk test; ISWT – incremental shuttle walk test; ESWT – endurance shuttle walk test; CPET – cardiopulmonary exercise test; HRQOL – health-related
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quality of life
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Table 2. Study characteristics and key findings.
FEV1 % pd
Exercise training
Newall
n=32, 19%
8wk outpatient program, 3
200516
male, range
times/wk (2 sessions
54 to 69%
supervised, 1 unsupervised
pd
at home).
Control group
Outcomes
No IMT or ET
Maximal
Key findings*
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Pulmonary rehabilitation /
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N, % male,
No change in peak VO2 uptake
(1.96 with IMT or 0.35 with sham
treadmill test
IMT vs -1.91ml/min/kg with
(modified Balke
control) following 8wks of training.
protocol),
Significant improvement in
Endurance
endurance exercise capacity
achieved on initial IET for
exercise capacity
(increase of 607m with IMT or
treadmill walking, cycling,
(set at 85% peak
393m with sham IMT) compared to
VO2 uptake of
a decline of -113m in control group.
activity).
maximal
Improvement in ISWT (111m vs
Home program: 45mins
incremental
11m).
walking (once per wk)
treadmill test),
Improvement sustained at 3
Supervised: Endurance
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Intensity: 80% peak HR
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incremental
stair climbing (15mins per
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Twice daily IMT training:
ISWT, SGRQ
walk capacity or ISWT for PR with
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IMT at 30% Pimax, increased by 5% per week
IMT, but not for PR with sham IMT.
until 60% Pimax, 15mins per
No change in SGRQ between
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session (2/day) for 8wks.
groups (p=0.422).
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Sham IMT at 7cmH20, 8br/min, 15mins per session, 2/day for 8wks.
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Educational program (disease pathology,
months post rehab for endurance
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medication, training, coping,
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relaxation, nutrition,
smoking, physiotherapy).
Mandal
n=27, 52%
8wk outpatient program, 2
Oscillating PEP
ISWT, EWT, LCQ,
Improvement in intervention group
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times/wk.
with Acapella,
76%
Endurance intensity: 85% of
20-30min
VO2 max for treadmill, bike
sessions, twice
and ski machine (10mins per daily for 8 wks.
IRM, with 3x10 repetitions, progression to 70% and 80%
and week 5.
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Education: coping with
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for UL and LL ex at week 3
breathlessness, self-
EWT (change of 193m vs -36m). Improvement sustained 3 months
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Strength intensity: 60% of
compared to control group with ISWD (change of 57m vs -5m) and
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activity).
SGRQ
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male, 72 to
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post intervention in ISWD (80m) and ESWD (248m) with intervention, no change in control group. Improvement in disease (SGRQ 8 units) and cough-specific HRQOL (LCQ 2.3 units) with intervention compared to control group.
management, dietician,
Improvement sustained at 3
ACTs, use of Acapella with
months post intervention (SGRQ
offer of free gym
4.4 units, LCQ 4 units), no change in
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membership for next 6
control group.
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months
n=85, 28%
8wk outpatient program (2
Recommended
ISWT, 6MWT,
Improvement in intervention group
201418
male, 70-
times/wk).
to undertake 30
SGRQ, CRDQ,
compared to the control group in
77% pd
Endurance Intensity: 75% of
mins of physical
LCQ, HADS,
ISWD (64m vs 2m) and 6MWD
VO2 max of ISWT for
activity, 3/wk.
Number of
(32m vs -11m).
treadmill/walking training
Telephone
exacerbations.
Reduction in dyspnea (2.3 vs
(15mins of activity). 60%
support for
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1.2ppi) and fatigue (1.1 vs -0.8ppi)
general care,
with intervention compared to
(15mins of activity).
with no
control group. No change in
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max of 6MWT for cycling
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Strength Intensity: To
achieve RPE 12-14 for UL
discussion of
emotional function or mastery. No
exercise.
difference in anxiety or depression
and LL training,
between groups.
commencing at 60% of IRM,
No change in LCQ total or
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components scores. Improvement
Review as necessary of ACT
in SGRQ total score (-3.1 vs 0.7)
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with 3x10 repetitions.
routine.
with intervention and symptoms,
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no change in impact or activity.
Ward PT: ACT.
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Endurance Intensity: Daily
p=0.012)#, with longer time to first exacerbation.
No difference in ESWD, ISWD,
and supervision
hospital
SGRQ total score or quadriceps
of mobility with
admissions,
strength at discharge, 6 weeks, 3
with speed set at 85% of
smoking
mortality. ISWT,
months and 12 months between
VO2 of ESWT (duration
cessation advice.
ESWT, SGRQ,
groups.
range NR). Progressed
No supervised or
maximum
No reduced risk of exacerbations
walking during admission
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% NR, 1.10L
months with intervention (2 vs 1,
Ward PT: ACT, Ax Unplanned
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Greening n=20, male
Fewer exacerbations over 12
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progressive
quadriceps
over 12 months follow up
Strength intensity: Based on
exercise training
strength.
(intervention: 75% vs control: 50%).
1RM: 3 sets 8 repetitions of
during admission
UL and LL exercises daily.
or on discharge.
NMES: 30 mins to
Outpatient PR
quadriceps daily.
offered 3 months
Self-management program:
post admission.
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education and psychosocial support using the SPACE
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manual. Program
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introduced via motivational interviewing during
inpatient stay and used in telephone discussions.
No difference in mortality at 12
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months (intervention: 50% vs
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daily walking exercise,
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based on Borg dyspnea 3-5.
control: 17%).
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Telephone support provided
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on discharge for overall program at 48 hrs following discharge, 2 and 4 wks to
*Data are mean unless otherwise stated; # median
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exercise progression.
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determine adherence and
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N – number; FEV1 – Forced expiratory volume in one second; pd – predicted, wk – week; HR – heart rate, IMT – inspiratory muscle training; VO2 – peak oxygen uptake; ISWT – incremental shuttle walk test, SGRQ – St Georges Respiratory questionnaire; IRM – one repetition maximum, Pimax – maximal inspiratory mouth pressure, cmH20 – cm of water pressure, br/min – breaths per minute, UL – upper limb, LL – lower limb, ACT – airway clearance techniques, PEP – positive expiratory pressure; EWT – endurance walk test, LCQ – Leicester cough questionnaire; HRQOL – health-related quality of life; 6MWT – 6-minute walk test, RPE – rate of perceived exertion, CRDQ – Chronic respiratory disease questionnaire; HADS – hospital anxiety and depression scale, ISWD – incremental shuttle walk distance; 6MWD – 6-minute walk distance, ppi – points per item; NR – not reported, NMES – neuromuscular electrical stimulation, PT – physiotherapy, SPACE - Self management programme of Activity, Coping and Education.
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Table 3. Quality assessment (Cochrane Risk of Bias Tool).
Incomplete Data
Selective Reporting
Other biases
Unclear
Low
Low
-
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Blinding
Low
Low
-
Low
Low
Low
-
Low
Low
Low
-
Allocation Concealment
Participants
Therapists
Outcome assessors
Newall 200516
Low
Unclear
Unclear
Unclear
Mandal 201217
Low
Unclear
Unclear
Unclear
Lee 201418
Low
Low
High
Unclear
Unclear
Unclear
High
Unclear
Unclear
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Greening 201426
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Study
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Randomisation Sequence
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Supplementary Table S1. Search strategy used for Medline Search strategy
#2 MeSH DESCRIPTOR Bronchiectasis Explode All
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#1 BRONCH:MISC1
#3 bronchiect* OR non-cystic fibrosis bronchiect* or non-CF bronchiect* or non-cyst* fibros* bronchiect*
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#4 Kartegener’s syndrome or ciliary motility dis* #5 #1 or #2 or #3 or #4
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#6 (exercise therapy or exerc* ther* or exercise training or exer* train*).
#7 (pulmonary rehabilitation or pulmonary rehab* or pulm* rehabilitation or pulm* rehab*). #8 #6 and #7
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#9 (quality of life or life quality or qual* of life).
#10 (dyspnea or dyspnoea or dys* or breathlessness or breathless* or breath*) #11 (fatigue or perceiv* exertion or perceiv* fatigue).
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#12 (Exercise capacity or exerc* capacity or exercise tolerance or exerc* tolerance). #13 (anxiety or anxious or anx*).
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#14(depression or depress*).
#15 (healthcare utilisation or healthcare utilization or healthcare utilis* or health* utilis* or healthcare utiliz* or health* utiliz*). #16 (mortality or mortal* OR survival or survive or surviv* or death or dead). #17 (#9 or #10 or #11 or #12 or #13 or #14 or #15 or #16) #18 #5 and #8 and #17
S0003-9993(16)30246-5
DOI:
10.1016/j.apmr.2016.05.017
Reference:
YAPMR 56577
To appear in:
ARCHIVES OF PHYSICAL MEDICINE AND REHABILITATION
Received Date: 15 March 2016 Revised Date:
27 April 2016
Accepted Date: 17 May 2016
Please cite this article as: Lee AL, Hill CJ, McDonald CF, Holland AE, Pulmonary rehabilitation in individuals with non-cystic fibrosis bronchiectasis - a systematic review, ARCHIVES OF PHYSICAL MEDICINE AND REHABILITATION (2016), doi: 10.1016/j.apmr.2016.05.017. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Running title: Rehabilitation in bronchiectasis
Pulmonary rehabilitation in individuals with non-cystic fibrosis bronchiectasis - a
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Annemarie L Lee, PhD
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Catherine J Hill, PhD
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Christine F McDonald, PhD Anne E Holland, PhD
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systematic review
West Park Healthcare Centre, Toronto, Ontario, Canada
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Department of Physical Therapy, University of Toronto, Ontario, Canada
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Institute for Breathing and Sleep, Austin Health,
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Department of Physiotherapy, Austin Health
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Department of Respiratory and Sleep Medicine, Austin Health
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Department of Physiotherapy, Alfred Health
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Physiotherapy, La Trobe University
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Corresponding author:
Annemarie Lee, Department of Respiratory Medicine, West Park Healthcare Centre, 82 Buttonwood Ave, Toronto M6M 2J5. Email: [email protected] Phone: 011 416 243 2653, Fax: 011 416 243 3747
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Pulmonary rehabilitation in individuals with non-cystic fibrosis bronchiectasis - a
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systematic review
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The authors have no conflict of interest to declare.
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Abstract
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Objective: To examine the effect of pulmonary rehabilitation (PR) (exercise and education) or
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exercise training (ET) on exercise capacity, health-related quality of life (HRQOL), symptoms,
4
frequency of exacerbations and mortality compared to no treatment in adults with bronchiectasis.
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Data sources: Computer-based databases were searched from their inception to February 2016.
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Study selection: Randomized controlled trials of PR or ET versus no treatment in adults with
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bronchiectasis were included.
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Data Extraction: Two reviewers independently extracted data and assessed methodological
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quality using the Cochrane Risk of Bias tool.
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Data synthesis: Four trials with 164 participants were included, with variable study quality.
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Supervised outpatient PR or ET of eight weeks improved incremental shuttle walk distance
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(weighted mean difference (WMD): 67m; 95% CI 52 to 82m) and disease-specific HRQOL
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(WMD -4.65, 95% CI -6.7 to -2.6 units) immediately following intervention, but these benefits
14
were not sustained at six months. There was no effect on cough-related QOL (WMD 1.3, 95% CI
15
-0.9 to 3.4 units) or psychological symptoms. PR commenced during an acute exacerbation and
16
continued beyond discharge had no effect on exercise capacity or HRQOL. The frequency of
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exacerbations over 12 months reduced with outpatient ET (median 2 versus 1, p=0.013), but PR
18
initiated during an exacerbation had no impact on exacerbation frequency or mortality.
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Conclusion: Short term improvements in exercise capacity and HRQOL were achieved with
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supervised PR and ET programs, but sustaining these benefits is challenging in people with
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bronchiectasis. The frequency of exacerbations over 12 months was reduced with ET only.
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Key words: bronchiectasis, rehabilitation, exercise, exercise tolerance, quality of life, disease
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exacerbation
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Abbreviations:
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CF – cystic fibrosis
3
ET – exercise training
4
PR – pulmonary rehabilitation
5
HRQOL – health-related quality of life
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PRISMA - Preferred Reporting Items for Systematic Reviews and Meta-Analyses
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PEDro – Physiotherapy Evidence Database
8
WMD – weighted mean difference
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SMD – standardized mean difference
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IMT – inspiratory muscle training
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ISWT – incremental shuttle walk test
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ISWD – incremental shuttle walk distance
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6MWT – 6-minute walk test
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6MWD – 6-minute walk distance
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SGRQ – St George’s Respiratory Questionnaire
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LCQ – Leicester Cough Questionnaire
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RR – Relative Risk
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MID – minimal important difference
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COPD – chronic obstructive pulmonary disease
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QOL – quality of life
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Introduction
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Non-cystic fibrosis (CF) bronchiectasis is characterized by bronchial dilatation with impaired
4
mucociliary clearance and accumulation of secretions.1 Common symptoms include chronic
5
cough and sputum production, dyspnoea and fatigue.1,2 The disease trajectory is commonly
6
punctuated by acute exacerbations, associated with chronic bacterial colonization and
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inflammation, which lead to worsening lung damage and accelerated disease progression.3-5
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Other features include reduced peripheral muscle strength, reduced exercise capacity6,7 and low
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levels of physical activity.8
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International guidelines for the treatment of bronchiectasis recommend incorporating exercise
12
training (ET) or pulmonary rehabilitation (PR), which involves a combination of exercise
13
training and education.9,10 Retrospective studies of ET programs and PR have demonstrated
14
improvements in submaximal and maximal exercise capacity and specific measures of
15
HRQOL.11-14 An earlier systematic review of physical training in non-CF bronchiectasis was
16
undertaken in 2002 and supported the treatment approach, with improvements in endurance
17
exercise capacity and HRQOL with the combination of inspiratory muscle training (IMT) and
18
ET.15 Since that review, further prospective studies have been undertaken using a mix of
19
different approaches to ET and PR16-18 and exploring the short and long term effects on outcomes
20
such as cough-related quality of life19 and incidence of acute exacerbations of bronchiectasis.20
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The effects of PR or ET on these outcomes have not been systematically reviewed.
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The aim of this study was to systematically review the effects of PR or ET in non-CF
2
bronchiectasis on 1) measures of exercise capacity and muscle strength, 2) HRQOL; 3)
3
symptoms and 4) frequency of exacerbations and mortality. This review was undertaken
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according to PRISMA recommendations21 and is registered with PROSPERO
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(CRD42015019684).
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Methods
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Search strategy
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The primary search strategy utilized electronic databases of Medline, CINAHL, EMBASE,
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PubMed, Cochrane Database of systematic reviews and Physiotherapy Evidence Database
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(PEDro) from inception to May 2015. The search was updated in February 2016. The key terms
14
were ‘bronchiectasis/non-cystic fibrosis bronchiectasis/non-CF bronchiectasis/ciliary motility
15
disease /Kartagener’s syndrome’, ‘rehabilitation/respiratory therapy/exercise/exercise movement
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techniques/exercise therapy/physical fitness’,
17
‘dyspnea/dyspnoea/breathlessness/fatigue/perceived exertion/cough’, ‘exercise capacity/exercise
18
tolerance’, ‘quality of life/health-related quality of life’, ‘anxiety/depression’, ‘healthcare
19
utilisation/mortality/survival’. The search strategy used for Medline is shown in Supplementary
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Table S1 and was adapted for use in the other databases. Secondary searches involved hand
21
searching of reference lists from identified articles, citation tracking of included articles and use
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of the PubMed ‘related articles’ option.
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Inclusion criteria
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Two investigators (AL and CH) reviewed titles and abstracts independently and potentially
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relevant articles were identified and retrieved in full text for independent assessment using the
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inclusion criteria. Any disagreements were resolved by consensus or in consultation with a third
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reviewer (AH) when necessary. Abstracts were included if sufficient data could be obtained. The
7
inclusion criteria are outlined on Table 1.
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Data Extraction and Quality Assessment
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Two investigators (AL and AH) independently assessed the quality of the randomized
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(controlled and cross-over) studies using the Cochrane risk of bias tool22 and included items
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relating to the randomization process, blinding, and selective outcome reporting. Assessment was
14
completed independently with discrepancies resolved to ensure complete agreement. Authors
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were contacted when necessary to obtain further information. Two reviewers independently
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extracted the data (AL and AH) which were clarified by consensus discussion.23
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Data Analysis
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Meta-analysis was planned for two or more studies which were considered clinically
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homogenous.23 Data were entered using Review Manager 5.3 (Cochrane Collaboration’s
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Information Management system), with outcomes treated as continuous variables. Where studies
23
included two intervention groups, intervention groups were combined to enable a single
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comparison.24 Weighted mean difference (WMD: same metric scale) or standardised mean
2
differences (SMD: different metric scale) using either a fixed-effects or random-effects model25
3
were selected when estimating the total effect of pooled data at a given follow up period. Forest
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plots were generated to depict results, and heterogeneity was tested according to the overlap in
5
confidence intervals, interpreting the chi-squared test, and the I2 statistic, with substantial
6
heterogeneity represented by an I2 > 50%.25 When study findings could not be combined, a
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narrative format was used to report results. Additional information was retrieved from two
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studies following direct author correspondence.18,26
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Results
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A total of 119 studies were originally retrieved in the search. Following removal of duplicates, a
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total of 82 articles were retrieved. Of these trials, a total of four studies were included (Figure
14
1),16-18,26 with reasons for study exclusion outlined in Figure 1 and strong agreement (k=0.82)
15
achieved between reviewers for study selection. A total of 164 participants were included with
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the underlying cause of bronchiectasis reported in one study,16 which included idiopathic
17
bronchiectasis and childhood illness (pneumonia and whooping cough).
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19
Three studies included hospital-based outpatient, supervised ET of eight weeks16-18 with
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education sessions also incorporated in two studies16,17 (Table 2). One study incorporated
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supervised ET within 48 hours of admission for an acute exacerbation to hospital, with
22
instructions for daily walking (unsupervised) upon discharge over 12 months.26 Telephone
23
consultation at 48 hours, two and four weeks post discharge was provided to measure adherence
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and for exercise progression.26 Long term follow up during which home exercise training was
2
recommended ranged from three months,16,17 to 12 months.18,26 One study compared ET only to
3
no intervention,18 one compared ET (which included IMT or sham IMT) and education to no
4
intervention,16 one compared ET, education with airway clearance therapy to education and
5
airway clearance therapy alone17 and the inpatient study compared ET plus self-management
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commenced during an acute admission and continuing upon discharge, to usual care.26 Three
7
studies included a combination of endurance and upper and lower limb strength training,17,18,26
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while one study examined endurance training and IMT.18 The duration of endurance training
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ranged from 30 to 45 minutes in outpatient ET or PR,16-18 while strength training duration was
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unspecified. Participant compliance with ET was reported in one study, with 90% of participants
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achieving this target (defined as attending 12 out of 16 sessions).18 The remaining three studies
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did not report patient adherence.
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There was consistent agreement between reviewers for study quality (Table 3). Most studies
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reported random allocation16-18 but only one reported randomization sequence concealment.18
16
While assessor blinding was applied in two studies,18,26 this was not consistently applied.16,17 An
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unclear or high level of bias for participant blinding was evident in all studies. We acknowledge
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such blinding is difficult to achieve with this type of intervention. All studies included complete
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reporting for outcomes with adequate follow-up.
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Exercise capacity
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The findings between groups for all studies are outlined on Table 2. Exercise capacity was
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measured using the incremental shuttle walk test (ISWT) in four studies.16-18,26 and the endurance
3
shuttle walk test in two studies.17,26 Following two months of supervised outpatient PR or ET, the
4
WMD for the incremental shuttle walk distance (ISWD) was 67m (95% CI 52 to 82m) in favour
5
of the intervention (Figure 2). Although peak oxygen uptake did not change, endurance exercise
6
capacity (incremental treadmill test at 85% of peak oxygen uptake or endurance shuttle walking
7
test) improved with outpatient supervised PR compared to no treatment,16 or when compared to
8
oscillating positive expiratory pressure therapy alone17 (Table 2). In one study of two months of
9
ET alone significant improvement in the 6-minute walk distance (6MWD) by 32m (95% CI 18 to
10
42m) was achieved at the end of training.18 However, th improvements in ISWD or 6MWD were
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not sustained at six or 12 months post intervention.18 The combination of in-and outpatient PR
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did not change ISWD or endurance shuttle walk distance at hospital discharge, six weeks, three
13
months or 12 months (Table 2).26
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Muscle strength
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The combined approach of inpatient and outpatient PR did not alter quadriceps muscle strength
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immediately post-discharge or over the follow up period.26
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HRQOL and symptoms
Disease-specific
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Three studies evaluated HRQOL using the SGRQ with data pooled from two studies,17,18 with
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information obtained following author correspondence from one study;18 further details were
3
also requested for an additional study but were unable to be procured.16 Outpatient supervised PR
4
or ET were associated with improvement in the St George’s Respiratory questionnaire (SGRQ)
5
total score (WMD -4.65 (95% CI -6.70 to -2.60 units) (Figure 3). At three months post PR, this
6
improvement was still evident,17 although it was absent at six months post ET alone.18 The
7
combination of in- and outpatient PR did not change the SGRQ total score at hospital discharge
8
or over longer term follow up (Table 2).26 Lee et al18found less dyspnea and fatigue on the
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Chronic Respiratory Disease Questionnaire with ET only, however these improvements were
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not sustained at six months (Table 2) and there were no effects on emotional function or
11
mastery.18
12
Cough related QOL
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Of the two studies examining the effects on Leicester Cough Questionnaire (LCQ),17,18 no
15
significant change was evident in the total LCQ score (WMD 1.27 (95% CI -0.89 to 3.42 units)
16
immediately following supervised outpatient PR or ET (Figure 4).
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Psychological Symptoms
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One study explored the effects of ET on psychological symptoms,18 with no change in anxiety or
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depression levels post intervention, or over the longer term follow up based on the Hospital
22
Anxiety and Depression Scale.
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Exacerbations and mortality
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The frequency of acute exacerbations was reduced with ET only (median 2 versus 1, p=0.013),
4
with a longer time to first exacerbation (median of eight months versus six months, p=0.047)
5
compared to no treatment.18 In contrast, a combined in- and outpatient PR did not lower the
6
hospital admission rate (RR 1.5 (95% CI 0.75 to 3.0), nor the mortality rate between groups (RR
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3.0 (95% CI 0.74 to 12.7).26
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Discussion
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This systematic review included recent studies of PR or ET in individuals with non-CF
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bronchiectasis. Short term benefits in endurance and functional exercise capacity, cough-related
13
symptoms and disease-specific HRQOL, with reductions in dyspnea and fatigue levels were
14
evident with supervised outpatient programs in stable patients, but improvements were not
15
sustained beyond three months. This intervention did not alter anxiety or depression. For PR
16
initiated during an exacerbation requiring hospitalization and continued beyond discharge, there
17
were no benefits for exercise capacity, muscle strength or HRQOL. The effect on exacerbation
18
frequency was variable, with a reduction in frequency of acute exacerbations over 12 months
19
following ET training in stable patients, but no difference with a combined in- and outpatient
20
program approach in patients post exacerbation over the same time period.
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The magnitude of improvement in functional exercise capacity was consistent with previous
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retrospective studies of PR, in which the benefit ranged from 25 to 91m.11-14,27 The minimal
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important difference (MID) of the incremental shuttle walk test (ISWT) and the 6-minute walk
2
test (6MWT) for COPD and bronchiectasis has been reported to be 35 to 48m28,29 and between
3
22 and 33m respectively.29,30 The pooled improvement of 67m in the ISWD and change of 32m
4
in the 6MWD in favour of ET suggests that the degree of improvement is clinically significant.
5
All studies applied principles of exercise prescription based on those applied for COPD.31 These
6
outcomes are promising, but the lack of change in peak exercise capacity suggests that the
7
duration, frequency of exercise sessions and the model of ET which enable optimal benefits in
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bronchiectasis have not yet been identified. An additional relevant factor is patient compliance to
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the exercise protocol. Low levels of adherence to treatment, including respiratory medications,
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antibiotic therapy and airway clearance therapy have been reported in individuals with
11
bronchiectasis.32 In this review, only one study outlined patient rates of completion and inferred
12
compliance with an exercise protocol.18 In the absence of further details of adherence to PR, it is
13
difficult to determine the influence of this factor. However, adherence to the exercise protocols
14
was likely to affect outcomes related to exercise capacity. Further exploration of the effect of
15
adherence to exercise training on outcomes of ET or PR in bronchiectasis is required.
16
The lack of sustained improvement in exercise capacity with outpatient PR or ET only is
17
consistent with the effects of such programs in COPD,31 implying that a model of maintenance
18
PR or ET may be necessary to sustain beneficial effects in this population. The lack of a positive
19
impact of PR on physical activity in individuals with COPD,33 together with the reduced levels of
20
physical activity in bronchiectasis recently reported8 indicates that achieving long term changes
21
in exercise capacity is a current challenge in management of bronchiectasis and may require
22
broader approaches to PR and ET, including behavioural change.
23
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The clinically significant improvement in SGRQ following both ET and PR suggests that
2
supervised, outpatient ET is a key component in improving HRQOL in these patients. The added
3
benefit of education, which included instruction in self-management, the importance of airway
4
clearance techniques and nutritional advice, may account for the greater magnitude of benefit in
5
HRQOL in one study17 and the lack of change in mastery or emotional function with ET only.18
6
However, the ideal approach to education as part of PR in this patient population is unclear. The
7
recent development of a disease-specific HRQOL questionnaire, designed specifically for
8
bronchiectasis,34 may capture more detailed insights into the effects of PR or ET on HRQOL. It
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may also provide direction as to relevant educational topics within PR which could be studied
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prospectively.
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High levels of anxiety and depression are evident in individuals with bronchiectasis35 and are
13
linked to poorer HRQOL.36 Although amenable to change following PR in COPD,37 such change
14
was not evident in the one study which examined this question in bronchiectasis, although it is
15
noted low levels of anxiety and depression were present at baseline.18 Although the results of this
16
review should be interpreted with caution for this reason and only examined in one study, there
17
is a need for further prospective studies in individuals with higher baseline levels of
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psychological distress.
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The absence of improvement in cough-related QOL with PR or ET may relate to the fact that
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both studies which included this outcome actively incorporated instruction and/or review of
22
airway clearance therapy for all participants, irrespective of group assignment.17,18 This may
23
account for the non-significant change following this intervention.
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1
This review included the only study to date which has examined the effects of applying PR
3
during an acute exacerbation of bronchiectasis.26 While supervised for exercise training during
4
the inpatient stay, only three telephone calls were provided during the first four weeks post
5
discharge, with no further supervision or contact over the remaining 11 months of the study.26
6
Motivational interviewing techniques were used during the calls to discuss participant concerns,
7
give advice for ongoing management, monitor adherence and progress exercise. This model
8
differs from the standard PR approach.31 The lack of benefit with a combined in- and outpatient
9
PR program suggests that a longer duration of supervision in the recovery phase may be critical
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to gain and maintain improvements if participants commence training when acutely unwell.
11
However, this is derived from one study only, which may be insufficiently powered to determine
12
this effect. Future studies of this approach to PR in this subgroup of individuals with
13
bronchiectasis with adequate sample size are required.
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The positive impact of ET on exacerbation frequency for stable patients is likely to be clinically
16
important. Although the precise mechanism behind this effect over 12 months and longer time to
17
first exacerbation is unknown, these findings are encouraging. From the one study which
18
examined this outcome, they are unlikely to be related to maintenance of exercise benefits, a
19
theory supported by the lack of long term improvement in exercise capacity at 12 months.18,26
20
With exacerbations negatively impacting on HRQOL,20 the means by which ET achieves a
21
reduction in exacerbations is a focus of further exploration.
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This review offers some insight into the baseline functional capacity, extent of dyspnea and
2
severity of lung disease of individuals with non-CF bronchiectasis who may benefit from ET or
3
PR. Exercise capacity prior to training ranged from an ISWD of 288m to 474m (77% predicted
4
normal value).17,18 Although the magnitude of change in ISWD was greater in those with more
5
impairment16 compared to those with more preserved capacity,18 results suggests that individuals
6
with both high and low baseline exercise capacity can benefit and should be considered for these
7
interventions. Although dyspnea is not the primary symptom of bronchiectasis,38 clinical
8
improvements in dyspnea were achieved in one study.18 Together with other common symptoms
9
of this condition, this may partially contribute to the improvement in HRQOL.
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Study limitations
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This review is limited by the small number of trials, the heterogeneity in PR or ET programs
14
included and the influence of this on outcomes. The lack of concealed allocation and lack of
15
clarity in the blinding of therapists or assessors has the potential to introduce bias, particularly
16
for outcomes which are dependent on patient reporting. While all authors of included studies
17
were contacted when necessary for further information, some details were not provided and this
18
limited the data included in specific meta-analyses.
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Conclusions
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Programs of PR or ET initiated during the stable state have clinically significant benefits, but
22
there appears to be no benefits if initiated during an acute exacerbation and continued beyond
23
discharge. The improvements in exercise capacity and HRQOL are of a short duration. Further
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exploration to identify the effects of these interventions on disease severity and optimal
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approaches to maintain positive outcomes are needed.
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36. Olveira C, Olveira G, Gaspar I, Dorado A, Cruz I, Soriguer F, Quittner AL, Espildora F.
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Depression and anxiety symptoms in bronchiectasis: association with health-related
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quality of life. Qual Life Res 2013;22:597-605.
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37. Coventry PA. Does pulmonary rehabilitation reduce anxiety and depression in chronic
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obstructive pulmonary disease. Curr Opin Pulm Med 2009:15:143-9.
38. King PT, Holdsworth SR, Freezer NJ, Villanueva E, Holmes PW. Characterisation of the
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onset and presenting clinical features of adult bronchiectasis. Respir Med 2006;100:2183-
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9.
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Figure 1. Study flow from identification to inclusion
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Figure 2. The effect of PR or ET vs no treatment on incremental shuttle walk distance
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immediately following 8 weeks of intervention.
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Figure 3. The effect of PR or ET vs no treatment on St George’s Respiratory Questionnaire
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(Total score) immediately following 8 weeks of intervention.
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8
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immediately following 8 weeks of intervention.
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Figure 4. The effect of PR or ET vs no treatment on Leicester Cough Questionnaire (Total score)
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Table 1. Inclusion criteria for studies Participants
Individuals diagnosed with non-cystic fibrosis (CF) bronchiectasis according to physician diagnosis or clinical evidence or high
Studies of randomized controlled or cross-over trials of: •
Exercise training only
•
Exercise training and education
•
Exercise training combined with another treatment (eg.
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Intervention
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resolution computed tomography
airway clearance therapy, medication, inhaled therapy)
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Exercise could be supervised or unsupervised, but included endurance/aerobic exercise and/or resistance exercise. Comparison
Control condition (no exercise training) or another type of intervention not involving exercise (usual care) (eg. Airway clearance therapy)
Outcomes
Exercise capacity (Field walking tests [6MWT, ISWT, ESWT],
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maximal exercise testing (CPET))* Symptoms (dyspnea, fatigue using self-reported or specific questionnaires)*
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Health-related quality of life (HRQOL using generic and disease specific questionnaires or self-reported measures)* Functional performance or activity (self-reported and generic and
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disease-specific measures of functional performance [measuring extent of engagement in daily activities to meet basic needs, fulfill usual roles and maintain health and well-being], measures of physical activity (objective or self-reported measures)* Upper and lower limb strength Psychological symptoms of anxiety or depression (questionnaires, self-reported)*
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Exacerbations (frequency, rate of, incidence of hospitalization) Mortality *Outcomes measures included instruments or formal tests which may or may not have
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established reliability and validity in the bronchiectasis population. CF – cystic fibrosis; 6MWT – 6-minute walk test; ISWT – incremental shuttle walk test; ESWT – endurance shuttle walk test; CPET – cardiopulmonary exercise test; HRQOL – health-related
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quality of life
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Table 2. Study characteristics and key findings.
FEV1 % pd
Exercise training
Newall
n=32, 19%
8wk outpatient program, 3
200516
male, range
times/wk (2 sessions
54 to 69%
supervised, 1 unsupervised
pd
at home).
Control group
Outcomes
No IMT or ET
Maximal
Key findings*
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Pulmonary rehabilitation /
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N, % male,
No change in peak VO2 uptake
(1.96 with IMT or 0.35 with sham
treadmill test
IMT vs -1.91ml/min/kg with
(modified Balke
control) following 8wks of training.
protocol),
Significant improvement in
Endurance
endurance exercise capacity
achieved on initial IET for
exercise capacity
(increase of 607m with IMT or
treadmill walking, cycling,
(set at 85% peak
393m with sham IMT) compared to
VO2 uptake of
a decline of -113m in control group.
activity).
maximal
Improvement in ISWT (111m vs
Home program: 45mins
incremental
11m).
walking (once per wk)
treadmill test),
Improvement sustained at 3
Supervised: Endurance
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Intensity: 80% peak HR
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incremental
stair climbing (15mins per
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Twice daily IMT training:
ISWT, SGRQ
walk capacity or ISWT for PR with
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IMT at 30% Pimax, increased by 5% per week
IMT, but not for PR with sham IMT.
until 60% Pimax, 15mins per
No change in SGRQ between
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session (2/day) for 8wks.
groups (p=0.422).
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Sham IMT at 7cmH20, 8br/min, 15mins per session, 2/day for 8wks.
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Educational program (disease pathology,
months post rehab for endurance
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medication, training, coping,
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relaxation, nutrition,
smoking, physiotherapy).
Mandal
n=27, 52%
8wk outpatient program, 2
Oscillating PEP
ISWT, EWT, LCQ,
Improvement in intervention group
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times/wk.
with Acapella,
76%
Endurance intensity: 85% of
20-30min
VO2 max for treadmill, bike
sessions, twice
and ski machine (10mins per daily for 8 wks.
IRM, with 3x10 repetitions, progression to 70% and 80%
and week 5.
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Education: coping with
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for UL and LL ex at week 3
breathlessness, self-
EWT (change of 193m vs -36m). Improvement sustained 3 months
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Strength intensity: 60% of
compared to control group with ISWD (change of 57m vs -5m) and
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activity).
SGRQ
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male, 72 to
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post intervention in ISWD (80m) and ESWD (248m) with intervention, no change in control group. Improvement in disease (SGRQ 8 units) and cough-specific HRQOL (LCQ 2.3 units) with intervention compared to control group.
management, dietician,
Improvement sustained at 3
ACTs, use of Acapella with
months post intervention (SGRQ
offer of free gym
4.4 units, LCQ 4 units), no change in
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membership for next 6
control group.
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months
n=85, 28%
8wk outpatient program (2
Recommended
ISWT, 6MWT,
Improvement in intervention group
201418
male, 70-
times/wk).
to undertake 30
SGRQ, CRDQ,
compared to the control group in
77% pd
Endurance Intensity: 75% of
mins of physical
LCQ, HADS,
ISWD (64m vs 2m) and 6MWD
VO2 max of ISWT for
activity, 3/wk.
Number of
(32m vs -11m).
treadmill/walking training
Telephone
exacerbations.
Reduction in dyspnea (2.3 vs
(15mins of activity). 60%
support for
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1.2ppi) and fatigue (1.1 vs -0.8ppi)
general care,
with intervention compared to
(15mins of activity).
with no
control group. No change in
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max of 6MWT for cycling
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Strength Intensity: To
achieve RPE 12-14 for UL
discussion of
emotional function or mastery. No
exercise.
difference in anxiety or depression
and LL training,
between groups.
commencing at 60% of IRM,
No change in LCQ total or
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components scores. Improvement
Review as necessary of ACT
in SGRQ total score (-3.1 vs 0.7)
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with 3x10 repetitions.
routine.
with intervention and symptoms,
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no change in impact or activity.
Ward PT: ACT.
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Endurance Intensity: Daily
p=0.012)#, with longer time to first exacerbation.
No difference in ESWD, ISWD,
and supervision
hospital
SGRQ total score or quadriceps
of mobility with
admissions,
strength at discharge, 6 weeks, 3
with speed set at 85% of
smoking
mortality. ISWT,
months and 12 months between
VO2 of ESWT (duration
cessation advice.
ESWT, SGRQ,
groups.
range NR). Progressed
No supervised or
maximum
No reduced risk of exacerbations
walking during admission
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% NR, 1.10L
months with intervention (2 vs 1,
Ward PT: ACT, Ax Unplanned
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Greening n=20, male
Fewer exacerbations over 12
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progressive
quadriceps
over 12 months follow up
Strength intensity: Based on
exercise training
strength.
(intervention: 75% vs control: 50%).
1RM: 3 sets 8 repetitions of
during admission
UL and LL exercises daily.
or on discharge.
NMES: 30 mins to
Outpatient PR
quadriceps daily.
offered 3 months
Self-management program:
post admission.
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education and psychosocial support using the SPACE
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manual. Program
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introduced via motivational interviewing during
inpatient stay and used in telephone discussions.
No difference in mortality at 12
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months (intervention: 50% vs
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daily walking exercise,
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based on Borg dyspnea 3-5.
control: 17%).
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Telephone support provided
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on discharge for overall program at 48 hrs following discharge, 2 and 4 wks to
*Data are mean unless otherwise stated; # median
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exercise progression.
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determine adherence and
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N – number; FEV1 – Forced expiratory volume in one second; pd – predicted, wk – week; HR – heart rate, IMT – inspiratory muscle training; VO2 – peak oxygen uptake; ISWT – incremental shuttle walk test, SGRQ – St Georges Respiratory questionnaire; IRM – one repetition maximum, Pimax – maximal inspiratory mouth pressure, cmH20 – cm of water pressure, br/min – breaths per minute, UL – upper limb, LL – lower limb, ACT – airway clearance techniques, PEP – positive expiratory pressure; EWT – endurance walk test, LCQ – Leicester cough questionnaire; HRQOL – health-related quality of life; 6MWT – 6-minute walk test, RPE – rate of perceived exertion, CRDQ – Chronic respiratory disease questionnaire; HADS – hospital anxiety and depression scale, ISWD – incremental shuttle walk distance; 6MWD – 6-minute walk distance, ppi – points per item; NR – not reported, NMES – neuromuscular electrical stimulation, PT – physiotherapy, SPACE - Self management programme of Activity, Coping and Education.
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Table 3. Quality assessment (Cochrane Risk of Bias Tool).
Incomplete Data
Selective Reporting
Other biases
Unclear
Low
Low
-
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Blinding
Low
Low
-
Low
Low
Low
-
Low
Low
Low
-
Allocation Concealment
Participants
Therapists
Outcome assessors
Newall 200516
Low
Unclear
Unclear
Unclear
Mandal 201217
Low
Unclear
Unclear
Unclear
Lee 201418
Low
Low
High
Unclear
Unclear
Unclear
High
Unclear
Unclear
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Greening 201426
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Randomisation Sequence
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Supplementary Table S1. Search strategy used for Medline Search strategy
#2 MeSH DESCRIPTOR Bronchiectasis Explode All
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#1 BRONCH:MISC1
#3 bronchiect* OR non-cystic fibrosis bronchiect* or non-CF bronchiect* or non-cyst* fibros* bronchiect*
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#4 Kartegener’s syndrome or ciliary motility dis* #5 #1 or #2 or #3 or #4
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#6 (exercise therapy or exerc* ther* or exercise training or exer* train*).
#7 (pulmonary rehabilitation or pulmonary rehab* or pulm* rehabilitation or pulm* rehab*). #8 #6 and #7
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#9 (quality of life or life quality or qual* of life).
#10 (dyspnea or dyspnoea or dys* or breathlessness or breathless* or breath*) #11 (fatigue or perceiv* exertion or perceiv* fatigue).
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#12 (Exercise capacity or exerc* capacity or exercise tolerance or exerc* tolerance). #13 (anxiety or anxious or anx*).
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#14(depression or depress*).
#15 (healthcare utilisation or healthcare utilization or healthcare utilis* or health* utilis* or healthcare utiliz* or health* utiliz*). #16 (mortality or mortal* OR survival or survive or surviv* or death or dead). #17 (#9 or #10 or #11 or #12 or #13 or #14 or #15 or #16) #18 #5 and #8 and #17