Accepted Manuscript

Effects of Exercise Training on Pulmonary Function in Adults with Chronic Lung

Disease: A Meta-Analysis of Randomized Controlled Trials

Pablo A. Salcedo, MD, Jacob B. Lindheimer, PhD, Jacquelyn C. Klein-Adams, MS,

Anays M. Sotolongo, MD, Michael J. Falvo, PhD

PII: S0003-9993(18)30223-5
DOI: 10.1016/j.apmr.2018.03.014
Reference: YAPMR 57204

To appear in: ARCHIVES OF PHYSICAL MEDICINE AND REHABILITATION

Received Date: 28 December 2017

Revised Date: 28 February 2018
Accepted Date: 17 March 2018

Please cite this article as: Salcedo PA, Lindheimer JB, Klein-Adams JC, Sotolongo AM, Falvo
MJ, Effects of Exercise Training on Pulmonary Function in Adults with Chronic Lung Disease:
A Meta-Analysis of Randomized Controlled Trials, ARCHIVES OF PHYSICAL MEDICINE AND
REHABILITATION (2018), doi: 10.1016/j.apmr.2018.03.014.

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 ACCEPTED MANUSCRIPT

RUNNING HEAD: Exercise improves lung function

Title:
Effects of Exercise Training on Pulmonary Function in Adults with Chronic Lung
Disease: A Meta-Analysis of Randomized Controlled Trials

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Authors:
Pablo A. Salcedo, MD1-2*
1,3*
Jacob B. Lindheimer, PhD
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Jacquelyn C. Klein-Adams, MS

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Anays M. Sotolongo, MD
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Michael J. Falvo, PhD

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*
These authors contributed equally to this work.

Affiliations:
1
War Related Illness and Injury Study Center, Veterans Affairs New Jersey Health Care System; East
Orange, New Jersey, USA

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New Jersey Medical School, Rutgers Biomedical and Health Sciences; Newark, New Jersey, USA
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Department of Kinesiology, University of Wisconsin-Madison; Madison, Wisconsin, USA
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Correspondence:
Michael J. Falvo, PhD
VA NJ Health Care System – WRIISC
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385 Tremont Ave, Mail Stop 129

East Orange, NJ 07018
Michael.Falvo@va.gov
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Acknowledgements:
The authors would like to thank Dr. Rodney K. Dishman, Dr. Michael Fedewa, and Dr. Hayley MacDonald
for technical assistance with performance of multi-level modeling analyses. This research did not receive
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any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. The contents
do not represent the views of the U.S. Department of Veterans Affairs or the United States Government.

Conflicts of Interest:
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No authors have any conflicts of interest to report.

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1 TITLE:
2 Effects of Exercise Training on Pulmonary Function in Adults with Chronic Lung Disease: A Meta-Analysis
3 of Randomized Controlled Trials
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5 RUNNING HEAD:
6 Exercise improves lung function

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7 ABSTRACT

9 Objective: To quantify the effect of exercise training on indices of pulmonary function in adults with

10 chronic lung disease using meta-analytic techniques. Whole body exercise training is well-known to

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11 confer favorable adaptations to multiple organ systems; however, exercise-induced adaptations to the

12 respiratory system are assumed to be limited, if present at all, but have not been systematically reviewed.

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14 Data Sources: Eligible trials were identified using a systematic search of Medline, Web of Science,

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15 Physiotherapy Evidence Database (PEDro) and GoogleScholar databases.

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17 Study Selection: Randomized controlled trials that evaluated pulmonary function before and after whole-

18 body exercise training among adult patients (≥ 19 years) with chronic lung disease were included.
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20 Data Extraction: Data was independently extracted from each study by three authors. Random-effects
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21 models were used to aggregate a mean effect size (Hedges’ d; ∆) and 95% confidence interval (CI), and

22 multi-level linear regression with robust maximum likelihood estimation was used to adjust for potential
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23 nesting effects.
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25 Data Synthesis: Among 2,923 citations, a total of 105 weighted effects from 21 randomized controlled
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26 trials were included. After adjusting for nesting effects, exercise training resulted in a small (∆= 0.18; 95%

27 CI, 0.07, 0.30) and significant (p=0.002) improvement in a composite measure of pulmonary function.
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28 Tests of heterogeneity of the mean effect size were non-significant.

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30 Conclusions: Contrary to prior assumptions, whole-body exercise training is effective for improving

31 pulmonary function in adults with chronic lung disease, particularly spirometric indices. Subsequent

32 studies are necessary to determine the optimal exercise training characteristics to maximize functional

33 improvement.

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35 Keywords:

36 Exercise therapy; respiratory function tests; meta-analysis; lung diseases

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38 Abbreviations:

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39 ATS: American Thoracic Society

40 COPD: chronic obstructive pulmonary disease

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41 ERS: European Respiratory Society

42 ERV: expiratory reserve volume

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43 DLCO: lung diffusing capacity of carbon monoxide

44 FEV1: forced expiratory volume in one second

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45 FRC: functional residual capacity
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46 FVC: forced vital capacity

47 ILD: interstitial lung disease

48 IMT: inspiratory muscle training

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49 IPF: idiopathic pulmonary fibrosis

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IVC: inspiratory vital capacity

51 MEP: maximal expiratory pressure

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52 MIP: maximal inspiratory pressure

53 MVV: maximal voluntary ventilation

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54 PEDro: Physiotherapy Evidence Database

55 PEF: peak expiratory flow

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56 PImax: maximal inspiratory pressure

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57 Pm: mouth pressure

58 Pm/PImax: ratio of mouth pressure to maximal inspiratory pressure

59 PRISMA: Preferred Reporting Items for Systematic Reviews and Meta-Analyses

60 RME1: respiratory muscle endurance (progressive test)

61 RME2: respiratory muscle endurance (endurance test)

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62 RV: residual volume

63 sRAW: specific airway resistance

64 TLC: total lung capacity

65 VC: vital capacity

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66 Strong evidence supports clinical efficacy of pulmonary rehabilitation programs for reducing symptom

67 severity and improving exercise tolerance and quality of life for individuals with chronic obstructive
1
68 pulmonary disease , as well as other chronic respiratory diseases such as interstitial lung disease,
2-4
69 asthma, and cystic fibrosis . Exercise training is a fundamental component of effective pulmonary

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70 rehabilitation programs and can minimize exertional dyspnea through enhancement of ventilatory

71 efficiency, cardiovascular and peripheral muscle function 5. Despite significant exercise-induced

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72 adaptations across oxygen transport pathways (i.e., heart and vasculature, muscles and blood) in both

73 health and disease, there appears broad consensus that exercise fails to stimulate adaptation within the

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6, 7
74 lungs, with some describing the respiratory system as ‘left behind’ or ‘overbuilt’ . The perception that

75 exercise training does not improve lung function has extended to clinical populations and is reinforced in

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8, 9 10
76 medical textbooks and by government health agencies. However, growing recognition of inter-
11, 12
77 individual variability in the physiological response to exercise training may question whether the
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78 respiratory system is in fact ‘left behind’ for all individuals.

79
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80 Age, sex and ethnicity are not determinants of the heterogeneous response to exercise training 12-14, nor
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81 is training responsiveness fully explained by genomic-based predictors . Baseline physical function,
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82 however, has been shown to be predictive of exercise training responsiveness such that individuals with
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12, 13
83 poorer baseline function exhibit greater functional improvement . Whereas these studies have

84 focused on cardiorespiratory fitness outcomes, it remains unclear whether similar heterogeneity may be
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85 expected for lung function, particularly for individuals with poor baseline lung function such as those with

86 chronic lung disease. In addition, the aforementioned studies examining inter-individual variability in
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87 exercise responsiveness consider a standardized training program designed to enhance functional

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11-14
88 capacity , which may be suboptimal for respiratory system adaptation. In fact, whole-body exercise

89 designed to enhance cardiorespiratory fitness may not impose sufficient ventilatory loading necessary to

90 elicit training-induced adaptation. Although the ventilatory loading characteristic of endurance training

91 may be suboptimal for respiratory system adaptation in the healthy lung, this stimulus may be sufficient

92 for those with chronic lung disease. To address this question, we conducted a systematic review and

93 meta-analysis of the published literature to determine whether exercise training elicits adaptations in lung
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94 function in adults with chronic lung disease. In the present study, we included only randomized controlled

95 trials whereby patients were assigned to either whole-body exercise training or a no-exercise condition for

96 a minimum of 3 weeks, with objective measurement of pulmonary function before and after the

97 intervention. Since there is no single gold standard measure for pulmonary function, the overall mean

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98 effect was calculated as a composite of any clinically relevant measure of lung function that was reported

99 in these trials.

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101 METHODS

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102 A systematic review was conducted in accordance with Preferred Reporting Items for Systematic Reviews
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103 and Meta-Analyses (PRISMA) guidelines.

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105 Search Strategy and Data Sources

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106 Articles published before May 1, 2017 were located using PubMed, Medline, Web of Science,

107 Physiotherapy Evidence Database (PEDro), and Google Scholar databases to identify articles examining
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108 the effects of exercise training on respiratory system outcomes in adult humans. Reference sections of

109 eligible papers were also manually searched for additional citations, and we included published or in
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110 press studies that were available in English language. For example, we conducted a PubMed database
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111 search using the following criteria: (("Exercise"[Mesh]) OR ("Rehabilitation"[Mesh])) AND ("Respiratory

112 Function Tests"[Mesh] AND (“Lung Diseases”[Mesh])). Results were filtered by ‘randomized controlled
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113 trial’, ‘humans’, and ‘Adults: 19+ years’, and limitations were ‘English language’ from the inception of

114 PubMed to 1 May 2017.

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115
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116 Inclusion and Exclusion Criteria

117 Three authors (PS, JKA and MF) screened and assessed study eligibility. Only randomized controlled

118 trials that were ≥ 3 weeks in duration were included. The P.I.C.O. model for evidence-based medicine

119 was utilized to establish specific inclusion and exclusion criteria of studies obtained from our multi-

120 database search. Adults of both sexes, ≥ 19 years, and all ethnicities were included. Studies without a

121 control group in which whole body exercise training was withheld were excluded. Only studies examining
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122 subjects with chronic lung disease were included. The study intervention must have included whole body

123 exercise training (i.e., aerobic or resistance exercise) alone or in combination with other therapies (e.g.,

124 education, counseling, disease management strategy). Studies were excluded if their outcome measures

125 did not include at least one assessment of pulmonary function or capacity (e.g., spirometry, lung volumes,

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126 lung diffusion, and/or respiratory muscle strength). Although exercise-induced changes in exercise

127 capacity, oxygen saturation, and/or metabolism involves the respiratory system, these associated

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128 variables were not considered in the mean effect size calculation as they reflect adaptations across

129 multiple organ systems.

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130

131 Data Extraction for Effect Size Calculation and Study Description

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132 Three authors (PS, JKA and MF) independently extracted means and standard deviations for calculation

133 of effect sizes and inter-rater reliability was assessed with a two-way (Effects X Raters) intra-class
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134 correlation coefficient for absolute agreement. The initial intra-class correlation coefficient was 0.82 (95%

135 CI, 0.76 – 0.86) and all discrepancies between raters were resolved prior to conducting the mean effect
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136 size calculation. Additional details are provided in the Online Resource.

137
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138 There were three potential reasons why effects were not extracted from an included study: (i) In two
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139 studies that included multiple intervention groups, effects were extracted only for those groups that met
16, 17 17
140 our operational definition of whole-body exercise. For instance, Larson et al. allocated participants
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141 to inspiratory muscle training, cycling, or a combination. Because inspiratory muscle training is not

142 considered whole body exercise training, effects were only extracted for the cycling and combined
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143 groups, (ii) one study reported pulmonary function data at 3 months and 12 months. However, due to
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144 dissimilar maintenance therapy between experimental groups following the 3 month measurement time-

145 point, data reported at the 12 month time-point was not extracted, 18 (iii) two studies reported results for a

146 given index of pulmonary function (e.g., FEV1, FVC) in both percent predicted and liters. Although

147 standardized mean differences allow comparisons to be made across different units of measurement, we
19, 20
148 only extracted data reported in liters to avoid redundancy.

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150 Study Quality

151 Study quality was independently assessed by three authors (PS, JKA and MF) using a modified PEDro
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152 scale. Inter-rater reliability for PEDro scores was assessed with a two-way (Scores X Raters) intra-class

153 correlation coefficient for absolute agreement. The initial intra-class correlation coefficient was 0.63 (95%

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154 CI, 0.40 – 0.80) and all discrepancies between raters were resolved. Additional details on study quality

155 and PEDro scores are provided in the Online Resource.

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157 Effect Size Calculation

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158 Author JL performed all statistical calculations of extracted study data. Standardized mean difference

159 effect sizes were calculated using procedures for meta-analysis of randomized controlled studies

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160 recommended by Hedges and Olkin. Briefly, the mean change from baseline in the control group was

161 subtracted from the mean change from baseline in the experimental group and the difference was divided
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162 by the pooled standard deviation of the baseline scores. To account for sampling error, effects were
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163 converted to Hedges’ d using Hedges and Olkin’s small sample size adjustment. A positive effect size
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164 indicates an improvement in pulmonary function in the experimental group. Because a mean increase is

165 considered to represent an improvement in a majority of the indices of pulmonary function that were
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166 reported, effects from outcomes for which a mean decrease represents improved pulmonary function
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167 were reverse coded (i.e., specific airway resistance [sRAW] and residual volume).

168
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169 We also took into account the fact that several domains of pulmonary function were present in the overall

170 mean effect size calculation and aggregating across these domains may limit the interpretation and
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171 generalizability of the results. Therefore, we elected to calculate a mean effect size for each domain of
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172 pulmonary function that was represented. That is, in addition to the overall mean effect size, a separate

173 mean effect size was calculated for (i) gas exchange (i.e., DLCO), (ii) pressure (i.e., MEP, MIP, PM,

174 PM/PImax, PImax, RME1, RME2), (iii) spirometry (FEV1, FEV1/FVC, FVC, MVV, PEF), and (iv) volumes

175 (ERV, FRC, IVC, RV, TLC, VC). A description of these variables is provided in the legend accompanying

176 Table 1. Note that all variables were included in these separate domain-level analyses with the exception

177 of sRAW, which was excluded due to the lack of an appropriate domain assignment.
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178

179 Cases in which exact means or standard deviations were not reported for the baseline or post-

180 intervention time-points were dealt with in the following ways: (i) when scores were reported as change
16, 18, 23, 24
181 from baseline , the absolute value for the post-baseline measurement time-point was determined

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182 by subtracting the absolute mean value reported at baseline from the mean change score, (ii) when exact

183 standard deviations were not provided by the study authors, estimates were calculated from 95%

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184 confidence intervals, or (iii) were directly requested and received from the corresponding author.
23, 25, 27
185

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187 Data synthesis and analysis

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188 Effects were weighted using the inverse variance method and aggregated using a random-effects model
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189 . The overall mean effect size and 95% confidence interval was calculated with SPSS version 23 (SPSS
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190 IBM, Armonk, NY, USA) using a macro developed by Lipsey and Wilson (MeanES). Heterogeneity and
2 29, 30
191 consistency in the mean effect size was assessed with Q and I statistics . Presence of publication
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192 bias was determined by visual inspection of forest and funnel plots and Egger’s test for publication bias.31
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193 The number of effects needed to overturn the result (N+) was also calculated.
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194
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195 In the overall mean effect size calculation, there were several cases in which multiple effects were
16, 18-20, 23-27, 33-41
196 extracted from a given study due to multiple measures of pulmonary function or
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17, 19, 25, 34, 36

197 intervention groups. To account for the potential influence of nesting effects on the mean

198 effect size calculation, multi-level linear regression with robust maximum likelihood estimation was used
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199 to adjust for potential between-study variance and correlated effects within studies according to standard
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200 procedures using SAS 9.4 (SAS Institute Inc., Cary, NC, USA).

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203 RESULTS

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205 Search Results

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206 Out of 2,923 records identified via electronic databases, 118 full text articles were assessed for eligibility.

207 Of the 118 full text articles, 97 were excluded, yielding 21 trials which met inclusion criteria for our meta-
17-19, 25, 36
208 analysis (Figure 1). Five of 21 trials included multiple intervention arms yielding 27 total

209 interventions. Data on pulmonary function outcomes was extracted from 1,034 patients with chronic lung

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210 disease.

211

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212 Characteristics of Included RCTs

213 A tabular summary of participant characteristics (Online Resources, Table S1) exercise program

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214 characteristics (Online Resources, Table S2) as well as mean effect changes in exercise capacity (Online

215 Resources, Table S3) are provided in the Online Resource. Overall, 6 unique chronic lung diseases were

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216 included in our analysis with half of the trials comprised of patients with COPD (11 of 21). Exercise
18, 19, 23, 24, 27, 36, 37, 39, 40
217 training was performed in an outpatient hospital setting in 9 trials, 10 were home-
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16, 17, 20, 26, 34, 35, 38, 41, 45, 46 25, 33
218 based, and the remaining trials took place in a fitness or recreational center.
17, 19, 25, 27, 36, 45
219 Six trials evaluated exercise alone whereas the majority (15/21) of trials utilized exercise in
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220 combination with other treatment.16-18, 20, 23-27, 33-40, 46 On average, the training interventions took place over

221 13.6±12.0 weeks, with 4.0±2.0 sessions per week. The average training session lasted 46.4±16.1
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222 minutes per day. Exercise intensity was reported in 71.4% of studies and ranged from mild to moderate
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223 intensities. The exercise interventions included aerobic, resistance or a combination as modes of
18, 26, 35, 36, 39-41, 45, 46
224 exercise. Fewer than half (n = 9) of the studies, however, met the recommended
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225 physical activity goal of 150 minutes of moderate-to-vigorous activity per week. For pulmonary function
17 24, 27,
226 outcomes, all but one study included spirometry, and at least five studies assessed gas-exchange,
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35, 39, 40 17, 19, 35, 36, 40 23, 24, 35-37, 40 35, 40
227 pressure or respiratory muscle strength, and volumes. Only two studies
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228 included measures across all four domains of pulmonary function.

229

230 Quality Assessment

231 Only five of the 21 (23.8%) studies specifically reported using American Thoracic or European

232 Respiratory Society (ATS/ERS) criteria for pulmonary function test performance or interpretation.
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233 Additional descriptions and overall study design quality assessment scores, using the modified PEDro

234 scale, are reported in the Online Resource (Tables S3 - S4).

235

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236 Overall effect of exercise training on lung function

237 The unadjusted mean effect size was small (∆= 0.17; 95% CI, 0.10, 0.23), significant (p < .0001, z =

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238 5.10), and homogeneous (Q = 95.38; p = 0.72, I = 0). After adjusting for nesting effects in the multi-level

239 model, the mean effect size remained small (∆= 0.18; 95% CI, 0.07, 0.30) and significant (p=0.002). The

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240 distribution of total effects (k = 105) ranged from -0.82 to 1.9 and was positively skewed (1.10, SE =

241 0.24). Seventy percent of the effects were greater than 0, favoring an improvement in pulmonary function

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242 following the exercise training intervention. The fail-safe number of effects was n = 608.
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244 A non-significant Egger’s test for bias, t (1,103) = 0.90, p = 0.37, suggested an absence of publication
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245 bias, however, k =5 outlying effects were identified during visual inspection of funnel (Figure 2) and forest
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246 plots (Figure 3). A subsequent sensitivity analysis that excluded these effects yielded a similar effect size

247 that remained small (∆= 0.13; 95% CI, 0.06, 0.20), significant (p = .0001, z = 3.91), and homogeneous (Q
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248 = 56.52; p = 0.99, I = 0).

249
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250 Effect of exercise training on, spirometry, pressure, gas exchange and volume
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251 A total of 20 out of 21 studies reported data for spirometry based outcomes. The mean effect size for the
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252 spirometry model (k=58) was small (∆= 0.16; 95% CI, 0.08, 0.24), significant (p <.0001, z = 3.83), and
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253 homogeneous (Q = 41.99; p = 0.93, I = 0). The distribution of total effects ranged from -0.30 to 1.9 and

254 was positively skewed (2.21, SE = 0.31). Sixty-nine percent of the effects were greater than 0, favoring an

255 improvement in spirometry following the exercise training intervention. The fail-safe number of effects was

256 n = 162.
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257

258 A non-significant Egger’s test for bias, t (1,56) = 0.38, p = 0.71, suggested an absence of publication bias,

259 however, k =1 outlying effect was identified during visual inspection of funnel (Online Resources, Figure

260 S1) and forest plots (Online Resources, Figure S2). A subsequent sensitivity analysis that excluded the

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261 effect yielded a similar effect size that remained small (∆= 0.15; 95% CI, 0.07, 0.23), significant (p =
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262 .0004, z = 3.57), and homogeneous (Q = 31.51; p = 0.99, I = 0).

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263

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264 A total of 5 out of 21 studies reported data for pressure based outcomes. The mean effect size for the

265 pressure model (k=26) was small (∆= 0.27; 95% CI, 0.05, 0.48), significant (p =.02, z = 2.40), and

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266 heterogeneous (Q = 40.55; p = 0.03, I = 40.81). The distribution of total effects ranged from -0.82 to 1.44
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267 and was positively skewed (0.29, SE = 0.46). Sixty-two percent of the effects were greater than 0,

268 favoring an improvement in pressure following the exercise training intervention. The fail-safe number of
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269 effects was n = 48.

270
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271 A non-significant Egger’s test for bias, t (1,24) = -0.46, p = 0.65, suggested an absence of publication
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272 bias, however, k =4 outlying effects were identified during visual inspection of funnel (Online Resources,

273 Figure S3) and forest plots (Online Resources, Figure S4). A subsequent sensitivity analysis that
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274 excluded these effects yielded a smaller mean effect size (∆= 0.17; 95% CI, -0.01, 0.35), that was no
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275 longer significant (p = .06, z = 1.87), or heterogeneous (Q = 16.25; p = 0.76, I = 0).
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276
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277 A total of 5 out of 21 and 8 out of 21 studies reported effects for gas exchange and volume based

278 outcomes, respectively. Mean effect sizes for the gas exchange (k=5; ∆= 0.08; 95% CI, -0.15, 0.32) and

279 volume (k=15; ∆= 0.13; 95% CI, -0.05, 0.31) models were non-significant (p ≥ 0.15).

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281 DISCUSSION

282 This meta-analysis investigated the effect of exercise training, alone or as part of a pulmonary

283 rehabilitation program, on pulmonary function in adult patients with chronic lung disease. Our aggregated

284 results of 21 randomized controlled trials indicate that exercise training is effective for improving

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285 pulmonary function in adults with chronic lung disease in comparison to non-exercise controls. Though

286 the overall adjusted effect is small (∆= 0.18; 95% CI, 0.07, 0.30), this finding was robust, comparable

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287 across studies, and significant despite a modest exercise dose. Sensitivity analyses revealed that among

288 multiple domains of pulmonary function (i.e., gas-exchange, pressure, spirometry, and volumes), only

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289 spirometry demonstrated a significant effect (∆= 0.16; 95% CI, 0.08, 0.24). Our results, therefore, partially

290 contradict traditionally held views that whole-body exercise training fails to elicit favorable adaptations in

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291 lung function and capacity among patients with chronic lung disease.
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47, 48 49, 50
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293 That exercise training does not confer significant adaptations in the lungs in humans or animals
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294 has previously been described and is well-accepted. There have been exceptions, however, such as
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51, 52
295 evidence of supra-normal lung volumes in trained swimmers. Though cross-sectional studies cannot
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296 account for genetic endowment, Clanton et al. reported small but significant increases in lung volume
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297 following 12 weeks of intense swim training. Characteristics of swimming – i.e., enhanced inspiratory

298 loading, restricted breathing patterns, and repeated expansion to total lung capacity54 – may provide the
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299 optimal mechanical stress necessary for growth in healthy adults. Mechanical stimulus-response
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300 relationships for lung growth are an area of active research, and mechanical stress has been
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301 recognized by the ATS as a major factor in stimulating lung growth in experimental models. As reviewed
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302 elsewhere, exercise training may not always confer favorable adaptations as evidenced by an
58, 59
303 increased risk of asthma due to intensive chronic exercise training, particularly that which takes place
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304 in cold dry ambient conditions. This seemingly paradoxical effect of exercise training may suggest that

305 the respiratory system is indeed capable of adaptation, or more aptly, maladaptation in response to

306 exercise. Taken together, the spectrum of exercise-induced adaptation within the respiratory system (i.e.,

307 positive to deleterious adaptation) in healthy adults underscores the concept of optimal dosing. In light of
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308 the present study’s findings, patients with chronic lung disease may be more likely to improve lung

309 function from whole-body exercise training than healthy adults.

310

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311 The ATS/ERS Statement on pulmonary rehabilitation emphasizes that to be effective, the exercise dose

312 must be tailored to the patient’s capacity, exceed loads encountered during daily activities and be

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313 progressed over time. These general principles for exercise training in patients with chronic lung disease
5 -1
314 are similar to those for a healthy population, which is minimally defined as 150 min·wk of moderate-

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315 intensity aerobic activity and muscle strengthening activity on ≥ 2 d·wk . Only 9 of 21 trials (42.9%)
-1 18, 26, 35, 36, 39-41, 45, 46
316 included in this meta-analysis met or exceeded 150 min·wk of exercise, and 5 of
18, 35, 36, 39, 40
317

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these 9 trials specifically included muscle strengthening activity. On average, exercise

318 interventions were performed 4.0 days·wk-1 (range: 2 – 7) for 46.4 minutes per session (range: 20 – 60)
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319 over 13.6 weeks (range: 4 – 52) (See Table S2 in the Online Resource). Further, only half of the studies

320 objectively defined exercise intensity either by a percentage of heart rate, capacity or perceived exertion
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17, 19, 23-25, 27, 35, 37, 40, 41, 45

321 making it challenging to fully quantify the exact dose of exercise. Despite this

322 relatively modest exercise prescription, patients were still able to improve their pulmonary function (Figure
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323 3).
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325 To better understand what component of pulmonary function may be uniquely improved with exercise, we

326 separately examined exercise-induced changes in pulmonary function with respect to unique domains
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327 (i.e., gas-exchange, spirometry, pressure and volume). After accounting for outliers, only the spirometry

328 model remained significant (∆= 0.16; 95% CI, 0.08, 0.24) suggesting that exercise may be especially
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329 beneficial for improving spirometric parameters compared to parameters from other domains of

330 pulmonary function. There are several potential explanations for why spirometry, but not gas-exchange,

331 pressure or volumes were significantly improved secondary to exercise. First, spirometry based outcomes

332 were included in all but one study that met our inclusion criteria (Table 1); therefore, a greater number of

333 effects were considered in response to exercise relative to the other domains. Spirometry based
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334 outcomes may also be more responsive to exercise training in the present analysis given that the majority

335 of studies (62%) included patients with COPD. In COPD, lung volumes and gas-exchange are commonly

336 within normal limits, but airflow limitation is present as detected by spirometry. Therefore, poorer baseline

337 spirometry may be more responsive to exercise training and result in improvements in airflow. This

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338 interpretation is supported by the literature whereby individuals with poorer baseline physical function

339 exhibit the greatest functional improvement secondary to exercise training.12, 13 Although we observed

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340 some evidence to suggest that the pressure domain (i.e., respiratory muscle strength) also exhibited

341 exercise-induced improvements, the mean effect size was no longer significant after removal of outliers.

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342 Whereas the majority of studies focused predominantly on spirometric variables, future studies may

343 consider a more complete characterization of pulmonary function secondary to exercise training and a

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344 more diverse group of patients with lung disease.
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345

346
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347 Several meta-analyses of pharmacologic therapies have observed large effects for pulmonary function
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61 62 63
348 improvement for phosphodiesterase-4 inhibitor therapy, corticosteroid therapy, and oral theophylline

349 in patients with COPD. Similar effects have been observed in non-COPD conditions such as
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350 immunotherapy for asthma with a mean FEV1 improvement of 0.45 (0.03, 0.87); however, 12 months of

351 cyclophosphamide treatment in patients with systemic sclerosis and interstitial lung disease did not
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352 significantly improve FVC or diffusing capacity. To our knowledge, we are aware of only one other meta-

353 analysis that has evaluated the efficacy of a non-pharmacologic therapy (i.e., nocturnal noninvasive
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354 positive pressure ventilation ) in patients with COPD which showed no improvement in lung function or
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355 gas-exchange. Therefore, the present meta-analysis is the first to report a significant improvement in lung

356 function secondary to non-pharmacologic therapy among adults with chronic lung disease. Although we

357 suspected features of the exercise training program or patient populations would account for potential

358 effects, heterogeneity across studies was not observed.

359
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360 Pulmonary rehabilitation is effective in terms of minimizing physical and mental health symptom burden,
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361 enhancing quality of life and improving exercise capacity, and these improvements are independent of
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362 underlying disease severity. Moreover, the cost per quality-adjusted life year associated with pulmonary
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363 rehabilitation is considerably less than pharmacologic therapy. Despite these benefits, the

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364 implementation and delivery of pulmonary rehabilitation is impeded by a variety of challenges, including

365 patient awareness 71 as well as justifying reimbursement from insurance providers.72 Regarding the latter,

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366 Vogiatzis et al. highlighted that improvements in the documentation of the effects of pulmonary

367 rehabilitation on standard clinical outcomes will aid in this justification. The present findings of our meta-

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368 analysis may assist in this regard, thereby increasing insurance provider knowledge and awareness of

369 the efficacy of whole-body exercise training on pulmonary function in patients with chronic lung disease.

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370
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371 STUDY LIMITATIONS
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372 Over 70% of the studies included in this meta-analysis evaluated whole-body exercise in combination

373 with other treatment (e.g., education, breathing exercises, etc.). Although this approach is consistent with
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374 recommendations for a comprehensive pulmonary rehabilitation program and likely imparts various

375 important non-pulmonary benefits, we cannot fully exclude the possibility that other treatment in addition
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376 to whole-body exercise contributed to the observed improvements in pulmonary function. To address this

377 potential limitation, we conducted a sensitivity analysis that computed separate mean effect sizes for
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17, 19, 25, 27, 36, 45 16-18, 20, 23-

378 those studies that evaluated exercise alone or in combination with other treatment
27, 33-40, 46
379 (additional details in the Online Resource). Our analysis indicated a larger mean effect size from
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380 effects that were derived from intervention arms restricted to exercise alone (∆= 0.25; 95% CI, 0.12, 0.39)
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381 compared to those that combined exercise with other treatment (∆= 0.14; 95% CI, 0.06, 0.22). Therefore,

382 our interpretation that whole-body exercise training improves lung function in adults with chronic lung

383 disease is supported. Moreover, the larger mean effect size observed for intervention arms that focused

384 exclusively on whole-body exercise training alone underscores the importance of exercise as part of a

385 pulmonary rehabilitation program, and may even suggest its prioritization.
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386

387 The lack of statistically significant heterogeneity between studies was unexpected when considering that

388 there were several sources of variability in studies that met our inclusion criteria (e.g., study quality,

389 pulmonary function indices, and frequency, intensity, duration and modes of the exercise treatment). This

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390 finding is consistent with one previous meta-analysis of 13 randomized controlled trials that evaluated the
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391 effects of a phosphodiesterase-4 inhibitor on pulmonary function in patients with COPD . Conversely,

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392 several previous meta-analyses of the effect of exercise on functional outcomes in other physiological
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393 systems have reported heterogeneous mean effect sizes. Thus, one potential implication of this finding

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394 is that, in meta-analytic reviews of randomized controlled trials involving exercise training, pulmonary

395 function is an outcome that is especially robust to between-study differences. A future meta-analysis of

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396 studies that directly compare the effect of exercise training across functional outcomes from multiple
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397 physiological systems (e.g., pulmonary, cardiovascular, skeletal muscle) would allow this hypothesis to be

398 empirically tested. Such an approach may be particularly relevant in the contexts of pulmonary
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399 rehabilitation, which imparts effects across several systems.

400
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401
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402 CONCLUSIONS
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403 The mature lung has long been considered resistant to exercise-induced adaptation; therefore, pulmonary

404 rehabilitation strategies for patients with chronic lung disease have focused primarily on reducing
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405 symptom burden and enhancing functional capacity. The aggregated results of 21 randomized controlled
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406 trials as part of this meta-analysis suggests that whole-body exercise training, alone or in combination

407 with other treatment, elicits a small (∆= 0.18; 95% CI, 0.07, 0.30) but significant improvement in

408 pulmonary function among patients with chronic lung disease compared to a control group. Sensitivity

409 analyses demonstrated an enhanced treatment effect when exercise was performed alone (∆= 0.25; 95%

410 CI, 0.12, 0.39) as compared to being combined with other treatment (∆= 0.14; 95% CI, 0.06, 0.22).

411 Further, additional analyses suggested that exercise-induced improvements in pulmonary function may
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412 be limited only to spirometry. Future studies are necessary to optimize the mode and dose of exercise for

413 different lung diseases; yet still, patients and health care providers should recognize that whole-body

414 exercise training in patients with chronic lung disease improves pulmonary function.

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415 References

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592 Figure Legends

593 Figure 1 Flow chart describing the selection process of included randomized controlled trials and
594 justification for exclusion.

595 Figure 2 Funnel plot of Hedges’ d effect sizes (k=105) compared to study standard error.

596 Figure 3 Forest of individual Hedges’ d effect sizes (k=105) and 95% confidence intervals for exercise

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597 compared with control. Positive values favor exercise and negative values favor control. The broken
598 horizontal line represents the overall weighted mean effect size (∆ = 0.17).

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Table 1 Characteristics of randomized controlled trials examining the effects of exercise training on pulmonary function in patients with chronic lung disease.

Number of Exercise Frequency, Program

Reference Patient PFT Outcomes PEDro Score
Effects (k) Mode Length
Aerobic,
Ries et al. 39 2 COPD 7 d·wk-1, 8 weeks FEV1, DLCO 10/11
Resistance
18 -1 FEV1, FEV1/FVC,
Roman et al. 6 COPD Resistance 3 d·wk , 12 weeks 9/11

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FVC
Aerobic +
38 -1
Oh 2 COPD IMT + 7 d·wk , 8 weeks FEV1, FEV1/FVC 5/11

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Resistance
26 -1
Du Moulin et al. 2 COPD Aerobic 7 d·wk , 24 weeks FEV1, FEV1/FVC 10/11
DLCO, FEV1,

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Aerobic + FEV1/FVC, FRC,
Wadell et al. 40 9 COPD 3 d·wk-1, 8 weeks 9/11
Resistance MEP, MIP, RV,
sRaw, TLC
Aerobic,

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FEV1, FVC, MEP,
36 Resistance, -1
Lake et al. 21 COPD 3 d·wk , 8 weeks MIP, RME1, RME2, 9/11

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Aerobic +
TLC
Resistance
16 -1
Chan et al. 2 COPD Aerobic 2 d·wk , 12 weeks FEV1, FVC 8/11
41 -1
Wijkstra et al. 2 COPD Aerobic 7 d·wk , 12 weeks FEV1, IVC 9/11

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Aerobic,
17 Resistance -1 Pm, Pm/PImax,
Larson et al. 6 COPD 5 d·wk , 16 weeks 9/11
Aerobic + PImax

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46 -1
Singh et al. 1 COPD Aerobic 7 d·wk , 4 weeks FEV1 10/11

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DLCO , FEV1,
35 Aerobic + -1 FEV1/FVC, FVC,
Fernandez et al. 8 COPD 5 d·wk , 52 weeks 9/11
Resistance MIP, MEP, RV,
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TLC
20 Aerobic +
Ghanem et al. 2 COPD 7 d·wk-1, 8 weeks FEV1, FVC 8/11
Resistance
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FEV1, FVC,
19 -1
Duruturk et al. 14 COPD Aerobic 3 d·wk , 6 weeks FEV1/FVC, VC, 9/11
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MVV, MIP, MEP

34 Aerobic + -1 FEV1, FEV1/FVC,
deGrass et al. 3 Tuberculosis ? d·wk , 6 weeks 6/11
Resistance FVC
25 Aerobic, -1
Kriemler et al. 4 Cystic Fibrosis 3 d·wk , 24 weeks FEV1, FVC 10/11
Resistance
Aerobic +
Beaudoin et al. 45 2 Cystic Fibrosis 3 d·wk-1, 12 weeks FEV1, FVC 8/11
Resistance
37 Aerobic + -1
Nishiyama et al. 3 IPF 2 d·wk , 10 weeks FEV1, FVC, TLC 8/11
Resistance
Vainshelboim et al. Aerobic + -1 DLCO, FEV1,
24 6 IPF 2 d·wk , 12 weeks 8/11
Resistance FEV1/FVC, FVC,
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33 -1 FEV1, FEV1/FVC,
Arandelovic et al. 4 Asthma Aerobic 2 d·wk , 24 weeks 7/11
FVC, PEF
23 Aerobic + -1 ERV, FEV1, FVC,
Freitas et al. 4 Asthma 2 d·wk , 12 weeks 10/11
Resistance TLC
27 Aerobic + -1
Holland et al. 2 ILD 2 d·wk , 8 weeks DLCO, FVC 10/11
Resistance

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COPD: chronic obstructive pulmonary disease; DLCO: lung diffusing capacity of carbon monoxide; ERV: expiratory reserve volume; FEV1: forced expiratory volume
in one second; FRC: functional residual capacity; FVC: forced vital capacity; ILD: interstitial lung disease; IPF: idiopathic pulmonary fibrosis; IMT: inspiratory
muscle training; IVC: inspiratory vital capacity; MEP: maximal expiratory pressure; MIP: maximal inspiratory pressure; MVV: maximal voluntary ventilation; PEDro:

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Physiotherapy Evidence Database; PEF: peak expiratory flow; PImax: maximal inspiratory pressure; Pm: mouth pressure; Pm/PImax: ratio of mouth pressure to
maximal inspiratory pressure; RME1: respiratory muscle endurance (progressive test); RME2: respiratory muscle endurance (endurance test); RV: residual volume;
-1
SRaw: specific airway resistance; TLC: total lung capacity; VC: vital capacity; d·wk : days per week.

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Table 1: Participant and Study Characteristics

Mean
Experimental Sample Size % Female Age ± SD BMI
Reference Control Group Combined
Group (Exp, Ctrl) (Exp, Ctrl) (Exp, Ctrl) (Exp, Ctrl)
Age (yrs)

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12 Pulmonary
Ries et al. Education 57, 62 26%, 27% 62±8.0, 64±6.3 62.6 23, 22.9
Rehab
3 Pulmonary

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Roman et al. Usual Care 22, 23 18%, 17% 64±4.1, 63±3.0 63.8 27.6, 28.4
Rehab
Pulmonary
Roman et al. 3 Usual Care 26, 23 15%, 17% 65±6.9, 63±3.0 64.2 29.8, 28.4
Rehab

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11 Pulmonary
Oh Education 15, 8 33%, 50% 65±7.8, 67±12.3 65.8 ----
Rehab
10 Pulmonary
Du Moulin et al. Usual Care 10, 10 30%, 30% 67±6.9, 72±6.1 69.5 27.4, 27.8

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27 Pulmonary

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Wadell et al. Education 17, 24 47%, 46% 67±5.0, 66±7.0 66.5 27.3, 29.1
Rehab
5
Lake et al. Exercise Only Usual Care 6, 7 0, 14% 62±7.0, 66±3.5 63.9 ----
5
Lake et al. Exercise Only Usual Care 6, 7 0, 14% 72±3.3, 66±3.5 68.8 ----
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Lake et al. Exercise Only Usual Care 7, 7 43%, 14% 66±6.8, 66±3.5 66.0 ----
Exercise and
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Chan et al. Breathing Usual Care 69, 67 12%, 13% 74±7.5. 74±7.4 73.6 21.7, 22.0

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14 Pulmonary
Wijkstra et al. Usual Care 28, 15 18%, 7% 64±5.0, 62±5.0 63 ----

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Rehab
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Larson et al. Exercise Only Usual Care 14, 12 ---- 66±6.0, 62±7.0 64 26, 26
6
Larson et al. Exercise Only Usual Care 13, 12 ---- 66±5.0, 62±7.0 64 28, 26
Pulmonary
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Singh et al.28 Usual Care 20, 20 20%, 20% ---- ---- ----
Rehab
29 Pulmonary
Fernandez et al. Not Described 27, 15 ---- 66±8.0, 70±5.0 68 28.4, 28.9
Rehab
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30 Pulmonary
Ghanem et al. Usual Care 25, 14 ---- 57±11.6, 56±9.0 56.7 ----
Rehab
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Duruturk et al. Exercise Only Usual Care 15, 13 27%, 15% 61±5.0, 64±5.7 62.5 26.7, 25.4
4
Duruturk et al. Exercise Only Usual Care 14, 13 7%, 15% 61±5.1, 64±5.7 62.5 28.4, 25.4
9 Pulmonary
deGrass et al. Education 34, 33 50%, 52% ---- ---- ----
Rehab
2
Kriemler et al. Exercise Only Usual Care 17, 10 24%, 50% 24±5.0, 20±5.1 22.1 19.4, 19.6
2
Kriemler et al. Exercise Only Usual Care 12, 10 42%, 50% 19±5.0, 20±5.1 19.7 19.4, 19.6
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Beaudoin et al. Exercise Only Usual Care 8, 6 63%, 60% 32±11.6, 36±20.8 33.7 23.3, 24.2
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32 Pulmonary
Nishiyama et al. Not Described 13, 15 8%, 40% 68±8.9, 65±9.1 66.3 23, 22.9
Rehab
33 Pulmonary
Vainshelboim et al. Usual Care 15, 17 33%, 35% 69±6.0, 66±9.0 67.4 28.3, 28.8
Rehab
Exercise +
Arandelovic et al.1

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Not Described 45, 20 24%, 25% 33±9.8, 34±10.9 33.3 ----
Education
Exercise +
34 Weight Loss
Freitas et al. Weight Loss 26, 25 96%, 100% 46±7.7, 49±9.6 47.2 38.1, 36.7
Program

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Program
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Holland et al. Exercise Only Education 37, 20 51%, 35% 70±8.0, 67±13.0 68.5 ----

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BMI: body mass index; COPD: chronic obstructive pulmonary disease; Exp,Ctrl = experimental, control; ILD: interstitial lung disease; IPF:
idiopathic pulmonary fibrosis

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Table 2: Exercise Training Program Characteristics

Characteristics n Mean ± SD Range

Program Length 21 13.6 ± 12.0 4 – 52

Frequency 21 4.0 ± 2.0 2–7
Intensity
Oxygen uptake (%VO2 max) 4 64.4 ± 4.3 60 – 70
Borg Rating of perceived exertion (0-10) 3 4.2 ± 1.3 3 – 5.5

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Work Rate (% max work rate) 5 68 ± 16.4 50 – 90
One repetition maximum (%) 2 53.8 ± 19.4 40 – 68
Duration 17 46.4 ± 16.1 20 – 60
Setting

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Outpatient 9 42.9%
Home 10 47.6%
Other fitness Center 2 9.5%
Mode

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Aerobic 8 48.1%
Combined Aerobic and Resistance 13 51.9%
Exercise + other treatment (breathing,
15 71.4%
education, etc.)

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Exercise treatment only 6 28.6%
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Table 3: Individual effect sizes for changes in exercise capacity in intervention group compared with control

Exercise Mean Effect

Reference Exercise Mode Unit
Capacity [Hedge’s d; (95% CI)]
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Ries et al. Aerobic, Resistance Peak VO2 l/min 0.15 (-0.21, 0.51)
3
Roman et al. Resistance 6MWD m -
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Oh Aerobic + IMT, Resistance 6MWD m 1.10 (0.19, 2.02)

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10
Du Moulin et al. Aerobic 6MWD m 0.88 (-0.04, 1.80)
27
Wadell et al. Aerobic, Resistance 6MWD m 0.20 (-0.42, 0.82)
5
Lake et al. Upper-Limb Training Peak VO2 % pred -0.96 (-2.11, 0.19)
Lake et al. 5

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Lower-Limb Training Peak VO2 % pred 0.52 (-0.59, 1.63)
5
Lake et al. Upper + Lower Limb Training Peak VO2 % pred 0.00 (-1.05, 1.05)
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Chan et al. Aerobic 6MWD m 0.01 (-0.33, 0.35)

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14
Wijkstra et al. Aerobic Peak VO2 l/min 0.65 (0.01, 1.30)
6
Larson et al. Cycling Peak VO2 l/min -0.19 (-0.97, 0.60)
6
Larson et al. Cycling + IMT Peak VO2 l/min -0.22 (-1.00, 0.55)
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Singh et al. Aerobic 6MWD m 0.34 (-0.28, 0.96)

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Fernandez et al. Aerobic, Resistance 6MWD m 0.85, (0.17, 1.52)
30

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Ghanem et al. Aerobic, Resistance 6MWD m 3.69 (2.65, 4.74)
Duruturk et al. 4 Aerobic Peak VO2 l/min 0.83 (0.06, 1.61)
4
Duruturk et al. Calisthenics Peak VO2 l/min 0.31 (-0.45, 1.07)
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deGrass et al. Aerobic, Resistance 6MWD m -0.07 (-0.55, 0.41)

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Kriemler et al. Aerobic, Resistance - - -
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Beaudoin et al. Aerobic, Resistance Peak VO2 ml/kg/min -0.34 (-1.40, 0.73)
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Nishiyama et al. Aerobic, Resistance 6MWD m 0.36 (-0.38, 1.11)

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Vainshelboim et al. Aerobic, Resistance Peak VO2 ml/kg/min 0.78 (0.06, 1.50)
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Arandelovic et al. Aerobic - - -

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Freitas et al. Aerobic, Resistance Peak VO2 ml/kg/min 0.42 (-0.14, 0.97)
Holland et al. 35 Aerobic, Resistance Peak VO2 % pred 0.34 (-0.21, 0.89)
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6MWD: six minute walking distance; Peak VO2: peak oxygen consumption; %pred: percent of predicted maximum; l/min: liters per minute; m: meters; ml/kg/min:
milliliters per kilogram per minute.
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Table 4: Study Design Quality Assessment Categories

Criteria Description

1 Eligibility criteria specified (yes/no)

2 Subjects were randomly allocated to groups
3 ACSM guidelines of 150 min per week met
4 Groups were similar at baseline regarding the most important prognostic factors
5 Exercise training characteristics (≥2)
6 Adherence and/or supervision
7 Blinding of all assessors who measured at least one key outcome

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8 Measures of at least one key outcome were obtained from more than 85% of the subjects
initially allocated to groups
9 Intent to treat analysis

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10 The results of between-group statistical comparisons are reported for at least one key
outcome
11 The study provides both point measures and measures of variability for at least one key
outcome

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Table 5: Study Design Quality Assessment (utilizing the PEDro Scale)

Modified PEDro Criteria

Reference 1 2 3 4 5 6 7 8 9 10 11 TOTAL
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Ries et al. + + + + + + + + - + + 10/11
3
Roman et al. + + - + + + + - + + + 9/11
11
Oh + + - + - - - - - + + 5/11
10
Du Moulin et al. + + + + + + + - + + + 10/11
27
Wadell et al. + + + + + + - + - + + 9/11

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Lake et al. 5 + + + + + + - + - + + 9/11
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Chan et al. + + - + - + + - + + + 8/11
14
Wijkstra et al. + + + + + + - + - + + 9/11
6
Larson et al. + + + + + + + - - + + 9/11

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Singh et al. + + + + + + - + + + + 10/11
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Fernandez et al. + + + + + + - + - + + 9/11
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Ghanem et al. + + - + + - - + + + + 8/11
4

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Duruturk et al. + + - + + + + + - + + 9/11
9
deGrass et al. + + - + - - + - - + + 6/11
Kriemler et al.2 + + - + + + + + + + + 10/11
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Beaudoin et al. + + + + + + - - - + + 8/11
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Nishiyama et al. + + - + + + - + - + + 8/11

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Vainshelboim et al. + + - + + + - + - + + 8/11
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Arandelovic et al. + + - + + - - + - + + 7/11
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Freitas et al. + + - + + + + + + + + 10/11
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Holland et al. + + - + + + + + + + + 10/11

Note that criteria (1-11) are defined in Table 4

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ONLINE RESOURCE

The accompanying online resource is included to provide more detailed description of our data extraction

procedures and study quality rankings, as well as funnel- and forest-plot figures for our sub-domain

analysis of pulmonary function variables.

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1. Data Extraction Procedures:

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A predefined spreadsheet (Microsoft Excel) was used to enter data that was extracted from each study

selected for review. In order to describe the characteristics of each study, the following information was

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recorded: publication year, country of origin, and for both control and experimental groups—total sample

size, gender distribution, body mass index (BMI), average BMI, mean age and standard deviation, mean

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combined age, chronic pulmonary disease of study participants, study arms, if exercise occurred alone or

in combination with another treatment, exercise mode, exercise intensity, exercise location, exercise
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supervision, O2 supplementation, exercise frequency in days per week as well as exercise duration in

minutes. An abbreviated list of participant characteristics is provided in Table S1.

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Additionally, control group characteristics, exercise program length in weeks, fulfillment of recommended
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guidelines of 150 min·wk of exercise, exercise adherence, blinding of test administrators, lung function
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variables (pre and post mean changes) measured and whether primary or secondary outcomes were

measured. Exercise capacity measures such as six-minute walk distance and peak oxygen consumption
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were also recorded. A description of standard exercise training variables across included studies, when

available, is summarized in Table S2. We also report individual effect sizes for changes in exercise
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capacity for each study (Table S3). Effects were not calculated for three studies due to missing pre- and
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post-intervention exercise capacity measures or because data were not reported as means or standard

deviations 2, 3. In addition, for those studies with multiple exercise conditions 4-6, we report separate

effects for each group in comparison to control.

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2. Study Quality:
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We modified the Physiotherapy Evidence Database (PEDro) scale to better characterize the

methodological quality of studies included in this meta-analysis. Specifically, we included quality

measures that evaluated whether, 1) exercise adherence and/or supervision was monitored during

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exercise training, 2) exercise training prescriptions were consistent with recommended guidelines for

adults (i.e., 150 min·wk-1), and 3) exercise training protocols were appropriately detailed (i.e., adequate

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description of ≥ 2 training variables such as intensity or mode). In addition, we also separately assessed
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whether pulmonary function testing was performed and/or interpreted using ATS/ERS or other

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standardized criteria. A description of these study design quality assessment categories is provided in

Table 4. Three authors (PS, JK and MF) independently rated study quality using this modified PEDro

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scale. Scores were individually tabulated by counting the number of checklist criteria satisfied for each

randomized control trial. In general, higher scores reflect greater methodological quality and final PEDro
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scores are reported in Table S5.
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3. Sensitivity Analyses

3.1 Pulmonary Function Domains:

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As described in the main manuscript, we computed separate mean effect sizes was for (i) gas exchange
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(i.e., DLCO), (ii) pressure (i.e., MEP, MIP, PM, PM/PImax, PImax, RME1, RME2), (iii) spirometry (FEV1,

FEV1/FVC, FVC, MVV, PEF), and (iv) volumes (ERV, FRC, IVC, RV, TLC, VC).. Results of these
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analyses are provided in the main manuscript; however, this supplement includes forest and funnel plots

for each domain (Figures S1 – S8).

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3.2 Exercise Alone vs. Exercise Plus Other Treatment:

To examine the potential influence of interventions that combined whole-body exercise training with

additional treatment (e.g., pulmonary rehabilitation, inspiratory muscle training) on the significance and

magnitude of the overall mean effect size, we calculated and compared separate mean effect sizes
9-14
between effects from studies that reported using exercise training alone and those that reported
2, 7, 9, 11, 12, 14-26
combining exercise training with additional treatment .
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The mean effect of exercise alone on overall pulmonary function (k=46) was small (∆= 0.25; 95%

CI, 0.12, 0.39) and significant (p < .001, z = 3.57). The mean effect of exercise in combination with

additional treatment (k=59) was small (∆= 0.14; 95% CI, 0.06, 0.22) and significant (p < .001, z = 3.63).

Thus, after excluding effects that were derived from studies that combined exercise with additional

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treatment, the effect of exercise alone on pulmonary function remained significant.

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Table and Figure Legends:

Table S1: Participant and Study Characteristics

BMI: body mass index; COPD: chronic obstructive pulmonary disease; Exp,Ctrl = experimental, control;
ILD: interstitial lung disease; IPF: idiopathic pulmonary fibrosis

Table S2: Exercise Training Program Characteristics

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Table S3: Individual effect sizes for changes in exercise capacity in intervention group compared
with control
6MWD: six minute walking distance; Peak VO2: peak oxygen consumption; %pred: percent of predicted
maximum; l/min: liters per minute; m: meters; ml/kg/min: milliliters per kilogram per minute.

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Table S4: Study Design Quality Assessment Categories

Table S5: Study Design Quality Assessment (utilizing the PEDro Scale)

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Note thaht criteria (1-11) are defined in Table 4

Figure S1 – Forest Plot for Spirometry Based Outcomes

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Figure S2 – Funnel Plot for Spirometry Based Outcomes

Figure S3 – Forest Plot for Pressure Based Outcomes

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Figure S4 – Funnel Plot for Pressure Based Outcomes

Figure S5 – Forest Plot for Gas Exchange Based Outcomes

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Figure S6 – Funnel Plot for Gas Exchange Based Outcomes

Figure S7 – Forest Plot for Volume Based Outcomes

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Figure S8 – Funnel Plot for Volume Based Outcomes

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