After adjusting for confounders (see Tables’ footnote), per each 1000 steps of more PA at baseline, patients declined 7 mL less FEV1 per year (P < 0.01), 9 mL less FVC per year (P = 0.03) and 0.10 mL·min−1·mm Hg−1 less DLco per year (P = 0.04); similarly, they increased 0.4 points less (P = 0.03) in the SGRQ symptom domain per year (Table 3). Associations with other outcomes were not statistically significant (see Supplementary Table 3, Supplemental Digital Content 4, Change in exercise capacity, respiratory muscle force, and other domains of health status related to baseline step count, http://links.lww.com/MSS/B465). Bivariate associations were similar with MVPA (see Supplementary Figure 1, Supplemental Digital Content 5, COPD progression according to baseline MVPA levels, http://links.lww.com/MSS/B466) or sedentary time (see Supplementary Figure 2, Supplemental Digital Content 6, COPD progression according to baseline sedentary time levels according to baseline sedentary time levels, http://links.lww.com/MSS/B467). After adjusting for confounders (see footnotes), more time in MVPA was associated with lower decline in FEV1 and FVC, and higher sedentary time was related to worsening of FEV1, FVC, DLco, and SGRQ symptoms score (Table 3). Linear regression goodness of fit tests did not reveal any abnormality.
Additional and sensitivity analyses
Stratification of PA models based on baseline smoking status showed a stronger association between PA and FEV1 decline in active smokers so, per each additional 1000 steps, smokers declined FEV1 by 11.0 mL·yr−1 (4.2 mL·yr−1) less (vs 4.6 mL·yr−1 [3.2 mL·yr−1] in former smokers; P value for interaction = 0.06). This effect modification was not observed for the other outcomes. Stratification of sedentary time models according to patients’ MVPA level did not show any relevant effect modification (see Supplementary Table 4, Supplemental Digital Content 7, change in lung function and symptoms domain of health status related to baseline sedentary time, according to baseline MVPA, http://links.lww.com/MSS/B468). Forty-three percent of patients had at least one exacerbation (severe and/or moderate) during follow-up. The inclusion of this variable in the multivariable models did not change the associations (see Supplementary Table 5, Supplemental Digital Content 8, change in lung function and symptoms domain of health status related to baseline step count, with and without having exacerbations during follow-up as a covariate, http://links.lww.com/MSS/B469).
The subgroup of patients (n = 92) with PA data at both time points declined from 7734 (4621) to 5857 (4059) steps per day (P < 0.001). When dividing these patients into persistently inactive, persistently active and PA decliners (see Supplementary Figure 3, Supplemental Digital Content 9, COPD progression according to physical activity changes status, http://links.lww.com/MSS/B470), while emulating the methodology by Waschki (5), the declines in FEV1, FVC, DLco, and SGRQsymptom domain were faster in persistently inactive than in persistently active patients. The other outcomes did not significantly differ.
Sensitivity analyses yielded very similar results. See:
- Supplementary Table 6, Supplemental Digital Content 10, Change in lung function and symptoms domain of health status related to step count, sedentary time and MVPA at baseline after excluding extreme values of physical activity variables, http://links.lww.com/MSS/B471
- Supplementary Table 7, Supplemental Digital Content 11, Change in lung function and symptoms domain of health status related to step count, sedentary time, and MVPA at baseline (multivariable mixed model), http://links.lww.com/MSS/B472
- Supplementary Table 8, Supplemental Digital Content 12, Change in lung function and symptoms domain of health status related to step count, sedentary time, and MVPA at baseline after excluding patients participating in a pulmonary rehabilitation program at baseline (n = 4), http://links.lww.com/MSS/B473.
This study shows that PA is associated with attenuated 2 to 3 yr deterioration of some (lung function and symptoms domain of health status) relevant components of disease progression, after adjusting for confounders and irrespective of their baseline values.
The most novel finding is the association between PA and lung function decline. This is in variance with a previous study that found a weak but significant correlation (r = 0.24, P = 0.04), but did not retain PA as an independent predictor of FEV1 decline (20) and the observation that persistent inactivity was not related to lung function changes (5). Because patients of the latter study had similar characteristics, the same accelerometer was used and that we emulated their statistical approach, we suggest that a residual confounding effect could contribute to explain this discrepancy. In line with evidence in the general population (21), we found a stronger association in active smokers, pointing to biological mechanisms shared by PA and smoking in their association with lung function decline. Finally, to our knowledge, no previous longitudinal study has assessed the relationship between PA and DLco in COPD, albeit a positive cross-sectional association was found based on the PAC-COPD study (22) and DLco was shown to be related to PA in (ex-) smokers with airflow obstruction (23).
Several, nonmutually exclusive, mechanisms can contribute to explain the observed association between PA and lung function decline: 1) PA can have an anti-inflammatory or antioxidant effect (21,24–26) likewise, 2) PA might theoretically reduce the frequency of COPD exacerbations (14) which, in turn, preserves lung function (27) and health status (28). However, our results do not support this contention (see Supplementary Table 5, Supplemental Digital Content 8, Change in lung function and symptoms domain of health status related to baseline step count, with and without having exacerbations during follow-up as a covariate, http://links.lww.com/MSS/B469); and finally 3) PA can influence respiratory muscle strength. However, this is likely a less important contributor in COPD patients because the relationship between respiratory muscle strength and lung function is weak (29) and increases in strength do not lead to changes in lung function (30).
As a second relevant finding, we found that PA was associated with lower health status (symptoms domain) worsening, in agreement with previous reports (14). Surprisingly, PA was not associated with changes in the SGRQ activity domain. It is of note that the activity domain refers to “activities that cause or are limited by breathlessness.” This lack of association may be therefore in line with previous studies showing that the amount of PA and experienced difficulties with PA are distinct concepts (31).
Finally, we did not find an association between PA and changes in functional exercise capacity, muscle strength or body composition outcomes. Although PA relates cross-sectionally to these outcomes, research on their association over time is scarce (5,22,32). A previous study found a faster decline in functional exercise capacity and FFM in persistently inactive patients (5). That the functional decline in our cohort was slightly slower might have limited our ability to identify differences, albeit the magnitude of this association is estimated to be small (see Supplementary Table 3, Supplemental Digital Content 4, Change in exercise capacity, respiratory muscle force and other domains of health status related to baseline step count, http://links.lww.com/MSS/B465). Because the modification of functional exercise capacity and muscle strength require regularly scheduled intense activities (33) and that activities of daily living are generally of low intensity, a lack of association may be conceivable. In fact, a previous study that found a relation between PA and functional exercise capacity decline used the self-reported “hard activity” as PA measurement (32). Moreover, like in previous studies (14), we did not have available data on quadriceps muscle strength so, regrettably, whether PA is associated with this decline could not be explored. Because this muscle is often affected in COPD (34), although other can still be preserved, future studies aiming to investigate the association between PA and muscle strength should consider including quadriceps muscle strength in the analysis.
Potential clinical implications
First, while we acknowledge that any clinically meaningful preservation of lung function requires a large increase in PA, the modest association for every 1000 steps is somehow comparable to the effect of pharmacotherapy on FEV1 decline, ranging between 2 and 16 mL·yr−1 of less decline in the treatment arm compared with the placebo one (35,36). In this context, it is also important to note that an increase of 1000 steps is meaningful (37), feasible (38) and neither induces adverse events nor related costs. Second, smoking cessation is the key therapeutic intervention in patients with COPD with the greatest impact on the natural history of COPD and the only behavioral factor that has been related to disease progression. The ECLIPSE study showed a 21 mL greater annual decline in FEV1 in current smokers compared with nonsmokers (1). The attenuation seen for every 1000 steps of more physical activity can thus in magnitude be seen as one third of the effect observed by smoking cessation, an effect with no doubt of clinical relevance. Third, most importantly, the observed benefits of PA occurred on top of the pharmacologic treatment (69% of patients used combination therapy, see Table 1) regardless of smoking behavior. Fourth, the fact that PA relates to DLco decline may be clinically relevant since DLco is an excellent functional marker of pulmonary emphysema and a strong mortality predictor in COPD (39). DLco is an important marker of disease progression with a prognostic value higher than that of airflow limitation (40), is a sign of arterial oxygen desaturation during exercise and relates to the decline in exercise performance (41). Finally, along with previous research, a proportion of patients remained stable over time (1). The current results suggest that different PA levels can contribute to explain the heterogeneity of COPD progression (1).
Our results provide relevant information for future research, particularly for the selection of PA parameters. First, using MVPA resulted in similar results than step count but it was of lower magnitude and less statistical power. We suggest that future studies aiming to assess the effects of PA in chronically diseased subjects like COPD should focus on parameters of “light” PA, as previously proposed (19,42). Second, we assessed PA and sedentary time independently, as well as their interaction, based on previous research in healthy individuals (43). Physical activity and sedentary time rendered similar results (although of opposite direction) in their association with COPD progression, hence representing a similar concept in this population.
Strengths and limitations
Our study has several strengths: 1) This is one of the first studies analyzing the longitudinal association between objectively measured PA and several a priori selected components of disease progression; 2) it considers potential confounders by investigating an extensively well-identified cohort (PAC-COPD), thus minimizing confounding; and finally, 3) by following patients longitudinally and including the baseline values of each outcome in the multivariable models, the potential of reverse causation (i.e., that the outcomes decline leads to a lower PA) as an additional explanation of our findings is reduced. Our study, however, also has shortcomings: 1) the analysis was restricted to 33% of the original cohort. Although these patients were found representative for the entire cohort (17), survival bias might have influenced the present estimates because patients who were lost for follow-up had a worse overall status at baseline (see Supplementary Table 1, Supplemental Digital Content 2, Baseline characteristics according to follow-up status, http://links.lww.com/MSS/B463). The most likely consequence, though, is underestimation of the observed associations because lost patients are expected to have a faster decline; 2) the sample of 114 patients represents a relatively large cohort in terms of objectively measured PA but it is a modest sample to investigate decline in outcomes with large (biological) variability, so the lack of statistical power could potentially have caused lack of statistical significant results for some outcomes (e.g., 6MWD); 3) based on expert opinion, the estimate in decline traditionally relies on more frequent data collection. Our study is limited by two measures, with a mean of 2.6 yr apart; 4) the results based on the current population, with a majority of male patients, cannot be directly extrapolated and need to be confirmed; and 5) the physical activity of the present cohort is higher than that observed in previous studies, which could be considered a limitation. However, when comparing clinical characteristics and physical activity of the present cohort and previous studies, differences can be seen among countries (for a similar severity of COPD) as well as within countries (differences in disease severity and/or setting). In addition, the present sample has a high proportion of male subjects (reflecting the COPD gender distribution in Spain), which could have also contributed to the higher physical activity.
This study shows that increased PA is associated with attenuated decline in lung function and reduced deterioration of the symptoms domain of health status (but not to changes in functional exercise capacity, muscle strength, other domains of health status or body composition) in patients with moderate-to-very severe COPD.
The “Phenotype and Course of COPD (PAC-COPD)” study group: J. M. Anto (principal investigator), J. Garcia-Aymerich (project coordinator), M. Benet, J. de Batlle, I. Serra, D. Donaire-Gonzalez and S. Guerra (all Centre for Research in Environmental Epidemiology (CREAL), Barcelona, Spain); J. Gea (center coordinator), E. Balcells, A. Gayete, M. Orozco-Levi and I. Vollmer (all Hospital del Mar-IMIM, Barcelona, Spain); J. A. Barbera (center coordinator), F. P. Gomez, C. Pare, J. Roca, R. Rodriguez-Roisin, A. Agustí, X. Freixa, D. A. Rodriguez, E. Gimeno-Santos and K. Portillo (all Hospital Clinic, Institute d’Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Barcelona, Spain); J. Ferrer (center coordinator), J. Andreu, E. Pallissa and E. Rodriguez (all Hospital General Universitari Vall D’Hebron, Barcelona, Spain); P. Casan (center coordinator), R. Güell and A. Gimenez (all Hospital de la Santa Creu i Sant Pau, Barcelona, Spain); E. Monso (center coordinator), A. Marin and J. Morera (all Hospital Universitari Germans Trias i Pujol, Badalona, Spain); E. Farrero (center coordinator) and J. Escarrabill (both Hospital Universitari de Bellvitge, Institut d’Investigacio Biomedica de Bellvitge (IDIBELL), L’Hospitalet de Llobregat, Spain); A. Ferrer (center coordinator; Hospital de Sabadell, Corporacio Parc Tauli, Institut Universitari Parc Tauli (Universitat Autonoma de Barcelona), Sabadell, Spain); J. Sauleda (center coordinator) and B. Togores (both Hospital Universitari Son Dureta, Palma de Mallorca, Spain); J. B. Galdiz (center coordinator) and L. Lopez (both Hospital Universitario de Cruces, UPV, Barakaldo, Spain); and J. Belda (Instituto Nacional de Silicosis, Oviedo, Spain).
The authors wish to thank the Conjunto Minimo Basico de Datos de Altas Hospitalarias (CMBDAH) from Catalonia, the Basque Country and the Balearic Islands (all Spain) for providing the information on hospitalization data.
Dr. Agusti reports grants from GSK, grants and personal fees from AstraZeneca, grants and personal fees from Menarini, personal fees from Chiesi, personal fees from Boehringer-Ingelheim, outside the submitted work. Dr. Rodriguez-Roison reports personal fees from AstraZeneca, personal fees from Boehringer-Ingelheim, and personal fees from Pearl Therapeutics, during the conduct of the study, all related to COPD. Dr. Judith Garcia-Aymerich’s institution has received consulting and lecture fees from AstraZeneca (not related to this study); she has received lecture fees from Esteve and Chiesi (not related to this study). For the remaining authors, none were declared. The results of the present study do not constitute endorsement by ACSM, and have been presented clearly, honestly, and without fabrication, falsification, or inappropriate data manipulation.
HD is the recipient of a joint ERS/SEPAR Fellowship (LTRF 2015) and is a postdoctoral research fellow of the FWO-Flanders. J. G. is supported by SAF2014-54371-R and FEDER funds. The PAC-COPD Study is funded by grants from Fondo de Investigación Sanitaria (FIS PI020541), Ministry of Health, Spain; Agència d’Avaluació de Tecnologia i Recerca Mèdiques (AATRM 035/20/02), Catalonia Government; Spanish Society of Pneumology and Thoracic Surgery (SEPAR 2002/137); Catalan Foundation of Pneumology (FUCAP 2003 Beca Marià Ravà); Red RESPIRA (RTIC C03/11); Red RCESP (RTIC C03/09), Fondo de Investigación Sanitaria (PI052486); Fondo de Investigación Sanitaria (PI052302); Fundació La Marató de TV3 (num. 041110); DURSI (2005SGR00392); and unrestricted educational grants from Novartis Farmacèutica, Spain, and AstraZeneca Farmacéutica, Spain. CIBERESP and CIBERES are funded by the Instituto de Salud Carlos III, Ministry of Health, Spain. ISGlobal is a member of the CERCA program, Generalitat de Catalunya. No involvement of funding sources in study design; in the collection, analysis, and interpretation of data; in the writing of the report; nor in the decision to submit the article for publication. Researchers are independent from funders.
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LONGITUDINAL ANALYSIS; LUNG FUNCTION; MUSCLE STRENGTH; HEALTH STATUS; EXERCISE CAPACITY
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