Abstract
The present study aims to disentangle the independent effects of the quantity and the intensity of physical activity on the risk reduction of chronic obstructive pulmonary disease (COPD) hospitalisations.
177 patients from the Phenotype Characterization and Course of COPD (PAC-COPD) cohort (mean±sd age 71±8 years, forced expiratory volume in 1 s 52±16% predicted) wore the SenseWear Pro 2 Armband accelerometer (BodyMedia, Pittsburgh, PA, USA) for eight consecutive days, providing data on quantity (steps per day, physically active days and daily active time) and intensity (average metabolic equivalent tasks) of physical activity. Information on COPD hospitalisations during follow-up (2.5±0.8 years) was obtained from validated centralised datasets.
During follow-up 67 (38%) patients were hospitalised. There was an interaction between quantity and intensity of physical activity in their effects on COPD hospitalisation risk. After adjusting for potential confounders in the Cox regression model, the risk of COPD hospitalisation was reduced by 20% (hazard ratio (HR) 0.79, 95% CI 0.67–0.93; p=0.005) for every additional 1000 daily steps at low average intensity. A greater quantity of daily steps at high average intensity did not influence the risk of COPD hospitalisations (HR 1.01, p=0.919). Similar results were found for the other measures of quantity of physical activity.
Greater quantity of low-intensity physical activity reduces the risk of COPD hospitalisation, but high-intensity physical activity does not produce any risk reduction.
Abstract
Greater quantity of low-intensity physical activity reduces the risk of COPD hospitalisation http://ow.ly/Oe2RE
Introduction
Reducing the frequency of exacerbations in patients with chronic obstructive pulmonary disease (COPD) is a major therapeutic goal [1], since exacerbations accelerate decline in lung function and exercise capacity and jeopardise both quality of life and survival in these patients [1–3]. Moreover, COPD exacerbations are the most frequent cause of medical consultation and hospitalisation in COPD and cause 50–75% of the healthcare costs associated with COPD.
Currently, tobacco smoking cessation and pharmacological treatment of COPD reduce and prevent COPD exacerbations, but lifestyle factors, such as physical activity or diet also modulate them beneficially [3–5]. The evidence from prospective studies supporting the beneficial effects of physical activity in preventing COPD exacerbations is consistent across studies involving different physical activity measures, severity of disease and geographical areas [6]. Yet common limitations of all these previous studies are the lack of control for the previous history of COPD exacerbations, which is now known to be the best predictor of further exacerbations [7], and, in most cases, the lack of an objective physical activity assessment. Similarly, whether these beneficial effects of physical activity are due to its quantity and/or its intensity has never been assessed, despite the fact that intensity of physical activity has been proven important for health benefits in other diseases [8, 9]. This is important because it may give guidance to the implementation of research findings in clinical practice, since no COPD-specific recommendations for an adequate physical activity are available so far.
We hypothesised that both higher quantity and intensity of physical activity could prevent COPD hospitalisations. To test this hypothesis, we assessed the independent effects of the quantity and intensity of objectively measured physical activity on the risk of hospitalisation due to a COPD exacerbation in the Phenotype Characterization and Course of COPD (PAC-COPD) study cohort [10].
Methods
Study design, participants and ethics
This is a prospective longitudinal study nested in the PAC-COPD project, whose methodology and main results have been reported previously [10]. In brief, COPD patients were enrolled during their first hospitalisation due to COPD exacerbation in nine teaching hospitals in Spain. Patients were evaluated 3 months after discharge, when clinically stable (baseline). The diagnosis of COPD was established according to the American Thoracic Society/European Respiratory Society (ERS) guidelines. Patients were invited to participate in a second visit for follow-up assessment 18–24 months later, while clinically stable. In this second visit, a sample of 177 patients, representative of the PAC-COPD cohort [11], accepted the monitoring of their physical activity with an accelerometer (see later). All patients were followed-up until December 31, 2010 or date of death, whichever came first (median 2.6 years). The ethics committees of all the participating hospitals approved the study, and written informed consent was obtained from each participant.
Measurements
Patients were instructed to wear an accelerometer (SenseWear Pro 2 Armband; BodyMedia, Pittsburgh, PA, USA) placed on the right arm during waking hours (08:00–10:00 h) over eight consecutive days. On average, they wore the accelerometer for 6 days and recorded a mean 95% of daytime hours (13.5 h of a maximum 14 h) [11]. The quantity of physical activity was assessed using 1) the number of steps per day; 2) the number of days per week that the patient could be considered physically active, operationally defined by ≥5000 steps per day [12]; and 3) time (minutes) per day spent in physical activity (defined as any minute with ≥1.5 metabolic equivalent tasks (METs)). The intensity of physical activity was assessed by the average METs over the time spent in physical activity.
The information about COPD hospitalisations (dates and diagnoses at discharge) during the 12 months prior to enrolment (from 2005 to 2006) and during follow-up (from 2006 until December 31, 2010) was obtained from a national administrative database (online supplementary material).
Other measurements included sociodemographic factors, pharmacological and nonpharmacological treatment, smoking habit, dietary habits, comorbidities, health-related quality of life, dyspnoea, complete lung function (including forced spirometry, body plethysmography, diffusing capacity and arterial blood gases), nutritional status, exercise capacity, lung density and structure and systemic inflammation (online supplementary material).
Statistical analysis
Provided that sample size was fixed by the primary scientific objectives of the PAC-COPD study, prior to any analysis we calculated the statistical power to answer our research question with 177 patients using the software GRANMO 7.10 (www.imim.cat/ofertadeserveis/en_granmo.html). Accepting an α risk of 0.05 in a two-sided test, and using our own data about the distribution of physically active:physically inactive COPD patients [11], the statistical power to recognise as statistically significant a risk reduction in COPD hospitalisation was 84%, similar to that reported in previous literature [6].
The relationship between baseline physical activity outcomes and risk of COPD hospitalisation was first tested using the Kruskal–Wallis test and then using Cox proportional hazard regression models. To test the independent effect of quantity and intensity of physical activity, we stratified the association between the three outcomes of quantity of physical activity and COPD hospitalisation according to the average of intensity of physical activity (categorised by its median value in our population (2.7 METs)). Because the effect of quantity variables was restricted to the low-intensity group, multivariate models included an interaction term between each variable of physical activity quantity and intensity (see Results). The treatment of potential confounders and the goodness-of-fit tests are detailed in the online supplementary material. Final models were stratified according to 1) severity of airflow limitation (≥50% and <50% forced expiratory volume in 1 s (FEV1)) [2] and 2) having had a COPD hospitalisation in the previous year. We performed additional analysis using the volume of physical activity (METs·min-1·day-1) as the exposure. As sensitivity analyses we 1) excluded subjects with extreme values (>95th percentile) in the accelerometer measures; 2) used COPD hospitalisation or all-cause mortality as the outcome; 3) used all-cause hospitalisation as the outcome; and 4) categorised intensity of physical activity in three groups. All analyses were conducted using R 3.0.1 (R Foundation for Statistical Computing, Vienna, Austria).
Results
We enrolled 177 COPD patients (94% male, mean±sd 71±8 years, FEV1 52±16% predicted). Table 1 shows their main anthropometric, clinical and functional characteristics. Table 2 shows that patients walked a mean±sd 6663±4675 steps·day-1 and were physically active (>5000 steps·day-1) a median 4 days per week. During follow-up, 67 (38%) patients suffered at least one COPD hospitalisation. Additionally, 10 patients died during follow-up without having had any hospitalisation; they exhibited lower physical activity levels in all variables than survivors (online supplementary table E1).
Sociodemographic, clinical and functional characteristics of participants
Characteristics of patients’ physical activity at baseline and according to hospitalisations for chronic obstructive pulmonary disease (COPD) during follow-up
The number of daily steps and physically active days at baseline was lower in patients who were hospitalised during follow-up than in those who were not, while no differences were observed with regard to time in activity or intensity of physical activity (table 2). All physical activity variables decreased according to increased severity of airflow limitation in a statistically significant linear pattern (online supplementary table E2). When patients were stratified above or below the median of the average intensity of physical activity (≥2.7 METs), we observed that the relationship between variables describing the quantity of physical activity and risk of COPD hospitalisations was restricted to those with low average intensity of physical activity (online supplementary table E3). Consequently, physical activity intensity was included as an interaction term in all subsequent analyses.
The multivariate Cox model, adjusted both for potential confounders and the interaction term between intensity and daily steps, showed that for every additional 1000 daily steps at low average intensity, the risk of COPD hospitalisation was reduced by ∼20% (hazard ratio (HR) 0.79, 95% CI 0.67–0.93; p=0.005) (table 3). However, increasing the number of daily steps when average intensity of physical activity was high did not result in any reduction in risk of COPD hospitalisation (table 3). This is illustrated in figure 1. Similar results were observed for the other two variables describing the quantity of physical activity (number of physically active days and time in activity) (table 3). After stratification according to airflow limitation, in patients with severe to very severe airflow limitation (FEV1 <50% pred) high quantity of activity at high average intensity was associated with a higher risk of COPD hospitalisation (fig. 2 and online supplementary table E4). Stratification of patients by hospitalisation for COPD in the previous year (online supplementary table E5), additional analysis using volume of physical activity as the exposure (online supplementary table E6), as well as the sensitivity analyses (online supplementary tables E7, E8, E9 and E10) all yielded similar results.
Dose–response relationship between steps per day and hazard ratio (HR) of hospitalisation for chronic obstructive pulmonary disease (COPD), according to intensity of physical activity (multivariate Cox proportional hazards regression). Hazard ratio was computed at each intensity value as the rate between hazard at each intensity value and average hazard of the sample. The model was adjusted for confounders as detailed in table 3.
Dose–response relationship between steps per day and hazard ratio (HR) of hospitalisation for chronic obstructive pulmonary disease (COPD), according to intensity of physical activity and severity of airflow limitation: a) mild to moderate (forced expiratory volume in 1 s (FEV1) ≥50% pred); b) severe to very severe (FEV1 <50% pred). Hazard ratio was computed at each intensity value as the rate between hazard at each intensity value and the average hazard of the sample. The model was adjusted for confounders as detailed in table 3.
Adjusted# association between physical activity variables and hospitalisation for chronic obstructive pulmonary disease (COPD) (multivariate Cox proportional hazards regression)
Discussion
The main finding of our study is that increased quantity of physical activity reduces the risk of future COPD hospitalisations when the average intensity of physical activity is low. The finding that high quantity of physical activity at high average intensity of physical activity may be unhelpful in COPD patients with severe to very severe airflow limitation was unexpected and will require replication. The sensitivity analyses showed that our results were very stable in relation to changes in the selection of subjects, variables and the use of different outcome measures.
Comparison with previous studies
This is the first study that unravels the independent role of the quantity and the intensity of physical activity on the risk of COPD hospitalisations. Previous research consistently demonstrated that higher quantity of physical activity reduces the risk of future COPD exacerbation/hospitalisation [6]. However, some of these previous studies [14–16] measured the quantity of physical activity using variables of energy expenditure (MET-h per week or -kcal per day) that also included intensity in their calculation [17]. In view of the results of the study, this should be taken into account more carefully since it could reduce the beneficial effects of physical activity on COPD hospitalisation risk. It is worth noting that the only study that has used an objective tool (pedometer) to assess the quantity of physical activity found a risk reduction almost identical to that observed in the study (20% for every additional 1000 steps) [18].
The modifying effect of intensity of physical activity in the reported associations between its quantity and the risk of future hospitalisation is a novel finding in the COPD literature, although it has been previously reported in healthy elderly people, where health benefits were mainly related to low intensity of physical activity [8, 19, 20]. Specifically in the elderly, low-intensity physical activity has been shown to provide wellbeing benefits that were not found with moderate-to-vigorous physical activity [19]. It has been suggested that individuals engaging in more activities in the low intensity range (e.g. leisure-time walking) are more likely to have less stress, increased socialisation and greater quality of life [19]. Furthermore, low-intensity physical activity shows slight advantages over vigorous physical activity in reducing tumour necrosis factor-α and rising insulin-like growth factor binding protein-3 levels in aged people [20].
Interpretation of findings
The interpretation of the results for intensity of physical activity requires prior clarification. First, the intensity of physical activity is usually measured by METs, which express the ratio of energy expenditure during a specific physical activity in relation to the energy expenditure at rest. However, the relative metabolic demand (and, as a result, symptom perception) produced by a specific physical activity does not depend only on its MET value but also on the maximum intensity achievable by each subject. In fact, it is well known that for a given activity, COPD patients use a higher proportion of their metabolic and ventilatory capacities than their healthy peers [21]. Thus, the consideration about what is low- or high- intensity physical activity differs depending on the population under study [17]. Second, it is also important to consider that the intensity was defined in our study as the average of METs during all periods spent in physical activity. This included basic activities of daily living, which represent the greater part of patients' time, and have an intensity of ∼1.5 METs. Thus, to achieve a mean of 3 METs over 1 week, patients need to spend a large proportion of time at very high intensities most days of the week. Third, similarly to the framework that considers physical activity and exercise as different concepts [22], our average intensity of physical activity was conceptually different to an average intensity of exercise. Consequently, our results should not be interpreted as a contradiction of pulmonary rehabilitation programmes, which may include exercise of high intensity, because the impact of the latter on the daily average intensity of physical activity will be very small. In summary, our results support a beneficial effect of physical activity when the average of intensity is low, i.e. if only a small proportion of the daily time in physical activity is spent at high intensity levels. By contrast, when a large proportion of the time in physical activity is spent at higher intensities, physical activity appears no longer beneficial, a finding that will require replication.
Several mechanisms have been proposed as responsible for the beneficial effects of physical activity in COPD patients which could ultimately reduce the risk of exacerbations (and subsequent hospitalisations). First, moderate levels of physical activity have been shown to reduce the circulating levels of a number of inflammatory markers, both in experimental and observational studies, as well as in COPD populations [23–25]. Second, the regular practice of physical activity promotes more efficient oxygen delivery to respiratory muscles and improves the oxidative capacity of the muscles in COPD patients [26]. Regular physical activity has also been associated with higher levels of diffusing capacity of the lung for carbon monoxide, maximal expiratory pressure, 6-min walking distance and maximal oxygen uptake in COPD patients [25]. Studies on the effects of physical activity suggest that additional mechanisms may play a role in our observed increased risk of hospitalisation in the inactive patients, including 1) reduced nitric oxide production leading to deleterious vascular effects and loss of its bronchodilator effect [27]; 2) deregulation of gene expression of the β2-adrenergic receptor, therefore possibly inducing a poorer response to therapy [28]; and 3) increased susceptibility to respiratory infections in COPD patients due to a reduction in the number and function of cells mediating cytotoxic activity [29].
Our novel findings of an unhelpful effect of higher quantity of high-intensity physical activity in severe to very severe COPD patients are supported by previous research in COPD patients, healthy subjects, elite athletes and animals. First, strenuous exercise is accompanied by an increase in circulating pro-inflammatory and inflammation-responsive cytokines [30], a response that is exaggerated in specific populations, such as overweight children [31]. In COPD patients, high-intensity exercise alters the nitroso-redox balance, which cannot be balanced by antioxidant mechanisms [26]. Studies in elite athletes have shown an association between high intensity of physical activity and increased airways inflammatory cells, as well as respiratory infections [32], which has been attributed to exercise-induced immune-suppressive effects of exercise, mostly affecting cell immunity. Finally, studies in animals suggest additional effects of high intensity of physical activity, such as the induction to apoptosis of inflammatory cells, mostly in elderly animals [33]. The complex role of physical activity in the immune system is still a matter of debate, more so in diseases with a high inflammatory component, such as COPD [29].
Clinical implications of results
Several of the observations of our study can have clinical implications for the recommendations about daily physical activity to COPD patients. This is an added value in the management of these patients, since no COPD-specific recommendations are available so far [1, 2]. The linear dose–response relationship between quantity of low-intensity physical activity and the risk of COPD hospitalisations (fig. 2) suggests that there is no threshold, either low or high, to achieve clinical benefits. In addition to existing research [6], our results provide evidence to consider in the current COPD guidelines/strategies that COPD patients in general should be encouraged to perform an extra quantity of low-intensity physical activity during their daily life. Furthermore, the data suggest that research aiming to assess the effectiveness of physical activity interventions should consider several physical activity outcomes, including the proportion of individuals meeting certain physical activity goals [34], extra steps per day [35] and the changes, if any, in average intensity.
Strengths and limitations
Our study has several strengths and limitations. The extensive clinical, physiological and biological characterisation of participants within the framework of the PAC-COPD study [10] allowed the inclusion of potential confounders in the analysis, including history of previous COPD hospitalisations, which was not considered in previous studies [15, 16, 36]. Likewise, the use of an objective method to quantify physical activity (and the high compliance level) contrasts with previous studies that mainly used self-reported questionnaires [14, 15, 36, 37], reduces misclassification and allows the dissection of the role of different physical activity characteristics. In theory, our results could be explained by reverse causation, i.e. that hospitalisations reduce physical activity. Against this possibility is the fact that we recruited participants prospectively during their first COPD hospitalisation, that we followed them up for several years, that we restricted our current analysis to the next COPD hospitalisation and that we included the history of previous COPD hospitalisations as an adjusting variable. Another potential limitation of our study is the possibility of survival bias, namely that patients may die (and are therefore censored) before a COPD hospitalisation occurs. However, given that these patients performed low levels of physical activity (online supplementary table E1), the magnitude of the protective effect of physical activity on COPD hospitalisations is probably reduced. Likewise, the technological restrictions of the accelerometer to assess certain activities, such as cycling or swimming, could also be seen as a limitation. Similarly, the activity monitors can not yet be sufficiently accurate to identify small variations in the intensity of physical activities. However, it is now well recognised that accelerometers constitute the best tool to evaluate the quantity and intensity of physical activity during the activities of daily life; moreover, the specific accelerometer that we used is among the most valid [38]. It could also be argued that a single week of physical activity measurement may have resulted in some misclassification of patients' usual physical activity, because of season variation or low representativeness of that particular week. In either case, this would result in a reduction of the effect of physical activity. Our sample size was not large enough to assess the role of other physical activity characteristics such as frequency and duration of physical activity bouts, nor to assess the effects of physical activity on specific subgroups, such as patients with mild and very severe COPD. Finally, although the characteristics of our population, i.e. mainly retired, low socioeconomic status and having at least one previous COPD hospitalisation, may be characteristics that differ from other COPD cohorts, this probably does not affect the observed association of quantity and intensity of physical activity with COPD hospitalisations. In keeping with patterns of tobacco consumption in Europe, a majority of our patients were male; as there is evidence of sex-related differences in the effects of physical activity there is a need to replicate this study in females [39].
In conclusion, a greater quantity of low-intensity physical activity reduces the risk of COPD hospitalisation. The observation that high-intensity daily-life physical activity does not generate additional protective effects in the most severe COPD patients will require replication.
Acknowledgements
Members of the Phenotype Characterization and Course of COPD (PAC-COPD) Study Group are as follows. Josep M. Antó (Principal Investigator), Judith Garcia-Aymerich (project coordinator), Marta Benet, Jordi de Batlle, Ignasi Serra, David Donaire-Gonzalez and Stefano Guerra: Centre for Research in Environmental Epidemiology (CREAL), Barcelona, Spain; Joaquim Gea (centre coordinator), Eva Balcells, Àngel Gayete, Mauricio Orozco-Levi and Ivan Vollmer: Hospital del Mar-IMIM, Barcelona; Joan Albert Barberà (centre coordinator), Federico P. Gómez, Carles Paré, Josep Roca, Robert Rodriguez-Roisin, Àlvar Agustí, Xavier Freixa, Diego A. Rodriguez, Elena Gimeno-Santos and Karina Portillo: Hospital Clínic-Institut D'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona; Jaume Ferrer (centre coordinator), Jordi Andreu, Esther Pallissa and Esther Rodríguez: Hospital General Universitari Vall D'Hebron, Barcelona; Pere Casan (centre coordinator), Rosa Güell and Ana Giménez: Hospital de la Santa Creu i Sant Pau, Barcelona; Eduard Monsó (centre coordinator), Alicia Marín and Josep Morera: Hospital Universitari Germans Trias i Pujol, Badalona, Spain; Eva Farrero (centre coordinator) and Joan Escarrabill: Hospital Universitari de Bellvitge, Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), L'Hospitalet de Llobregat, Spain; Antoni Ferrer (centre coordinator): Hospital de Sabadell, Corporació Parc Taulí, Institut Universitari Parc Taulí (Universitat Autònoma de Barcelona), Sabadell, Spain; Jaume Sauleda (centre coordinator) and Bernat Togores: Hospital Universitari Son Dureta, Palma de Mallorca, Spain; Juan Bautista Gáldiz (centre coordinator) and Lorena López: Hospital Universitario de Cruces, UPV, Barakaldo, Spain; José Belda: Instituto Nacional de Silicosis, Oviedo, Spain.
The authors acknowledge Milo Puhan (Johns Hopkins University, Baltimore, MD, USA) for his helpful comments on a previous version of the manuscript, Esther Gracia and David Martinez from the Centre for Research in Environmental Epidemiology (CREAL) for their help in extracting data from the accelerometers, and the Conjunto Mínimo Básico de Datos de Altas Hospitalarias (CMBDAH) from Catalonia, the Basque Country and the Balearic Islands for providing the information on hospitalisation data.
Footnotes
This article has supplementary material available from erj.ersjournals.com
Support statement: Supported by Fondo de Investigación Sanitaria (FIS PI052292) and the Spanish Society of Pneumology and Thoracic Surgery (SEPAR 2004/136). The Phenotype Characterization and Course of COPD (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; the Spanish Society of Pneumology and Thoracic Surgery (SEPAR 2002/137); the 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 (041110); DURSI (2005SGR00392); and unrestricted educational grants from Novartis Farmacèutica (Spain) and AstraZeneca Farmacéutica (Spain). CIBERESP (CIBER Epidemiología y Salud Pública) and CIBERES (CIBER de Enfermedades Respiratorias) are funded by the Instituto de Salud Carlos III, Ministry of Health, Spain. There is 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. Funding information for this article has been deposited with FundRef.
Conflict of interest: Disclosures can be found alongside the online version of this article at erj.ersjournals.com
- Received September 17, 2014.
- Accepted May 28, 2015.
- Copyright ©ERS 2015