Background
Chronic Obstructive Pulmonary Disease (COPD) is a common disorder associated with significant morbidity and mortality, despite its preventable and treatable nature [
1]. In 2011, the Global Initiative for Obstructive Lung Disease (GOLD) [
2] added symptom burden tothe multidimensional assessment, to classify the patients into four quadrants (GOLD ABCD), combining it with the risk of exacerbations based on pulmonary function and history of exacerbations. In 2017, the classification system was simplified, separating the spirometric measures from the evaluation of respiratory symptoms and exacerbation history [
3].
The prevalence, intensity and variability of COPD symptoms have been extensively explored in the literature, demonstrating their significant impact on patients’ daily activities, health-related and overall quality of life [
4‐
11]. Early morning, daytime and night-time symptoms have been investigated either separately [
4,
8‐
11], or throughout the 24-h day [
7,
12], showing negative associations with a broad range of patient-reported outcomes such as exacerbations, anxiety, depression, sleep and physical activity.
Physical activity (PA) has emerged as an important functional outcome in COPD patients, based on its association with mortality and exacerbations [
13]. Consequently, increasing PA has become a significant non-pharmacological intervention in patients with COPD [
1]. Physical activity is a complex multidimensional construct characterized by frequency, duration, intensity and type of activity, [
14] and affected by individual, physiological, environmental and psycho-social factors [
15,
16]. Recognizing the patients at risk for low physical activity is crucial for clinicians and although many methods are available for the assessment of PA, no measure or guidance is standardized [
17‐
20].
In the light of recent changes in GOLD and the higher importance of PA in COPD evolution, a better understanding of the prevalence and severity of respiratory symptoms, physical activity level and the relationship between these two determinants of quality of life in real-life practice is needed. Therefore, the aims of our study were to explore in more depth the respiratory symptoms over a 24-h period in stable COPD patients, the patterns of self-reported physical activity and their relationship in various healthcare systems across Western and Central Eastern Europe and Israel.
Methods
Study population
Eligible patients were aged at least 40 years with an established COPD history (minimum 1 year since diagnosis). A post-bronchodilator forced expiratory volume in 1 s / forced vital capacity (FEV1/FVC) ratio of < 0.7 in the year before enrollment had to be documented. All patients were current or former smokers with a smoking history of at least 10 pack-years and stable disease (no exacerbation history or changes in current COPD maintenance treatment in the 2 months prior to enrollment). Exclusion criteria included: history of any chronic respiratory disease other than COPD or sleep apnea syndrome, any acute or chronic condition that would have limited the patients’ ability to complete the questionnaires, and concomitant enrollment in a clinical trial that would have influenced participation in the study. Patients with a previous diagnosis of asthma or non-idiopathic pulmonary fibrosis were included only if COPD was the main diagnosis. The enrollment started in December 2016 and lasted until August 2017.
Study design
The Symptoms and Physical Activity in COPD patients in Europe (SPACE study, NCT03031769) was a multinational, multicenter, observational, cross-sectional study conducted in 144 centers across 11 countries (Austria, Belgium, Bulgaria, Greece, Israel, The Netherlands, Poland, Portugal, Romania, Serbia, Slovakia). Patients were recruited from pulmonology and primary care practices and hospitals. Patients with stable COPD who fulfilled the eligibility criteria were identified at each site and invited to participate in the study. To minimize selection bias, each site was allowed to enroll a maximum quota of patients as determined at country level. The study had a single visit; no interventions or extra procedures beyond clinical practice were required.
At the study visit, the investigators collected the following information: socio-demographics, comorbidities, year of COPD diagnosis, current COPD treatment, spirometry, number of exacerbations and COPD related visits to general practitioners and specialists in the last year. An exacerbation was defined as an acute worsening of respiratory symptoms that resulted in additional therapy, e.g., bronchodilators only (mild exacerbation), bronchodilators plus antibiotics and/or oral corticosteroids (moderate exacerbation), or requiring hospitalization or emergency room visits (severe exacerbation). Information was collected from medical charts and during interviews with patients. The COPD specific comorbidities test (COTE) index [
21] and the combined index of body mass index, obstruction, dyspnea and exacerbations (BODEx) [
22] were calculated. Patients were allocated into groups A to D following the GOLD 2013 [
23] and GOLD 2017 recommendations [
3].
The study and the informed consent form were approved by Institutional Review Boards or Ethics Committees in each participating country according to the local applicable legislation on observational studies. All patients provided their written informed consent before enrollment.
Assessments
SPACE study participants completed several interviewer- and patient-administered questionnaires. Dyspnea was assessed based on the patient’s response according to the modified Medical Research Council (mMRC) scale [
24] (from 0 = breathlessness with strenuous exercise to 4 = too breathless to leave the house or breathless when dressing or undressing). Health status and symptomatic impact of COPD was determined using the COPD Assessment Test (CAT) [
25] with scores ranging from 0 to 40, where higher scores indicate a worse health status. The GOLD ABCD assessment tool considers either the cut-off of ≥2 for mMRC or ≥ 10 for CAT to separate the low- and high-symptom burden groups [
3,
23].
The COPD symptoms (dyspnea, cough and sputum and chest symptoms) were evaluated using dedicated questionnaires for each part of the day [
26‐
28]. The occurrence and severity of night-time symptoms, nocturnal awakenings and rescue medication use due to symptoms were assessed with the Night-time Symptoms of COPD Instrument (NiSCI) [
26]. Daytime symptoms were evaluated using a derivative instrument based on the Evaluating Respiratory Symptoms in COPD (E-RS™: COPD) questionnaire, which quantified the respiratory symptoms in stable patients using total score (RS-Total score) and subscale scores (RS-Chest symptoms, RS-Cough & Sputum, RS-Breathlessness) [
27]. Total score ranges were from 0 to 40, with higher scores indicating more severe symptoms. The occurrence and severity of early morning symptoms, rescue medication use and limitations of activities due to symptoms were assessed with the Early Morning Symptoms of COPD Instrument (EMSCI) [
28]. For EMSCI and NiSCI, responses were coded from 0 to 4 (e.g., 0 = no symptoms, 1 = mild, 2 = moderate, 3 = severe, 4 = very severe). For night-time and early morning symptoms, two separate scores were calculated: an overall COPD severity domain score and a 6-item symptom severity score. Printed versions of the NiSCI and EMSCI questionnaires, customized for the SPACE study, were used to collect patient responses.
At the study visit, the investigators assessed the physical activity level of patients, according to their clinical judgement, and classified patients as active (performing ≥150 min/week of moderate to vigorous exercise, such as brisk walking), insufficiently active (performing 1–149 min/week of moderate to vigorous exercise) or completely inactive (0 min/week of moderate to vigorous exercise) [
29]. Patients self-reported their level of physical activity by answering two questions during clinical interview. These questions were derived from the exercise vital sign (EVS) program [
30] and refer to the number of days per week that patients engage in moderate to strenuous exercise and the number of minutes spent doing such exercise. Response choices were categorical and the electronic Case Report Form (CRF) automatically calculated the total minutes per week of moderate to vigorous physical activity, without displaying these responses to the investigator. The categories of physical activity level that were used in these questions were the same as those used in the investigator’s assessment. The physical activity of patients was also evaluated with the Yale Physical Activity Survey (YPAS) [
31]. YPAS is a detailed interviewer-administrated questionnaire specifically developed for senior subjects and validated for use in COPD patients [
32]. The questionnaire is divided into two parts, with a checklist to estimate the time spent in different groups of activities in a typical week from the past month and a section with questions assessing the participation in different types of activities (e.g., vigorous activity, sitting, standing) [
31]. The summary index score, derived from the second part of the questionnaire, ranged from 0 to 137. A cut-off score of 51 has been proposed to identify the patients most at risk of sedentarism [
32] and this value was used in the SPACE study for this purpose.
Study objectives
The primary objectives of the SPACE study were to describe the prevalence and severity of early morning, day and night-time symptoms, as well as the patterns of physical activity, in stable COPD patients. The secondary objective of the study was to characterize the relationship between the 24-h symptoms and physical activity level and other COPD dimensions including, but not limited to, exacerbation history, severity of disease, comorbidities, level of dyspnea and health status.
Sample size estimation
A sample size of 2000 patients offered a maximum margin of error (minimum precision) of 2% for estimating the percentage of patients within each category of the primary endpoint (symptoms and insufficient physical activity levels), considering maximum indetermination (p = 40%) and a confidence interval of 95%. Estimating that approximately 5% of patients would not be evaluable, due to missing data or not meeting all eligibility criteria, the final sample size was established at 2100 patients.
Statistical analysis
All eligible patients who met all inclusion criteria and none of the exclusion criteria were included in full analysis set (FAS). All analyses were performed for FAS. Statistical analyses were of an explorative and descriptive nature. The differences in means or medians of continuous variables between two groups have been tested using the t-test for normally distributed variables, and Wilcoxon signed rank test for non-normally distributed variables. The mean differences between more than two groups were analyzed using one-way analysis of variance or Kruskal-Wallis Rank Sum test. The difference between the expected and the observed frequencies in one or more categories was assessed using the Chi-squared test. The relationship between two variables was assessed with the correlation analysis, using the Pearson or Spearman correlation coefficient, based on the distribution of variables. All statistical tests were two-sided and used a 5% significance level. All statistical analyses were performed using software R (
https://www.r-project.org/), version 3.3.3.
Discussion
This observational, cross-sectional study showed that despite regular treatment, the majority of stable COPD patients with moderate to severe disease continue to experience daily variable symptoms and to have a sedentary lifestyle. The percentage of inactive patients is high in any GOLD ABCD groups, a result consistent throughout each PA questionnaire used in the SPACE study. Comprehensively assessing 24-h respiratory symptoms and physical activity level in a large multinational cohort of COPD patients, our study found a modest, but consistent, correlation between physical activity level and symptoms. Although the self-reported overall physical activity level of patients was low, it nevertheless appeared to be overestimated by their physicians.
Assessing respiratory symptoms over 24 h, a high percentage of stable patients from our real-life cohort reported mild and moderate symptoms throughout the day, despite regular treatment. In line with other studies performed in a similar population of patients, our results indicate that symptom variability is higher than expected in stable COPD patients [
7,
8,
12]. Future prospective studies are needed to explore how symptoms change from early morning to daytime and night-time, in terms of individual symptom type and severity, and if any patterns can be identified to guide and tailor the treatment of patients.
The second component of the SPACE study co-primary objective was physical activity in stable COPD patients; this concept was evaluated in a non-interventional manner from both the patients’ and physicians’ perspective, using interviewer- and self-reported questionnaires and clinical judgement, respectively. YPAS, a validated tool in elderly subjects, which captures a broad spectrum of low-intensity activities usually not included in other questionnaires, was used to evaluate PAL [
31]. YPAS results indicated that almost two-thirds of patients in the SPACE study were sedentary, with less time spent in performing activities (approx. 3 h/day) compared to healthy subjects of the same age or older (approx. 4–9 h/day) [
31,
33]. These results are similar to those reported in the study which validates the YPAS in COPD [
32]. Apart from a shorter duration of activity, the study participants tended to spend a longer time not performing any activity, as reflected by the sitting and standing index scores, a result which is in line with previous papers on this topic [
34,
35]. Sedentary time and PA were recently found to be important risk factors for hospitalization in COPD patients [
36]. Additionally, a longer sitting time seems to correlate with an increased risk of mortality, independent of leisure time physical activity undertaken [
37]. Thus, clinicians should be encouraged to investigate the patterns of inactivity in COPD patients and educate inactive individuals with regard to interrupting their sitting times [
20,
38,
39].
To our knowledge, no other studies have investigated the physicians’ perception of physical activity in their COPD patients, nor compared it with patients’ self-reported physical activity. The SPACE study investigators were asked to use clinical judgement in assessing the level of physical activity of their patients, leaving at their discretion how to explore it. During the clinical interview at the study visit, patients answered two questions from the EVS program [
30] to report their PAL, but the eCRF did not disclose patients’ answers to investigators. Physicians overestimated the level of physical activity in this population of stable, yet sedentary, COPD patients. Besides a different perception of the concept of physical activity, the difference between physicians and patients in estimating PALs indicates that patients are less active than their physicians perceive them to be, that physicians do not commonly assess PAL in respiratory patients and lack the tools to do so. These results are an indirect indicator of how physicians may underestimate the consequences of the physical inactivity in their COPD patients. As the fourth leading risk factor for global mortality worldwide [
40], physical inactivity should be aggressively fought. A large prospective study [
41] has found that the introduction of lower levels of activity, such as 15 min walking 6 days per week, might be beneficial in reducing all-cause mortality. These results are more realistic for COPD patients, in whom replacing sedentary behavior with light activities would be much more feasible than increasing the time spent in moderate to vigorous activities [
20,
39,
42]. Nevertheless, all these findings serve to underline the unmet need for a set of standardized tools and guidance for physicians to evaluate, promote and monitor physical activity in COPD patients in everyday clinical practice.
Understanding the relationship between respiratory symptoms across the 24-h day and physical activity has the potential to provide valuable insights for the clinical management of COPD in the real-life setting. However, there is no well-defined approach to evaluating symptoms or physical activity level and, in general, these clinical determinants are not assessed together. Our results indicated significant, but weak, relationships between 24-h symptoms and physical activity, which is not allowing us to draw definite conclusions. The data about this relationship in the literature are divergent and it is not yet known which component of the symptoms is related to physical activity. Previous research indicated the existence of a significant association between COPD symptoms and physical activity [
4,
7], but no causality was proven. In the SPACE study, we used three different instruments to assess physical activity and the results were consistent across all of these. Moreover, other studies showed that dyspnea, for example, is not the main factor limiting exercise in individuals with COPD [
34] and many patients chose to reduce their physical activity level rather than being restricted by symptoms [
17,
43,
44]. One important finding from our study was that PAL decreased with increasing severity of exacerbations. Exacerbations cause not only worsening of symptoms, but also affect patients’ daily activities, while inactive patients tend to have more severe exacerbations compared to active patients [
45,
46]. Furthermore, PAL decreased with an increasing number of comorbidities. Data in the literature indicate that daily PAL in COPD patients is impaired by comorbidities, irrespective of their type and independent of the level of airflow obstruction [
47]. These findings show that other dimensions of physical activity such as comorbidities, environmental factors and previous history of physical activity [
44] should be explored, combined with symptoms, to better understand and address the low physical activity level in COPD patients. Modifying complex health behavior, such as increasing levels of physical activity, is a difficult task and requires a multidisciplinary approach [
42]. More studies exploring the multimodal interventions (pharmacological and behavioral) [
48], more specific recommendations for increasing PA in people with COPD [
17,
20] and, perhaps, a change in the mindset of healthcare professionals to adequately understand physical activity levels in their patients, are needed in order to guide clinicians in current practice.
One of the main findings of our study is that the percentage of sedentary patients in mild stages of COPD is higher than that anticipated by investigators, as shown by their clinical judgement, irrespective of the GOLD edition used. Primarily, this result supports previous findings showing an increased proportion of patients with low PAL even in mild stages of COPD [
38,
49‐
51]. Secondly, while patients tend to consider themselves more inactive, physicians tend to overestimate the PAL in each GOLD group. Importantly, the YPAS results indicate that more than half of stable COPD patients in our cohort were sedentary, irrespective of GOLD group. Previous studies showed that COPD patients experience a faster decline in PAL over time compared to healthy people [
52]. This observation and the constant association between PA and mortality emphasize the importance of a proactive screening of physical inactivity in COPD patients from earlier stages of disease. Maybe physical inactivity is indeed the “missing link” in understanding the progression of COPD [
53]. Further insights in PA patterns and clinical characteristics of patients would allow for a more tailored approach, adapted to their needs and living conditions. In this context, it seems reasonable to challenge the current paradigm of assessing and treating COPD and to consider physical activity level as one of the determinants of the GOLD ABCD groups, as well as including an increase of PAL in patients’ written action plans as an objective in disease management.
A strength of this study is the comprehensive assessment of respiratory symptoms and PAL using multiple, validated questionnaires. Furthermore, we believe that this large population of patients is representative of the stable COPD populations, since patients were enrolled in multiple countries from various healthcare settings, including public and private practices and hospitals. However, several limitations of this study should be mentioned and one is the fact that we cannot provide information about any causal relationship, as SPACE was a real-world evidence study with a cross-sectional design. Specific relationships between symptoms in any part of the 24-h day, physical activity and other outcomes should be explored in more depth, adjusting for confounding factors. In the SPACE study, patient-reported outcomes (PROs) were collected through printed versions of the questionnaires and were subject to missing data, as there was no mechanism to prevent omitting questions. Although the electronic PROs are attractive, their use is not yet implemented in current clinical practice in all participating countries, thus having an interventional character. Lastly, there are no standardized tools for assessing physical activity levels. In our study, physical activity was measured only subjectively, through interviews using tools validated in COPD patients (YPAS). Self-reported PA is often subject to recall bias, lacks precision and, in many cases, does not correlate well with objectively measured physical activity [
41]. However, even in this context, our results indicate a real need for educating clinicians to adequately evaluate and monitor physical activity levels in clinical practice and the introduction of validated, standardized questionnaires might be the simplest way of achieving this.