Factors associated with daily life physical activity in patients with asthma

Abstract Background and Objectives Little is known about the consequences of asthma on daily life physical activity (DLPA). The aim of this study was to evaluate DLPA and determine its relationship to clinical and functional parameters in patients with asthma. Methods This was a single‐center prospective study of DLPA conducted between May 2015 and June 2016 in northern France. Fifty‐one adult patients with asthma and 36 healthy control subjects were enrolled. Four DLPA parameters were assessed for 5 consecutive days with a physical activity monitor: number of steps walked per day (SPD), total energy expenditure (EE, in kcal/day), EE spent in physical activity requiring ≥3 metabolic equivalents (METs), and time (min) spent in activities requiring ≥3 METs. Clinical characteristics, pulmonary function tests, 6‐minute walk test, and four questionnaires (modified Medical Research Council [mMRC] for dyspnea, asthma control test [ACT], quality of life [AQLQ], and hospital anxiety and depression scale [HADS]), were evaluated. Comparisons of DLPA parameters between the two groups were performed using an analysis of covariance adjusted for age, sex, and body mass index (BMI). Relationships between DLPA parameters and patient characteristics were assessed in multivariable linear regression models. Results Compared with patients with mild/moderate asthma, those with severe asthma had lower mean (± standard deviation) forced expiratory volume in 1 s (FEV1) (66 ± 24 vs 94 ± 15% predicted, P < 0.001), ACT score (16.7 ± 4.5 vs 19.8 ± 4.2, P = 0.015), and AQLQ score (157 ± 40 vs 184 ± 33, P = 0.012). There were no significant differences between the two groups in SPD (6560 ± 3915 vs 8546 ± 3431; adjusted P = 0.95), EE in physical activity requiring ≥3 METs (620 ± 360 vs 660 ± 140 kcal/day; P = 0.86), time spent in activities requiring EE ≥3 (120 ± 54 vs 121 ± 32 min/day; P = 0.69), or total EE (2606 ± 570 vs 2666 ± 551 kcal/day; P = 0.80). These four DLPA measures showed strong inter‐parameter correlations in patients with asthma (r = 0.37–0.95, all P < 0.01). All four parameters were lower in the patients with asthma group than in the control group: SPD, 7651 ± 3755 vs 11704 ± 4054 (adjusted P < 0.001); EE in activities requiring ≥3 METs, 642 ± 360 vs 852 ± 374 kcal/day (adjusted P = 0.041); time spent in activities requiring ≥3 EE, 120 ± 73 vs 189 ± 85 min (adjusted P = 0.005); and total EE, 2639 ± 555 vs 2746 ± 449 kcal/day (adjusted P = 0.007). In the patients with asthma group, the number of SPD correlated with age, FEV1, mMRC score, 6‐minute walk test distance, and HADS scores, but not with BMI or ACT test score. Using multivariate analysis, the number of SPD was associated with only age, anxiety, and FEV1, whereas total EE was associated with mMRC score and BMI. Conclusion Age, anxiety, and FEV1 were significantly associated with the number of SPD in patients with asthma. Addressing anxiety should be further studied as way to attempt to increase physical activity in patients with asthma.


| INTRODUCTION
Asthma is a chronic inflammatory disease of the airways that is estimated by the World Health Organization to affect~300 million people worldwide. 1 According to the 2015 Global Initiative for Asthma, the degree to which physical activity is limited should be considered when assessing asthma control. 1 Physical activity is an important clinical parameter related to morbidity and mortality in many chronic diseases, 2,3 and higher levels of physical activity are associated with better lung function in asthma patients. 4 However, a recent review suggests that individuals with asthma are less likely than healthy subjects to engage in physical activity, despite its beneficial effects on symptom management, lung function, and mental health; conversely, physical inactivity was found to be associated with negative health consequences. 5 Patients with chronic obstructive pulmonary disease (COPD) also have low levels of physical activity, but this is not reflected in the clinical characteristics commonly used to determine disease severity. 6,7 Few studies have objectively evaluated daily life physical activity (DL PA ) levels in patients with asthma. Recently, Bahmer et al 8 and Cordova-Rivera et al, 9 using objective DL PA parameters, also reported that physical activity was reduced in severe asthma patients. van't Hul et al studied a large group of adults with bronchial asthma and found lower than average values for the number of steps per day, total energy expenditure (EE), and time spent in intensive physical activity; however, the study did not include patients with severe asthma. 10 In contrast, Sousa et al found no correlation between DL PA and asthma severity in children; indeed, DL PA levels were similar for children with good asthma control and those without asthma. 11 With these studies in mind, we sought to identify some of the factors, including anxiety and depression, that might influence DL PA in adult patients with severe or mild/moderate asthma. We examined the relationships between DL PA and the results of pulmonary function tests, the 6-minute walk test (6MWT), and of four questionnaires: the asthma control test (ACT), asthma quality of life questionnaire (AQLQ),

| Patients
We enrolled 51 consecutive patients with asthma (28 mild/moderate, 23 severe) who were referred to our hospital between December 2013 and January 2015 for routine follow-up. Severe asthma was defined as "asthma which requires treatment with high dose inhaled corticosteroids plus a second controller (and/or systemic corticosteroids) to prevent it from becoming 'uncontrolled' or which remains 'uncontrolled' despite this therapy." 12 The control group included 36 healthy subjects who were students or relatives of employees at the hospital. All control subjects had normal spirometry results. None of the patients or control subjects was engaged in exercise training programs prior to the study. All individuals gave informed consent.
Approval for the use of these data was provided by the Institutional Review Board of the French Learned Society for Pulmonology (CEPRO 2011-039).

| Pulmonary function tests
Forced vital capacity (FVC), forced expiratory volume in 1 s (FEV 1 ), and total lung capacity were measured by spirometry and plethysmography with a Jaeger-Masterlab® cabin. Values are expressed as the percentage of the predicted normal value. [13][14][15] The 6MWT was performed in accordance with international recommendations. 16

| Assessment of DL PA
Subjects were equipped with a physical activity monitor (SenseWear® Pro armband and SenseWear software version 8.0; BodyMedia Inc., Pittsburgh, PA, USA) and instructed to wear the device continuously, except while showering or bathing, for 5 consecutive days (3 weekdays and 2 weekend days). The device was positioned on the upper right arm, at the midpoint between the acromion and the olecranon.
This multiaxial device has been validated in diverse populations, including patients with chronic diseases. 8,17-19 DL PA was assessed by measuring four parameters: the average number of steps per day (SPD), the average time (min/day) spent in activities with an estimated EE of ≥3 metabolic equivalents (METs), the average EE spent in activities requiring ≥3 METs (kcal/day), and the average total daily EE (kcal/ day). METs reflect the energy cost of physical activity as a multiple of the patient's resting metabolic rate. 20 EE ≥ 3.0 METs is considered to be at least moderate activity. 21

| Evaluation of dyspnea
Subjects reported their perception of dyspnea occurring during DL PA using the mMRC self-administered questionnaire, which was assessed at the time of evaluation. The mMRC questionnaire is a unidimensional assessment of how dyspnea/breathlessness limits activity and affects functional ability, employment (disability), quality of life, and health status. 22 The questionnaire was developed in the 1950s by the Medical Research Council with the aim of detecting pneumoconiosis in coal workers, and was later standardized by Fletcher. 23 Since then, it has been validated in several chronic respiratory diseases, including asthma. 24 The five questions assess perceived breathlessness on a scale from 0 (not troubled by breathlessness except during strenuous exercise) to 4 (very severe dyspnea: too breathless to leave the house or breathless when dressing or undressing).

| Asthma control test (ACT)
The ACT survey is a self-administered questionnaire consisting of five items assessing asthma symptoms (daytime and nocturnal), use of rescue medications, and the effect of asthma on daily functioning. 25 Each item includes five response options corresponding to a five-point Likert-type rating scale. Responses for each of the five items are summed to yield a score ranging from 5 (poor control) to 25 (complete control). An ACT score > 19 indicates well-controlled asthma.

| Quality of life
The AQLQ comprises 32 items and is designed to identify the areas of functioning impaired by asthma in adult patients. 26

| Evaluation of anxiety and depression
The HADS questionnaire was designed to identify and quantify the two most common forms of psychological disorders in medical patients, anxiety and depression. 27 Both subscales range from 0 to 21, with a score of ≥8 indicating clinically relevant symptoms.

| Statistical analysis
Statistical analysis was performed using SAS statistical software, version 9.3 (SAS Institute Inc., Cary, NC) and GraphPad Prism 5 (GraphPad Software Inc., La Jolla, CA). Normal distribution of the data was checked graphically and using the Shapiro-Wilk test. predictors (at P < 0.1) were entered into multivariable linear regression models (one per DL PA parameter). Prior to the multivariable analysis, we first checked for the absence of co-linearity between candidate variables by calculating the variation inflation factor 28 and then tested all possible first-order interactions between candidate factors in separate linear regression models. To simplify the multivariable models, a backward-stepwise selection procedure was used with a removal criteria of P = 0.05. Statistical testing was done at the two-tailed α level of 0.05.

As shown in
In the asthma patient group, the mean number of SPD correlated  (Table S1). Interactions between age and FEV 1 , age and anxiety, and FEV 1 and anxiety on the number of SPD were significant at P < 0.1 and were included in the multivariable model together with the individually significant factors. After backward-stepwise selection, only age, interactions between age and FEV 1 , and interactions between FEV 1 and anxiety were associated with the number of SPD (R 2 = 0.51; Table 5).
While total EE correlated with the mMRC score (r = −0.30, P = 0.03), we did not observe significant correlations between total EE and HADS anxiety score (r = −0.27, P = 0.058) or BMI (r = 0.26, P = 0.063). No significant interactions between these parameters and total EE were found. In multivariate analysis, only BMI and mMRC score remained significantly associated with the total EE (Table S2).
The EE from activity requiring ≥3METs showed no significant correlation with HADS anxiety score (r = −0.27, P = 0.057) or mMRC score (r = −0.25, P = 0.077), and there was no interaction between these two parameters. In multivariate analysis, neither parameter remained significantly associated with EE ≥ 3 METS (Table S3).
No significant correlation was observed between the time spent in moderate activity (≥3 METs) and BMI (r = −0.25, P = 0.081), mMRC  score (r = −0.24, P = 0.088), or HADS anxiety score (r = −0.24, P = 0.094). No interactions were found in bivariate analysis. In multivariate analysis, only mMRC score was significantly associated with the time spent in moderate activity (Table S4).

| DISCUSSION
The results of this study show that DL PA is decreased in adult patients with asthma, and that the number of SPD is associated with age,   review of studies measuring physical activity in adults with an accelerometer determined that 3 to 5 days of monitoring were required to obtain reliable measurements. 29 In a recent study of COPD patients, physical activity was assessed over 10 days, and the data were evaluated from the last seven daily records. 30 The data presented here for asthma patients were collected over 5 consecutive days and were similar for weekdays and weekend days. Thus, the duration of data collection in our study is in line with the recommendation. Interestingly, the number of SPD walked by patients with severe asthma in our study was similar to that reported by Bahmer et al 8 33 We found that impairment of FEV 1 , which is representative of the magnitude of bronchial obstruction in asthma, was associated with the number of SPD. Bahmer reported that FEV 1 and peak expiratory flow were poor markers of physical activity in asthma patients, and they also found that reduced DL PA was associated with impulse oscillometric airway resistance and small airway dysfunction, 8 which was not evaluated in our study. Interestingly, no consistent association has been found between active lifestyle/physical inactivity and pulmonary function (after adjustment for confounding factors) in healthy subjects, lung-healthy adolescents, 34 or adult smokers. 35 In our study, the number of SPD was not associated with BMI, as previously reported for non-obese individuals. 36 However, we did detect a correlation between BMI and total EE, and this was stronger after adjust- in depressed compared with non-depressed COPD patients, 45 and anxiety is highly prevalent among asthma patients, [46][47][48] where it is associated with more exacerbations, 49 more hospital readmissions, 50 and poorer asthma control. 51,52 The molecular mechanisms responsible for anxiety are not well understood and might involve abnormal neural processing of stimuli. 53,54 Therefore, it is possible that asthma patients avoid exercise for fear of triggering symptoms, 55 which leads to a sustained overall aversion to exercise. 56 Studies of patients with other chronic diseases have failed to demonstrate that increases in DL PA can reduce symptoms of anxiety and depression. [57][58][59] However, it remains to be determined whether treatment for anxiety (medication or supportive psychotherapy) can increase DL PA in asthma patients. Encouragingly, two studies reported that asthma patients participating in a pulmonary rehabilitation program were able to increase their physical activity without exacerbating asthma, and in fact, it significantly improved their quality of life. 60,61 However, anxiety and depression were not evaluated in those studies.
The main limitation of our study is the small sample size. Therefore, we may have overlooked several interactions/associations due to inadequate statistical power. In addition, we acknowledge that we cannot exclude a degree of overfitting in the multivariate analyses given the number of variables analyzed. Further larger studies are warranted to confirm our findings.

| CONCLUSIONS
Age, anxiety, and FEV 1 are associated with the number of SPD in patients with asthma, who show reduced DL PA compared with healthy subjects. Addressing anxiety should be further studied as way to attempt to increase physical activity in patients with asthma. Abbreviations: FEV 1 , forced expiratory volume in 1 s; HADS, hospital anxiety and depression scale; SE, standard error.