Advertisement
Browse Subject Areas
?

Click through the PLOS taxonomy to find articles in your field.

For more information about PLOS Subject Areas, click here.

  • Loading metrics

Open Access

Peer-reviewed

Research Article

Impact of extrapulmonary comorbidities on physical activity in chronic obstructive pulmonary disease in Japan: A cross-sectional study

  • Makoto Yoshida ,

    Roles Conceptualization, Data curation, Investigation, Methodology, Project administration, Resources, Supervision, Validation, Visualization, Writing – original draft, Writing – review & editing

    yoshida.makoto.sv@mail.hosp.go.jp

    Affiliation Division of Respiratory Medicine, National Hospital Organization Fukuoka Hospital, Fukuoka, Japan

    ⨯
  • Tetsuya Hiramoto,

    Roles Formal analysis, Software, Writing – original draft

    Affiliation Division of Psychosomatic Medicine, National Hospital Organization Fukuoka Hospital, Fukuoka, Japan

    ⨯
  • Atsushi Moriwaki,

    Roles Investigation

    Affiliation Division of Respiratory Medicine, National Hospital Organization Fukuoka Hospital, Fukuoka, Japan

    ⨯
  • Hisayuki Osoreda,

    Roles Investigation

    Affiliation Division of Respiratory Medicine, National Hospital Organization Fukuoka Hospital, Fukuoka, Japan

    ⨯
  • Tomoaki Iwanaga,

    Roles Conceptualization, Project administration, Supervision, Writing – review & editing

    Affiliation Division of Respiratory Medicine, National Hospital Organization Fukuoka Hospital, Fukuoka, Japan

    ⨯
  • Hiromasa Inoue

    Roles Conceptualization, Funding acquisition, Supervision

    Affiliation Department of Pulmonary Medicine, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan

    ⨯

Abstract

Physical activity, which can be affected by airflow limitation and extrapulmonary comorbidities, has been reported to be reduced in patients with chronic obstructive pulmonary disease, and reduced physical activity is associated with higher risks of exacerbation and mortality. The aim of the present study is to elucidate the comprehensive effect of extrapulmonary comorbidities on physical activity in Japanese patients with chronic obstructive pulmonary disease, of which evidence is lacking. We conducted a cross-sectional study with a series of tests, including lung function, physical activity, symptom scores, and parameters for comorbidities. Sixty outpatients with stable disease were enrolled, and the relationship between the parameters and physical activity was evaluated. Physical activity was assessed over 7 consecutive days using a triaxial accelerometer, which records total daily energy expenditure, step count, and walking time. Cardiovascular status was assessed via echocardiography, and pulmonary artery pressure was estimated using Doppler sonography. As to mental status, depression and anxiety were assessed using the Self-Rating Depression Scale and State-Trait Anxiety Inventory, respectively. Physical activity level was significantly correlated with step count, walking time, body mass index, lean body mass index, lung function, pulmonary artery pressure, depression, anxiety, and serum total cholesterol level. In a median regression model analysis, low lung function, low lean body mass index, depression, and low serum total cholesterol level were independently associated with decreased physical activity level. These findings suggest that physical inactivity is affected by multiple extrapulmonary factors, including skeletal muscle dysfunction, depressive symptoms, and nutritional state, in Japanese patients with chronic obstructive pulmonary disease.

Citation: Yoshida M, Hiramoto T, Moriwaki A, Osoreda H, Iwanaga T, Inoue H (2022) Impact of extrapulmonary comorbidities on physical activity in chronic obstructive pulmonary disease in Japan: A cross-sectional study. PLoS ONE 17(7): e0270836. https://doi.org/10.1371/journal.pone.0270836

Editor: Davor Plavec, Srebrnjak Children’s Hospital, CROATIA

Received: May 10, 2021; Accepted: June 19, 2022; Published: July 27, 2022

Copyright: © 2022 Yoshida et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Data Availability: All relevant data are within the paper and its Supporting Information files.

Funding: This research is supported by Japan Agency for Medical Research and Development (AMED). The funders played no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Competing interests: The authors have declared that no competing interests exist.

Introduction

Chronic obstructive pulmonary disease (COPD) is characterised by persistent respiratory symptoms and airflow limitation that is due to airway and alveolar abnormalities usually caused by significant exposure to noxious gases [1]. Patients with COPD often experience shortness of breath or dyspnoea when they move, which makes them tire of moving and leads them to be more sedentary in their daily lives. Reduced physical activity causes further muscle weakness, which entraps them in a vicious downward spiral not only in their daily problems but also in the pathophysiology of the disease [2].

Exercise therapy in respiratory rehabilitation plays an important role in the management of COPD. Since exercise tolerance, or how much exercise a patient endures, is closely related to life prognosis in COPD [3], it has been used to evaluate athletic performance in respiratory rehabilitation. Recently, in addition to exercise tolerance, physical activity, which indicates how much the patient actually moves, has become recognised as one of the most important elements in the condition of COPD patients. Several observational studies have reported COPD patients with decreased physical activity disproportional to their restored exercise tolerance [4, 5].

Physical activity levels in CODP patients are reduced as compared to healthy adults without COPD, and such inactivity was observed even in Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage I, the earliest stage of the disease [6–8]. Studies using an accelerometer showed that an increase in physical activity level was associated with a lower risk of hospitalisation and death. A level of physical activity equivalent to walking or cycling 2 hours/week or more was associated with a 30–40% reduction in the risks of hospitalisation due to COPD and respiratory mortality [9]. Furthermore, physical activity level is reported to be the best discriminative property for 4-year survival and was associated with the highest relative risk of death [10]. A systematic review has shown that physical activity affects not only hospitalisation and mortality but also COPD exacerbation, health-related quality of life, dyspnoea, and exercise tolerance [11]. Taken together, these results indicate that even in the early stage of the disease, COPD patients showed a decrease in physical activity, which will lead to multiple adverse outcomes, especially poor survival prognosis. Therefore, the importance of physical activity is emphasised in COPD guidelines [1, 12].

Several factors have been reported to affect physical activity in COPD. It is well known that airflow obstruction is correlated with physical inactivity in COPD [8, 13, 14]. Other studies have shown that systemic inflammation, skeletal muscle disorders, and depression are associated with decreased physical activity [13, 15, 16]. One study inclusively investigated factors that influence physical activity in COPD using multiple regression analysis, and the authors showed that systemic inflammation and left ventricular diastolic dysfunction are associated with decreased physical activity [17].

According to these reports, it is becoming clear that not only lung function but also extrapulmonary comorbidities can lead to the physical inactivity of COPD patients, which is associated with higher risks of exacerbation and mortality. However, studies investigating the comprehensive influence of extrapulmonary comorbidities on physical activity in COPD patients of Asian race are lacking. Therefore, we conducted a cross-sectional study with a series of tests assessing lung function, symptoms, and comorbidities to elucidate the factors affecting physical activity in Japanese patients with COPD. The results of the present study will provide new insights into comprehensive strategies for future management of COPD.

Material and methods

Study subjects and design

The study was performed in the outpatient clinic of the National Hospital Organization Fukuoka National Hospital from June 2014 through March 2015. Diagnosis of COPD was based on cigarette smoking history and postbronchodilator forced expiratory volume in 1 second (FEV1)/ forced vital capacity (FVC) < 0.70 according to the Global Initiative for Chronic Obstructive Lung Disease [1]. COPD subjects who were stable over the previous 4 weeks were recruited. We conducted a cross-sectional study with a series of tests assessing physical activity, lung function, and comorbidities. The minimum sample size was calculated to be 46 using following parameters; anticipated effect size (f2) as 0.35, desired statistical power level as 0.8, probability as 0.05 and number of predictors as 6. The present study was approved by the ethics committee of the National Hospital Organization Fukuoka National Hospital (approval number: 26–11), and each participant gave written informed consent.

Physical activity measurement

We used a triaxial accelerometer, HJA-350IT (OMRON; Tokyo, Japan), which can record parameters including total daily energy expenditure, step count, walking time, and active time. Energy expenditure is expressed as Ex/day, which is calculated by multiplying metabolic equivalent of tasks (METs) by hours during the awake time of each day. Subjects wore a triaxial accelerometer for 7 consecutive days, and the mean values in each parameter were calculated.

Lung function and assessment of comorbidities

Spirometry was measured with a Chestac-8900 (Chest Co. Ltd., Tokyo, Japan). The diffusing capacity of lung for carbon monoxide (DLCO) was measured using the single breath-hold method. To assess metabolic and muscular states, body mass index (BMI; body weight in kilograms divided by squared height in metres) and lean body mass index (LBMI; lean body weight in kilograms divided by squared height in metres) were determined. Echocardiography was performed to measure the left ventricular ejection fraction (LVEF) and estimated systolic pulmonary artery pressure (esPAP), which was calculated by adding the trans-tricuspid gradient and right arterial pressure as described in a previous study [18]. Depression and anxiety statuses were measured using the Self-Rating Depression Scale (SDS) and State-Trait Anxiety Inventory (STAI), respectively [19, 20].

In order to assess other comorbidities, serum levels of C-reactive protein (CRP), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), albumin (Alb), triglyceride (TG), N-terminal pro-B-type natriuretic peptide (NT-proBNP), and blood glycated haemoglobin (haemoglobin A1c; HbA1c) were measured.

Statistical analyses

Data analyses were performed using STATA version 14 (StataCorp LLC, College Station, Texas, USA). Differences among patients in each GOLD stage of COPD were assessed via analysis of variance (ANOVA) for normally distributed variables and the Kruskal–Wallis test for non-normally distributed variables. The univariate analysis was assessed using Spearman’s rank correlation coefficient. To determine whether each parameter independently affected physical activity, the physical activity data were divided into 10 groups to minimise the effect of bias, and multiple regression analyses were performed. The data were divided into groups in order to fit multiple regression analysis, because they were not normally distributed even after logarithmic transformation. Number of groups were set enough to fit multiple regression analysis and to divide the data equally in size.

Results

Subject characteristics

Sixty-six patients were recruited. Six subjects were excluded from analyses because their mean wearing time of the accelerometer was less than 6 hours/day. We conducted analyses in 60 patients, and their demographic and clinical characteristics are summarised in Tables 1 and 2. There was no significant difference in ages among each stage of GOLD. Physical activity level, step counts, walk minutes, BMI, and LBMI gradually decreased significantly with the GOLD stages. The HbA1c level was significantly different between GOLD stages 3 and 4 (post hoc comparisons using the Scheffe test).

thumbnail
Download:
Table 1. Mean values of demographic characteristics and pulmonary function by GOLD stages.

https://doi.org/10.1371/journal.pone.0270836.t001

thumbnail
Download:
Table 2. Mean values of the parameters of extrapulmonary comorbidities by GOLD stages.

https://doi.org/10.1371/journal.pone.0270836.t002

Correlation between physical activity level and clinical parameters

As shown in Table 3, the results of univariate analysis showed that physical activity level was significantly correlated with the following parameters: step counts, walk minutes, BMI, LBMI, % predicted FVC, % predicted FEV1, % predicted DLCO, esPAP, SDS score, STAI1 score, and TC level.

thumbnail
Download:
Table 3. Relationship between physical activity and clinical characteristics assessed using Spearman’s rank correlation coefficient.

https://doi.org/10.1371/journal.pone.0270836.t003

In order to elucidate the factors independently affecting physical activity, we conducted a multiple regression analysis, in which we adopted parameters to minimise confounding. We set the mean daily physical activity level to a dependent variable, and % predicted FEV1, LBMI, esPAP, SDS score, and TC level were selected as independent variables for multivariate analysis, in order to evaluate impact of airflow limitation and following comorbidities; skeletal muscle dysfunction, pulmonary hypertension, depression, and metabolic disorder. As indicated in Table 4, % predicted FEV1, LBMI, and TC level were independent variables of the increase in physical activity level, while the SDS score was an independent variable of the decrease in physical activity level.

thumbnail
Download:
Table 4. Relationship between physical activity and clinical parameters assessed via multiple regression analysis.

https://doi.org/10.1371/journal.pone.0270836.t004

Discussion

To our knowledge, this is the first study to report that multiple extrapulmonary comorbidities significantly affect physical inactivity in stable Japanese COPD patients independently of airflow limitation based on multivariate analysis. We showed that respiratory functions, LBMI, esPAP, SDS score, and TC level were significantly related to physical activity. Among these related parameters, LBMI, SDS score, and TC level were independent factors according to multivariate analysis with a median regression model.

Evidence of the inclusive effect of extrapulmonary comorbidities on physical activity in COPD patients is limited, with only a single comprehensive study using multiple regression analysis [17], in which the fibrinogen level, NT-proBNP level, and left ventricular diastolic dysfunction assessed by the deceleration time of the early transmitral flow and the systemic inflammation were reported to be extrapulmonary factors significantly affecting physical activity. On the other hand, in the present study, although esPAP as an index of right-sided heart function was significantly correlated with physical activity level in univariate analysis, multivariate analysis showed that this parameter was not an independent factor. The difference between the previous report and our result might be due to the difference in data processing, sample size, and sample profiles including race, as all enrolled subjects were exclusively Asian in the present study. As to data processing, we did not adopt age or gender in the regression analysis because that information is included in the % predicted FEV1 value.

In the present study, we found that LBMI had a stronger independent correlation with physical activity level than did BMI. Previous studies have shown that the fat-free mass index correlated with exercise capacity [21] and that higher muscle mass in lower limbs, assessed by analysing computed tomography (CT) scan images of bilateral mid-thighs, was associated with increased physical fitness and physical activity [15]. LBMI (kg/m2) is calculated by dividing squared height by lean body weight, which is highly dependent on muscle mass, as it is a subtraction of body fat from total body weight, including amount of muscle, bone, viscera, and water. Taken together, the correlation of LBMI to physical activity level can be assumed to be explained by that of muscle mass to physical activity. Moreover, LBMI is a more useful index than muscle mass assessment calculated based on CT image, because it is more convenient, less invasive, and more comprehensive, as it reflects the total muscle amount of the whole body.

Several mechanisms underlying the decrease in skeletal muscle mass independent of lung function in COPD patients have been reported, including systemic inflammation [22], inadequate nutritional intake [23], and reduced physical inactivity, which facilitates the decrease in muscle mass via disuse atrophy as a consequence. In turn, the decrease in muscle mass makes COPD patients less active by impairing exercise tolerance, leading to a vicious downward spiral of disease progression [2]. As a risk factor, the fat-free mass index is reported to be the third strongest predictor of high mortality after physical activity and airflow limitation [10]. Taking into consideration that skeletal muscle decreases independently of airway obstruction and that a decrease in muscle can lead to poor prognosis both directly and indirectly via decreasing physical activity, intensive intervention with comprehensive rehabilitation should be encouraged in COPD management for better outcomes [2].

Previous studies have shown that depression was negatively correlated with physical activity level and walking time in patients with COPD [16, 24], which is consistent with our results showing that the depression score was an independent factor with a negative influence on the physical activity level. It has been reported that depression identified in patients with stable COPD was significantly associated with higher risks of exacerbation and hospitalisation [25]. As physical activity level per se was reported to be an independent prognostic factor for mortality and hospitalisation in COPD patients [26], taken together with our result, depression is an important risk factor for poor prognosis among COPD patients via both direct influence and indirect influence through physical inactivity. Furthermore, it has been reported that COPD patients with a depressive mental status tend to be more sedentary after pulmonary rehabilitation than those without depression. Therefore, mental status can affect the therapeutic effects of rehabilitation [27], and intervention with respect to mental status will provide an important therapeutic strategy for the management of COPD [28].

To our knowledge, this is the first study to report a significant relationship between TC level and physical activity level in COPD patients. In order to explore the underlying mechanisms, we first analysed the correlation between physical activity level and each fraction of cholesterol, high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C). There was no correlation between HDL-C level and physical activity level (r = 0.059, P = 0.514). Although the LDL-C level was significantly correlated with physical activity, its correlation coefficient (r = 0.340, P = 0.008) was smaller than that of the TC level (r = 0.432, P = 0.001). We next analysed the correlation between TC level and other clinical parameters to find a significant correlation with DLCO (0.284, P = 0.035), esPAP (r = 0.462, P < 0.001), BMI (r = 0.299, P = 0.027), NT-proBNP (r = -0.361, P = 0.007), serum albumin (r = 0.418, P = 0.002), and haemoglobin (r = 0.309, P = 0.022). These results suggest that the TC level might be related to the physical activity level through cardiac function and nutritional status. Further studies are needed to elucidate the precise mechanism(s) underlying these findings.

The present study has some limitations. First, all subjects were enrolled from a single facility, and the sample size was relatively small. In order to verify the results of the present study and obtain more accurate information, a multicentre study with larger sample size is needed. Second, esPAP was used to assess pulmonary artery pressure. Although right heart catheterisation is apparently preferable for accurate evaluation, we did not adopt this procedure because of its invasiveness.

Conclusion

In conclusion, low lung function, low LBMI, a high depression score, and a low TC level were independently associated with a decreased physical activity level in 60 Japanese patients with stable COPD in a median regression model analysis. These findings suggest that multiple extrapulmonary factors, including skeletal muscle dysfunction, depressive symptoms, and impaired nutritional state, lead to reduced physical inactivity and that intervention for these extrapulmonary comorbidities will provide new comprehensive strategies for better management of COPD.

References

  1. 1. Singh D, Agusti A, Anzueto A, Barnes PJ, Bourbeau J, Celli BR, et al. Global strategy for the diagnosis, management, and prevention of chronic obstructive lung disease: the GOLD science committee report 2019. Eur Respir J 2019; 53: 1900164. pmid:30846476
  2. 2. Marillier M, Bernard AC, Vergès S, Neder JA. Locomotor muscles in COPD: the rationale for rehabilitative exercise training. Front Physiol 2020; 10: 1590. pmid:31992992
  3. 3. Oga T, Nishimura K, Tsukino M, Sato S, Hajiro T. Analysis of the factors related to mortality in COPD: role of exercise capacity and health status. Am J Respir Crit Car Med 2003; 167: 544–549. pmid:12446268
  4. 4. Lareau SC, Meek PM, Press D, Anholm JD, Roos PJ. Dyspnea in patients with chronic obstructive pulmonary disease: does dyspnea worsen longitudinally in the presence of declining lung function? Heart Lung 1999; 28: 65–73. pmid:9915932
  5. 5. Sievi NA, Brack T, Brutsche MH, Frey M, Irani S, Leuppi JD, et al. "Can do, don’t do" are not the lazy ones: a longitudinal study on physical functioning in patients with COPD. Respir Res 2020; 21: 27. pmid:31959169
  6. 6. Gosker HR, Lencer NH, Franssen FM, van der Vusse GJ, Wouters EF, Schols AM. Striking similarities in systemic factors contributing to decreased exercise capacity in patients with severe chronic heart failure or COPD. Chest 2003; 123: 1416–1424. pmid:12740256
  7. 7. Pitta F, Troosters T, Spruit MA, Probst VS, Decramer M, Gosselink R. Characteristics of physical activities in daily life in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2005; 171: 972–977. pmid:15665324
  8. 8. Troosters T, Sciurba F, Battaglia S, Langer Da, Valluri SR, Martino L, et al. Physical inactivity in patients with COPD, a controlled multi-center pilot-study. Pespir Med 2010; 104: 1005–1011. pmid:20167463
  9. 9. Garcia-Aymerich J, Lange P, Benet M, Schnohr P, Antó JM. Regular physical activity reduces hospital admission and mortality in chronic obstructive pulmonary disease: a population based cohort study. Thorax 2006; 61: 772–778. pmid:16738033
  10. 10. Waschki B, Kirsten A, Holz O, Müller KC, Meyer T, Watz H, Magnussen H. Physical activity is the strongest predictor of all-cause mortality in patients with COPD: a prospective cohort study. Chest 2011; 140: 331–342. pmid:21273294
  11. 11. Gimeno-Santos E, Frei A, Steurer-Stey C, de Batlle J, Rabinovich RA, Raste Y, et al. Determinants and outcomes of physical activity in patients with COPD: a systematic review. Thorax 2014; 69: 731–739. pmid:24558112
  12. 12. Spruit MA, Singh SJ, Garvey C, ZuWallack R, Nici L, Rochester C, et al. An official American Thoracic Society/European Respiratory Society statement: key concepts and advances in pulmonary rehabilitation. Am J Respir Crit Car Med 2013; 188: e13–64. pmid:24127811
  13. 13. Garcia-Rio F, Lores V, Mediano O, Rojo B, Hernanz A, López-Collazo E, et al. Daily physical activity in patients with chronic obstructive pulmonary disease is mainly associated with dynamic hyperinflation. Am J Respir Crit Car Med 2009; 180: 506–512. pmid:19542481
  14. 14. Watz H, Waschki B, Meyer T, Magnussen H. Physical activity in patients with COPD. Eur Respir J 2009; 33: 262–272. pmid:19010994
  15. 15. Maddocks M, Shrikrishna D, Vitoriano S, Natanek SA, Tanner RJ, Hart N, et al. Skeletal muscle adiposity is associated with physical activity, exercise capacity and fibre shift in COPD. Eur Respir J 2014; 44: 1188–1198. pmid:24993908
  16. 16. Dueñas-Espín I, Demeyer H, Gimeno-Santos E, Polkey MI, Hopkinson NS, Rabinovich RA, et al. Depression symptoms reduce physical activity in COPD patients: a prospective multicenter study. Int J Chron Obstruct Pulmon Dis 2016; 11: 1287–1295. pmid:27354787
  17. 17. Watz H, Waschki B, Boehme C, Claussen M, Meyer T, Magnussen H. Extrapulmonary effects of chronic obstructive pulmonary disease on physical activity: a cross-sectional study. Am J Respir Crit Care Med 2008; 177: 743–751. pmid:18048807
  18. 18. Arcasoy SM, Christie JD, Ferrari VA, Sutton MS, Zisman DA, Blumenthal NP, et al. Echocardiographic assessment of pulmonary hypertension in patients with advanced lung disease. Am J Respir Crit Care Med 2003; 167: 735–740. pmid:12480614
  19. 19. Zung WW. A self-rating depression scale. Arch Gen Psychiatry 1965; 12: 63–70. pmid:14221692
  20. 20. Smith RC. Response bias in the State-Trait Anxiety Inventory: detecting the exaggeration of stress. J Psychol 1974; 86: 241–246. pmid:4818879
  21. 21. Luo Y, Zhou L, Li Y, Guo S, Li X, Zheng J, et al. Fat-free mass index for evaluating the nutritional status and disease severity in COPD. Respir Care 2016; 61: 680–688. pmid:26814217
  22. 22. Byun MK, Cho EN, Chang J, Ahn CM, Kim HJ. Sarcopenia correlates with systemic inflammation in COPD. Int J Chron Obstruct Pulmon Dis 2017; 12: 669–675. pmid:28255238
  23. 23. Nguyen HT, Collins PF, Pavey TG, Nguyen NV, Pham TD, Gallegos DL. Nutritional status, dietary intake, and health-related quality of life in outpatients with COPD. Int J Chron Obstruct Pulmon Dis 2019; 14: 215–226. pmid:30666102
  24. 24. Miravitlles M, Cantoni J, Naberan K. Factors associated with a low level of physical activity in patients with chronic obstructive pulmonary disease. Lung 2014; 192: 259–265. pmid:24477375
  25. 25. Xu W, Collet JP, Shapiro S, Lin Y, Yang T, Platt RW, et al. Independent effect of depression and anxiety on chronic obstructive pulmonary disease exacerbations and hospitalizations. Am J Respir Crit Care Med 2008; 178: 913–920. pmid:18755925
  26. 26. Garcia-Rio F, Rojo B, Casitas R, Lores V, Madero R, Romero D, et al. Prognostic value of the objective measurement of daily physical activity in patients with COPD. Chest 2012; 142: 338–346. pmid:22281798
  27. 27. Mesquita R, Meijer K, Pitta F, Azcuna H, Goërtz YMJ, Essers JMN, et al. Changes in physical activity and sedentary behaviour following pulmonary rehabilitation in patients with COPD. Respir Med 2017; 126: 122–129. pmid:28427543
  28. 28. Sohanpal R, Pinnock H, Steed L, Heslop Marshall K, Chan C, Kelly M, et al. Tailored, psychological intervention for anxiety or depression in people with chronic obstructive pulmonary disease (COPD), TANDEM (Tailored intervention for ANxiety and DEpression Management in COPD): protocol for a randomised controlled trial. Trials 2020; 21: 18. pmid:31907074