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Volume 15 No. 07
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Accepted Papers





Scientific Investigations
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Physical Activity in Overlap Syndrome of COPD and Obstructive Sleep Apnea: Relationship With Markers of Systemic Inflammation

Christine M. Fitzgibbons, MD1,2; Rebekah L. Goldstein, MPH1,3; Daniel J. Gottlieb, MD1,3,4,5; Marilyn L. Moy, MD, MSc1,3,5
1Pulmonary and Critical Care Medicine Section, VA Boston Healthcare System, Boston, Massachusetts; 2Pulmonary and Critical Care, Boston University School of Medicine, Boston, Massachusetts; 3Department of Veterans Affairs, Rehabilitation Research and Development Service, Washington, DC; 4Division of Sleep Medicine, Brigham and Women's Hospital, Boston, Massachusetts; 5Harvard Medical School, Boston, Massachusetts

ABSTRACT

Study Objectives:

Low physical activity (PA) is associated with poor health outcomes in chronic obstructive pulmonary disease (COPD). Overlap syndrome (OVS), the co-occurrence of COPD and obstructive sleep apnea (OSA), is highly prevalent. Little is known about PA in OVS, and its relationship with markers of systemic inflammation.

Methods:

We studied 256 persons with stable COPD, 61 (24%) of whom had OVS, who were well characterized in two previous PA studies. PA was directly assessed with the Omron HJ-720ITC pedometer. C-reactive protein (CRP) and interleukin-6 (IL-6) were assayed from peripheral blood. Linear regression models, adjusting for age and forced expiratory volume in 1 second (FEV1) % predicted, assessed daily step counts and CRP and IL-6 levels in OVS, compared to COPD alone. Linear regression models, adjusting for age, FEV1 % predicted, and coronary artery disease, assessed the relationships between PA and CRP and IL-6 in those with OVS versus those with COPD alone.

Results:

Compared to COPD alone, persons with OVS walked 672 fewer steps per day (95% CI -1,317 to -28, P = .041). Those with OVS had significantly higher levels of CRP and IL-6 compared to COPD alone. In OVS, each 1,000 fewer steps walked was associated with a 0.875 ng/mL (95% CI 0.767 to 0.997) increase in IL-6, independent of lung function.

Conclusions:

Persons with OVS have significantly lower levels of PA and higher levels of inflammatory biomarkers, compared to COPD alone. Lower PA is significantly associated with higher IL-6 levels in OVS.

Citation:

Fitzgibbons CM, Goldstein RL, Gottlieb DJ, Moy ML. Physical activity in overlap syndrome of COPD and obstructive sleep apnea: relationship with markers of systemic inflammation. J Clin Sleep Med. 2019;15(7):973–978.


BRIEF SUMMARY

Current Knowledge/Study Rationale: Low physical activity (PA) is associated with poor health outcomes in chronic obstructive pulmonary disease (COPD). Comorbid obstructive sleep apnea, overlap syndrome (OVS), is highly prevalent. Little is known about PA in OVS, and its relationship with markers of systemic inflammation.

Study Impact: Persons with OVS have significantly lower levels of PA, and higher levels of inflammatory biomarkers, compared to COPD alone. Lower PA is significantly associated with higher levels of IL-6 in OVS, independent of lung function. It is important to diagnose OVS in persons with COPD and promote PA.

INTRODUCTION

Chronic obstructive pulmonary disease (COPD), a chronic lung disease that includes emphysema and chronic bronchitis, is a common cause of morbidity and mortality that affects about 10% of the adult population.1 Obstructive sleep apnea (OSA), a disorder characterized by recurrent upper airway collapse that results in periods of apnea and hypopnea during sleep, is also common with prevalence estimated to be 9% in middle-aged women and 24% in middle-aged men.2 The co-occurrence of these two disorders, COPD and OSA, known as the overlap syndrome (OVS), is estimated to affect at least 1% of the general adult population.35

OVS is associated with a worse clinical prognosis, including increased risk for cardiovascular morbidity, hospitalization due to COPD acute exacerbation, and all-cause mortality, when compared to patients with COPD alone.68 The underlying mechanisms explaining the observed increased morbidity and mortality in OVS are unknown.911 COPD is a systemic disease characterized by elevation in markers of systemic inflammation during stable states and acute exacerbations.1214 Alterations in gas exchange and elevations in inflammatory biomarkers during disturbances in the sleep-wake cycle have been implicated in the etiology for cardiovascular morbidity and mortality in OVS.9,15 There may be an additive effect of OVS to increase inflammatory cytokines due to more pronounced nocturnal oxygen desaturation, hypercapnia, pulmonary hypertension, decreases in physical activity (PA), disordered sleep and sleepiness, elevated body mass index (BMI), cigarette smoking, and comorbidities and medications.8,9,11,15

In COPD, engagement in PA is a positive health behavior that is associated with better outcomes.1624 Those who walk the most have the lowest risk of acute exacerbations, hospitalization, and death in COPD, independent of lung function.1724 Exercise and PA have also been shown to be reduced in OSA alone, independent of BMI.2527 Since lower PA is associated with worse cardiovascular health, higher levels of markers of systemic inflammation, and increased risk for acute exacerbations in COPD, it may be a modifiable behavior that is a plausible causative link between OVS and the observed morbidity and mortality. The relationships between PA and markers of systemic inflammation have not been characterized in OVS.

In two previous PA studies,28,29 we directly measured PA as daily step counts in participants with OVS and COPD alone. We also measured C-reactive protein (CRP), an acute-phase inflammatory protein associated with acute exacerbations in COPD,12,13 and interleukin-6 (IL-6) which is predictive of cardiovascular disease in OSA.9,11 In this secondary analysis, we aim to (1) characterize directly measured PA and markers of systemic inflammation, CRP and IL-6, in OVS compared to COPD alone, and (2) understand the relationships between PA and levels of CRP and IL-6 in OVS.

METHODS

Study Design and Participants

We analyzed baseline data from 256 persons with stable COPD who were well characterized in two PA studies.28,29 These studies, including inclusion and exclusion criteria, have been previously described.28,29 Briefly, study one assessed PA in an observational cohort of 176 participants with COPD enrolled from the general pulmonary clinics between 2009–2011.28 Eligible participants were over 40 years of age and had a smoking history of ≥ 10 pack-years and a ratio of forced expiratory volume in 1 second (FEV1) to forced vital capacity < 0.70. All participants were in stable clinical state at the time of assessments, without an acute exacerbation in the 4 weeks prior to assessment. The protocol (#1961) was approved by the VA Boston Healthcare System Committee on Human Research, and written informed consent obtained from each participant.

Study two examined the efficacy of a technology-based PA intervention, and enrolled 114 participants with COPD from the pulmonary clinics between 2012–2016.29 Participants were ≥ 40 years of age; had a smoking history of ≥ 10 pack years and a ratio of FEV1 to forced vital capacity < 0.70 or emphysema on a clinical chest CT; and had access to the internet.29 Participants were at their baseline clinical status and received medical clearance from a health care provider to participate. The protocol (#2328) was approved by the VA Boston Healthcare System Committee on Human Research, and informed consent was obtained from each participant. Study two was a randomized trial registered on ClinicalTrials.gov (registration number NCT01772082).

Clinical Characteristics, Cardiac Disease, and Cardiovascular Risk Factors

At study entry in both studies, we obtained a comprehensive medical history to characterize the cohorts. The diagnosis of OSA was self-reported; participants were asked specifically if they had a diagnosis of OSA. Cardiac disease assessed included coronary artery disease (CAD) and congestive heart failure. Cardiovascular risk factors assessed included active cigarette smoking, hypertension, diabetes mellitus, and obesity defined as BMI ≥ 30 kg/m2. Weight and height were measured to calculate BMI. Participants underwent measurement of FEV1 using an Eaglet spirometer (nSpire Health, Inc.).30,31 The 6-minute walk test was performed following American Thoracic Society guidelines.32 Health-related quality of life was assessed using the St. George's Respiratory Questionnaire,33 with lower scores indicating better health-related quality of life (range 0–100). Dyspnea was assessed using the modified Medical Research Council dyspnea scale, (responses 0–4 with 4 being the most dyspneic).34

Physical Activity Assessment

The Omron HJ-720 ITC pedometer accurately measures step counts in persons with COPD.35 Baseline daily step count was collected in all participants using an Omron for 14 days (study one) or 7 days (study two). Participants were instructed to wear the Omron during all awake hours and to perform their usual physical activities. Participants received no step-count feedback since a sticker covered the pedometer display. Participants returned the Omron by mail and staff downloaded date and time stamped step-count data via the embedded USB port. Daily step count was averaged from at least 5 of 14 valid wear-days (study one) and 5 of 7 valid wear-days (study two). No-wear days, defined as days with < 200 steps recorded and < 8 hours of wear time, were excluded from the analysis.35,36

Markers of Systemic Inflammation

Peripheral blood was collected by venipuncture into vacutainer tubes with ethylenediaminetetraacetic acid anticoagulant. Blood was collected between 9:30 am and 3:00 pm at the baseline in-clinic visit. Plasma was obtained by centrifugation of tubes at 1,459×g for 15 minutes. The samples were stored at −80°C until analyzed. CRP and IL-6 were measured by the Clinical and Epidemiologic Research Laboratory, Children's Hospital, Boston, Massachusetts. CRP and IL-6 were determined using a high-sensitivity immunoturbidimetric assay with a sensitivity of 0.03 mg/L and 0.094 pg/mL, respectively.17

Statistical Analysis

We compared characteristics between those with OVS (n = 61) and those with COPD alone (n = 195) using unpaired t test, Wilcoxon rank sum test, chi square test, or Fisher exact test, as appropriate. Regression models (PROC GLM, SAS 9.4) were used to assess the independent relationships between group (OVS versus COPD alone), and daily step counts and levels of CRP and IL-6. All models adjusted for age and FEV1 % predicted. Levels of CRP and IL-6 were converted to the natural logarithmic (ln) values to best approximate a normal distribution. In the subgroups of OVS or COPD alone, linear regression models, adjusting for age, FEV1 % predicted, and CAD, assessed the relationship between daily step counts and levels of CRP and IL-6.

RESULTS

Characteristics, Cardiac Disease, and Cardiovascular Risk Factors in Overlap Syndrome

The cohort consisted of 256 participants, 195 (76%) with COPD alone and 61 (24%) with OVS. Average age was 71 ± 8 years, average FEV1 was 1.67 ± 0.62 L, 58 ± 21 % predicted, and 98% were male (Table 1). Participants with OVS had a significantly higher prevalence of CAD and congestive heart failure. There was no difference between those with OVS compared to those with COPD alone with respect to age, pack-years, and FEV1. BMI was significantly higher in the OVS group than the COPD alone group, with median values of 33 versus 27 kg/m2, P < .0001. BMI was significantly associated with CAD, congestive heart failure, hypertension, diabetes mellitus, and active cigarette smoking. BMI was not significantly correlated with either daily step counts or levels of CRP and IL-6.

Baseline characteristics.

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Table 1

Baseline characteristics.

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Physical Activity in Overlap Syndrome

Participants with OVS had significantly lower daily step count compared to persons with COPD alone (median values of 1,745 versus 2,411 steps per day, P = .046), (Table 1). Compared to COPD alone, those with overlap walked on average 672 fewer steps per day, (95% CI -1,317 to -28; P = .041, adjusting for age and FEV1 % predicted) (Table 2).

Daily step count in persons with OVS, compared to COPD alone.

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Table 2

Daily step count in persons with OVS, compared to COPD alone.

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Systemic Inflammation in Overlap Syndrome

Participants with OVS had significantly higher levels of CRP and IL-6, compared to COPD alone (Table 1). They had average CRP levels 1.57 mg/L (95% CI 1.13, 2.19; P = .008) and average IL-6 levels 1.36 ng/mL (95% CI 1.10, 1.69; P = .005) higher than persons with COPD alone, independent of age and lung function (Table 3).

Markers of systemic inflammation, ln(CRP) and ln(IL-6), in persons with OVS, compared to COPD alone.

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Table 3

Markers of systemic inflammation, ln(CRP) and ln(IL-6), in persons with OVS, compared to COPD alone.

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Physical Activity and Systemic Inflammation in Overlap Syndrome

Daily step count was significantly associated with IL-6 in OVS or COPD alone, independent of lung function. In a separate model that included OVS or COPD alone and daily step counts as an interaction term, the term was not statistically significant (P = .32). For each 1,000-step decrease, there was an average increase in IL-6 levels of 0.875 ng/mL (95% CI 0.767, 0.997) in the OVS group and 0.953 ng/mL (95% CI 0.913, 0.995) in the COPD alone group (Table 4 and Table 5). These relationships were not significant between daily step count and CRP. For each 1,000-step decrease, there was an average increase in CRP levels of 0.970 mg/L (95% CI 0.811, 1.16) in the OVS group and 0.955 mg/L (95% CI 0.889, 1.03) in the COPD alone group (Table 4 and Table 5).

In OVS, multivariable models of associations between daily step count and ln(IL-6) and ln(CRP).

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Table 4

In OVS, multivariable models of associations between daily step count and ln(IL-6) and ln(CRP).

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In COPD alone, multivariable models of associations between daily step count and ln(IL-6) and ln(CRP).

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Table 5

In COPD alone, multivariable models of associations between daily step count and ln(IL-6) and ln(CRP).

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DISCUSSION

We show that persons with self-reported OVS have significantly lower PA assessed as daily step counts and higher levels of CRP and IL-6, compared to persons with COPD alone. Lower daily step counts is significantly associated with higher levels of CRP and IL-6 in persons with OVS, as in persons with COPD alone.

A recent American Thoracic Society statement concluded that research priorities for sleep-disordered breathing in patients with COPD should include “observational studies that compare clinical outcomes among patients with OVS to clinical outcomes among patients with OSA alone or COPD alone.”37 In our cohort, persons with OVS had lower PA compared to persons with COPD alone. While reduced PA has been reported in persons with OSA and COPD individually, this is the first report to date to objectively and directly quantify PA in persons OVS. It is striking that person with OVS walk on average 672 fewer steps per day than persons with COPD alone. This difference of 672 steps per day is within the range of 350–1,100 steps per day, reported as the minimum clinically important difference for daily step counts in stable COPD.38,39

Since lower PA is associated with poor pulmonary-specific and general outcomes in COPD, these results further highlight the importance for detection of OSA in persons with COPD. Our results extend our current knowledge by demonstrating elevations in CRP and IL-6 in a cohort of patients with self-reported OVS, compared to COPD alone. Although there are no “normal” values for CRP and IL-6 published for patients with OVS, we found that CRP and IL-6 values in stable COPD can be quite variable. A mean CRP level of 5.0 ± 1.5 mg/L was reported in 88 patients with stable COPD,40 while a mean CRP level of 10.97 ± 14.00 mg/L was reported in 35 stable patients.41 Plasma levels of IL-6 changed from 6.38 ± 0.72 pg/mL during an acute exacerbation to 2.80 ± 0.79 pg/mL during recovery.42 The levels of CRP and IL-6 observed in the current analyses are within the published ranges.

In this cohort, daily step count was inversely associated with IL-6 levels in persons with OVS and COPD alone. While higher IL-6 levels have previously been associated with lower step counts in persons with COPD, this is a novel finding in persons with OVS.17 Our findings demonstrate that it is plausible that elevations in inflammatory markers in OVS may mediate the observed morbidity and mortality. The nature of the relationship between PA and IL-6 is similar in OVS and COPD alone, given that the interaction term was not significant. For a given low daily step count, those with OVS did not have significantly higher levels of IL-6, compared to COPD alone.

The well-characterized cohorts and the directly measured PA are strengths of this analysis. We show that the prevalence of cardiac disease and cardiovascular risk factors is higher in OVS, compared to COPD alone. Our study has several limitations. The data rely upon participant self-reported diagnosis of OSA and comorbidities. The severity and treatment of OSA are unknown. Therefore, no conclusion can be drawn regarding the influence that OSA severity may have on these findings. We also did not assess nocturnal oxygen desaturations which affects systemic inflammation. Our cohorts are small and preclude analysis of effect modification by CAD and cardiovascular risk factors on the relationships between PA and levels of CRP and IL-6. Future studies in OVS are needed to assess the impact of CAD, hypertension, diabetes mellitus, and obesity on levels of CRP, IL-6, and other markers of systemic inflammation. Our results are descriptive and do not prove causality. While results are drawn from two separate cohorts, only baseline values are reported and the cohorts are from a similar COPD population. Finally, both cohorts included participants who voluntarily enrolled in studies examining PA and thus a healthy user bias may influence the generalizability of results.

Given the high prevalence and increased morbidity associated with COPD and OSA, further knowledge is needed regarding the interrelationship of both disorders. Here we expand the limited literature by reporting that persons with OVS have significantly lower levels of PA and higher levels of CRP and IL-6, compared to COPD alone. We also show that lower PA is significantly associated with higher levels of IL-6. Future work is needed to assess whether engagement in PA may be a modifiable behavior that impacts risk for acute exacerbations and cardiovascular risk factors in OVS.

CONCLUSIONS

Persons with OVS have significantly lower PA assessed by daily step counts, compared to COPD alone. They also have higher levels of CRP and IL-6. Lower daily step count is significantly associated with higher levels of IL-6, independent of lung function and history of CAD. Additional studies are needed to assess whether promoting PA in persons with OVS, as in persons with COPD alone, may decrease systemic inflammation and, consequently, risk for pulmonary- and cardiovascular-related morbidity and mortality.

DISCLOSURE STATEMENT

All authors have seen and approved the manuscript. The work was performed at VA Boston Healthcare System. The authors report no conflicts of interest.

ABBREVIATIONS

BMI

body mass index

CAD

coronary artery disease

COPD

chronic obstructive pulmonary disease

CRP

C-reactive protein

FEV1

forced expiratory volume in 1 second

IL-6

interleukin-6

OSA

obstructive sleep apnea

OVS

overlap syndrome

PA

physical activity

REFERENCES

1 

Global Initiative for Chronic Obstructive Lung Disease. Global Strategy for the Diagnosis, Management and Prevention of Chronic Obstructive Pulmonary Disease: 2017 Report. Fontana, WI: Global Initiative for Chronic Obstructive Lung Disease; 2017.

2 

Young T, Palta M, Dempsey J, Skatrud J, Weber S, Badr S. The occurrence of sleep-disordered breathing among middle-aged adults. N Engl J Med. 1993;328(17):1230–1235. [PubMed]

3 

Du W, Liu J, Zhou J, Ye D, OuYang Y, Deng Q. Obstructive sleep apnea, COPD, the overlap syndrome, and mortality: results from the 2005-2008 National Health and Nutrition Examination Survey. Int J Chron Obstruct Pulmon Dis. 2018;13:665–674. [PubMed Central][PubMed]

4 

Zohal MA, Yazdi Z, Kazemifar AM, Mahjoob P, Ziaeeha M. Sleep quality and quality of life in COPD patients with and without suspected obstructive sleep apnea. Sleep Disord. 2014;2014:508372[PubMed Central][PubMed]

5 

Chaouat A, Weitzanblum E, Krieger J, Ifoundza T, Oswald M, Kessler R. Association of chronic obstructive pulmonary disease and sleep apnea syndrome. Am J Respir Crit Care Med. 1995;151(1):82–86. [PubMed]

6 

Sharma B, Neilan TG, Kwong RY, et al. Evaluation of right ventricular remodeling using cardiac magnetic resonance imaging in co-existent chronic obstructive pulmonary disease and obstructive sleep apnea. COPD. 2013;10(1):4–10. [PubMed]

7 

Ganga HV, Nair SU, Puppala VK, Miller WL. Risk of new-onset atrial fibrillation in elderly patients with the overlap syndrome: a retrospective cohort study. J Geriatr Cardiol. 2013;10(2):129–134. [PubMed Central][PubMed]

8 

Marin JM, Soriano JB, Carrizo SJ, Boldova A, Celli BR. Outcomes in patients with chronic obstructive pulmonary disease and obstructive sleep apnea: the overlap syndrome. Am J Respir Crit Care Med. 2010;182(3):325–331. [PubMed]

9 

McNicholas WT. Chronic obstructive pulmonary disease and obstructive sleep apnea: overlaps in pathophysiology, systemic inflammation, and cardiovascular disease. Am J Respir Crit Care Med. 2009;180(8):692–700. [PubMed]

10 

Jen R, Li Y, Owens RL, Malhotra A. Sleep in chronic obstructive pulmonary disease: evidence gaps and challenges. Can Respir J. 2016;2016:7947198[PubMed Central][PubMed]

11 

McNicholas WT. COPD-OSA overlap syndrome: evolving evidence regarding epidemiology, clinical consequences, and management. Chest. 2017;152(6):1318–1326. [PubMed]

12 

Agustí AG, Noguera A, Sauleda J, Sala E, Pons J, Busquets X. Systemic effects of chronic obstructive pulmonary disease. Eur Respir J. 2003;21(2):347–360. [PubMed]

13 

Faner R, Sobradillo P, Noguera A, et al. The inflammasome pathway in stable COPD and acute exacerbations. ERJ Open Res. 2016;2(3)

14 

Gan WQ, Man SF, Senthilselvan A, Sin DD. Association between chronic obstructive pulmonary disease and systemic inflammation: a systematic review and a meta-analysis. Thorax. 2004;59(7):574–580. [PubMed Central][PubMed]

15 

Lavie L. Obstructive sleep apnoea syndrome: an oxidative stress disorder. Sleep Med Rev. 2003;7(1):35–51. [PubMed]

16 

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(9):972–977. [PubMed]

17 

Moy ML, Teylan M, Weston NA, Gagnon DR, Danilack VA, Garshick E. Daily step count is associated with plasma C-reactive protein and IL-6 in a US cohort with COPD. Chest. 2014;145(3):542–550. [PubMed]

18 

Watz H, Pitta F, Rochester CL, et al. An official European Respiratory Society statement on physical activity in COPD. Eur Respir J. 2014;44(6):1521–1537. [PubMed]

19 

Waschki B, Kirsten A, Holz O, et al. Physical activity is the strongest predictor of all-cause mortality in patients with COPD. A prospective cohort study. Chest. 2011;140(2):331–342. [PubMed]

20 

Vaes AW, Garcia-Aymerich J, Marott JL, et al. Changes in physical activity and all-cause mortality in COPD. Eur Respir J. 2014;44(5):1199–1209. [PubMed]

21 

Moy ML, Gould MK, Liu IA, Lee JS, Nguyen HQ. Physical activity assessed in routine care predicts mortality after a COPD hospitalisation. ERJ Open Res. 2016;2(1)

22 

Moy ML, Teylan M, Weston NA, Gagnon DR, Garshick E. Daily step count predicts acute exacerbations in a US cohort with COPD. PLoS One. 2013;8:e60400[PubMed Central][PubMed]

23 

Nguyen HQ, Chu L, Amy Liu IL, et al. Associations between physical activity and 30-day readmission risk in chronic obstructive pulmonary disease. Ann Am Thorac Soc. 2014;11(5):695–705. [PubMed]

24 

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(9):772–778. [PubMed Central][PubMed]

25 

Hargens TA, Martin RA, Strosnider CL, Giersch GEW, Womack CJ. Obstructive sleep apnea negatively impacts objectively measured physical activity. Sleep Breath. 2019;23(2):447–454. [PubMed]

26 

Mendelson M, Marillier M, Bailly S, et al. Maximal exercise capacity in patients with obstructive sleep apnoea syndrome: a systematic review and meta-analysis. Eur Respir J. 2018;51(6)

27 

Simpson L, McArdle N, Eastwood PR, et al. Physical inactivity is associated with moderate-severe obstructive sleep apnea. J Clin Sleep Med. 2015;11(10):1091–1099. [PubMed Central][PubMed]

28 

Moy ML, Danilack VA, Weston NA, Garshick E. Daily step counts in a US cohort with COPD. Respir Med. 2012;106:962–969. [PubMed Central][PubMed]

29 

Wan ES, Kantorowski A, Homsy D, et al. Promoting physical activity in COPD: Insights from a randomized trial of a web-based intervention and pedometer use. Respir Med. 2017;130:102–110. [PubMed Central][PubMed]

30 

Miller MR, Hankinson J, Brusasco V, et al. Standardisation of spirometry. Eur Respir J. 2005 8;26(2):319–338. [PubMed]

31 

Hankinson JL, Odencrantz JR, Fedan KB. Spirometric reference values from a sample of the general U.S. population. Am J Respir Crit Care Med. 1999;159(1):179–187. [PubMed]

32 

ATS Committee on Proficiency Standards for Clinical Pulmonary Function Laboratories. ATS statement: guidelines for the six-minute walk test. Am J Respir Crit Care Med. 2002;166(1):111–117. [PubMed]

33 

Jones PW, Quirk FH, Baveystock CM, Littlejohns P. A self-complete measure of health status for chronic airflow limitation. The St. George's Respiratory Questionnaire. Am Rev Respir Dis. 1992;145(6):1321–1327. [PubMed]

34 

Bestall JC, Paul EA, Garrod R, Garnham R, Jones PW, Wedzicha JA. Usefulness of the Medical Research Council (MRC) dyspnoea scale as a measure of disability in patients with chronic obstructive pulmonary disease. Thorax. 1999;54(7):581–586. [PubMed Central][PubMed]

35 

Danilack VA, Okunbor O, Richardson CR, Teylan M, Moy ML. Performance of a pedometer to measure physical activity in a US cohort with COPD. J Rehabil Res Dev. 2015;52(3):333–342. [PubMed]

36 

Matthews CE, Hagströmer M, Pober DM, Bowles HR. Best practices for using physical activity monitors in population-based research. Med Sci Sports Exerc. 2012;44 1 Suppl 1:S68–S76. [PubMed Central][PubMed]

37 

Malhotra A, Schwartz AR, Schneider H, et al. Research priorities in pathophysiology for sleep-disordered breathing in patients with chronic obstructive pulmonary disease. An Official American Thoracic Society Research Statement. Am J Respir Crit Care Med. 2018;197(3):289–299. [PubMed]

38 

Teylan M, Kantorowski A, Homsy D, Kadri R, Richardson C, Moy M. Physical activity in COPD: minimal clinically important difference for medical events. Chronic Resp Dis. 2019;16:1479973118816424

39 

Demeyer H, Burtin C, Hornikx M, et al. The minimal important difference in physical activity in patients with COPD. PLoS One. 2016;11(4):e0154587[PubMed Central][PubMed]

40 

Pinto-Plata VM, Müllerova H, Toso JF, et al. C-reactive protein in patients with COPD, control smokers and non-smokers. Thorax. 2006;61(1):23–28. [PubMed]

41 

Karadag F, Kirdar S, Karul AB, Ceylan E. The value of C-reactive protein as a marker of systemic inflammation in stable chronic obstructive pulmonary disease. Eur J Intern Med. 2008;19(2):104–108. [PubMed]

42 

Pinto-Plata VM, Livnat G, Girish M, et al. Systemic cytokines, clinical and physiological changes in patients hospitalized for exacerbation of COPD. Chest. 2007;131(1):37–43. [PubMed]