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Original Research: COPD |

Daily Step Count Is Associated With Plasma C-Reactive Protein and IL-6 in a US Cohort With COPDDaily Step Count and Inflammatory Biomarkers in COPD FREE TO VIEW

Marilyn L. Moy, MD; Merilee Teylan, MPH; Nicole A. Weston, BS; David R. Gagnon, MD, PhD; Valery A. Danilack, MPH; Eric Garshick, MD
Author and Funding Information

From the Department of Veteran Affairs (Drs Moy and Garshick), Veterans Health Administration, Rehabilitation Research and Development Service, Boston, MA; Pulmonary and Critical Care Medicine Section (Drs Moy and Garshick and Mss Teylan, Weston, and Danilack), VA Boston Healthcare System, Boston, MA; Division of Pulmonary and Critical Care Medicine (Dr Moy) and Channing Division of Network Medicine (Dr Garshick), Department of Medicine, Brigham and Women’s Hospital, Boston, MA; Harvard Medical School (Drs Moy and Garshick), Boston, MA; Department of Biostatistics (Dr Gagnon), Boston University School of Public Health, Boston, MA; VA Cooperative Studies (Dr Gagnon), Boston, MA; and Department of Epidemiology (Ms Danilack), Brown University, Providence, RI.

Correspondence to: Marilyn L. Moy, MD, VA Boston Healthcare System, Pulmonary and Critical Care Section, 1400 VFW Parkway, Mail Code 111PI, West Roxbury, MA 02132; e-mail: marilyn.moy@va.gov


Funding/Support: This research was supported by the Department of Veteran Affairs, Veterans Health Administration, Rehabilitation Research and Development Service through a VA Career Development Award to Dr Moy. It also was supported in part by the Center for Integration of Medicine and Innovative Technology, Boston, MA (Dr Moy), and in part by the VA Rehabilitation Research and Development Service [Grant B6618R to Dr Garshick].

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details.


Chest. 2014;145(3):542-550. doi:10.1378/chest.13-1052
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Background:  Physical activity is an important clinical marker of disease status in COPD. COPD is also characterized by low-grade systemic inflammation. However, the relationship between physical activity and systemic inflammation in COPD is unclear.

Methods:  We monitored daily step count, a directly measured physical activity, using the StepWatch Activity Monitor, an ankle-worn accelerometer, in 171 people with stable COPD. Exercise capacity was assessed with the 6-min walk test (6MWT). We measured plasma C-reactive protein (CRP) and IL-6 levels. Linear regression models examined the cross-sectional associations of daily step count and 6MWT distance with CRP and IL-6 levels.

Results:  Subjects had a mean age 72 ± 8 years and mean FEV1 1.5 ± 0.57 L (54 ± 20% predicted). Median daily step count was 5,203 (interquartile range [IQR], 3,627-7,024], CRP level was 2.4 mg/L (IQR, 1.2-5.0), and IL-6 level was 2.9 pg/mL (IQR, 2.0-5.1). Each 1,000-step increase in daily step count was associated with a 0.94 mg/L and 0.96 pg/mL decrease in CRP (P = .020) and IL-6 (P = .044) levels, respectively, adjusting for age, FEV1 % predicted, pack-years smoked, cardiac disease, current statin use, history of acute exacerbations, and season. There was a significant linear trend of increasing daily step count by quartiles and decreasing CRP (P = .0007) and IL-6 (P = .023) levels. Higher 6MWT distance was also significantly associated with lower CRP and IL-6 values.

Conclusion:  People with COPD who walked the most had the lowest plasma CRP and IL-6 levels. These results provide the conceptual basis to study whether an intervention to promote walking will reduce systemic inflammation in people with COPD.

COPD, a major cause of global morbidity, is projected to become the third leading cause of death in the world by 2020.1,2 Level of physical activity (PA) is an important clinical marker of disease status in COPD. Higher levels of PA are associated with better functional status, fewer hospital admissions, and lower mortality.37 Daily step count is a direct measure of PA that is easy to understand, can be accurately monitored, and can be potentially targeted for intervention.810 A higher daily step count in COPD is associated with a lower risk of future acute exacerbations (AEs) and COPD-related hospitalizations11 and with lower mortality,12 independent of % predicted FEV1.

COPD is characterized by low-grade systemic inflammation.1316 People with COPD have elevated levels of C-reactive protein (CRP) and IL-6 in the stable clinical state13,14; these become even higher during AEs.14,17 Elevated CRP level is associated with reduced lung function,13 lower exercise capacity,18 higher risk of future AEs,15 and higher risk of COPD-related hospitalizations.19 Elevated CRP level is also positively associated with all-cause15,20 and COPD-related mortality.19

The few studies that have examined the relationship between PA and inflammation in COPD have had conflicting results.2126 One previous study reported that a higher plasma fibrinogen level was associated with a lower daily step count in COPD.21 However, that study did not account for season of PA monitoring,27 prior exacerbations, or statin use. Garcia-Rio et al22 found no significant relationship between daily PA (vector magnitude units) and IL-6 and tumor necrosis factor-α receptor 1 in exhaled breath condensate, rather than plasma. A separate study showed significant associations between lower CRP and tumor necrosis factor-α levels with higher PA assessed by questionnaire, which tends to overestimate PA and assesses activities not typically performed by patients with COPD.23,28,29 Small studies assessing the effects of exercise intervention on systemic inflammation have shown equivocal results.2426 These studies enrolled participants who completed a pulmonary rehabilitation program, limiting the generalizability of results.24,25

In the current cross-sectional study, our primary aim was to examine the independent relationship between PA, directly measured with an accelerometer, and plasma markers of systemic inflammation in a well-characterized cohort of people with COPD. Specifically, we hypothesized that higher daily step count would be associated with lower plasma CRP and IL-6 levels, independent of exacerbation history, statin use, and season. As a secondary aim, we assessed results of the 6-min walk test (6MWT), a commonly used, clinic-based test of exercise capacity, and examined its relationship with plasma CRP and IL-6 values.

Study Design and Participants

Between January 2009 and November 2011, 176 participants with COPD were enrolled from the general pulmonary clinics. All 176 subjects had one assessment; in addition, 98 of the 176 subjects had a second assessment a median of 3.9 months after the first assessment as part of a previously published observational study characterizing daily step count in COPD.8,11 Clinical variables, inflammatory biomarkers, and PA were measured at each assessment.

Eligible participants were aged > 40 years and had COPD defined as a smoking history of at least 10 pack-years and a ratio of FEV1 to FVC < 0.70. Exclusion criteria were inability to ambulate or collect daily step-count data. All subjects were in stable clinical state at the time of assessments. We defined a patient with stable COPD as one who had not had an AE in the 4 weeks prior to assessment and who reported being at baseline clinical status at the time of assessment.30 The protocol (#1961) was approved by the VA Boston Healthcare System Committee on Human Research, and written informed consent was obtained from each participant.

Clinical Variables

We measured weight and height to calculate BMI. We obtained a medical history of cigarette use; coronary artery disease; congestive heart failure; medication use, including statins, inhaled corticosteroids, and nonsteroidal antiinflammatory drugs (NSAIDs); prior participation in pulmonary rehabilitation; and occurrence of AE in the year prior to enrollment.11,30 At each assessment, participants underwent measurement of FEV1 using an Eaglet spirometer (nSpire Health, Inc).31 The 6MWT was performed following American Thoracic Society guidelines.32 Health-related quality of life was assessed using the St. George’s Respiratory Questionnaire (SGRQ),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.34

Inflammatory Biomarkers

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 each in-clinic assessment. Plasma was obtained by centrifugation of tubes at 1,459 × g for 15 min. The samples were stored at −80°C until analyzed. Plasma CRP and IL-6 levels were measured by the Clinical & Epidemiologic Research Laboratory, Children’s Hospital, Boston, Massachusetts. CRP and IL-6 levels were determined using a high-sensitivity immunoturbidimetric assay with a sensitivity of 0.03 mg/L and 0.094 pg/mL, respectively.

Physical Activity Assessment

The StepWatch Activity Monitor (SAM) (Orthocare Innovations LLC), an ankle-worn accelerometer, accurately measures step counts in people with COPD.8 After each in-clinic assessment, participants were sent home to wear the SAM for 14 consecutive days and were instructed to perform their usual PAs. Subjects were blinded to step-count data, since the instrument does not provide feedback. Subjects returned the SAM by mail and staff downloaded date- and time-stamped step-count data via a docking station. No-wear days, defined as days with < 200 steps recorded and < 8 h of wear time, were excluded from the analysis.8,11,35 Five of the 176 subjects, who were unable to complete daily step count monitoring and had ≥ 8 no-wear days, were excluded from the final analysis.

Statistical Analysis

Descriptive results at study entry for 171 subjects are reported as median (interquartile range [IQR]), mean ± SD, or percentage, as appropriate. Levels of CRP and IL-6 were converted to the natural logarithmic values to best approximate a normal distribution. To analyze all collected data and maximize power, the final linear regression models included 269 assessments (171 assessments in all subjects plus 98 assessments in those who had a second assessment). The statistical approach used accounts for the correlation between the repeated measurement of CRP level, IL-6 level, and daily step count in these 98 subjects. Models have CRP or IL-6 level as the dependent variable and daily step count as the independent variable. We used mixed models (PROC MIXED in SAS; SAS Institute Inc) with a first-order autoregressive covariance structure to perform the linear regression analyses. This statistical program accounts for repeated measures of daily step count and inflammatory biomarkers in people with two assessments, but can also include those with one assessment in the analysis. Potential confounders were also assessed in the models.15 Variables with P < .20 in univariate models were subsequently examined in multivariable models. In separate regression models (PROC MIXED), we assessed linear trends across quartiles of daily step count with levels of CRP and IL-6 by assigning each quartile a score based on the median step count for that quartile. Statistical significance was defined as P < .05.

Mean age was 72 ± 8 years, there were two female subjects, and mean FEV1 was 1.5 ± 0.57 L (54 ± 20% predicted36) (Table 1). All four GOLD (Global Initiative for Chronic Obstructive Lung Disease) stages were represented, predominantly GOLD II (45%) and GOLD III (34%).2 Median daily step count was 5,203 (IQR, 3,627-7,024). Of 3,766 days monitored [(171 × 14) + (98 × 14)], only 3% (n = 122) met the definition of a no-wear day. Daily step count was moderately correlated with 6MWT distance (Pearson correlation coefficient R = 0.59). Median CRP level was 2.4 mg/L (IQR, 1.2-5.0), and median IL-6 level was 2.9 pg/mL (IQR, 2.0-5.1). Seventy-two subjects (42%) had a CRP level ≥ 3 mg/L, and 128 (75%) had an IL-6 level ≥ 2 pg/mL, levels that have been associated with greater COPD-related mortality.37 Seventy-one subjects (42%) had cardiac disease, 112 (66%) were currently using a statin, 22 (13%) were currently using an NSAID, 115 (67%) were currently using an inhaled corticosteroid, and 40 (23%) were current cigarette smokers. Fifty-two subjects had a history of AE in the year prior to study enrollment. There was no significant difference in initial age, daily step count, 6MWT distance, SGRQ total score, and CRP and IL-6 levels among the 73 subjects with one assessment and 98 subjects with two assessments. Subjects with one assessment had a slightly higher FEV1 % predicted (58 ± 22% predicted) compared with subjects with two assessments (51 ± 18% predicted, P = .03). The 98 subjects who had two assessments were clinically stable over time with no significant changes in FEV1 % predicted, 6MWT distance, and CRP or IL-6 levels over the two time points. Daily step count decreased an average of 693 steps at the second time point, most likely due to changes in season, as previously described.8

Table Graphic Jump Location
Table 1 —Subject Characteristics (N = 171)

Data are given as median (IQR), No. (%), or mean ± SD. 6MWT = 6-min walk test; AE = acute exacerbation; CRP = C-reactive protein; GOLD = Global Initiative for Chronic Obstructive Lung Disease; IQR = interquartile range; MMRC = modified Medical Research Council; NSAID = nonsteroidal antiinflammatory drug; SGRQ-TS = St. George’s Respiratory Questionnaire Total Score.

a 

n = 170.

b 

n = 169.

In univariate models, higher daily step count was significantly associated with lower plasma CRP and IL-6 levels (Table 2). Each 1,000 greater steps walked per day was significantly associated with a 0.92 mg/L and 0.95 pg/mL decrease in CRP level (P = .0016) and IL-6 level (P = .0015), respectively. There was a significant linear trend of increasing daily step count by quartiles with lower CRP (P < .0001) and IL-6 (P = .0006) levels. Similarly, a higher 6MWT distance was significantly associated with lower CRP and IL-6 levels (Table 2). FEV1 % predicted, pack-years, history of AE, and season were associated with CRP level, while age, pack-years, cardiac disease, current statin use, and season were associated with IL-6 levels. These variables were subsequently examined in multivariable models. BMI, current inhaled steroid use, current cigarette smoking, and prior participation in pulmonary rehabilitation were not significantly associated with CRP or IL-6 levels.

Table Graphic Jump Location
Table 2 —Univariate Predictors of ln(CRP) and ln(IL-6)

ln = natural logarithm. See Table 1 legend for expansion of other abbreviations.

a 

For continuous variables, the coefficient (β) and (SE) are presented. For categorical variables, the mean ln(CRP) or mean ln(IL-6) is presented.

b 

Daily step count was studied as both a continuous and categorical variable in two separate models.

c 

30-m increase in 6MWT distance corresponds to the published minimum clinically important difference.38

Multivariable models adjusting for age, FEV1 % predicted, pack-years, cardiac disease, current statin use, history of AE, and season showed significant associations between higher daily step count and lower plasma CRP and IL-6 levels (Table 3). Each 1,000-step increase in daily step count was significantly associated with a 0.94 mg/L and 0.96 pg/mL decrease in CRP level (P = .020) and IL-6 level (P = .044), respectively. There was a significant linear trend of increasing daily step count by quartiles and decreasing CRP (P = .0007) and IL-6 (P = .023) levels (Table 4). Similar multivariable models showed significant associations between higher 6MWT distance and lower CRP and IL-6 levels (Table 5). Corresponding to the published minimum clinically important difference,38 for each 30-m increase in 6MWT distance, there was a 0.94 mg/L decrease in CRP level (P = .020) and 0.96 pg/mL decrease in IL-6 level (P = .034). In multivariable models with CRP and IL-6 levels as the dependent variables and daily step count as the primary independent variable of interest, adjustment for NSAID use (along with age, FEV1 % predicted, pack-years, cardiac disease, current statin use, history of AEs, and season) did not change the β coefficient or significance of daily step count.

Table Graphic Jump Location
Table 3 —Multivariable Models of Associations Between Daily Step Count and ln(CRP) and ln(IL-6)

See Table 1 and 2 legends for expansion of abbreviations.

a 

For continuous variables, the coefficient (β) and (SE) are presented. For categorical variables, the mean ln(CRP) or mean ln(IL-6) is presented.

Table Graphic Jump Location
Table 4 —Multivariable Models of Associations Between Daily Step Count in Quartiles and ln(CRP) and ln(IL-6)

See Table 1 and 2 legends for expansion of abbreviations.

a 

For continuous variables, the coefficient (β) and (SE) are presented. For categorical variables, the mean ln(CRP) or mean ln(IL-6) is presented.

Table Graphic Jump Location
Table 5 —Multivariable Models of Associations Between 6MWT Distance and ln(CRP) and ln(IL-6)

See Table 1 and 2 legends for expansion of abbreviations.

a 

For continuous variables, the coefficient (β) and (SE) are presented. For categorical variables, the mean ln(CRP) or mean ln(IL-6) is presented.

b 

30-m increase in 6MWT distance corresponds to the published minimum clinically important difference.38

We show that people with COPD who have higher PA have significantly lower levels of markers of systemic inflammation. Specifically, those who had the highest daily step counts had the lowest plasma CRP and IL-6 levels, independent of age, FEV1 % predicted, pack-years, cardiac disease, current statin use, history of AE, and season. These novel findings are supported by the significant associations over the entire range of daily step counts with CRP and IL-6 levels. Our results are further strengthened by similar significant associations between 6MWT distance, a clinic-based measure of exercise capacity, and CRP and IL-6 levels.

Our study significantly extends the current literature by examining plasma levels of CRP and IL-6, markers of systemic inflammation that are associated with reduced lung function, exacerbations, and greater mortality in COPD.1320,37 Second, the direct measure of PA with daily step count is a strength of our study since it is a simple metric that is meaningful to most patients, can be accurately measured with an unobtrusive device, and can be potentially targeted for intervention.8,9 Finally, we address limitations of previous studies by assessing exacerbation history, cardiac disease, current statin use, and season of PA monitoring, and adjusting for these factors in the analyses.

In the general population, it has been hypothesized that systemic inflammation (as measured by CRP level) may mediate the relationship between PA and cardiovascular disease risk.3942 People with higher levels of self-reported PA have lower CRP levels and fewer cardiovascular disease events.39,40 In people with COPD, PA may modify the effect of airflow obstruction on endothelial function and cardiovascular disease risk.43 In addition, elevated inflammatory biomarkers are associated with increased risk of noncardiovascular comorbidities in COPD.44 Elevated CRP level is associated with reduced lung function,13 lower exercise capacity,18 higher risk of future AEs,15 and higher risk of COPD-related hospitalizations.19 Elevated CRP level is also positively associated with all-cause15,20 and COPD-related mortality.19 Thus, in people with COPD, it is plausible that systemic inflammation may, in part, mediate the relationship between PA and risk of COPD-related morbidity and mortality. To date in the general population, studies examining the effects of exercise-training interventions41 or longitudinal changes in self-reported PA42 on inflammatory biomarkers have shown mixed results. In people with COPD, a few small studies examining the effects of pulmonary rehabilitation and exercise training on systemic inflammation had equivocal results.2426 We acknowledge that our cross-sectional associations between daily step count and plasma CRP and IL-6 levels do not demonstrate causality. We believe our current observational study provides the conceptual basis and rationale for future interventional studies to examine the effect of promotion of PA (daily step count) on biomarker levels. Well-designed clinical trials are needed to examine whether interventions to promote walking will lead to reductions in systemic inflammation and lower risk of COPD-related morbidity.

The blood samples for CRP and IL-6 analyses were obtained at each in-person assessment, between 9:30 am and 3:00 pm, and then followed by the 14-day step-count monitoring period at home. It has been shown that there is no diurnal variation in CRP level.45 Studies that have evaluated the 24-h secretory pattern of IL-6 levels in healthy young adults suggest that IL-6 is secreted in a biphasic circadian pattern with two nadirs at about 8:00 am and 9:00 pm, and two zeniths at about 7:00 pm and 5:00 am.46 In our study, blood samples were obtained well within the 8:00 am nadir and 7:00 pm zenith. There was no significant relationship between time of blood draw and CRP or IL-6 level.

We explored the association between daily step count and CRP and IL-6 levels among those with the greatest inflammation, as defined by CRP level > 3 mg/L and IL-6 level > 2 pg/mL, and among those with the least inflammation who had CRP level < 3 mg/L and IL-6 level < 2 pg/mL.15,37 In our study, 67 people had the greatest inflammation, while 38 people had the least (a very small subgroup). In univariate analyses, daily step count was significantly associated with IL-6 level among those with the greatest inflammation. Daily step count was not significantly associated with CRP level among those with the greatest inflammation. Daily step count was not significantly associated with either CRP or IL-6 level among those with the least inflammation. Future studies are needed to assess whether the relationship between PA and inflammatory markers may be different among subgroups of patients.

Some limitations need to be considered. All subjects did not have two assessments, but there was no systematic bias in selecting participants who had two assessments and those who had one assessment. Subjects with one assessment had slightly higher initial lung function than those with two assessments, arguing against the possibility that subjects did not return for a second assessment because they had more severe COPD. Four weeks may not have been enough time for those subjects who had an AE prior to study enrollment to return to usual step counts and biomarker levels. However, it has been reported that > 75% of people with COPD returned to baseline symptoms and CRP and IL-6 levels by day 14 after an AE.17 We have studied a mainly male COPD population. Additional studies with analyses performed separately for men and women are needed to fully understand the relationship between daily step count and CRP and IL-6 levels in women. The SAM did not capture upper extremity activities. However, total daily PA has been shown to be closely related to leg activity in people with COPD.47 The SAM did not measure the intensity of walking or activities such as swimming or bicycling. Previously, devices that have captured all forms of PA reported various activity units that are difficult to understand and do not allow comparison between studies.48 The RT3 accelerometer (Stayhealthy Inc) reports PA movements as vector magnitude units; the Dynaport activity monitor (McRoberts BV) reports movement intensity or time spent in walking, cycling, standing, sitting, or lying; the Actigraph (Actigraph LLC) reports activity counts; and the SenseWear armband (BodyMedia Inc) reports total daily energy expenditure, which is then converted to a “physical activity level.”4,5,48 Depew et al10 have shown that daily step count is a surrogate for physical activity level. We focus on daily step count because it is relevant to patients, easy to understand, and can be potentially targeted for intervention.9

In conclusion, people with COPD who walk the most have the lowest plasma CRP and IL-6 levels. Our results provide the rationale to study walking promotion as an intervention strategy to reduce systemic inflammation.

Author contributions: Dr Moy had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis, including and especially any adverse effects. Dr Moy assumes full responsibility for the integrity of the submission as a whole, from inception to published article.

Dr Moy: contributed substantially to the study design, data analysis and interpretation, and the writing of the manuscript.

Ms Teylan: contributed substantially to the data analysis and interpretation and the writing of this manuscript.

Ms Weston: contributed substantially to data collection and the writing of this manuscript.

Dr Gagnon: contributed substantially to the data analysis, data interpretation, and the writing of this manuscript.

Ms Danilack: contributed substantially to the data interpretation and the writing of this manuscript.

Dr Garshick: contributed substantially to the study design, data interpretation, and the writing of this manuscript.

Financial/nonfinancial disclosures: The authors have reported to CHEST that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

Role of sponsors: This study was initiated by the investigators. The sponsor had no role in the design of the study, the collection and analysis of the data, or the preparation of the manuscript.

Other contributions: The results of the present study do not constitute endorsement of the StepWatch Activity Monitor by the authors. Orthocare Innovations LLC had no involvement in the study design, the collection, analysis, and interpretation of data, in the writing of the manuscript, or in the decision to submit the paper for publication.

6MWT

6-min walk test

AE

acute exacerbation

CRP

C-reactive protein

GOLD

Global Initiative for Chronic Obstructive Lung Disease

IQR

interquartile range

NSAID

nonsteroidal antiinflammatory drug

PA

physical activity

SAM

StepWatch Activity Monitor

SGRQ

St. George’s Respiratory Questionnaire

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Lichtman SW, Pisarska K, Berman ER, et al. Discrepancy between self-reported and actual caloric intake and exercise in obese subjects. N Engl J Med. 1992;327(27):1893-1898. [CrossRef] [PubMed]
 
Albert RK, Connett J, Bailey WC, et al; COPD Clinical Research Network. Azithromycin for prevention of exacerbations of COPD. N Engl J Med. 2011;365(8):689-698. [CrossRef] [PubMed]
 
Miller MR, Hankinson J, Brusasco V, et al; ATS/ERS Task Force. Standardisation of spirometry. Eur Respir J. 2005;26(2):319-338. [CrossRef] [PubMed]
 
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. [CrossRef] [PubMed]
 
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. [CrossRef] [PubMed]
 
Mahler DA, Wells CK. Evaluation of clinical methods for rating dyspnea. Chest. 1988;93(3):580-586. [CrossRef] [PubMed]
 
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. [CrossRef] [PubMed]
 
Hankinson JL, Odencrantz JR, Fedan KB. Spirometric reference values from a sample of the general US population. Am J Respir Crit Care Med. 1999;159(1):179-187. [CrossRef] [PubMed]
 
Celli BR, Locantore N, Yates J, et al; ECLIPSE Investigators. Inflammatory biomarkers improve clinical prediction of mortality in chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2012;185(10):1065-1072. [CrossRef] [PubMed]
 
Polkey MI, Spruit MA, Edwards LD, et al; ECLIPSE Investigators Six-minute-walk test in COPD: minimally clinically important difference for death or hospitalization. Am J Respir Crit Care Med. 2013;187(4):382-386. [CrossRef] [PubMed]
 
Mora S, Cook N, Buring JE, Ridker PM, Lee IM. Physical activity and reduced risk of cardiovascular events: potential mediating mechanisms. Circulation. 2007;116(19):2110-2118. [CrossRef] [PubMed]
 
Hamer M, Stamatakis E. Physical activity and risk of cardiovascular disease events: inflammatory and metabolic mechanisms. Med Sci Sports Exerc. 2009;41(6):1206-1211. [CrossRef] [PubMed]
 
Woods JA, Wilund KR, Martin SA, Kistler BM. Exercise, inflammation and aging. Aging Dis. 2012;3(1):130-140. [PubMed]
 
Hamer M, Sabia S, Batty GD, et al. Physical activity and inflammatory markers over 10 years: follow-up in men and women from the Whitehall II cohort study. Circulation. 2012;126(8):928-933. [CrossRef] [PubMed]
 
Clarenbach CF, Senn O, Sievi NA, et al. Determinants of endothelial function in patients with COPD. Eur Respir J. 2013;42(5):1194-1204. [CrossRef] [PubMed]
 
Thomsen M, Dahl M, Lange P, Vestbo J, Nordestgaard BG. Inflammatory biomarkers and comorbidities in chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2012;186(10):982-988. [CrossRef] [PubMed]
 
Meier-Ewert HK, Ridker PM, Rifai N, Price N, Dinges DF, Mullington JM. Absence of diurnal variation of C-reactive protein concentrations in healthy human subjects. Clin Chem. 2001;47(3):426-430. [PubMed]
 
Vgontzas AN, Bixler EO, Lin HM, Prolo P, Trakada G, Chrousos GP. IL-6 and its circadian secretion in humans. Neuroimmunomodulation. 2005;12(3):131-140. [CrossRef] [PubMed]
 
Walker PP, Burnett A, Flavahan PW, Calverley PMA. Lower limb activity and its determinants in COPD. Thorax. 2008;63(8):683-689. [CrossRef] [PubMed]
 
Rabinovich RA, Louvaris Z, Raste Y, et al; on behalf of the PROactive consortium. Validity of physical activity monitors during daily life in patients with COPD. Eur Respir J. 2013;42(5):1205-1215. [CrossRef] [PubMed]
 

Figures

Tables

Table Graphic Jump Location
Table 1 —Subject Characteristics (N = 171)

Data are given as median (IQR), No. (%), or mean ± SD. 6MWT = 6-min walk test; AE = acute exacerbation; CRP = C-reactive protein; GOLD = Global Initiative for Chronic Obstructive Lung Disease; IQR = interquartile range; MMRC = modified Medical Research Council; NSAID = nonsteroidal antiinflammatory drug; SGRQ-TS = St. George’s Respiratory Questionnaire Total Score.

a 

n = 170.

b 

n = 169.

Table Graphic Jump Location
Table 2 —Univariate Predictors of ln(CRP) and ln(IL-6)

ln = natural logarithm. See Table 1 legend for expansion of other abbreviations.

a 

For continuous variables, the coefficient (β) and (SE) are presented. For categorical variables, the mean ln(CRP) or mean ln(IL-6) is presented.

b 

Daily step count was studied as both a continuous and categorical variable in two separate models.

c 

30-m increase in 6MWT distance corresponds to the published minimum clinically important difference.38

Table Graphic Jump Location
Table 3 —Multivariable Models of Associations Between Daily Step Count and ln(CRP) and ln(IL-6)

See Table 1 and 2 legends for expansion of abbreviations.

a 

For continuous variables, the coefficient (β) and (SE) are presented. For categorical variables, the mean ln(CRP) or mean ln(IL-6) is presented.

Table Graphic Jump Location
Table 4 —Multivariable Models of Associations Between Daily Step Count in Quartiles and ln(CRP) and ln(IL-6)

See Table 1 and 2 legends for expansion of abbreviations.

a 

For continuous variables, the coefficient (β) and (SE) are presented. For categorical variables, the mean ln(CRP) or mean ln(IL-6) is presented.

Table Graphic Jump Location
Table 5 —Multivariable Models of Associations Between 6MWT Distance and ln(CRP) and ln(IL-6)

See Table 1 and 2 legends for expansion of abbreviations.

a 

For continuous variables, the coefficient (β) and (SE) are presented. For categorical variables, the mean ln(CRP) or mean ln(IL-6) is presented.

b 

30-m increase in 6MWT distance corresponds to the published minimum clinically important difference.38

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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(7):743-751. [CrossRef] [PubMed]
 
Garcia-Rio F, Lores V, Mediano O, et al. Daily physical activity in patients with chronic obstructive pulmonary disease is mainly associated with dynamic hyperinflation. Am J Respir Crit Care Med. 2009;180(6):506-512. [CrossRef] [PubMed]
 
Garcia-Aymerich J, Serra I, Gómez FP, et al; Phenotype and Course of COPD Study Group. Physical activity and clinical and functional status in COPD. Chest. 2009;136(1):62-70. [CrossRef] [PubMed]
 
Bolton CE, Broekhuizen R, Ionescu AA, et al. Cellular protein breakdown and systemic inflammation are unaffected by pulmonary rehabilitation in COPD. Thorax. 2007;62(2):109-114. [CrossRef] [PubMed]
 
Vogiatzis I, Stratakos G, Simoes DCM, et al. Effects of rehabilitative exercise on peripheral muscle TNFalpha, IL-6, IGF-I and MyoD expression in patients with COPD. Thorax. 2007;62(11):950-956. [CrossRef] [PubMed]
 
Rabinovich RA, Figueras M, Ardite E, et al. Increased tumour necrosis factor-α plasma levels during moderate-intensity exercise in COPD patients. Eur Respir J. 2003;21(5):789-794. [CrossRef] [PubMed]
 
Sewell L, Singh SJ, Williams JEA, Morgan MD. Seasonal variations affect physical activity and pulmonary rehabilitation outcomes. J Cardiopulm Rehabil Prev. 2010;30(5):329-333. [CrossRef] [PubMed]
 
Pitta F, Troosters T, Probst VS, Spruit MA, Decramer M, Gosselink R. Quantifying physical activity in daily life with questionnaires and motion sensors in COPD. Eur Respir J. 2006;27(5):1040-1055. [CrossRef] [PubMed]
 
Lichtman SW, Pisarska K, Berman ER, et al. Discrepancy between self-reported and actual caloric intake and exercise in obese subjects. N Engl J Med. 1992;327(27):1893-1898. [CrossRef] [PubMed]
 
Albert RK, Connett J, Bailey WC, et al; COPD Clinical Research Network. Azithromycin for prevention of exacerbations of COPD. N Engl J Med. 2011;365(8):689-698. [CrossRef] [PubMed]
 
Miller MR, Hankinson J, Brusasco V, et al; ATS/ERS Task Force. Standardisation of spirometry. Eur Respir J. 2005;26(2):319-338. [CrossRef] [PubMed]
 
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. [CrossRef] [PubMed]
 
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. [CrossRef] [PubMed]
 
Mahler DA, Wells CK. Evaluation of clinical methods for rating dyspnea. Chest. 1988;93(3):580-586. [CrossRef] [PubMed]
 
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. [CrossRef] [PubMed]
 
Hankinson JL, Odencrantz JR, Fedan KB. Spirometric reference values from a sample of the general US population. Am J Respir Crit Care Med. 1999;159(1):179-187. [CrossRef] [PubMed]
 
Celli BR, Locantore N, Yates J, et al; ECLIPSE Investigators. Inflammatory biomarkers improve clinical prediction of mortality in chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2012;185(10):1065-1072. [CrossRef] [PubMed]
 
Polkey MI, Spruit MA, Edwards LD, et al; ECLIPSE Investigators Six-minute-walk test in COPD: minimally clinically important difference for death or hospitalization. Am J Respir Crit Care Med. 2013;187(4):382-386. [CrossRef] [PubMed]
 
Mora S, Cook N, Buring JE, Ridker PM, Lee IM. Physical activity and reduced risk of cardiovascular events: potential mediating mechanisms. Circulation. 2007;116(19):2110-2118. [CrossRef] [PubMed]
 
Hamer M, Stamatakis E. Physical activity and risk of cardiovascular disease events: inflammatory and metabolic mechanisms. Med Sci Sports Exerc. 2009;41(6):1206-1211. [CrossRef] [PubMed]
 
Woods JA, Wilund KR, Martin SA, Kistler BM. Exercise, inflammation and aging. Aging Dis. 2012;3(1):130-140. [PubMed]
 
Hamer M, Sabia S, Batty GD, et al. Physical activity and inflammatory markers over 10 years: follow-up in men and women from the Whitehall II cohort study. Circulation. 2012;126(8):928-933. [CrossRef] [PubMed]
 
Clarenbach CF, Senn O, Sievi NA, et al. Determinants of endothelial function in patients with COPD. Eur Respir J. 2013;42(5):1194-1204. [CrossRef] [PubMed]
 
Thomsen M, Dahl M, Lange P, Vestbo J, Nordestgaard BG. Inflammatory biomarkers and comorbidities in chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2012;186(10):982-988. [CrossRef] [PubMed]
 
Meier-Ewert HK, Ridker PM, Rifai N, Price N, Dinges DF, Mullington JM. Absence of diurnal variation of C-reactive protein concentrations in healthy human subjects. Clin Chem. 2001;47(3):426-430. [PubMed]
 
Vgontzas AN, Bixler EO, Lin HM, Prolo P, Trakada G, Chrousos GP. IL-6 and its circadian secretion in humans. Neuroimmunomodulation. 2005;12(3):131-140. [CrossRef] [PubMed]
 
Walker PP, Burnett A, Flavahan PW, Calverley PMA. Lower limb activity and its determinants in COPD. Thorax. 2008;63(8):683-689. [CrossRef] [PubMed]
 
Rabinovich RA, Louvaris Z, Raste Y, et al; on behalf of the PROactive consortium. Validity of physical activity monitors during daily life in patients with COPD. Eur Respir J. 2013;42(5):1205-1215. [CrossRef] [PubMed]
 
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