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• W2956659330 abstract "Free AccessObstructive Sleep Apnea - Relationships - COPD - Diabetes - Hypertension - Congestive Heart Failure - Smoking - Physical Activity - Behavior - Scientific InvestigationsPhysical Activity in Overlap Syndrome of COPD and Obstructive Sleep Apnea: Relationship With Markers of Systemic Inflammation Christine M. Fitzgibbons, MD, Rebekah L. Goldstein, MPH, Daniel J. Gottlieb, MD, Marilyn L. Moy, MD, MSc Christine M. Fitzgibbons, MD Pulmonary and Critical Care Medicine Section, VA Boston Healthcare System, Boston, Massachusetts Pulmonary and Critical Care, Boston University School of Medicine, Boston, Massachusetts Search for more papers by this author , Rebekah L. Goldstein, MPH Pulmonary and Critical Care Medicine Section, VA Boston Healthcare System, Boston, Massachusetts Department of Veterans Affairs, Rehabilitation Research and Development Service, Washington, DC Search for more papers by this author , Daniel J. Gottlieb, MD Pulmonary and Critical Care Medicine Section, VA Boston Healthcare System, Boston, Massachusetts Department of Veterans Affairs, Rehabilitation Research and Development Service, Washington, DC Division of Sleep Medicine, Brigham and Women's Hospital, Boston, Massachusetts Harvard Medical School, Boston, Massachusetts Search for more papers by this author , Marilyn L. Moy, MD, MSc Address correspondence to: Marilyn L. Moy, MD, MSc, VA Boston Healthcare System, Pulmonary and Critical Care Section, 1400 VFW Parkway, Mail Code 111PI West Roxbury, MA 02132(857) 203-6622(857) 203-5670 E-mail Address: [email protected] Pulmonary and Critical Care Medicine Section, VA Boston Healthcare System, Boston, Massachusetts Department of Veterans Affairs, Rehabilitation Research and Development Service, Washington, DC Harvard Medical School, Boston, Massachusetts Search for more papers by this author Published Online:July 15, 2019https://doi.org/10.5664/jcsm.7874Cited by:2SectionsAbstractPDF ShareShare onFacebookTwitterLinkedInRedditEmail ToolsAdd to favoritesDownload CitationsTrack Citations AboutABSTRACTStudy 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 SUMMARYCurrent 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.INTRODUCTIONChronic 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.3–5OVS 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.6–8 The underlying mechanisms explaining the observed increased morbidity and mortality in OVS are unknown.9–11 COPD is a systemic disease characterized by elevation in markers of systemic inflammation during stable states and acute exacerbations.12–14 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.8,9,11,15In COPD, engagement in PA is a positive health behavior that is associated with better outcomes.16–24 Those who walk the most have the lowest risk of acute exacerbations, hospitalization, and death in COPD, independent of lung function.17–24 Exercise and PA have also been shown to be reduced in OSA alone, independent of BMI.25–27 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.METHODSStudy Design and ParticipantsWe 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 FactorsAt 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).34Physical Activity AssessmentThe 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.35,36Markers of Systemic InflammationPeripheral 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.17Statistical AnalysisWe 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.RESULTSCharacteristics, Cardiac Disease, and Cardiovascular Risk Factors in Overlap SyndromeThe 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.Table 1 Baseline characteristics.Table 1 Baseline characteristics.Physical Activity in Overlap SyndromeParticipants 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).Table 2 Daily step count in persons with OVS, compared to COPD alone.Table 2 Daily step count in persons with OVS, compared to COPD alone.Systemic Inflammation in Overlap SyndromeParticipants 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).Table 3 Markers of systemic inflammation, ln(CRP) and ln(IL-6), in persons with OVS, compared to COPD alone.Table 3 Markers of systemic inflammation, ln(CRP) and ln(IL-6), in persons with OVS, compared to COPD alone.Physical Activity and Systemic Inflammation in Overlap SyndromeDaily 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).Table 4 In OVS, multivariable models of associations between daily step count and ln(IL-6) and ln(CRP).Table 4 In OVS, multivariable models of associations between daily step count and ln(IL-6) and ln(CRP).Table 5 In COPD alone, multivariable models of associations between daily step count and ln(IL-6) and ln(CRP).Table 5 In COPD alone, multivariable models of associations between daily step count and ln(IL-6) and ln(CRP).DISCUSSIONWe 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.38,39Since 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.CONCLUSIONSPersons 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 STATEMENTAll authors have seen and approved the manuscript. The work was performed at VA Boston Healthcare System. The authors report no conflicts of interest.ABBREVIATIONSBMIbody mass indexCADcoronary artery diseaseCOPDchronic obstructive pulmonary diseaseCRPC-reactive proteinFEV1forced expiratory volume in 1 secondIL-6interleukin-6OSAobstructive sleep apneaOVSoverlap syndromePAphysical activityREFERENCES1 Global Initiative for Chronic Obstructive Lung DiseaseGlobal Strategy for the Diagnosis, Management and Prevention of Chronic Obstructive Pulmonary Disease: 2017 Report2017Fontana, WIGlobal Initiative for Chronic Obstructive Lung Disease Google Scholar2 Young T, Palta M, Dempsey J, Skatrud J, Weber S, Badr SThe occurrence of sleep-disordered breathing among middle-aged adultsN Engl J Med19933281712301235 CrossrefGoogle Scholar3 Du W, Liu J, Zhou J, Ye D, OuYang Y, Deng QObstructive sleep apnea, COPD, the overlap syndrome, and mortality: results from the 2005-2008 National Health and Nutrition Examination SurveyInt J Chron Obstruct Pulmon Dis201813665674 CrossrefGoogle Scholar4 Zohal MA, Yazdi Z, Kazemifar AM, Mahjoob P, Ziaeeha MSleep quality and quality of life in COPD patients with and without suspected obstructive sleep apneaSleep Disord20142014508372 CrossrefGoogle Scholar5 Chaouat A, Weitzanblum E, Krieger J, Ifoundza T, Oswald M, Kessler RAssociation of chronic obstructive pulmonary disease and sleep apnea syndromeAm J Respir Crit Care Med199515118286 CrossrefGoogle Scholar6 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 apneaCOPD2013101410 CrossrefGoogle Scholar7 Ganga HV, Nair SU, Puppala VK, Miller WLRisk of new-onset atrial fibrillation in elderly patients with the overlap syndrome: a retrospective cohort studyJ Geriatr Cardiol2013102129134 Google Scholar8 Marin JM, Soriano JB, Carrizo SJ, Boldova A, Celli BROutcomes in patients with chronic obstructive pulmonary disease and obstructive sleep apnea: the overlap syndromeAm J Respir Crit Care Med20101823325331 CrossrefGoogle Scholar9 McNicholas WTChronic obstructive pulmonary disease and obstructive sleep apnea: overlaps in pathophysiology, systemic inflammation, and cardiovascular diseaseAm J Respir Crit Care Med20091808692700 CrossrefGoogle Scholar10 Jen R, Li Y, Owens RL, Malhotra ASleep in chronic obstructive pulmonary disease: evidence gaps and challengesCan Respir J201620167947198 CrossrefGoogle Scholar11 McNicholas WTCOPD-OSA overlap syndrome: evolving evidence regarding epidemiology, clinical consequences, and managementChest2017152613181326 CrossrefGoogle Scholar12 Agustí AG, Noguera A, Sauleda J, Sala E, Pons J, Busquets XSystemic effects of chronic obstructive pulmonary diseaseEur Respir J2003212347360 CrossrefGoogle Scholar13 Faner R, Sobradillo P, Noguera A, et al.The inflammasome pathway in stable COPD and acute exacerbationsERJ Open Res201623 CrossrefGoogle Scholar14 Gan WQ, Man SF, Senthilselvan A, Sin DDAssociation between chronic obstructive pulmonary disease and systemic inflammation: a systematic review and a meta-analysisThorax2004597574580 CrossrefGoogle Scholar15 Lavie LObstructive sleep apnoea syndrome: an oxidative stress disorderSleep Med Rev2003713551 CrossrefGoogle Scholar16 Pitta F, Troosters T, Spruit MA, Probst VS, Decramer M, Gosselink RCharacteristics of physical activities in daily life in chronic obstructive pulmonary diseaseAm J Respir Crit Care Med20051719972977 CrossrefGoogle Scholar17 Moy ML, Teylan M, Weston NA, Gagnon DR, Danilack VA, Garshick EDaily step count is associated with plasma C-reactive protein and IL-6 in a US cohort with COPDChest20141453542550 CrossrefGoogle Scholar18 Watz H, Pitta F, Rochester CL, et al.An official European Respiratory Society statement on physical activity in COPDEur Respir J201444615211537 CrossrefGoogle Scholar19 Waschki B, Kirsten A, Holz O, et al.Physical activity is the strongest predictor of all-cause mortality in patients with COPD. 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