Comorbidities and Systemic Effects of Chronic Obstructive Pulmonary Disease Gourab Choudhury, MBBS, MRCP(UK)*, Roberto Rabinovich, MBBS, MD, PhD, William MacNee, MBChB, MD, FRCP(G), FRCP(E) INTRODUCTION Chronic obstructive pulmonary disease (COPD) is a major cause of morbidity and mortality world- wide. It has been projected to move from the sixth to the third most common cause of death world- wide by 2020, while rising from fourth to third in terms of morbidity within the same time frame. 1 The prevalence of COPD in the general popula- tion is estimated to be around 1% of the adult pop- ulation, but rises sharply among those 40 years and older. The prevalence continues to climb appreciably higher with age. 2 COPD is known primarily to affect the lung structure and function, resulting in emphysema- tous destruction of lung tissue and large and small airway disease that occur in varying proportion and severity within individuals. 3 Besides the lung abnormalities, COPD is now recognized to be a condition that has an impact on other organs, the so-called systemic effects and comorbidities of COPD. 4–6 Conventionally, co- morbidity has been defined as a disease coexisting with the primary disease of interest. In COPD, how- ever, the definition becomes more perplexing, as certain coexisting illnesses may be a consequence of the patients’ underlying COPD when it could termed as more of a systemic effect. It is as yet unclear whether these associations are a consequence of shared risk factors such as cigarette smoking or poor physical activity, or whether COPD is a true causal factor. Neverthe- less, these extrapulmonary features of COPD add to the challenge and burden of assessing and managing the disease. This article reviews the types, possible mecha- nisms, and clinical implications of these systemic effects and comorbidities on COPD patients. CLASSIFICATION Table 1 lists the systemic effects and comorbid- ities associated with COPD. Table 2 summarizes the results of a PubMed search investigating the prevalence of COPD and comorbidities in various studies performed in the past. CARDIOVASCULAR DISEASE COPD is now well known to be a risk factor for the development of atherosclerosis and consequent cardiovascular complications. 7,8 ELEGI and COLT Laboratories, Queen’s Medical Research Institute, 47 Little France Crescent, EH16 4TJ Edinburgh, UK * Corresponding author. E-mail address: [email protected]KEYWORDS Chronic obstructive pulmonary disease Comorbidities Systemic effects Inflammation Management strategy KEY POINTS Definitive types of systemic effects and co-morbidities have been seen in COPD patients. There are possible contributory mechanisms to these effects. There are clinical implications of these co-morbidities in the cohort. Novel therapies reduce the burden of observed effects. Clin Chest Med 35 (2014) 101–130 http://dx.doi.org/10.1016/j.ccm.2013.10.007 0272-5231/14/$ – see front matter Ó 2014 Elsevier Inc. All rights reserved. chestmed.theclinics.com
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Comorbidities and SystemicEffects of Chronic ObstructivePulmonary DiseaseGourab Choudhury, MBBS, MRCP(UK)*,Roberto Rabinovich, MBBS, MD, PhD,William MacNee, MBChB, MD, FRCP(G), FRCP(E)
INTRODUCTION
Chronic obstructive pulmonary disease (COPD) isa major cause of morbidity and mortality world-wide. It has been projected to move from the sixthto the third most common cause of death world-wide by 2020, while rising from fourth to third interms of morbidity within the same time frame.1
The prevalence of COPD in the general popula-tion is estimated to be around 1% of the adult pop-ulation, but rises sharply among those 40 yearsand older. The prevalence continues to climbappreciably higher with age.2
COPD is known primarily to affect the lungstructure and function, resulting in emphysema-tous destruction of lung tissue and large and smallairway disease that occur in varying proportionand severity within individuals.3
Besides the lung abnormalities, COPD is nowrecognized to be a condition that has an impacton other organs, the so-called systemic effectsand comorbidities of COPD.4–6 Conventionally, co-morbidity has been defined as a disease coexistingwith the primary disease of interest. In COPD, how-ever, the definition becomes more perplexing, ascertain coexisting illnesses may be a consequence
of the patients’ underlying COPD when it couldtermed as more of a systemic effect.
It is as yet unclear whether these associationsare a consequence of shared risk factors such ascigarette smoking or poor physical activity, orwhether COPD is a true causal factor. Neverthe-less, these extrapulmonary features of COPDadd to the challenge and burden of assessingand managing the disease.
This article reviews the types, possible mecha-nisms, and clinical implications of these systemiceffects and comorbidities on COPD patients.
CLASSIFICATION
Table 1 lists the systemic effects and comorbid-ities associated with COPD. Table 2 summarizesthe results of a PubMed search investigating theprevalence of COPD and comorbidities in variousstudies performed in the past.
CARDIOVASCULAR DISEASE
COPD is now well known to be a risk factor for thedevelopment of atherosclerosis and consequentcardiovascular complications.7,8
ELEGI and COLT Laboratories, Queen’s Medical Research Institute, 47 Little France Crescent, EH16 4TJEdinburgh, UK* Corresponding author.E-mail address: [email protected]
! Definitive types of systemic effects and co-morbidities have been seen in COPD patients.
! There are possible contributory mechanisms to these effects.
! There are clinical implications of these co-morbidities in the cohort.
! Novel therapies reduce the burden of observed effects.
Clin Chest Med 35 (2014) 101–130http://dx.doi.org/10.1016/j.ccm.2013.10.0070272-5231/14/$ – see front matter ! 2014 Elsevier Inc. All rights reserved. chestm
Cardiovascular disease is undoubtedly the mostsignificant nonrespiratory contributor to bothmorbidity and mortality in COPD.In a large cohort of patients with COPD admitted
to a Veterans Administration Hospital or clinic, theprevalence of coronary artery disease was 33.6%,appreciably higher than the 27.1% prevalenceseen in a matched cohort without COPD.9 In theLung Health Study,10 which assessed deaths andhospitalizations over a 5-year period in a cohortof COPD patients, mortality in 5887 patientsaged 35 to 46 years with COPD with mild to mod-erate airways obstruction was 2.5%, of whom25% died of cardiovascular complications. More-over, in these patients with relatively mild COPD,cardiovascular disease accounted for 42% of thefirst hospitalization and 44% of the second hospi-talization over a follow-up period of 5 years. Bycomparison, only 14% of the hospitalizations inthis cohort were from respiratory causes.Divo and colleagues11 looked at 1664 patients
with COPD over 4 years to evaluate COPD comor-bidities and mortality risk. Using a multivariateanalysis, they generated a COPD comorbidity in-dex (COPD-specific comorbidity test) based onthe comorbidities that increase mortality risk. Theprevalence of coronary artery disease in this studywas unsurprisingly highest at 30.2%, with conges-tive heart failure (HF) and dysrhythmias making upanother 15.7% and 13% of the cases, respec-tively, and correlated strongly with the associationfor increased risk of death (P<.05).Holguin and colleagues12 assessed the preva-
lence of COPD deaths in United States between1979 and 2001, and found approximately 47million hospital discharges (8.5% of all hospitaliza-tions in adults) with a primary or secondary diag-nosis of COPD (21% and 79%, respectively). Thereported hospital mortality in this cohort wasrelated to heart disease in 43%, taking the major
share for the cause of death, compared with37% related to respiratory failure and another25% related to pneumonia.Forced expiratory volume in 1 second (FEV1) is
also known to be an independent predictor of car-diovascular complications in COPD patients. Inthe Lung Health Study, for every 10% decreasein FEV1, cardiovascular mortality increased byapproximately 28% and nonfatal coronary eventsincreased by approximately 20% in mild to moder-ate COPD.10 Even a moderate reduction of expira-tory flow volumes multiplies the risk ofcardiovascular morbidity and sudden cardiacdeaths by 2 to 3 times, independent of other riskfactors.13–16
COPD patients also have shown evidence ofatherosclerotic plaque burden as assessed byincreased carotid intimal medial thickening(CIMT),17 and are associated with increased car-diovascular and all-cause mortality.18
Pathogenesis
The pathogenesis of atherosclerosis in COPD ismultifactorial.19 Box 1 summarizes the potentialmechanisms that have been linked directly or indi-rectly to the cardiovascular complications seen inthis cohort. Fig. 1 summarizes the presumedmechanisms for cardiovascular disease in COPDpatients.
InflammationInflammation is considered to be a potential path-ogenic mechanism in atherosclerosis. Recentstudies, however, indicate that sustained systemicinflammation occurs only in a proportion of pa-tients with COPD, and its relationship to the devel-opment of cardiovascular disease has as yet notbeen fully established.20 Patients with COPD andcoexistent cardiovascular disease neverthelesstend to have higher systemic levels of biomarkers,such as interleukin (IL)-6 and fibrinogen, thanthose without this comorbidity.21 In addition, sys-temic inflammation increases exacerbations ofCOPD when there is an increased risk of cardio-vascular events.22,23
The specific cellular mechanisms by which sys-temic inflammation plays a role in the pathogen-esis of cardiovascular disease are complex.However, studies have revealed the importanceof inflammation in atherosclerotic plaque initiation,development, and rupture (see Fig. 1).24,25
18F-Fluorodeoxyglucose positron emission to-mography imaging has also shown direct evidenceof inflammation in the vascular wall of the aorta,presumably associated with atherosclerotic pla-ques, in patients with COPD when comparedwith smoking control subjects.26
Table 1Observed systemic effects and comorbidities inthe COPD population
Table 2Data from various studies (PubMed search) looking at the prevalence of COPD and comorbidities
FirstAuthor Journal Type of Study
PatientSize (n)
Cardiac(%)
Hypertension(%)
Diabetes(%)
Psychiatric(%)
Cancer(%)
Osteoporosis(%)
van Manen et al J Clin Epidemiol Observational 1145 13 23 5 9 6 —
Almagro et al Chest Retrospectivematched cohort
2699 22 — — 10 4 —
Sidney et al Chest Retrospectivematched cohort
45,966 18 18 2 — — —
Schnell et al BMC Pulm Med Cross-Sectional 995 12.7 — — 20.6 16.5 16.9
Feary et al Thorax Cross-Sectional 29,870 28 — 12.2 — — —
— signifies no data available.
Comorbiditie
sandSyste
mic
Effects
ofCOPD
103
Systemic inflammation is discussed in more de-tails later in this article.
HypoxiaPatients with COPD are subjected to hypoxia:either sustained hypoxia in patients with severedisease, or intermittent hypoxia during exerciseor exacerbations. There are several effects of hyp-oxia that can influence atherogenesis, includingsystemic inflammation and oxidative stress, upre-gulation of cell-adhesion molecules, and hemody-namic stress.27–29 Animal studies have shownhypoxia to be a contributor to atherosclerosis inthe presence of dyslipidemia, as increased lipidperoxidation, a marker of oxidative stress, andreduced levels of the antioxidant superoxide dis-mutase are found in the myocardial tissue of ratsexposed to hypoxic environments.30,31
Hypoxia also induces hemodynamic stress,increasing the heart rate and cardiac index,32
and affects the renal circulation, reducing renalblood flow and activating the renin-angiotensinsystem, resulting in increased peripheral vasocon-striction and oxidative stress.33 Respiratory failurein patients with COPD is also associated with acti-vation of the sympathetic nervous system,34 whichis associated with an increased risk for cardiovas-cular disease.35
Effect of cigarette smokingChronic cigarette smoking is an independent riskfactor for the development of cardiovascular com-plications in COPD patients.36 Possible mecha-nisms include increased systemic oxidativestress, altered nitric oxide (NO) bioavailability,endothelial dysfunction, and influence on thelevels of other major risk factors, such as bloodpressure.37–39
However, studies have also shown that inde-pendent of current smoking, plasma levels offibrinogen and other markers of coagulation aresignificantly higher in patients with stable COPDthan in healthy subjects.40,41 This amplified pro-coagulant activity in COPD may principally be aconsequence of inflammation, initiating the coagu-lation cascade by promoting tissue factor geneexpression in endothelial cells, hence contributingto increased thrombotic events.42
PolycythemiaSecondary polycythemia is a known complicationof COPD, and occurs mainly as a result of chronichypoxemia. A prospective study by Cote and col-leagues,43 however, had shown that only 6% oftheir 683 COPD patients developed secondarypolycythemia, perhaps because the developmentof polycythemia in COPD has been less commonin recent times, and is thought to be due to moreeffective management of hypoxia in COPD suchas the use of long-term oxygen therapy (LTOT) inpatients who meet the criteria.However, when present in COPD polycythemia
can contribute to the development of pulmonaryhypertension and pulmonary endothelial dysfunc-tion with reduced cerebral and coronary bloodflow, thus adding to the pathogenic cascade.44
Hypercapnic acidosisRespiratory acidosis resulting from hypercapnia isa well-known occurrence in patients with COPD,particularly in the advanced phase. A recent study
Fig. 1. The putative mechanisms for the pathogenesis of cardiovascular disease in COPD. MMP, matrix metallopro-teinase; PARC/CCL-18, pulmonary and activation-regulated chemokine CC chemokine ligand 18; PSGL, P-selectinglycoprotein ligand 1; SIRT, sirtuin 1. (From Maclay JD, MacNee W. Cardiovascular disease in COPD: mechanisms.Chest 2013;143(3):798–807. http://dx.doi.org/10.1378/chest.12-0938; with permission.)
Box 1Potential pathogenic mechanisms ofcardiovascular disease in COPD
by Minet and colleagues45 has shown that respira-tory acidosis could be one of the potent mecha-nisms behind endothelial dysfunction, adding tothe burden of cardiovascular complications.
Abnormalities in vascular endothelial function/vessel wallSome,46,47 but not all studies48 have demon-strated abnormal endothelial function in COPD pa-tients in comparison with smokers who have notdeveloped COPD.
Arterial stiffness can be assessed using carotid-femoral pulse-wave velocity (PWV), a measure thatis predictive of cardiovascular events in healthy in-dividuals and in patients with ischemic heart dis-ease.49 Arterial stiffness is increased in COPDpatients in comparison with healthy smokers50,51
and is associated with the FEV1 percent predictedemphysema and systemic inflammation,52 andmay result from increased elastolysis in the vesselwall.53
Common Cardiovascular Complications
HF is common in COPD patients, and COPD iscommon in HF patients. In a survey of COPD pa-tients in primary care, 20% had previously unrec-ognized HF,54 which is associated with a worseprognosis in COPD patients.55
A study of 186 consecutive patients with leftventricular systolic dysfunction in an HF clinicfound that 39% had COPD diagnosed by spirom-etry, and those patients with HF and severe COPDhad a worse prognosis than the HF patients withmild to moderate COPD or normal lung function.56
Higher mortality was again reported among pa-tients with COPD when compared with individualswithout lung disease in a study of 4132 patientshospitalized with cardiac failure in Norway.57
In another prospective prognostic study per-formed as part of the EchoCardiography and HeartOutcome Study (ECHOS), 532 patients admittedwith a clinical diagnosis of HF were studied.58
The prevalence of COPD in these patients wasfound to be 35% and was associated with a worseprognosis.
COPD is indeed a predictor of mortality in HF.30
Studies have shown 5-year survival in HF patientswith COPD to be as low as 31%, comparedwith 71% in its absence.57 HF in COPD patientshas often been postulated to be secondaryto increased intrathoracic pressure–inducedimpaired low-pressure ventricular filling, as is ex-pected with hyperinflated lungs in this popula-tion.59 However, Barr and colleagues60 haveshown that computed tomography (CT)-quantifiedemphysema scores negatively correlated withventricular filling even in a group without COPD
and minor emphysema, in whom hyperinflation isunlikely to play a role. The investigators hypothe-sized that endothelial dysfunction associatedwith emphysema could contribute to impairedleft ventricular filling and the consequent failurecascade.
Patients with COPD also have increased risk forcardiac arrhythmias.61 Following surgery for non–small cell lung carcinoma, patients with spiro-metric evidence of COPD had an increased riskfor supraventricular tachycardia, and were foundto be refractory to first-line treatment.62 Atrial fibril-lation (AF) is also more common in COPD followingcoronary artery bypass grafting.63 In a study con-ducted in Finland on 738 patients with COPD, AFwas found to be an independent predictor ofincreased mortality and poor health-related qualityof life (HRQoL) in comparison with the generalpopulation.64
Coronary artery disease is also common and isundertreated in patients with COPD.65 In a groupof healthy Japanese men, CIMT (a surrogate mea-sure strongly associated with atherosclerotic pla-que burden) was significantly increased inindividuals who smoked and had airflow limitationcompared with matched smokers and non-smokers.17 This finding suggests that smokerswith a spirometric-based diagnosis of COPDmay have evidence of subclinical atherosclerosisindependent of cigarette smoking.
The presence of COPD in patients with myocar-dial infarction (MI) is also associated with a poorerprognosis. In a study of 14,703 patients with acuteMI, all-cause mortality was 30% in patients withCOPD versus 19% in those without COPD.66
Campo and colleagues14 assessed 11,118consecutive patients with ST-elevation MI (STEMI)stratified according to the presence or absence ofCOPD. At the 3-year follow-up, COPD was foundto be an independent predictor of mortality (hazardratio [HR] 1.4, 95% confidence interval [CI]1.2–1.6). Hospital readmissions from recurrent MI(10% vs 6.9%, P<.01) and HF (10% vs 6.9%,P<.01) were significantly more frequent in patientswith COPD when compared with those without.Also hospital readmission for COPD was foundto be a strong independent risk factor for recur-rence of MI (HR 2.1, 95% CI 1.4–3.3) and HF (HR5.8, 95% CI 4.6–7.5).
In a study of exacerbations of COPD from theUnited Kingdom Health Improvement Database,the incidence rate of MI was 1.1 per 100 patient-years, with a 2.27-fold increased risk of MI 1 to5 days after exacerbation.67
In another prospective study, 242 COPD pa-tients admitted to hospital with an exacerbationwere studied to observe the prevalence of MI
Comorbidities and Systemic Effects of COPD 105
following hospitalization.22 Twenty-four patients(10%) were found to have elevated troponin,among whom 20 (8.3%; 95% CI 5.1%–12.5%)had chest pain and/or serial electrocardiographicchanges, in keeping with MI. Overall, 1 in 12 pa-tients met the criteria for MI.
Interventions to Reduce CardiovascularComplications
Smoking cessationA recent meta-analysis assessing the impact ofsmoking has shown a decline of acute coronarysyndrome risk in 30 of 35 estimates with a 10%(95% CI 6–14, P<.001) pooled relative risk reduc-tion, supporting the fact that smoking is an inde-pendent risk factor toward development ofcardiovascular complications.68 Smoking cessa-tion therefore unsurprisingly remains one of theprimary cornerstones of cardiovascular riskmanagement.
Effective management of COPDIt is well known that for every 10% decrease inFEV1, cardiovascular mortality increases by about28%, and nonfatal coronary events increase byabout 20% in mild to moderate COPD.16 There-fore, early detection and effective managementof the disease is of importance in reducing theassociated complications of this condition.The use of current medications to treat COPD,
however, has not been shown to be definitive to-ward reduction of cardiovascular events. Whereasobservational studies have suggested that inhaledcorticosteroids (ICS) may potentially confer benefiton cardiovascular events or mortality,69 random-ized controlled trials (RCTs) have failed to showany significant effect of ICS therapy on MI or car-diovascular death. The use of long-acting inhaledb-agonists does not appear to produce anincreased risk of cardiovascular deaths.70 Thelong-acting antimuscarinic, tiotropium, appearsto confer an increased risk of cardiovascular deathwhen used in a higher dose in the Respimat inhalerbut not in the Handihaler formulation,71 which mayeven be associated with a decrease in cardiovas-cular mortality.72
Cardiovascular drugsMedications currently associated with cardiovas-cular risk reduction, such as b-blockers (BB),angiotensin-converting enzyme (ACE) inhibitors,statins, and angiotensin II receptor blockers(ARBs), have been shown in retrospective phar-macoepidemiologic studies to have an impact onthe clinical outcome of COPD patients by reducingthe cardiovascular events and mortality.73–75
These observational studies, however, suffer
from immortal time bias, and prospective studiesare required to definitively assess the benefits ofthese drugs in this population.BB are known to improve survival of patients
within a large spectrum of cardiovascular dis-eases, including ischemic heart disease andHF.76–80 In a large observational study involving2230 COPD patients, the association of BB usagewith all-cause mortality and risk of exacerbationwas studied.81 Use of BB was found to be associ-ated with a reduction in mortality as well as the riskof exacerbations in a broad spectrum of patientswith COPD with concurrent cardiovascular dis-ease. Importantly in a subgroup analyses,including patients with COPD but without overtcardiovascular disease, but with hypertension asthe main remaining indication for the prescriptionof BB, similar outcomes were noted. This resultfurther indicates the potential protective benefitof BB in COPD even in those with no known historyof heart disease.However, BB have been underprescribed in pa-
tients with COPD cardiovascular disease,82 largelybecause of the potential to worsen airflow limita-tion and consequent theoretical respiratory sideeffects (namely bronchospasm).A recent meta-analysis of studies in COPD pa-
tients has shown that cardioselective BB, givenas a single dose or for longer duration, producedno change in FEV1 or respiratory symptomswhen compared with placebo, and did notaffect the FEV1-guided treatment response tob2-agonists.83
Another recent study also explored the associa-tion between BB therapy and outcomes in patientshospitalized with acute exacerbations of COPDwith underlying ischemic heart disease, HF, or hy-pertension. The study accounted for the problemof immortal time bias, and found no improvementor worse mortality in COPD patients using BB.84
Judicious use of BB may therefore be warrantedin patients with severe COPD and respiratory fail-ure on LTOT in whom the use of BB was associ-ated, in one study, with increased mortality.85
Similarly, statins, ACE inhibitors, and ARBs arealso widely used for the treatment and preventionof cardiovascular disease, and their potential rolein other disease states has become increasinglyrecognized. Mortensen and colleagues86 studiedthe association of prior outpatient use of statinsand ACE inhibitors on mortality for subjects of65 years or older who were hospitalized with acuteCOPD exacerbations. A total of 11,212 subjectswith a mean age of 74.0 years were studied inthis group, of whom 32.0% were using ACE inhib-itors or ARBs, the use of which was associatedwith significant reduction in 90-day mortality
Choudhury et al106
(odds ratio [OR] 0.55, 95% CI 0.46–0.66). A similarpharmacoepidemiologic study done by Manciniand colleagues75 suggested that statins in combi-nation with either ACE inhibitors or ARBs improvedcardiovascular and pulmonary outcomes not onlyin the high-risk but also in the low-risk COPDpopulations.
SKELETAL MUSCLE EFFECTS
A striking systemic consequence of COPD is thereduction in peripheral muscle mass, resulting inmuscle wasting and dysfunction. Muscle dysfunc-tion, with or without evidence of atrophy, can bedefined physiologically as the failure to achievethe basic muscle functions of strength and resis-tance, the latter being inversely related to an in-crease in the fatigability of the muscle.
Reduced quadriceps strength in COPD isassociated with reduced exercise capacity,87,88
compromised health status,89 increased need forhealth care resources,90 and mortality indepen-dent of airflow obstruction.91 Skeletal muscleweakness, particularly quadriceps weakness, hasalso recently been shown to be a feature of earlydisease,92 and its development is likely to bemulti-factorial with inflammation and oxidative stress93
being the predominant factors, coupled with phys-ical inactivity.94,95 Several other factors such asprotein synthesis/degradation imbalance and hyp-oxia have also been postulated to explain the initi-ation and the progression of muscle wasting inCOPD patients.88,96
Prevalence
Eighteen percent to 36%of COPDpatients presentwith net loss of muscle mass, which is responsiblefor weight loss in 17% to 35% of such patients.97
However, muscle wasting is also present in 6% to21%of patients of normal weight.98 The reductionsin mass and cross-sectional area of limb musclesof COPD patients have been linked to the impairedmuscle strength seen in these patients.When limb-muscle strength is normalized per unit of massor cross-sectional area, no differences can beobserved between control subjects and COPD pa-tients, suggesting that atrophy is indeed an impor-tant causative factor in the reduced limb-musclestrength and endurance inCOPD.97Hence, it couldbe argued that muscle wasting is a better predictorof HRQoL and survival than is body weight.99
Unintentional loss of muscle mass, unsurpris-ingly, has a significant impact on the quality oflife, and can be associated with prematuredeath.100
Fig. 2 illustrates the various pathophysiologicchanges that are observed in skeletal muscles of
COPD patients and the possible mechanismsimplicated.
Fiber redistribution results in an increase in thenum-ber of type IIx muscle fibers,101,102 which, in turn, isassociated with significant muscle atrophy.102
Alterations in muscle bioenergetics in skeletallimb muscle of COPD patients correlate with exer-cise tolerance. For example, the early lactaterelease that occurs during exercise, the increasedphosphate/phosphocreatine relationship duringsubmaximal exercise, and the reduced activity ofoxidative enzymes in these patients all indicate achange in muscle bioenergetics.103
Altered capillary structuration has also beenfound in the skeletal muscle of COPD patients.Electron and optic microscopy studies showreduced capillary density and the number of con-tacts between capillaries and fibers in skeletalmuscles of COPD patients.104
Factors Contributing to Muscle Dysfunction
Several factors, such as protein synthesis/degra-dation imbalance, hypoxia, inactivity, inflamma-tion, and oxidative stress, have been proposedto explain the initiation and the progression ofmuscle wasting in COPD.96,97 Mitochondrialdysfunction, apoptosis, and oxidative stress haveall also been implicated to the wasting anddysfunction observed in COPD.
Mitochondrial dysfunction is manifested asreduced citrate synthase activity that correlateswith time to fatigue of the muscle,105 whilereduced mitochondrial oxidative phosphorylationand coupling have been associated with reducedmuscle mass and endurance.106
Other factors that contribute to this muscledysfunction include the following.
! Abnormal protein metabolism. A substantialproportion of COPD patients is characterizedby low fat-free mass with altered muscle andplasma amino acid levels, suggestingabnormal protein metabolism.107 The sig-naling pathways that govern muscle hypertro-phy and/or atrophy have yet to be fullydefined. However, several key factors havebeen identified. Fig. 3 summarizes the salientpathways governing skeletal muscle meta-bolism. Marked activation of the ubiquitin-proteasome pathway is found in muscle ofpatients with COPD, and is thought to beone of the key factors in muscle atrophy anddysfunction as seen in COPD patients.108,109
Comorbidities and Systemic Effects of COPD 107
! Poor nutritional intake and unmatched calorieexpenditure are further factors contributingto muscle wasting in COPD patients. Chronicusage of oral corticosteroids is also a well-known contributor to myopathy in thisgroup.110 Previous studies have shown thatthe histology of steroid-induced myopathy inpatients with COPD is of global myopathyaffecting both type IIa and IIb fibers, andtype I fibers to a lesser extent.111 However,administration of corticosteroids for relativelyshort periods of time, for example during anexacerbation, has not been shown to causeany significant deleterious effect on the skel-etal muscle of COPD patients.112
! Hypoxia is implicated in mitochondrialbiogenesis, oxidative stress, inflammation,and autophagy. It results in enhanced cyto-kine production by macrophages, contrib-uting to the activation of the tumor necrosisfactor (TNF) system. Significant inverse corre-lations between partial pressure of arterialoxygen and circulating TNF-a and soluble
TNF-receptor levels have been reported in pa-tients with COPD,113 limiting the production ofenergy and possibly affecting the protein syn-thesis also.114
! Hypercapnic acidosis can inhibit the oxidativeenzymes, further contributing toprotein degra-dation and the process of muscle wasting.115
! Inflammation, as in cardiovascular complica-tions, is another mechanism contributing toskeletal muscle dysfunction in COPD pa-tients. Relatively fewer data are currentlyavailable on the concentration of cytokinesin muscle of COPD patients, the most studiedbeing TNF-a. High levels of TNF-a protein inserum have been associated with quadricepsweakness,116 and COPD patients with lowfat-free mass (FFM) are reported to showhigh mRNA levels of TNF-a in the quadriceps,together with lower body mass index(BMI).117 Of interest, high levels of C-reactiveprotein (CRP) have been found to beinversely related to the distance covered ina 6-minute walking test in COPD patients,
Fig. 2. The common manifestations and underlying pathophysiologic changes of skeletal muscle dysfunction inCOPD patients.
Choudhury et al108
suggesting a role for chronic inflammation inthese patients.118
Interventions to Improve Skeletal MuscleDysfunction
! Exercise training is the single most importanttherapeutic intervention to treat muscledysfunction/wasting in patients withCOPD.119 Improving exercise tolerance byenhancing muscle strength, with consequentimproved endurance and reduced fatigue,have all proved to be very effective.119 Exer-cise training improves body weight byimproving FFM, enhancing oxygen deliveryto the muscle mitochondria and fiber-typeredistribution.119,120
! Oxygen therapy and consequent correction ofhypoxia in suitable candidates have also beenshown to improve the mitochondrial oxidativecapacity in COPD patients.120,121
! Smoking cessation is likely to be an importantaspect in improving muscle dysfunction.Chronic smoking has been associated withdiverse mitochondrial respiratory chain(MRC) dysfunction in lymphocytes. In a study
of MRC function in peripheral lymphocytes of10 healthy chronic smokers before and aftercessation of smoking,122 smokers showed asignificant decrease in complex IV MRC activ-ity and respiration compared with control lym-phocytes, which returned to normal valuesafter cessation of tobacco smoking.
! Other novel therapies such as the antioxidantN-acetylcysteine123 and peroxisomeproliferator-activated receptors (such as poly-unsaturated fatty acids)120,124 are potentialinterventions that may improve muscle insuffi-ciency in COPD patients, and are currently inthe process of being tried and tested.
OSTEOPOROSIS
Osteoporosis is a systemic skeletal disorder char-acterized by low bone mineral density (BMD) andmicroarchitectural changes, leading to impairedbone strength and increased risk of fracture.4
Low BMI, advanced age, female sex, chronicuse of oral corticosteroids, and endocrinologicdisorders such as hyperthyroidism and primaryhyperparathyroidism have all been implicated asrisk factors in the development of osteoporosis in
Fig. 3. Pathways governing skeletal muscle hypertrophy and atrophy.
Comorbidities and Systemic Effects of COPD 109
the general population.125 Predictably, osteopo-rosis is a well-recognized comorbidity of COPDpatients and is an important area of considerationfor therapeutic interventions.126
The most commonly used tool to measure BMDis dual-energy x-ray absorptiometry (DEXA), whichis used to define osteoporosis and provides a use-ful estimate of fracture risk.127 The T score is oneof the principal parameters used to measureBMD, and is calculated by subtracting the meanBMD of a young-adult reference population fromthe patient’s BMD and dividing it by the standarddeviation of the reference population. Accordingto the World Health Organization (WHO), a T scoregreater than "1 is accepted as normal, T scoresbetween "1 and "2.5 are classified as osteope-nia, and T scores of less than "2.5 are definedas osteoporosis.127
Prevalence of Osteoporosis in COPD
The prevalence of osteoporosis in COPD variesbetween 4% and 59%, depending on the diag-nostic methods used and the severity of theCOPD population.128
A recent systematic review calculated an over-all mean prevalence of osteoporosis of 35% from14 articles by measuring BMD in a COPD popula-tion. The individuals in these studies had a meanage of 63 and a mean FEV1 percent predicted of47%.128
More than half of the patients with COPD re-cruited for the large TORCH (Toward a Revolutionin COPD Health) trial (6000 patients) had osteopo-rosis or osteopenia as determined by DEXAscan.129
In another cross-sectional study, the prevalenceof osteoporosis was 75% in patients with GlobalInitiative for Chronic Obstructive Lung Disease(GOLD) stage IV disease, and strongly correlatedwith reduced FFM.130,131 Another importantfinding in this study was that the prevalence ratewas high even for males, with an even higher inci-dence in postmenopausal women.Another large cohort of 1634 COPD subjects
was studied longitudinally with 259 smoker and186 nonsmoker controls132 in a study evaluatingCT bone attenuation of the thoracic and lumbervertebrae, the extent of emphysema and coronaryartery calcification on CT scans, and clinical pa-rameters and outcomes. Bone attenuation waslower in the COPD patients than in control sub-jects, and correlated positively with FEV1 (P 5.014), FEV1/forced vital capacity ratio (P<.001),FFM index (P<.001), and CRP (P<.001), and nega-tively with the extent of emphysema (P<.001).Lower CT bone attenuation was also found to be
associated with higher exacerbation (P 5 .022)and hospitalization rates (P 5 .002).In a Norwegian cross-sectional study of 1004
consecutively admitted COPD patients attendinga 4-week rehabilitation program, the prevalenceof vertebral deformities was found to be signifi-cantly higher in COPD patients than in thecontrol group (P<.0001).133 An increase in severityof airflow limitation from GOLD stage II to stage IIIwas associated with an almost 2-fold increase inthe average number of vertebral deformities. Ofnote, significant differences between COPD pa-tients and controls were also found for pack-years (P<.0001), and use of calcium/vitamin D(P<.0001) and oral corticosteroids (P<.0001).
Potential Contributors to Osteoporosis inCOPD
CorticosteroidsOral glucocorticosteroids (OGCS) have both directadverse effects on bone and indirect effects attrib-utable to muscle weakening and atrophy.134
OGCS are known to cause a decrease in vascularendothelial growth factor, skeletal angiogenesis,bone hydration, and strength.135 These effectsare both dose-dependent and duration-dependent. Fewer adverse effects are seen inepisodic usage of OGCS in comparison withcontinuous use, but lower continuous doseshave fewer detrimental effects on bone thanfrequent high-dose therapy,136 because systemicusage of corticosteroids can cause rapid boneloss within the first few months of treatment, fol-lowed by a slower 2% to 5% loss per year withchronic use.137 However, ICS have not beenshown to aggravate the bone mineral loss inCOPD patients.138
InflammationStudies suggest that COPD and associated sys-temic inflammation is a risk factor for osteoporosisindependent of other potentiators such as age andoral corticosteroid therapy.50,139 In a Chinesestudy, the presence of systemic inflammationwas associated with a greater likelihood of lowBMD, and multivariate logistic regression analysisshowed that TNF-a and IL-6 were independentpredictors of low BMD.139 Both these factors areknown to stimulate osteoclasts and increasebone resorption through receptor activator of nu-clear factor (NF)-kB ligand (RANKL)-mediatedbone resorption in vitro.50,140 In addition, manyother cytokines have been found to interact withthe osteoprotegerin/RANKL system, supportingthe concept that inflammatory mediators possiblycontribute to the regulation of bone remodeling inCOPD patients.141
Choudhury et al110
Calcification paradoxMounting data support a calcification paradox,whereby reduced BMD is associated withincreased vascular calcification. Furthermore,BMD is more prevalent in older persons with lowerBMI.142 Therefore, although BMI and coronary ar-tery calcification (CAC) exhibit a positive relation-ship in younger persons, it is predicted that inolder persons and/or those at risk for osteopo-rosis, an inverse relationship between BMI andCAC may apply. Kovacic and colleagues142 stud-ied 9993 subjects who underwent percutaneouscoronary intervention. Index lesion calcification(ILC) was analyzed with respect to BMI. In multi-variable modeling, BMI was an independentinverse predictor of moderate to severe ILC (OR0.967, 95% CI 0.953–0.980; P<.0001).
Therapeutic Interventions
Prevention and treatment of osteoporosis involvesboth pharmacologic and nonpharmacologicinterventions.
Nonpharmacologic measuresNonpharmacologic interventions include simplemeasures such as smoking cessation, and alcoholconsumption in moderation along with good nutri-tion. As discussed earlier, exercise training, partic-ularly weight-bearing and strengthening exerciseperformed at least 3 times per week, may be effec-tive for maintaining skeletal health, given the asso-ciation of reduced physical activity with bone lossand fracture in elderly COPD patients.136,143,144
Pharmacologic measuresCOPD patients, with or without diagnosed osteo-porosis, should be encouraged to take calcium(1000 mg/d) and vitamin D (800 IU/d) supplementsroutinely, as these have been shown to reduce therisk of fracture in this cohort.126,136
Definitive therapy is recommended in docu-mented fragility hip or vertebral (clinical ormorphometric) fracture; or T score lower than"2.5; or with less marked bone loss (T score be-tween "1 and "2.5) and 1 major criterion (use ofsystemic corticosteroids [3 months/year], majorfragility fracture [spine-hip] and so forth).128,139
An oral bisphosphonate, such as alendronateand risedronate, is currently considered as the firstline of treatment of osteoporosis together withvitamin D and calcium supplementation.145,146 Bi-sphosphonates act by inhibiting bone resorption,and have also been shown to prevent osteoblastand osteocyte apoptosis.145
Anabolic drugs such as the human parathyroidhormone (PTH) analogue teriparatide (PTH1–34) arealso being increasingly used to treat osteoporosis
in COPD patients, particularly in postmenopausalwomen and men with advanced osteoporosis.These agents act by stimulating bone formationthrough effects on osteoblasts and osteocytes,and therefore have great relevance predominantlyin OGCS-induced osteoporosis.134,147
Efforts should be made to detect and treat lowBMD in COPD patients to minimize fracture risk.Bone densitometry is widely available and shouldbe used to screen patients at risk of low BMD,particularly those with low BMI, as current ratesof detection and treatment of osteoporosis arelow. Lehouck and colleagues126 have suggesteda more aggressive approach to the diagnosisand management of low BMD in COPD, and thisshould be widely implemented to minimize therisk of osteoporotic complications.148 In thiscontext the term FRAX has been described.126
FRAX is a computer-based algorithm (http://www.shef.ac.uk/FRAX) that offers models forassessment of fracture likelihood in both menand women from the evidence provided from clin-ical risk factors such as age, sex, BMI, priorfragility fracture, smoking status, ethanol abuse,and prior use of corticosteroids. With FRAX, the10-year fracture probability can be derived usingthese clinical risk factors, alone or in conjunctionwith femoral neck BMD, to enhance fracture-riskprediction and to differentiate the patients whowill benefit most from definitive treatment.149 It ishoped that FRAX will become an increasinglyused tool in the future, but for the moment theidentification of patients who need antiresorptivetreatment remains based on clinical history,BMD, and prevalent fracture status.
NUTRITIONAL EFFECTS IN COPD
Nutritional abnormalities are also a common prob-lem in COPD patients. There are 3 types of nutri-tional abnormality that occur in this population:semistarvation (low BMI with normal or above-normal FFM index), muscle atrophy (normal orabove-normal BMI with low FFM index), andcachexia (low BMI with low FFM index).150
Prevalence and Implications
Weight loss has been reported in about 50% of pa-tients with severe COPD and, although less com-mon, it is still observed in about 10% to 15% ofmild to moderate COPD.5
Several studies have shown an association be-tween malnutrition and impaired pulmonary statusin patients with COPD.151 Poor nutritional statusand consequent weight loss in these patients isknown to be associated increased gas trapping,lower diffusing capacity, and lower exercise
tolerance compared with their normal nourishedcounterparts.152 Impairment of skeletal musclefunction along with reduction in diaphragmaticmass, with a decrease in strength and enduranceof the respiratory muscle that could occur in amalnourished state, have all been implicated incausing these adverse effects on pulmonaryfunction.Loss of skeletal muscle bulk is the main contrib-
utor to weight loss in COPD, with loss of fat masscontributing to a lesser extent.153 It is important torecognize that if nutritional assessment includesonly body weight and unintentional weight loss,some patients with normal BMI would go unde-tected despite being depleted of FFM.154,155 In across-sectional study154 involving 300 COPD pa-tients requiring LTOT, 17% of patients had a lowBMI, whereas the prevalence of FFM depletionwas 2 times higher (around 38%).This finding is of therapeutic importance, as
improving the nutrition in COPD patients canlead to improvement in anthropometric measuresand muscle strength, thus resulting in improvedand better quality of life and survival rates in thesepatients. Post hoc analysis of COPD patientswho gain weight has suggested a decrease inmortality.156 At least one study has reportedimproved immune function as a result of nutritionalsupport.157
Factors Contributing to Nutritional Depletion
The cause of nutritional abnormalities in COPD pa-tients seems to be multifactorial, as with other sys-temic effects.5,158 Box 2 lists the importantcontributory mechanisms.
Therapeutic Interventions
Dietary intervention following a proper nutritionalassessment remains one of the primary corner-stones in the management of this condition.A meta-analysis of 13 RCTs on the effects of
nutritional support in stable COPD patients151
showed significant improvements in favor of nutri-tional support for body weight (P<.001; in 11studies) and grip strength (P<.050; in 4 studies)associated with greater increases in mean totalprotein and energy intakes following theintervention.Similar results have been produced by Ferreira
and colleagues,152 who assessed 17 RCTs fromthe Cochrane Airways Review Group Trials Regis-ter. The meta-analysis showed that nutritional sup-plementation produced significant weight gain inpatients with COPD, especially in those whowere malnourished. In the 11 RCTs that studied325 undernourished patients, there was a meandifference of 1.65 kg (95% CI 0.14–3.16) in favorof supplementation. Nourished patients, however,may not respond to supplemental feeding to thesame degree as their undernourished counter-parts (1 RCT with 71 participants: standardizedmean difference [SMD] of 0.27, 95% CI "0.20–0.73).Ferreira and colleagues152 found a significant
change from baseline in FFM index (overallSMD 0.57, 95% CI 0.04–1.09), which becameeven more significant in undernourished patients(3 RCTs, 125 participants: SMD 1.08, 95% CI0.70–1.47). This study also emphasized the signif-icant improvement in respiratory muscle strengthand HRQoL that occurs in undernourished pa-tients following a nutritional intervention.This nutritional intervention can be in the form of
oral supplementation, enteral nutrition, or, in someextreme cases, parenteral nutrition.158 A diet richin protein and fat content is desirable, as an in-crease in fat calories with a decrease in carbohy-drate calories helps to limit the amount of carbondioxide production while still maintaining anadequate intake of protein for lean musclemass.158,159
In addition, the diet of these patients shouldinclude a good supply of vitamins, minerals, andantioxidants. In this context, u-3 fatty acid hasbeen shown to be of some value in combatingthe anti-inflammatory properties of TNF-a.158,160
Therefore, this could potentially be of novel thera-peutic benefit in achieving good nutritional statusin these patients.
OBESITY AND OBSTRUCTIVE SLEEP APNEA INCOPD
The prevalence of obesity, defined as BMI greaterthan 30 kg/m2, has multiplied during the last de-cades, and varies from 10% to 20% in most Euro-pean countries to 32% in the United States.161 Itplays a major role in the development of the meta-bolic syndrome, and has been identified as an
Box 2Factors governing the nutritional depletion inCOPD
! Drugs such as b2-agonists increasing meta-bolic rate
! Chronic systemic inflammation
Choudhury et al112
important risk factor for chronic diseases such astype 2 diabetes mellitus and cardiovascular dis-ease. A link between obesity and COPD is alsobeing increasingly recognized.162 The risk ofdeveloping obesity is increased in patients withCOPD as a result of physical inactivity in daily lifein these patients in comparison with healthy age-matched controls.163 In addition, patients withCOPD who receive repeated courses of systemicOGCS are at increased risk of truncal obesity asa result of steroid-mediated redistribution ofstored energy and the stimulatory effect onintake.164
As discussed previously, low BMI is associatedwith increased all-cause and COPD-related mor-tality, unrelated to disease severity.154 By contrast,the relative risk for mortality seems somewhatdecreased in overweight and obese patients withCOPD, particularly in GOLD stage 3 to 4, impartinga sort of protective effect, the so-called obesityparadox, as mortality is increased in those withdisease of GOLD stage 1 to 2 with obesitytraits.156,165
Chronic low-grade inflammation is also a hall-mark of obesity, insulin resistance, and type 2 dia-betes.166,167 Besides the presence of chronicairflow obstruction, low-grade systemic inflamma-tion could therefore be one of the common mech-anisms that may be responsible for the observedmortality and morbidity in obese COPD patients.
In this context, mention should also be made ofobstructive sleep apnea (OSA). OSA syndrome (ie,OSA and excessive daytime sleepiness) affects atleast 4% to 5% of middle-aged persons.168 Well-recognized risk factors include excess bodyweight, nasal congestion, alcohol, smoking, andmenopause in women.169
Epidemiologic studies have shown that 20% ofpatients with OSA also have COPD, whereas10% of patients with COPD have OSA indepen-dent of disease severity.170–172 Such bidirectionalinterplay between OSA and COPD has been giventhe term overlap syndrome.172 Possible sharedmechanistic links include increased parasympa-thetic tone, hypoxemia-related reflex bronchocon-striction/vasoconstriction, irritation of upperairway neural receptors, altered nocturnal neuro-hormonal secretion, proinflammatory mediators,within-breath and interbreath interactions be-tween upper and lower airways, and lung vol-ume–airway dependence.172
Management of OSA and COPD
It is currently unclear whether long-term positiveairway pressure therapy for COPD patientswithout OSA affects outcomes. In one such study,
122 COPD patients hospitalized with respiratoryfailure were randomized to LTOT versus noninva-sive nocturnal ventilation (positive airway pres-sure) plus oxygen therapy. There was animprovement in HRQoL and reduction in lengthof stay in the intensive care unit in the noninvasiveventilation group, but no difference in mortality orsubsequent hospitalizations was found.173
Thus the overlap syndrome represents acondition with important phenotypic characteriza-tion, and clarifies the frequent association, symp-tomatic load, and mortality consequences noted.However, the use of positive airway pressure inoverlap syndrome needs further assessment.
ANEMIA IN COPD
As discussed earlier, in severe COPD, polycy-themia with a raised hematocrit is known to be acommon phenomenon. However, just as for otherchronic conditions, COPD could also be associ-ated with anemia.
The WHO defines anemia as a disease associ-ated with low hemoglobin (males <13.0 g/dL andfemales <12 g/dL).174
Prevalence
Key findings of studies of anemia in COPD aresummarized in Table 3.
A study by Rutten and colleagues177 in theNetherlands involved 321 patients with COPDadmitted for pulmonary rehabilitation, and foundanemia in 20% of the patients and polycythemiain another 8%. There was no difference indisease-related outcomes or other comorbiditiesin the patients with and without anemia. However,after adjustment for confounders, anemia wasfound to be an independent determinant for higherCRP levels and lower BMD.
Low blood count can also be defined by hemat-ocrit (<39% in men and <36% in women). In aFrench study involving severe COPD patientswho required LTOT, a reduced hematocrit levelwas associated with increased mortality, whereasa raised hematocrit level was protective, indepen-dent of other markers of mortality.176
Pathogenesis
The anemia of chronic illness is typically a normo-cytic anemia and is most commonly observed inpatients with infectious disease, and inflammatoryor neoplastic diseases.
COPD fulfills the criteria of a chronic, inflamma-tory, multisystem disease that would be expectedto result in anemia. John and colleagues175 stud-ied 101 COPD patients and determined the
Comorbidities and Systemic Effects of COPD 113
Table 3PubMed search: anemia/anemia AND COPD OR chronic obstructive pulmonary disease in title/abstract
Authors,Ref. Year Journal Study Type Prevalence (%) Outcome Comment
John et al,175 2005 Chest Prospective (N 5 101) 13/101 5 13 No outcome dataEPO resistance?
Outpatients
John et al, 2006 Int J Cardiol Retrospective hospital records(N 5 312)
Abbreviations: EPO, erythropoietin; Hb, hemoglobin; HRQoL, health-related quality of life; LTOT, long-term oxygen therapy; NA, no data available; PaO2, partial pressure of oxygen inarterial blood.
Choudhury
etal
114
prevalence of anemia and its relationship to bodymass and weight loss, inflammatory parameters,and erythropoietin levels. Anemia was diagnosedin 13 patients (12.8%). These patients showedelevated erythropoietin levels and had increasedsystemic inflammation markers (raised CRP) incomparison with the nonanemic patients. Thisfinding raises the possibility that erythropoietinresistance, as is possible in the COPD cohort, ispotentially mediated by chronic inflammation.
Management
As for any other anemia of chronic disease, treat-ment of the underlying disease is the therapeuticapproach of choice for anemia in COPD.178
The level of hemoglobin is strongly and indepen-dently associated with increased functional dys-pnea and poorer exercise tolerance, and istherefore an important contributor to poor qualityof life.43 Schonhofer and colleagues179 demon-strated that correction of anemia with blood trans-fusions (among 20 patients with severe COPD)significantly reduced disease-related elevationsin minute ventilation and work of breathing, sug-gesting that anemia correction may be beneficialin alleviating dyspnea and improving exercise ca-pacity. Therefore, blood transfusion in selectedcases may be necessary, as erythropoietin is un-likely to work in this cohort because of end-organ resistance. Iron supplements, likewise, areunlikely to be useful and possibly could have adeleterious effect by adding to the burden of sys-temic oxidative stress.6
Autonomic Dysfunction
The autonomic nervous system (ANS) controlsphysiologic processes such as regulation of theairway smooth muscle tone, fluid transportthrough the airway epithelium, capillary perme-ability, bronchial circulation, and release of media-tors from inflammatory cells.180 Autonomicdysfunction (AD) is a known phenomenon inCOPD patients,181 and may be an important factorin the pathogenesis of the disease because of themultiple parameters that are under control of theANS such as the arterial and cardiac barorecep-tors,182 the bronchopulmonary C fibers, and pul-monary stretch receptors, which are capable oftriggering ventilation, bronchomotor, and cardio-vascular effects.183,184
Recurrent hypoxemia, hypercapnea, increasedintrathoracic pressure swings resulting fromairway obstruction, increased respiratory effort,and systemic inflammation along with the use ofb-sympathomimetics have all been implicated astrigger factors for AD as observed in COPD.181
Prevalence and Clinical Implications
Tug and colleagues185 assessed the prevalenceof AD according to disease severity in 35 stableCOPD patients. Sympathetic system (SS) wasevaluated with sympathetic skin response (SSR),and QT- and QTc-interval (milliseconds) analyses.The parasympathetic system was evaluated withthe variations in heart-rate interval. AD was de-tected in 20 patients (57%), parasympatheticdysfunction (PD) in 14 (40%), mixed-typedysfunction in 5 (14%), and sympathetic dysfunc-tion (SD) in only 1 patient (3%). For the 12 patientswith mild COPD, there were cases of isolated SDin 1 patient (8.5%), isolated PD in 5 (42%), and ADin 6 (50%). For the 23 moderate to severe COPDpatients, mixed AD was detected in 5 patients(22%), isolated PD in 9 (39%), and AD in 14(61%).
This imbalance in the autonomic nervous activ-ity can contribute to airway narrowing via an effecton the airway smooth muscle, bronchial vessels,and mucous glands in the bronchial wall, andtherefore could add to disease progression andseverity.
Correction of hypoxia and control of the sys-temic inflammation seem reasonable target strate-gies that may help to improve health status inCOPD patients.
LUNG CANCER AND COPD
With a shared common environmental risk factor inexposure to cigarette smoke, it is understandablewhy lung cancer is one of the most frequent co-morbidities and one of the commonest causes ofdeath in COPD patients.
Prevalence
Previous studies have shown that COPD is an in-dependent risk factor for the development oflung cancer and that having moderate to severeCOPD can increase the risk of developing lungcancer up to almost 5-fold.186,187
Thirty-eight percent of deaths in individuals withmild to moderate airflow limitation in the LungHealth Study died of lung cancer.10 In addition tothese 57 deaths, another 35 participants werediagnosed with the disease but survived to theend of follow-up.
An inverse correlation between the degree ofairflow obstruction and the risk for lung cancerwas demonstrated in an analysis of 22-yearfollow-up data of 5402 participants from the firstNational Health and Nutrition Examination Survey(NHANES I), including a total of 113 cases oflung cancer.188 Tockman and colleagues189 and
Comorbidities and Systemic Effects of COPD 115
Skillrud and colleagues190 have previously demon-strated that the incidence of lung cancer increasedin individuals with COPD as their FEV1 declined, arelationship that withstood correction for lifetimecigarette smoke dosage.Fig. 4 summarizes the inverse relationship
observed between lung cancer and lung functionvalues as seen in COPD patients.188 Unsurpris-ingly, lung cancer along with cardiovascular dis-eases comprises two-thirds of all deaths inCOPD patients.191
Recent studies also indicate that emphysemaand airflow limitation are risk factors for lung can-cer, independent of exposure to cigarettesmoke.192 Cross-sectional studies have shownthat after allowing for cigarette-smoke exposure,reduced FEV1 (as seen in COPD) is the singlemost important risk factor for lung cancer, andthat these 2 diseases are linked by more thansmoking exposure alone.188,193
An Italian study has also shown that airflow lim-itation is primarily a risk factor for squamous celllung cancer (95% CI 1.63–18.5; P 5 .006),whereas symptoms of chronic bronchitis withoutCOPD is a risk factor (risk greater than 4-fold)for adenocarcinoma of the lung. In a subset anal-ysis, the association of concurrent bronchiticsymptoms and COPD imparted a 3-fold increasedrisk for squamous cell carcinoma of the lung,further consolidating the link between these 2conditions.194
Pathogenesis and Clinical Implications of LungCancer in COPD
The pathogenic mechanism linking these condi-tions remains unclear, although like other comor-bidities in COPD it seems to be multifactorial.
Inflammation and oxidative stress seem to playimportant roles. The process of epithelial-to-mesenchymal transition (EMT), in which cells un-dergo a switch from an epithelial phenotype to amesenchymal phenotype, is an important phe-nomenon that occurs in both patients with lungcancer and COPD patients.195,196
Studies have also shown that inflammationdirectly promotes EMT by inducing the expressionof E-cadherin transcriptional repressors, whichcould explain the connecting link between these2 conditions.187,196 An exaggerated inflammatoryresponse, leading to aberrant airway epithelialand matrix remodeling characterized by exces-sive growth factor release and elevated matrixmetalloproteinases (MMP), has also been postu-lated as a possible mechanism connecting the 2conditions.197,198
NF-kB activation has also been suggested as alink between inflammation and lung cancer.199
Synergistic effects of latent infection and cigarettesmoking cause chronic airway inflammationthrough enhanced expression of cytokines andadhesion molecules, possibly through NF-kB–mediated activation.200,201 Some of the cytokinescan also inhibit apoptosis, interfering with cellularrepair and promoting angiogenesis.202
Retrospective studies have also suggested thatreducing pulmonary inflammation with ICS or sys-temic inflammation with statin therapy may reducethe risk of lung cancer in COPD patients, addingfurther support for a role for inflammation as acommon link in both of these conditions.203,204
Studies have also suggested specific candidategene loci as potential genetic links connecting lungcancer and COPD.205,206 The genes identified inthese studies suggest that this common geneticsusceptibility may be mediated through receptorsexpressed on the bronchial epithelium that impli-cate common molecular pathways underlyingboth COPD and lung cancer.The transcription factor, nuclear factor erythroid
2-related factor 2 (Nrf2), which regulates multipleantioxidant and detoxifying genes, has beenshown to be downregulated in COPD lungs207
and may contribute to the increased susceptibilityof COPD patients to lung cancer, because Nrf2plays an important role in defense against carcin-ogens in tobacco smoke by regulating the expres-sion of several detoxifying enzymes.208 Epidermalgrowth factor receptor (EGFR), which promotesepithelial proliferation, also has increased expres-sion in the lungs of COPD patients, which couldpromote carcinogenesis.209
As the increased risk of lung cancer inCOPDmaybe a reflection of increased inflammation andoxidative stress in the lungs, anti-inflammatory
Fig. 4. Inverse relationship between degree of lungfunction obstruction and incidence of lung cancer.(Reproducedwith permission of the European Respira-tory Society. Sin DD, Anthonisen NR, Soriano JB, et al.Mortality in COPD: role of comorbidities. Eur Respir J2006;28(6);1250; http://dx.doi.org/10.1183/09031936.00133805.)
therapies or antioxidants should hypotheticallydiminish the risk of lung cancer.
PSYCHOLOGICAL EFFECTS IN COPD
Anxiety and depression are common in patientswith COPD, and have an impact on the psychoso-cial aspects of the management of this disease.Prognostic studies involving patients with COPDhave mostly focused on physiologic variables,with less attention given to the psychologicalaspects of the disease.
Prevalence
The prevalence of generalized anxiety disorder inCOPD patients ranges between 10% and 33%,and that of panic attacks or panic disorder be-tween 8% and 67%.210 Disease severity inCOPD has not clearly been associated with themagnitude of anxiety/depression.211,212
Estimates of the prevalence of depression anddepressive symptoms vary in COPD patients,ranging from 6% to 60%.213–215 Hanania andcolleagues216 studied the prevalence and deter-minants of depression in COPD patient in theECLIPSE study. The study cohort consistedof 2118 subjects with COPD, 335 smokerswithout COPD (smokers), and 243 nonsmokerswithout COPD (nonsmokers). A total of 26%,12%, and 7% of COPD, smokers, and non-smokers, respectively, suffered from depression.Using a multivariate logistic regression model,increased fatigue, higher score for St George’sRespiratory Questionnaire for COPD patients,younger age, female sex, history of cardiovascu-lar disease, and current smoking status were allsignificantly associated with depression in thiscohort.
Clinical Implications
Depression in COPD might result from a viciouscycle of sedentary lifestyle, smoking habits, andpoor nutritional and health status. There isincreasing evidence that inflammation itself couldbe a mediator of depression in COPD patients.217
Depressive symptoms were found to be strongpredictors of mortality (OR 1.9, 3.6, and 2.7,respectively), independent of other markers of dis-ease severity and risk factors, in COPD patients in3 studies,218–220 whereas one other study found noassociation between mortality and depressionafter adjustment for disease severity.221
Therefore, the effect of depression on function inCOPD patients and the early recognition and treat-ment of symptoms remain inherent importantaspects in the management of this cohort.
DIABETES AND METABOLIC SYNDROME INCOPDPrevalence and Pathogenesis
Studies have shown prevalence rates for diabetesof between 1% and 16% in patients withCOPD.222,223 Large population studies have alsoshown that there is an increased prevalence ofdiabetes among COPD patients (risk ratio [RR]1.5–1.8), even in patients with mild disease.6,224
Poulain and colleagues225 looked at a cohort of28 male patients with COPD, and divided patientsaccording to their body habitus. The study showedthat presence of obesity, particularly abdominalobesity, was associated with metabolic and in-flammatory abnormalities that are typically associ-ated with the development of cardiovasculardiseases and diabetes, such as increased levelsof insulin, TNF-a, and IL-6, and may mediate insu-lin resistance by blocking signaling through the in-sulin receptor. This finding further cements thecommon inflammatory pathway theory in the path-ogenesis of the systemic effects of COPD.
Rana and colleagues224 also performed a pro-spective cohort study in which they looked at therelationship of COPD and asthma with the devel-opment of type 2 diabetes. During 8 years offollow-up, a total of 2959 new cases of type 2 dia-betes were documented. The risk was significantlyhigher for patients with COPD than for thosewithout (multivariate RR 1.8, 95% CI 1.1–2.8), butthis was not the case among the asthmatics.This finding would further corroborate the factthat COPD is potentially a risk factor for the devel-opment of diabetes.
Management and Clinical Implications
Hyperglycemia, especially during acute exacerba-tions of COPD, is associated with poorer out-comes of acute noninvasive ventilation,226 longerinpatient stay, and higher rates of in-hospital mor-tality.148,227 Therefore, it is important to identify un-derlying hyperglycemic status in COPD patients toreduce the burden of morbidity and mortality aswell as unnecessary utilization of health careresources.
The metabolic syndrome is a complex disorderand an emerging clinical challenge, recognizedclinically by the findings of abdominal obesity,elevated triglycerides, atherogenic dyslipidemia,elevated blood pressure, and high blood glucoseand/or insulin resistance.228 It is also associatedwith a prothrombotic state and a proinflammatorystate. Patients with COPD often have 1 or morecomponents of the metabolic syndrome,228 whichare, at least in part, independent of treatment withsteroids and/or physical inactivity.229
Comorbidities and Systemic Effects of COPD 117
Clini and colleagues230 also postulated that themetabolic syndrome was more likely to be presentin COPD patients, as augmented levels of circula-tory proinflammatory proteins from both the lungand adipose tissue (adipokines) overlap in thesepatients. This coexistence perhaps rests onseveral factors including the presence of physicalinactivity, systemic inflammation partly related tosmoking habit, sedentary lifestyle, airway inflam-mation, adipose tissue, and inflammatory markeractivation, among others.Apart from the risks per se from high glucose
level already described, COPD patients with hy-perglycemia are likely to have more than one spe-cies of bacteria grown from sputum, suggestingimpaired immunity.148 Although some nondiabeticCOPD patients have hyperglycemia induced bysystemic corticosteroids during exacerbations,this is more likely in the context of diabetes,
therefore oral hypoglycemic medications or insulinmay be a necessity.Preventive measures include lifestyle advice
including dietary guidance, and regular screeningof those at higher risk, given the higher prevalenceand adverse clinical impact of diabetes on COPDpatients. This approach would potentially enableearlier diagnosis and prevention of complications.There should also be more focus on global
interventions intended at altering factors such asphysical deconditioning and obesity, as such anapproach may help slow the metabolic complica-tions seen in COPD patients, particularly thosewith features of the metabolic syndrome.
SYSTEMIC INFLAMMATION IN COPD
As described earlier, systemic inflammation is awell-established occurrence in COPD patients.
Table 4Mediators of systemic inflammation in COPD
Mediators Actions
Cytokines Interleukin (IL)-6 Cardiovascular and skeletal muscledysfunction6,21
Tumor necrosis factor (TNF)-a Metabolic and skeletal muscle dysfunction(SMD)113,114,139
IL-1b Cachexia in COPD6
CXCL8 (IL-8) and otherCXC chemokines
Neutrophil and monocyte recruitment and alsocontributes to SMD6
Adipokines such as leptins Possible role in cachexia in COPD6
Acute-phaseproteins
C-reactive protein Raised in infective exacerbations potentiatescardiovascular effects and SMD4,118
Fibrinogen Cardiovascular complications40,41
Surfactant protein D Derived from lung tissue; is a good marker oflung inflammation248
Serum amyloid A (SA-A) Released by circulating proinflammatorycytokines, SA-A levels are raised during acuteexacerbations of COPD and its concentrationsare correlated with the severity ofexacerbation6,249
Circulating cells Neutrophils Inverse correlation between neutrophil numbersin the circulation and FEV1,
250 increasedturnover in smokers,6 enhanced production ofreactive oxygen species251
Monocytes Increase macrophage accumulation in the lungswith defective phagocytic property,6 increasematrix metalloproteinase-9 productioncompared with nonsmokers252
Lymphocytes Increased apoptosis of peripheral T lymphocytesfrom COPD patients, with increased expressionof Fas, TNF-a, and transforming growth factorb,6,253 increase in apoptosis of CD81 T cells inCOPD254
Natural killer (NK) cells Reduction of cytotoxic and phagocytic functionof circulating NK cells has been reported inCOPD6,255
Choudhury et al118
Fig. 5. (A) Box plot (log scale) of the different biomarkers determined at baseline in COPD patients, smokers withnormal lung function (S), and nonsmokers (NS). IL, interleukin; TNF, tumor necrosis factor. (B) Proportion of pa-tients with no, 1, or 2 (or more) biomarkers (white blood cell count, C-reactive protein, interleukin-6, and fibrin-ogen) in the upper quartile of the COPD distribution, at baseline (left bars) and after 1 year of follow-up (rightbars). (From Agusti A, Edwards LD, Rennard SI, et al. Persistent systemic inflammation is associated with poorclinical outcomes in COPD: a novel phenotype. PLoS One 2012;7(5):e37483.)
Comorbidities and Systemic Effects of COPD 119
Numerous studies have provided evidence of sys-temic inflammation in COPD patients, as shown bythe presence of inflammatory mediators such asacute-phase proteins, as well as markers of oxida-tive stress and immune responses that areincreased in the peripheral blood in COPD patientsin comparison with smokers who have not devel-oped the disease.231–233
However, the presence of systemic inflamma-tion is poorly defined in COPD patients; moststudies have been cross-sectional and indicatethat not all COPD patients have a systemic inflam-matory response. Systemic inflammation, asalready discussed, is a known risk factor for devel-oping many of the conditions described conven-tionally as comorbidities of COPD.222,231,234,235
Smoking, a major cause of airway inflammationin COPD, is known to be associated with systemicinflammation, and is a potential link between thepulmonary and systemic inflammation in COPDand its comorbidities.232,236–240 Smoking andreduced FEV1 also have been found to have anadditive effect on systemic inflammatorymarkers.241
While increasing evidence suggests that thesystemic inflammatory pathway provides thecommon link between COPD and its comorbid-ities,234,236,239,242 the mechanisms by which thesystemic inflammation arises are unclear. Thereis much debate around whether the systemicinflammation in COPD arises from a spill-over ofinflammatory mediators from lung inflamma-tion,6,231,243 or whether the systemic inflammationin COPD represents a systemic component of thedisease that develops in parallel with, or before,pulmonary inflammation.231,243 The absence of arelationship between inflammatory biomarkers inthe sputum and blood of COPD patients hasprovided some evidence against the spill-overtheory.231,237,244 Smoking, lung hyperinflation, tis-sue hypoxia, skeletal muscle, bone marrow stimu-lation, immunologic disorders, and infections areall cited as possible sources of systemic inflamma-tion as seen in COPD.231,242,245
Several studies and meta-analyses have shownthat in patients with stable COPD there are oftenelevated levels of systemic inflammatory markers,such as increased circulating leukocytes, CRP,IL-6, IL-8, fibrinogen, and TNF-a.233,234,245–247
Table 4 summarizes the various inflammatorymediators as described in COPD.However, the prevalence of systemic inflamma-
tion in COPD has not been well studied, and manyof the earlier published data are derived fromshort-term, cross-sectional studies with smallsample sizes.256 These studies show a wide in-tersubject validation in systemic biomarkers.
Moreover, there is no agreed consensus on thetype, number, and value of inflammatory bio-markers needed to define systemic inflammation.These cross-sectional studies are unable to fullyestablish the relationship between biomarkersand key health outcomes, owing to the chronic na-ture of COPD and its comorbidities. Data from theEvaluation of COPD Longitudinally to Identify Pre-dictive Surrogate Endpoints (ECLIPSE) study257 inmore than 2000 COPD patients, control smokers,and nonsmokers assessed longitudinally over3 years was used to evaluate systemic inflamma-tory biomarkers. Many systemic inflammatory bio-markers were found to be reproducible over time,with fibrinogen being the most repeatable.258 Asshown in other studies, differences in several bio-markers can be shown between COPD subjectsand control smokers and nonsmokers, includingperipheral white blood cell count, IL-6, CRP, andfibrinogen, despite large variability within eachgroup (Fig. 5A), whereas others such as IL-8 andTNF-a appear to be higher in smokers than inCOPD patients.20 When the proportion of COPDpatients with 0, 1, or 2 (or more) of these bio-markers (white blood cell count, high-sensitivityCRP, IL-6, and fibrinogen) were in the upper quar-tile of the COPD distribution, 28% of patients had2 or more of these biomarkers elevated at the timeof recruitment and 56% of these subjects still had2 or more systemic inflammatory biomarkerselevated at 1 year (see Fig. 5B), whereas 43% ofpatients had no raised systemic inflammatory bio-markers at baseline and 70% of these patients stillhad none of the systemic biomarkers elevated at1 year. Thus, from this study and according tothis definition, approximately 16% of COPD pa-tients have sustained systemic inflammation.Those patients with sustained systemic
Fig. 6. Role of systemic inflammation in the patho-genesis of COPD.
Choudhury et al120
inflammation were more breathless, with poorerexercise capacity, higher exacerbation rate, andhigher mortality. Those patients with sustainedsystemic inflammation had a higher prevalenceof cardiovascular disease. This study thereforesuggests that there may be a systemic inflamedCOPD phenotype of COPD, which can bedescribed as a phenotype of COPD because itonly occurs in a percentage of patients, is stableover time, and is associated with clinical and func-tional characteristics and poor clinical outcomes.It is possible that targeting these individuals withappropriate treatment may improve outcomes.
Vanfleteren and colleagues259 looked at 213COPD patients with the aim of clustering 13
clinically identified comorbidities, and to charac-terize the comorbidity clusters in terms of clinicaloutcomes and systemic inflammation. A total of97.7% of all patients had 1 or more comorbiditiesand 53.5% had 4 or more comorbidities. Fivecomorbidity clusters were identified: (1) less co-morbidity, (2) cardiovascular, (3) cachectic, (4)metabolic, and (5) psychological. An increased in-flammatory state was observed only for TNF re-ceptors in the metabolic cluster and for IL-6 inthe cardiovascular cluster, suggesting a role forlow-grade systemic inflammation in the pathogen-esis of COPD comorbidities.
Fig. 6 summarizes the interrelation betweeninflammation and the comorbidities and systemiceffects as observed in COPD, although some ofthe effects described as systemic could also beinterchangeably described as comorbidity, asdescribed earlier.
SUMMARY
The extrapulmonary effects of COPD are trulymultifarious, and have an adverse effect on func-tion and outcomes in COPD.
Fig. 7 summarizes the impact of comorbiditieson all-cause mortality in COPD patients.
The clinical management of this conditionshould therefore be directed toward identifyingand treating these extrapulmonary effects, whichmay lead to improved outcomes for this condition.Novel therapies particularly targeted toward theinflammation associated with COPD should bedeveloped.
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Fig. 7. The impact of comorbidities on all-causemortal-ity in COPD patients. Prediction of all-cause mortalitywithin 5 years of COPD patients by modified GOLDcategory and the presence of no (▒), 1 (,), 2 (▓), or 3(-) comorbid diseases (diabetes, hypertension, or car-diovascular disease). The reference group (normal)was subjectswith normal lung function for each comor-bid disease. Models were adjusted for age, sex, race,smoking status, education level, and body mass index.Subjects were from the Atherosclerosis Risk in Commu-nities Study during 1986 to 1989 and theCardiovascularHealth Study during 1989 to 1990. GOLD 3/4: forcedexpiratory volume in 1 second (FEV1)/forced vital capac-ity (FVC) <0.70 and FEV1 <50%predicted; GOLD 2: FEV1/FVC <0.70 and FEV1 #50 to <80% predicted; GOLD 1:FEV1/FVC <0.70 and FEV1 #80% predicted; restricted(R): FEV1/FVC #0.70 and FVC <80% predicted; GOLD0: presence of respiratory symptoms in the absence ofany lung function abnormality and no lung disease.(Reproducedwith permission of the European Respira-tory Society. Mannino DM, Thorn D, Swensen A, et al.Prevalence and outcomes of diabetes, hypertensionand cardiovascular disease in COPD. Eur Respir J2008;32(4):967; http://dx.doi.org/10.1183/09031936.00012408.)
