systemic effects of chronic obstructive pulmonary disease

Review

10.1586/17476348.1.1.75 © 2007 Future Drugs Ltd ISSN 1747-6348 75www.future-drugs.com

Systemic effects of chronic obstructive pulmonary diseaseDavid MG Halpin

Royal Devon & Exeter Hospital, Barrack Road, Exeter, EX2 5DW, UKTel.: +44 139 240 2133Fax: +44 139 240 [email protected]

KEYWORDS: cardiovascular disease, COPD, inflammation, skeletal muscle dysfunction, systemic effect, weight loss

Chronic obstructive pulmonary disease (COPD) is associated with important extrapulmonary, or systemic, effects. There is systemic as well as pulmonary inflammation in COPD and this, together with systemic oxidative stress, contributes to their development. Skeletal muscle dysfunction contributes to exercise limitation. There is a loss of muscle mass and a reduction in the proportion of type 1 fibers. Sedentarism, hypoxia, corticosteroid therapy, nutritional depletion and systemic inflammation may contribute to its development. Weight loss is another important effect. It is associated with a worse prognosis, which changes with therapy and may be due to reductions in calorie intake, changes in intermediate metabolism and effects of systemic inflammation. Cardiovascular disease is a frequent cause of death in COPD and coronary artery disease, left ventricular failure and arrhythmias are systemic effects of COPD, as well as comorbidities sharing a common etiology. Exacerbations of COPD may increase the risk of coronary events by increasing the level of systemic inflammation. Osteoporosis is more common in COPD (even after adjusting for corticosteroid usage) and may be due to a combination of inactivity and the effects of systemic inflammation. COPD is also associated with systemic endothelial dysfunction and CNS abnormalities (including depression), which may also be due to the effects of systemic inflammation. These systemic effects respond to COPD treatments, including pulmonary rehabilitation, nutritional supplementation and inhaled corticosteroids, as well as specific drugs, such as bisphosphonates or diuretics. There is growing evidence that novel approaches, such as the use of statins, may also be of value.

Expert Rev. Resp. Med. 1(1), 75–84 (2007)

COPD as a systemic diseaseModern interest in chronic obstructive pulmo-nary disease (COPD) in the UK began whenmany patients died during the London smogsof the late 1950s [1]. At the same time spiro-metry was becoming available and this lead tothe observation that airflow obstruction wasthe key factor in determining disability andmortality [2]. These studies, and confusionregarding the best terminology to use in epide-miological studies, led to the 1958 Ciba sym-posium, which suggested definitions ofchronic bronchitis, emphysema, and variableand fixed airflow obstruction [3]. The intro-duction of the physiological concept of airflowlimitation as a diagnostic term was new andled to the use of the term chronic obstructiveairways disease (COAD). However, it was

soon realized that the condition not onlyaffected the airways but also affects the lungparenchyma and the pulmonary circulation:hence the term COPD was introduced in theearly 1960s. More recently, it has become clearthat COPD also has effects outside the lung,systemic effects, and this is reflected in thewording of the latest definitions of COPDdeveloped by the American Thoracic Soci-ety/European Respiratory Society: “AlthoughCOPD affects the lungs, it also produces sig-nificant systemic consequences” [4] and in thelatest (2006) update of the Global Initiativefor Chronic Obstructive Lung Disease(GOLD) guidelines: “COPD is a preventableand treatable disease with some significantextrapulmonary effects that may contribute tothe severity in individual patients” [201].

CONTENTS

COPD as a systemic disease

Systemic inflammation in COPD

Systemic effects of COPD

Conclusions

Expert commentary

Five-year view

Financial disclosure

Key issues

References

Affiliation

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Halpin

76 Expert Rev. Resp. Med. 1(1), (2007)

Systemic inflammation in COPDThere is now good evidence that COPD is associated withinflammatory changes in the lung but there is equally com-pelling evidence to show that COPD is also associated withsystemic inflammation [5–7]. Circulating levels of proinflam-matory cytokines (including TNF-α and IL-8) and acute-phase proteins, particularly C-reactive protein (CRP) are ele-vated in patients with COPD [9]. CRP levels are inverselyrelated to disease severity as assessed by the forced expiratoryvolume in 1 s (FEV1) [9]. There is also evidence of increasedoxidative stress [10,11] and increased numbers of circulatinginflammatory cells [13], which show evidence of activation [13].Exacerbations appear to increase the level of systemic inflam-mation [14,15]. There are also increased levels of anti-inflam-matory proteins, including soluble IL-1 and TNF receptors [16],which inhibit the effects of the proinflammatory cytokines.Thus, the effects of systemic inflammation depend on thebalance of these pro- and anti-inflammatory mediators and itis conceivable that this balance may be different at differentsystemic sites.

The origin of systemic inflammation is not clear and anumber of mechanisms that are not mutually exclusive may beresponsible. It may be due to systemic effects of tobacco smokeor to spill over of pulmonary inflammation, with release ofcytokines produced in the lungs into the systemic circulation. Itmay be due to inflammation induced in systemic tissues byconsequences of COPD, such as hypoxia, and it has been sug-gested that there may be an autoimmune component to its gen-eration [17]. Whatever the origin, it appears that systemicinflammation is important in the development, at least in part,of some, if not all of the systemic effects of COPD.

Systemic effects of COPDSkeletal muscle dysfunctionThe observation that leg fatigue was an important cause ofexercise limitation in COPD was first made by Killian et al.[18,19] and it has since become clear that the development of legfatigue is in large part due to skeletal muscle dysfunction. Skel-etal muscle dysfunction is an important systemic feature ofCOPD. Along with the increased work of breathing anddynamic hyperinflation due to the airflow limitation, skeletalmuscle dysfunction is a major factor in the exercise limitationthat occurs in COPD [20]. In patients with COPD there is a sig-nificant reduction in both the strength and endurance of theskeletal muscles compared with healthy subjects [21–23].

Apart from the diaphragm, which behaves differently (seelater), skeletal muscles in patients with COPD show two prin-ciple abnormalities: a net loss of muscle mass and dysfunctionof the remaining muscle [6]. Several studies have shown a prefer-ential loss of muscle mass in patients with COPD, especially inthe lower extremities; athough skeletal muscle dysfunction iscommon, the underpinning pathophysiology it remains uncer-tain [24]. A number of possible mechanisms have been pro-posed. These include indirect effects of lung abnormalities inCOPD on skeletal muscle (e.g., deconditioning and hypoxia),

effects of drug therapy (e.g., use of corticosteroids) and directeffects on the muscles as a result of nutritional depletion andsystemic inflammation.

Reduced physical activity due to breathlessness may also leadto a loss of muscle mass, as well as reducing the strength of themuscles and their resistance to fatigue. There are significantreductions in the proportion of type 1 fibers in the muscles ofsedentary healthy individuals from a norm of 60–65% toapproximately 40% and this is associated with a marked reduc-tion in the maximum volume of oxygen consumption(VO2max) [25]. However, in COPD there are even greaterreductions in the proportion of type 1 fibers, to approximately20% [22,26–28], which are unlikely to be due to reduced physicalactivity alone. Sedentarism does, however, induce changes incellular bioenergetics in skeletal muscle in COPD that can bepartly or completely reversed by physical rehabilitation [29–31].

Chronic hypoxia is also known to induce structural changes inskeletal muscle in animal models and in healthy subjects at alti-tude [32–34]. In patients with COPD there are structural andfunctional changes in skeletal muscle that correlate with thedegree of hypoxia [35,36]. Therefore, it is probable that in patientswho are chronically hypoxic, low muscle oxygen tensionscontribute to skeletal muscle dysfunction.

Although not recommended as part of long-term manage-ment, some patients receive frequent courses of oral steroids forexacerbations and some are prescribed long-term oral cortico-steroids. These drugs may also be partly responsible for skeletalmuscle dysfunction in COPD. Both long-term, high-dose andlow-dose and long-term intermittent oral steroid therapy resultsin significant changes in skeletal muscle [30,36,37] and Decrameret al. have shown that the degree of quadricep weakness isrelated to the average daily dose of corticosteroids [38]. A single14-day course of prednisolone does not appear to have anydetectable effect on quadricep strength or metabolic parametersduring exercise in stable outpatients with moderate-to-severeCOPD [39].

While inactivity, hypoxia and corticosteroid therapy mayaccount for some of the skeletal muscle dysfunction seen inCOPD, patients with mild-to-moderate COPD who maintainactivity levels, who are not hypoxic and have not received cortico-steroids also exhibit skeletal muscle dysfunction, with signifi-cant reductions in muscle strength, endurance capacity propor-tion of type 1 fiber and oxidative enzyme activity [21,27,40,41]. Itappears that systemic inflammation is another important causeof skeletal muscle dysfunction. Peripheral muscle wasting andweakness are associated with increased levels of CRP andinflammatory cytokines, particularly IL-8 and TNF-α [42–44].TNF-α can stimulate ubiquitin conjugation to muscle proteins[45] and can activate the ATP-dependent ubiquitin–proteasomepathway that is responsible for muscle protein degradation andcan lead to muscle atrophy [45–47]. Inflammatory mediators,such as TNF-α and IFNγ, may also affect skeletal muscle byinhibiting the formation of myofibers [48]. Reduced muscle massalso appear to be due to a reduction in the number of fibersas a result of the activation of apoptotic pathways. Excessive

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apoptosis has been described in skeletal muscle in patients withCOPD and weight loss, and this probably results from theeffects of systemic inflammation and elevated cytokine levelsfound in COPD since it has been known for many years thatTNF-α can induce apoptosis in many cell systems [49,50].TNF-α may alter muscle contractility through direct inhibitoryeffects on myofilaments [51].

Finally, recent evidence suggests that oxidative stress withinmuscles also contributes to skeletal muscle dysfunction inCOPD. In patients with COPD, systemic inflammation isassociated with an increased oxidant burden and excessive pro-duction of reactive oxygen or nitrogen species (RONS) withinmyocytes can lead to apoptosis and mitochondrial respiratorychain dysfunction [52,53].

As mentioned previously, the respiratory muscles, particularlythe diaphragm, appear to behave quite differently from skeletalmuscles in patients with COPD, from both structural andfunctional points of view [20]. Unlike peripheral muscles inpatients with COPD, the diaphragm contains a higher propor-tion of type 1 fibers [54]. These changes are similar to those seenin peripheral muscles after endurance training in healthy sub-jects [55,56] and may therefore reflect the fact that, unlike periph-eral muscles, the respiratory muscles are not rested as a result ofinactivity. On the contrary, they work against an increased load[54,57] and diaphragmatic energy expenditure as assessed by thediaphragmatic time–tension index is greatly increased, evenduring breathing at rest, in patients with severe COPD [58].Clearly there is no difference in the exposure of the diaphragmto chronic hypoxia, corticosteroid therapy and the effects of sys-temic inflammation. Moreover, there is evidence of activationof the ubiquitin–proteasome pathway in the diaphragm inpatients with COPD, suggesting that the diaphragm is subjectto the effects of systemic inflammation [59]. However, thereappear to be specific adaptations of these muscles that modu-late these systemic effects of COPD and, if they are related tothe increased work the diaphragm undertakes, may indicatethat exercise training of peripheral muscles may be able toattenuate some of the effects of systemic inflammation onskeletal muscle dysfunction.

Weight lossWeight loss is another important systemic effect of COPD.The UK National Institute for Clinical Excellence (NICE)COPD guidelines suggest that changes of more than 3 kg aresignificant [60]. Weight loss is a negative prognostic factor, inde-pendent of other prognostic indices based on the degree of pul-monary dysfunction, such as FEV1 or arterial pH (PaO2)[61–63]. It is also a prognostic factor that can be changed byintervention. Weight loss may be due to reductions in calorieintake, changes in intermediate metabolism and effects of sys-temic inflammation [64–68]. It is seen in up to 50% of patientswith severe COPD and in 10–15% of patients with mild-to-moderate disease being considered for pulmonary rehabilitation[66]. The main cause of weight loss is loss of muscle mass andsimilar changes in body composition can be seen in patients

with COPD even if there is no net change in overall weight[42,63,66,69]. Although calorie intake is reduced in some patientswith COPD, in most it is normal or increased and the patientsrespond poorly to nutritional support [70]. Their metabolic rateappears increased [71–73] and the increased calorie intake is notmet by an increased parallel nutritional intake [65], leading toweight loss. The reason for the increased metabolic rate is notknown definitely but several explanations have been proposed.Increased energy consumption as a result of the increased workof breathing of the respiratory muscles was one of the firstmechanisms proposed [74] and therapy with drugs such asβ2-agonists may also increase metabolic rate [75]. Tissue hypoxiamay also lead to an increased metabolic rate [76]. The most sig-nificant mechanism, however, is probably the effects of sys-temic inflammation [44]. There is now a well-known associationbetween elevated levels of TNF-α found in patients withCOPD and loss of body mass [43,77] and there may be both todirect effects of TNF-α on skeletal muscle and TNF-α-inducedincreases in metabolic rate [44,78]. Systemic inflammation mayalso affect body mass through effects on leptin [48]. Leptin regu-lates fat-free mass by providing a feedback signal to the brainthat reduces appetite and increases satiety [79]. Schols et al.have described a significant correlation between leptin levels inpatients with emphysema and levels of the soluble TNF recep-tor (sTNF-R55) [80]. The levels of leptin are also increasedduring exacerbations [81].

Cardiovascular effects of COPDCardiovascular disease is a common cause of death in patientswith COPD. Among patients in the placebo limb of theTORCH study, COPD accounted for 32% of deaths whilecardiovascular disease accounted for 31% [82]. It has recentlybecome clear that both coronary artery disease and left ventricu-lar dysfunction in patients with COPD may be exacerbated bythe presence of COPD and can therefore also be considered sys-temic effects of COPD rather that simply consequences of acommon risk factor, such as cigarette smoking.

Since the 1970s it has been known that a reduced FEV1predicts mortality independently of smoking in the generalpopulation and numerous studies have subsequently con-firmed this, including a 15-year follow-up study in Scotlandand 26 year follow-up study in Norway [83–85]. This observa-tion was mediated mainly through a higher risk of dying fromcardiovascular conditions and a significant association hasalso been reported between baseline levels of lung functionand the incidence of coronary heart disease (CHD) andstroke [86,87]. Furthermore, annual decline of FEV1 has alsobeen related to cardiovascular mortality independently ofbaseline FEV1, cigarette smoking and other common CHDrisk factors [88].

Although COPD is not the only cause of a reduced FEV1 inthe community, approximately 80% of adults (45 years andolder) with impaired FEV1 (i.e., <80% of predicted) have air-way obstruction [89]. Thus, reduced FEV1 among adults is areasonable surrogate for COPD in population-based studies

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and, overall, the epidemiological evidence linking COPD andcardiovascular morbidity and mortality is strong. After adjust-ment for traditional cardiovascular risk factors, patients withCOPD have a two- to threefold increase in the risk of cardio-vascular events, including death [90]. For every 10% decrease inFEV1, cardiovascular mortality increases by approximately28%, and nonfatal coronary events increase by approximately20% in mild-to-moderate COPD [90].

In a retrospective case-controlled cohort study of patientsdiagnosed specifically with COPD, the prevalence of cardio-vascular disease was higher in patients than in matched con-trols, with an overall risk ratio for cardiovascular mortality of2.07 (95% confidence interval [CI]: 1.82–2.36). After adjust-ing for cardiovascular risk, the odds ratios of prevalence ofangina and acute myocardial infarction were 1.61 (95% CI:1.47–1.76) and 1.61 (95% CI: 1.43–1.81), respectively, inpatients with COPD [91].

It is now recognized that the pathophysiology of coronaryatherosclerosis is more complex than simply a disorder of lipidmetabolism leading to deposition within the arterial wall, and itis now considered an inflammatory disease [92,93]. The develop-ment of atherosclerosis depends on the induction variouscytokines and cell adhesion molecules, including intercellularadhesion molecule (ICAM)-1 and vascular cell-adhesion mole-cule (VCAM)-1 [94]. These lead to increasing inflammatory cellattachment to endothelial cells and the expression of scavengerreceptors on monocytes/macrophages, promoting lipoproteiningestion [93]. In addition, vascular smooth muscle proliferatesand smooth muscle cells migrate into the intima from themedia where they produce extracellular matrix, which accumu-lates in the plaque to form fibro-fatty lesions [93]. Systemicinflammation in COPD may augment this process and accountfor the increased risk of CHD.

Elevated CRP levels also provide a link between COPDand the increased risk of coronary events. CRP has beenshown to predict adverse clinical events in both patients withestablished coronary disease and healthy individuals [95]. CRPlevels are elevated in patients with COPD and analysis of datafrom patients in the lung health study has shown that indi-viduals with CRP levels in the highest quintile had a relativerisk (RR) for all cause mortality of 1.79 (95% CI: 1.25–2.56)and RR for cardiovascular events of 1.51 (95% CI:1.20–1.90) [8,96].

Atherosclerotic coronary disease is not the only cardio-vascular effect of COPD. In the retrospective Saskatchewancase-controlled cohort study the odds ratios for the prevalenceof arrhythmia, congestive heart failure and stroke were 1.76(95% CI: 1.64–1.89), 3.84 (95% CI: 3.56–4.14) and 1.11(95% CI: 1.02–1.21), respectively, in patients with COPD [91].

A significant proportion of patients with COPD havecoexistent heart failure, which may represent another systemiceffect of COPD [97]. There is some evidence that left ventricu-lar function may be impaired in COPD, and it has been sug-gested that this may be due to effects on cardiac smooth musclesimilar to those observed in skeletal muscle [6,98]. As well as the

case-controlled data, there are also data on patients undergoinglung resections for lung cancer that suggest that patients withCOPD are more prone to cardiac arrhythmias [99]. It is diffi-cult to know whether this increased prevalence is due to sec-ondary effects of COPD, such as hypoxia, or to effects of ther-apy with arrhythmogenic drugs, such as β-agonists, orwhether it is related to the systemic inflammation present inCOPD. Recent studies have suggested a mechanistic linkbetween inflammation and the development of atrial fibrilla-tion (AF) [100] and again there is an association between CRPlevels and both the presence of AF and the risk of developingfuture AF [101,102].

Skeletal effectsThe prevalence of osteoporosis is increased in patients withCOPD [103–106]. Osteoporosis is also more common in patientstreated with oral and high-dose inhaled glucocorticoids. How-ever, patients with COPD who have never been treated withglucocorticoids also have a substantial risk of osteoporosiscompared with control subjects. Osteoporosis is more com-mon in people who are malnourished, sedentary and whosmoke. There is also substantial epidemiological evidence thatmany chronic inflammatory diseases (e.g., rheumatoid arthri-tis, systemic lupus, inflammatory bowel disease and celiac dis-ease) are associated with systemic bone loss [107] and in vitroTNF-α has been shown to increase bone resorption anddecrease bone formation [108].

Endothelial dysfunctionThere is good evidence that COPD causes endothelial dysfunc-tion in the pulmonary circulation [109]. There is also evidencefor endothelial dysfunction in the kidney in patients withCOPD [110,111], and there is evidence for abnormalities of circu-lating endothelin-1 levels in patients with COPD [112], whichworsen during exacerbations [113]. Hypoxia stimulates endothe-lin-1 release and this may partly account for the increased levels,but there is also evidence for increased renal tubular productionof endothelin-1 during exacerbations [113].

The origin of endothelial dysfunction and its clinical signifi-cance in the peripheral circulation are not known. It may becaused by hypoxia, but in the pulmonary circulation it can beseen in patients with mild disease who are not hypoxemic andthus other mechanisms may be important [114]. Oxidativestress and systemic inflammation may have similar effects inthe peripheral circulation to those they have in the pulmonarycirculation [114].

CNS abnormalitiesThere are also CNS abnormalities in patients with COPD.Nuclear magnetic resonance spectroscopy has shown recentlythat the bioenergetic metabolism of the brain is altered in thesepatients [115]. Whether this represents a physiological adapta-tion to chronic hypoxia, as occurs at altitude, or whether itmay be considered another systemic effect of COPD mediatedby other unknown mechanisms is unclear [116].



Depression is also found quite commonly in patients withCOPD [117–119]. This may simply be a reflection of the disabil-ity that COPD imposes, but it is also possible that it is, at leastin part, exacerbated by the systemic inflammation present inCOPD. TNF-α and other cytokines have been implicated inthe pathogenesis of depression [120–122]. Although studies assess-ing cytokines in depressive populations are basically correla-tional in nature, patients receiving cytokine immunotherapyfrequently show depressive symptoms, which may be attenu-ated by antidepressant medication, supporting a causal role forcytokines in depressive disorders.

Peripheral neuropathy has been reported in patients withCOPD [123]. Over 20 years ago it was shown that the majorityof patients with severe hypoxic COPD had electrophysiologicalevidence of peripheral nerve damage [124,125], although few hadsymptoms or clinical signs of this. It is thought that the neuro-nal damage is caused by chronic hypoxia, a mechanism that hasalso been proposed to be relevant to the pathogenesis of dia-betic neuropathy [126]. It has subsequently been shown thatpatients with COPD also have subclinical autonomic neuro-pathy [127,128]. The degree of autonomic dysfunction correlatedwith the degree of hypoxia, suggesting that hypoxic damagewas responsible for the development of the neuropathy. Inother conditions, such as diabetes and alcoholism, autonomicneuropathy is associated with silent myocardial ischemia andsudden death, but its relevance in patients with COPD remainsunclear [129,130].

Endocrine effectsLow serum testosterone levels have been described in menwith COPD [131–134] and the levels of systemic testosterone,IGF-1 and dehydroepiandrosterone (DHEA) have beenreported to be inversely correlated with serum levels of IL-6[135,136]. In healthy men, abnormally low testosterone levelsmay lead to diminished energy levels, libido, bone density andmuscle mass [137]; thus, hypogonadism may be important inpatients with COPD. However, when compared with theprevalence of hypogonadism in healthy, age-matched menthere is conflicting evidence as to whether this is a systemiceffect of the disease or simply a reflection of aging [138]. Whateverthe cause, it may have considerable relevance for the manage-ment of other systemic effects, in particular skeletal muscledysfunction and osteoporosis, and may affect the effectivenessof pulmonary rehabilitation.

A single study has also investigated thyroid function inpatients with COPD and found that in patients with an FEV1less than 50% of that predicted there was evidence of reducedconversion of thyroxin (T4) to triiodothyronine (T3) and themagnitude of this effect correlated with the degree of hypoxia[139]. The clinical significance of this is unclear.

Treatment of systemic effects of COPDThe systemic effects of COPD can be managed using a variety ofapproaches. Specific effects, such as osteoporosis and hypogonad-ism, can be treated using standard pharmacological approaches.

Other effects, such as weight loss and skeletal muscle dysfunc-tion, need a combined approach of nutritional supplementationand exercise training [3,60]. Stopping smoking and appropriateoxygen therapy to correct resting or exercise-induced hypoxiaare also important. However, there is particular interest in theeffects of treatment on systemic inflammation.

In a short study, Sin et al. demonstrated that inhaled cortico-steroids can suppress circulating CRP levels [140] and this mayaccount for the fact that database studies have shown that theuse of inhaled steroids is associated with a reduced risk of mor-tality and cardiovascular death in particular [141,142]. Theoreti-cally, antioxidants and phosphodiesterase inhibitors should alsosuppress systemic inflammation, but as yet there are no data tosupport this.

Recently, there has been considerable interest in the possibilitythat statins may have anti-inflammatory properties in additionto their lipid-lowering effects and that these may be of benefit inreducing systemic inflammation and its consequences in patientswith COPD. It is well established that statins reduce cholesterollevels and reduce cardiovascular risk; however, subgroup analyseshave shown that the benefits of statins are not exclusively due totheir lipid-lowering effects [143,144]. It is now known that statinshave effects on NO synthesis, T-cell activation and they or theirmetabolites are antioxidants [145–148].

Case-controlled retrospective studies in patients with COPDhave shown that statin therapy is associated with a reduced riskof death from COPD, a reduced risk of hospitalization and,importantly from the point of view of systemic effects ofCOPD, a reduced risk of cardiovascular events [149–151].

ConclusionsCOPD is now recognized to be associated with a number ofextrapulmonary effects. These contribute to the disabilitypatients experience and have an effect on survival. Some of thesystemic effects result from consequences of the pulmonaryeffects of COPD. Airflow limitation, hyperinflation and gasexchange abnormalities lead to reduced exercise capacity andhypoxia, which may lead to some of the systemic effects.However, there is now also good evidence that the systemicinflammation and increased oxidative stress that is present inpatients with COPD contributes to the development of thesystemic effects.

Current therapies, such as pulmonary rehabilitation andinhaled steroids, have beneficial effects on the systemic effects ofCOPD and new therapies, such as statins, may also prove effec-tive. Management of COPD is incomplete unless the systemiceffects are also taken into consideration.

Expert commentaryRecognition of the systemic effects of COPD has improved ourunderstanding of the impact of disease on patients, the causa-tion of disability and the causes of death in COPD. Under-standing the causes of these systemic effects opens up new ther-apeutic possibilities. It also defines important new outcomes tobe considered in clinical trials.

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Five-year viewIt is likely that studies in the next 5 years will throw morelight on the mechanisms underlying the systemic effects ofCOPD. In addition, we will have a better understanding ofthe effects of therapies available today on these systemiceffects and it is likely that drugs such as statins, which are notcurrently indicated in COPD, will have a defined role. It isalso possible that drugs that are presently in development willprove themselves to be effective at treating the systemic effectsof COPD.

Financial disclosureThe author has no relevant financial interests, includingemployment, consultancies, honoraria, stock ownership oroptions, expert testimony, grants or patents received or pending,or royalties related to this manuscript.

Key issues

• Chronic obstructive pulmonary disease (COPD) has effects outside the lungs, including skeletal muscle dysfunction, weight loss, cardiovascular disease, osteoporosis and CNS effects.

• Some of the systemic effects may be the consequence of indirect effects of COPD, such as sedenterism or hypoxia.

• There is considerable evidence that systemic inflammation contributes to the development of systemic effects.

• Treatment of the systemic effects of COPD includes exercise and dietary therapy, as well as drugs both to treat COPD itself and to treat the systemic effects directly.

• New therapies, such as statins, may have an important role in managing or preventing the systemic effects of COPD.

ReferencesPapers of special note have been highlighted as:• of interest•• of considerable interest

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•• This position statement reviews muscle biology, discusses the understanding of skeletal muscle dysfunction at the time and describes effective muscle-training strategies.



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Halpin


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• First study to show that reversal of weight loss in COPD is associated with a better prognosis.

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• Discusses the evidence that COPD is an independent risk factor for cardiovascular disease.

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Halpin


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• Database study that deomstrates that use of inhaled corticosteroids is associated with a reduced all-cause mortality, with a particularly noticeable effect on cardiovascular deaths.

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• Retrospective cohort study that demonstrated that the hazard ratio for death for COPD patients prescribed statins was 0.57 after adjustement for sex, age, smoking status, lung function and comorbidities. The effects of statin use appeared to be increased by coprescription of inhaled corticosteroids.

151 Mancini GB, Etminan M, Zhang B, Levesque LE, FitzGerald JM, Brophy JM. Reduction of morbidity and mortality by statins, angiotensin-converting enzyme inhibitors, and angiotensin receptor blockers in patients with chronic obstructive pulmonary disease. J. Am. Coll. Cardiol. 47(12), 2554–2560 (2006).

• This time-matched nested case–control study of two population-based retrospective cohorts showed that use of statins alone and in combination with angiotensin-converting enzyme inhibitors or angiotensin-receptor blockers was associated with a reduction in COPD hospitalization, myocardial infarction and total mortality in both the high and low cardiovascular risk cohorts.

Website

201 Global Initiative for Chronic Obstructive Pulmonary Disease. Global strategy for the diagnosis, management and prevention of chronic obstructive pulmonary disease, executive summary 2006.www.goldcopd.com.

• Discusses the systemic effects that are associated with COPD, their pathophysiology and their response to treatment.

Affiliation

• David MG HalpinConsultant Physician & Honorary Senior Clinical Lecturer, Royal Devon & Exeter Hospital, Barrack Road, Exeter, EX2 5DW, UKTel.: +44 139 240 2133Fax: +44 139 240 [email protected]

systemic effects of chronic obstructive pulmonary disease

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