Extrapulmonary comorbidities in chronic obstructive pulmonary disease: state of the art

All authors

Anant RC Patel & John R Hurst

https://doi.org/10.1586/ers.11.62

Published online:

09 January 2014

Figure 1. The impact of comorbidities on all-cause mortality in chronic obstructive pulmonary disease patients.

Prediction of all-cause mortality within 5 years of chronic obstructive pulmonary disease patients by modified GOLD category and the presence of three (black), two (spotted), one (gray) and zero (white) comorbidities from diabetes, hypertension and cardiovascular disease (defined as ischemic heart disease, heart failure, stroke and/or transient ischemic attack). Results from Cox proportional hazard models (presented as hazard ratio on a logarithmic scale with 95% CI). The reference group (normal) was subjects with normal lung function for each comorbid disease. Models were adjusted for age, sex, race, smoking status, education level and BMI. Subjects were from the Atherosclerosis Risk in Communities Study during 1986–1989 and the Cardiovascular Health Study during 1989–1990.

^†GOLD 3/4: FEV₁/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.

FEV₁: Forced expiratory volume in 1 s; FVC: Forced vital capacity; GOLD: Global initiative for obstructive lung disease.

Adapted with permission from .

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Extrapulmonary comorbidities in chronic obstructive pulmonary disease: state of the art

All authors

Anant RC Patel & John R Hurst

https://doi.org/10.1586/ers.11.62

Published online:

09 January 2014

Figure 2. Similar pathological appearances are found in lung and bone tissue of chronic obstructive pulmonary disease patients using scanning electron micrography.

(A) Healthy lung architecture; (B) emphysematous lung with marked connective tissue loss and abnormal continuity of airspaces; (C) healthy bone architecture; (D) low bone mineral density with spindles of bone instead of plates in a patient with osteoporosis. Images from four separate subjects.

(A & B) reproduced with permission from , (C & D) reproduced with permission from .

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Extrapulmonary comorbidities in chronic obstructive pulmonary disease: state of the art

All authors

Anant RC Patel & John R Hurst

https://doi.org/10.1586/ers.11.62

Published online:

09 January 2014

Figure 3. A proposed mechanism for microaspiration of gastric contents in chronic obstructive pulmonary disease.

(A) Diaphragms displaced caudally from hyperinflated lungs exert additional extrinsic pressure on the stomach. (B) Increased use of abdominal muscles from dyspnea and coughing exert extrinsic pressure on the stomach. (C) Stomach contents retrogradely pass through the lower esophageal sphincter, which relaxes more often from changes in vagal tone in chronic obstructive pulmonary disease. (D) Increased intrathoracic pressure from hyperinflation and cardiac movements exert extrinsic pressure on the esophagus, facilitating retrograde movement of refluxate (if present, hiatus hernia from a physically displaced diaphragm may act as a reservoir of refluxate in the thoracic cavity). (E) Small quantities of liquid refluxate spill over into the airway. (F) Constituents of aspirated refluxate enhace inflammation and increase susceptibility to exacerbation.

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Extrapulmonary comorbidities in chronic obstructive pulmonary disease: state of the art

All authors

Anant RC Patel & John R Hurst

https://doi.org/10.1586/ers.11.62

Published online:

09 January 2014

Figure 4. Complex pathway linking chronic obstructive pulmonary disease and its key comorbidities.

COPD: Chronic obstructive pulmonary disease.

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Chronic obstructive pulmonary disease (COPD) is a common and important condition with a rising global incidence. It is projected to be the fourth leading cause of death worldwide by 2020 . The Global Initiative for Obstructive Lung Disease (GOLD) defines the condition as:

“A preventable and treatable disease with some significant extrapulmonary effects that may contribute to the severity in individual patients. Its pulmonary component is characterized by airflow limitation that is not fully reversible. The airflow limitation is usually progressive and associated with an abnormal inflammatory response of the lung to noxious particles or gases.”

– Global Initiative for Chronic Obstructive Lung Disease .

This restructuring of the traditional airway-centered definition to emphasize the extrapulmonary effects reflects increasing recognition of their importance to COPD patients and their clinicians. For the purposes of this article, comorbidity is defined as the coexistence of another medical condition alongside COPD, and does not imply causation, potentiation or adverse outcome, although these will be described where appropriate. The aim of this article is to provide a state-of-the-art summary of extrapulmonary comorbidities in terms of prevalence, clinical relevance, pathophysiological links, and impact on COPD patients. Where possible, suggestions are made for assessment and therapeutic options. It should be noted that respiratory comorbidities in COPD, including lung cancer, bronchiectasis, TB and, arguably, asthma, although important, are beyond the scope of this article.

The diagnosis of clinically important COPD relies on three factors, each of which may be complicated by comorbidities.

First, there should be a history of chronic lower respiratory tract symptoms (exertional dyspnea, cough, sputum production or wheeze) which start or intensify in middle to later life onwards. There are several extrapulmonary conditions which may contribute to or mimic some of these symptoms such as heart failure, kyphosis and obesity. The majority of diseases manifest in later life in the general population and there is an increased chance of innocent coexistence alongside COPD.

Second, there should also be a plausible history of sufficient exposure to noxious vapours, gases, dusts or fumes to elicit the abnormal inflammatory response described in the GOLD definition. In the absence of a sufficient, identifiable triggering factor, there should be evidence of increased susceptibility such as a strong family history of COPD or demonstrable α-1 anti-trypsin deficiency. However, for most COPD patients, the trigger factor is tobacco smoke, thus putting them at risk from many other smoking-related disease processes such as atherosclerosis and cancer. There is evidence that the risk of some of these key diseases is further increased in smokers with COPD than equivalent smokers without COPD.

Third, confirmatory post-bronchodilator spirometry is essential to show an abnormal obstructive forced expiratory ratio. This procedure is markedly effort dependent and needs to be repeatable, which may be difficult with a concomitant muscle fatigue state. Moreover, even in the presence of convincing historical and perhaps radiological evidence for COPD, the ratio may be elevated (potentially over the threshold required for diagnosis) by a comorbid condition which leads to extrathoracic restriction such as obesity or kyphosis, therefore, not providing a true assessment of intrapulmonary airflow limitation. This will continue to be a problem in spirometric monitoring throughout life, and may be one of the reasons that forced expiratory volume in 1 s (FEV₁) alone is not tightly correlated with some key parameters such as health status.

Comorbidities in general have a significant impact on health status, healthcare utilization, all-cause hospital admissions and mortality in COPD patients. COPD patients are more likely to die from a comorbid disease than COPD itself. Data has often previously been gathered from death certification, which for several reasons is not always accurate. In a large, randomized controlled trial of inhaled combined fluticasone/salmeterol, its separate components and placebo, causes of death were meticulously recorded. All available clinical information was discussed by an adjudication panel of senior physicians. Although not derived from a population sample, and including only patients in whom FEV₁ was <60% predicted, this dataset is likely to represent the most accurate list of causes of death in COPD patients to date (Table 1). Of the 911 deaths in patients with well-characterized COPD, only 40% of the deaths were definitely or probably related to COPD. The remainder were mostly unrelated to COPD (50%) or unknown (9%). Judicious recognition, assessment and appropriate management of important comorbidities may have large mortality benefits.

Many comorbidities may occur coincidentally. Examples include osteoarthritis and Alzheimer’s disease, which are linked only by their occurrence in later life, and are therefore not discussed further in this article.

Many comorbid conditions have other shared risk factors but have not to date been shown to be any more common in COPD when these are adjusted for (e.g., smoking-related bladder, oral and laryngeal cancers).

However, many of the most prevalent and important comorbidities have an increased incidence when shared risk factors are accounted for and indeed these may be thought of as systemic consequences of, instead of or in addition to being comorbidities. Such analyses require comparison ideally with age- and sex-matched healthy controls with an equivalent smoking history, these groups are notoriously difficult to recruit and therefore some studies have used controls which may be younger, more likely to be female and have smoked less.

Systemic inflammation has been widely reported to be a key link between COPD and some comorbidities. The source of systemic inflammation in COPD may be the result of a spillover of airway and lung parenchymal processes. Alternatively there may be a degree of congenital or acquired susceptibility to inflammatory over-response when a sufficient trigger is encountered. Individuals with this predisposition may develop COPD as part of a systemic inflammatory syndrome which may include atherosclerotic diseases.

Aside from inflammation, there are some specific anatomical, mechanical and pathophysiological links with some comorbidities, these are described in the appropriate sections below. Many comorbidities interact with each other as well as with COPD and may form part of a wider network of disease.

COPD is markedly heterogeneous in terms of etiology, pathology, symptoms and health status. There is no single measure that encompasses all of these factors. There has therefore been a concerted attempt to describe different objective clinical or pathological phenotypes within COPD. Many comorbidities are related to specific phenotypes within COPD, which may in turn provide clues towards mechanistic links. Some comorbidities have associations with COPD-specific therapies such as orophayngeal candidiasis with the use of inhaled corticosteroids, or Cushingoid effects from frequent systemic steroids.

The potential impact of comorbidities on COPD and vice versa extends beyond stable progressive disease into acute exacerbations. These events represent deterioration of respiratory symptoms which may warrant a change in therapy. They may be defined by symptomatic changes and/or healthcare utilization. Exacerbations are of huge importance in COPD, it has been shown that those who suffer more frequent exacerbations have more systemic and airway inflammation, worse health status , an accelerated decline in lung function and increased mortality . The frequent exacerbator appears to be a relatively stable phenotype of COPD .

The measurement of the overall burden of comorbidity is fraught with difficulty as many of the scrutinized conditions are complex in their own right and measurement of their severity may be difficult particularly in COPD patients. It is also difficult to accurately judge each of their relative contributions in an individual patient. The most widely used score to date is the Charlson comorbidity index which was developed and validated in a secondary care population of hospitalized general medical and breast cancer patients in the 1980s , not wholly applicable to a modern, largely outpatient COPD population.

It is clear that COPD, with all of its complex facets, is inextricably linked, potentially from diagnosis to death, with a number of important comorbidities that each require recognition, assessment and appropriate management in order to maximize patient outcomes. The rest of this article will consider these issues with regard to individual comorbidities.

Cardiovascular diseases

Cardiovascular diseases, as they relate to COPD, in large part are due to atherosclerosis and are likely to have their roots in inflammation. This may be the reason why they are more common in COPD (and other chronic inflammatory diseases) than may be accounted for their shared etiological factors of age, gender, smoking, education level and socioeconomic deprivation. Cardiovascular diseases are the leading causes of death in patients with mild-to-moderate COPD, chief among which is ischemic heart disease (IHD). Most patients living with COPD fall into this category, although many remain undiagnosed. As lung disease becomes more severe, dying from a respiratory event becomes the most likely cause of death.

In a pooled analysis of two large population-based epidemiological studies (Atherosclerosis Risk in Communities [ARIC] Study and the Cardiovascular Health Study (CHS), n = 20,296 adults >44 years old), the prevalence of cardiovascular disease (defined as IHD, heart failure, stroke and/or transient ischemic attack) in COPD patients was found to be 20–22% compared with 9% in subjects without COPD . As was the case in COPD patients with diabetes or hypertension, the presence of a cardiovascular disease conferred a significantly higher risk of hospital admission and mortality within 5 years. Unsurprisingly, these increases were particularly amplified in COPD patients with GOLD stage III and IV disease rather than those with mild-to-moderate COPD (Figure 1).

In addition, given the shared symptomatology, it is a common and important clinical dilemma to quantify and differentiate the relationships and symptoms in those with COPD and cardiovascular diseases. Appropriate and targeted investigations are important in this context to optimize patient management. Many COPD-related studies have attempted to draw on relationships with cardiovascular disease as a whole entity rather than specific individual diagnoses. Below, we discuss IHD (and potential sequelae: myocardial infarction [MI], arrhythmias, heart failure) cerebrovascular disease (ischemic or hemorrhagic) and their risk factor conditions of hypertension, hypercholesterolemia and diabetes. We have separately reviewed these diseases as well as right heart failure secondary to COPD (cor pulmonale). Peripheral vascular disease has not yet been fully investigated in COPD patients, although it may impact on important parameters such as walking distance.

Modern medical therapies for cardiovascular diseases have been very effective in primary and secondary prophylaxis of events and reducing mortality (in contrast to COPD). There is emerging evidence of the benefit of statins and β-blockers on parameters of COPD, this may be true to a lesser extent for angiotensin pathway therapy. Appropriate large-scale trials are required to assess whether these drugs may be useful in COPD outside of their cardiovascular indication. However, when a clear primary indication exists, statins and β-blockers should be used.

Although widely reported in the literature, cardiovascular disease is not a useful clinical term and individual diagnoses such as IHD and congestive cardiac failure have specific management algorithms. Therefore, we have reviewed individual diagnoses where possible. However, given the difficulty of separating out cardiovascular diseases as they have been amalgamated and described in studies, many of the points outlined in the IHD section below may apply to other sections as well.

Ischemic heart disease

Soriano and colleagues demonstrated, using the UK General Practice Research Database, that in the year following clinical COPD diagnosis, the relative risks of diagnosed angina and MI were 1.67 and 1.75, respectively, when compared with subjects without COPD . A telephone survey of 1003 American COPD patients reported a prevalence of 22% for angina and 19% for a previous MI . In a large longitudinal Canadian health database study, COPD patients were found to have higher risk ratios for angina (2.02) and myocardial infarction (1.99) compared with matched controls following adjustment for known cardiovascular risk factors. Mortality due to cardiovascular disease in COPD patients was also approximately doubled compared with controls in this study . There are multiple sources of evidence demonstrating a high prevalence of IHD in COPD patients. In the Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) study, ‘heart trouble’ as opposed to IHD was reported in 26% of 2164 COPD patients compared with 11% of 337 smoking controls (p < 0.001), with a MI reported in 9 versus 3% (p < 0.001) . It should be noted that the controls in this study were on average 8 years younger and with a lower smoking pack-year history. The prevalence figures were not different between GOLD stages II, III and IV.

There appears to be a relationship between the severity of COPD and cardiovascular risk. Incident cardiovascular events were more frequent in COPD patients with a lower FEV₁ over a 15-year follow-up period in the ARIC study . This pattern was observed regardless of smoking status or whether or not the subjects had cardiovascular disease at baseline. Curkendall and colleagues stratified COPD patients in terms of descriptors found in medical records which were associated with hospital admission, including the presence of emphysema, recent nebulizer use, home oxygen, corticosteroid use, frequent bronchodilator use, pneumonia and exacerbations . The most severe quintile of patients according to these criteria had higher cardiovascular morbidity and mortality (odds ratio: 1.63) than the least severe quintile.

In another large population-based study from the UK, Feary and colleagues demonstrated that the relative risk of comorbid cardiovascular disease and subsequent MI and stroke events was higher in COPD patients than the rest of the population. The burden of cardiovascular disease and events was highest in older COPD patients, given that they constitute the majority of COPD patients, intriguingly, cardiovascular risk was consistently higher in younger age groups. This may represent a group of patients with a shared susceptibility phenotype to the development of COPD and cardiovascular disease.

Data from the third National Health and Nutritional Examination Survey demonstrated that COPD patients with higher serum C-reactive protein had more cardiac injury detected on electrocardiogram (ECG) , beyond shared risk factors such as age and smoking. It is a widely held belief in the field that chronic low-grade systemic inflammation is a major pathophysiological link between COPD and atherosclerotic diseases. Impaired vascular reactivity is an independent and early feature of and risk factor for atherosclerosis even before structural plaque changes are present. Endothelium-dependent and-independent vasodilatation has been found to be impaired in COPD patients without known cardiovascular disease compared with control subjects . The degree of endothelial dysfunction was related to lung function and serum C-reactive protein, providing another inflammatory link between COPD and atherosclerosis. Subclinical atherosclerosis is likely to start early in the course of COPD, as suggested by the findings of increased carotid artery intima-media thickness in middle aged smokers with airflow limitation .

Arterial stiffness, as measured noninvasively by aortic pulse wave velocity, is an established marker of cardiovascular events and mortality in the general population as well as large specific groups at increased risk of IHD including patients with hypertension, diabetes and renal failure. COPD patients have been shown to have increased arterial stiffness compared with age-and smoking-matched controls . Indeed the degree of arterial stiffness is related to worse disease severity in terms of FEV₁ and computed tomography (CT)-quantified emphysema .

Data regarding the symptomatic impact of IHD on COPD patients is lacking. It has been shown that COPD patients with heart disease (not specifically IHD) have a worse health status (assessed using the Short Form 36 questionnaire) and consume more healthcare resources .

Using The Health Improvement Network database to analyze more than 25,000 COPD patients, the risk of acute MI has been shown to be elevated 2.3-fold in the period 1–5 days following an exacerbation . Acute exacerbations of COPD are known to involve a rise systemic inflammation beyond that already seen in the stable state , including plasma fibrinogen , itself an independent risk factor for atherosclerotic diseases. However, the presence of IHD does not appear to be a risk factor for more frequent COPD exacerbations .

Antonelli Incalzi and colleagues followed up patients after hospital admission for exacerbation of COPD, they found that median survival was shorter in those who had ECG evidence of IHD (2.19 vs 3.26 years, p = 0.027) . The presence of COPD has an adverse impact on hospital admission rate and subsequent inpatient mortality in those with IHD , as well as survival following angiography .

It may be appropriate for clinicians to screen all COPD patients, or those with other risk factors, for previous silent myocardial damage with a 12-lead ECG and institute appropriate management earlier. Following potential symptoms of an acute coronary syndrome, the diagnosis of IHD may be more difficult in COPD patients as they may not be able to reach the physical threshold required for accurate exercise ECG testing. Other noninvasive alternatives such as stress echocardiograms and myocardial perfusion scans may be preferable. Coronary artery calcium scanning using CT could potentially have wider utility in COPD as a first line investigation, although further work is required to establish the optimal diagnostic pathway prior to angiography.

Given that the mechanistic links between COPD and IHD beyond their shared risk factors are not yet completely understood, it falls on clinicians who look after COPD patients to ensure that known entities are managed appropriately. For example, successful, lasting smoking cessation is the single most effective management strategy for COPD patients in the long term, which also has a profound impact on the prognosis of IHD. The optimal management of other conditions, such as hypertension and diabetes, which predispose to atherosclerosis are discussed in the sections below.

In terms of specific IHD pharmacotherapy, there is clear evidence that in the past, and probably to a lesser extent currently, many clinicians have been reluctant to prescribe β-blockers alongside the almost ubiquitous β-agonists used by COPD patients. Often less effective alternatives such as calcium channel blockers are employed as anti-anginals in their place . It has become apparent that cardioselective β-blockers such as atenolol and bisoprolol are safe in COPD . Such agents should not, therefore, be withheld from COPD patients if there is an appropriate indication . Indeed, there is emerging evidence that there may be some benefit of β-blockers in COPD outside of the context of cardiovascular disease , although as yet, this is far from established.

Concerns regarding COPD therapy increasing cardiovascular risk have not been supported by data from large trials . Therefore, COPD patients should not have appropriate bronchodilator therapy withheld for fear of risk of a cardiovascular event.

Cerebrovascular disease

In the telephone survey study by Barr and colleagues , 14% of COPD patients reported a previous cerebrovascular event. Feary and colleagues reported the prevalence of stroke as 9.9% in those with COPD compared with a background prevalence of 3.2% in the rest of the population . In the longitudinal part of the study, COPD was associated with a 2.8-fold increase in the incidence of acute stroke. The risk of stroke has been shown be elevated 1.3-fold in the first 7 weeks following an acute exacerbation of COPD 0. The pathophysiological links behind the excess risk of stroke in COPD are likely to be similar in large part to those for IHD.

There is a striking paucity of data on the symptomatic and functional impact of stroke in COPD given its reported prevalence and relative importance.

In the general population, most strokes are ischemic in nature and are caused by underlying cerebrovascular atherosclerosis or cardiac thromboemboli often associated with atrial fibrillation. Around 10% of strokes are hemorrhagic and may be associated with an underlying aneurysm. Given the heterogeneity of underlying mechanisms, it is of paramount importance to recognize and appropriately manage the common conditions responsible, particularly hypertension, hypercholesterolemia, diabetes and atrial fibrillation, as well as tobacco smoking. It may also be prudent for clinicians to examine for carotid artery bruits when examining COPD patients at risk for stroke, and to investigate thoroughly if there is clinical suspicion of a current or previous cerebrovascular event.

Aside from strokes, small vessel cerebrovascular disease is an area which requires much more work, particularly with regard to cognitive function and hypoxia (for a review, see ).

Heart failure

Heart failure is a complex clinical syndrome with many features in common with COPD, particularly the cardinal symptoms of dyspnea and fatigue. There are different types of heart failure, including right and left sided dysfunction, in isolation or together, in congestive cardiac failure. A large cohort study demonstrated that almost half of patients with clinical heart failure have a preserved ejection fraction and therefore have diastolic heart failure but have a similar prognosis to those with systolic dysfunction . There are many causes of heart failure but the most common are IHD and long-standing poorly controlled hypertension, both of which are common in COPD patients. Isolated right heart failure in patients with COPD is usually cor pulmonale mediated by the increased right-sided outflow pressures due to raised pulmonary vascular resistance often found in severe lung disease. In addition to intrinsic myocardial dysfunction, there is evidence of impaired ventricular filling associated with the severity of emphysema, raising the possibility of heart failure secondary to lung hyperinflation physically restricting cardiac preload.

Arrhythmias

The prevalence of cardiac arrhythmia in COPD is estimated at around 12–14% . The vast majority of these are atrial fibrillation and incident cases are more common with increasing disease severity and are likely to be related to underlying IHD and potentially a higher frequency of exacerbations.

Existing data does not support the idea that chronic respiratory medication induces cardiac arrhythmia, excluding sinus tachycardia . The management of COPD should not generally be altered for those with atrial fibrillation aside from any potential interactions with warfarin. As stated above, cardioselective β-blockers should not be withheld if indicated for stable COPD patients, however, their safety is less clear in the context of an acute exacerbation where there is little data as yet.

Hypertension

Hypertension is consistently one of the most prevalent comorbid diagnoses in COPD patients reported in 40–60% . Indeed, it is among the most prevalent conditions in middle age and later life in general, however, there appears to be an excess in COPD patients which increases with disease severity. Mannino and colleagues’ combined analysis of the ARIC and CHS population-based cohorts of more than 20,000 people reported a prevalence of hypertension of 34% in normal subjects, rising to 40% in GOLD stage I patients, 44% in GOLD stage II and 51% in GOLD stages III and IV . In the multivariate analysis, the odds ratio for having hypertension compared with normal subjects was 1.4 in GOLD stage II and 1.6 in GOLD stages II and IV .

The pathophysiological links of COPD and hypertension are not yet well described. However, it seems feasible that accelerated aging, loss of connective tissue and increased arterial stiffness may have a role. Hypertension and the pathology underlying COPD become much more common with age. Central arterial stiffness is related to peripheral blood pressure, and purported to be one of the main mechanisms leading to essential hypertension, particularly when there is isolated systolic hypertension. Arterial stiffness in COPD patients is related to the degree of emphysema , giving rise to the idea that elastic connective tissue loss in different compartments of the body may be worth investigating further.

Hypertension is generally asymptomatic and thus would not be expected to particularly impact on COPD patients. However, it is a key risk factor for atherosclerotic diseases, hemorrhagic stroke and cardiac arrhythmias, and therefore its sequelae may have a profound impact on COPD patients. Moreover, antihypertensives are the most common extrapulmonary medications prescribed to COPD patients and these may also have an effect.

Given its high prevalence in COPD, central role in many other conditions, effective therapies and simple diagnosis, hypertension should be a condition that should be aggressively managed in COPD patients, even when blood pressure is only moderately raised. It is not clear that any one class or regimen of antihypertensives is favorable in COPD, therefore it should be managed in accordance with local policies and guidance. Pulmonary rehabilitation has also recently been shown to reduce blood pressure .

Dyslipidemia

Cholesterol does not vary with lung function in normal subjects . Most studies have not demonstrated significant differences in the prevalence of dyslipidemia between COPD patients and control subjects . Chronic intermittent hypoxia has been shown to upregulate a hepatic enzyme of lipoprotein secretion, leading to elevated low-density lipoprotein cholesterol levels in patients with obstructive sleep apnea (OSA) . This is a potential mechanism for some observations of higher cholesterol values in selected very severe COPD patients.

There is no evidence that management of dyslipidemia in COPD should be different to that recommended for the general population, particularly in terms of lifestyle and diet modifications. However, there is a growing body of evidence that statin therapy is beneficial in COPD patients, beyond important effects on cardiovascular risk reduction. Due to their anti-inflammatory and immunomodulatory effects, statins have been proposed as direct therapy in COPD in terms of reducing lung function decline , respiratory morbidity and all-cause mortality . These findings from observational studies require further corroboration from ongoing prospective randomized controlled trials, which we await with interest.

Type II diabetes mellitus

Type II diabetes is more prevalent in moderate-to-very severe (but not mild) COPD than in the general population, with an overall prevalence of 12.7% in the combined ARIC and CHS cohorts and 12.2% in The Health Improvement Network dataset . The degree of excess diabetes appears to be a lesser extent than other cardiovascular risk contributing conditions. This finding has been corroborated by another large epidemiological study which showed a relative risk of incident diabetes of 1.8 in female COPD patients, following adjustment for confounders . Feary and colleagues showed that this may not hold true for older COPD patients who appeared to have a slightly reduced odds ratio of having diabetes in a cross sectional analysis . Although the reasons for this observation are not clear, others have shown higher hospital admission and lower survival of COPD patients with diabetes compared with those without .

The pathophysiological link between COPD and diabetes is not entirely understood, although thought to involve systemic inflammation with central roles for IL-6 and TNF-α .

Hyperglycemia during acute exacerbations of COPD requiring hospitalization is associated with poorer outcomes in terms of outcome of acute noninvasive ventilation , longer inpatient stay and in-hospital mortality . These patients were also likely to have more than one species of bacteria grown from sputum during the admission, raising the possibility of a poorer immune response. Although, some nondiabetic patients have hyperglycemia induced by systemic corticosteroids, this is more likely in the context of diabetes and therefore hypoglycemic medication may need adjustment. Further evidence for such an approach is clearly warranted.

In the absence of a preventative approach, aside from lifestyle advice, and given the high prevalence and adverse clinical impact of diabetes on COPD patients, it may be worthwhile screening those at higher risk. This would potentially enable earlier diagnosis and prevention of complications.

Hematological coagulopathy, polycythemia & anemia

In addition to high rates of atherothrombotic arterial cardiovascular events in COPD, as described in previous sections, there is also some evidence of excess venous thromboembolism mainly during acute exacerbations, although prevalence varies widely in the literature .

Fibrinogen levels are directly related to the incidence of cardiovascular events, and are higher in stable COPD patients than in healthy controls . It is further elevated during acute exacerbations of COPD, probably due to systemic inflammation . Fibrin clots in COPD patients are denser than in healthy subjects and therefore more resistant to lysis, although statin therapy may ameliorate this .

Platelet activation has been shown to be increased in stable COPD as detected by platelet-monocyte aggregates and further increased during exacerbations .

Measures to reduce the incidence of arterial and venous thromboembolism, are already standard practice such as appropriate antiplatelet therapy in the stable state and low-molecular weight heparin during hospital admission should be adhered to unless there are convincing contraindications.

Polycythemia in COPD patients as a result of chronic hypoxemia is less prevalent at approximately 6% than in the past due to the advent of LTOT. In severe COPD, polycythemia should be recognized and managed with institution or adjustment of LTOT, aspirin and appropriate venesection when the hematocrit exceeds 0.56 , in order to prevent thrombotic events due to increased blood viscosity.

Anemia of chronic disease is common in COPD with an estimated prevalence of 10–33%, increasing with additive chronic comorbidities. Anemic COPD patients are likely to be more symptomatic, have a lower exercise capacity, use more health care resources and have a shorter survival . Intervention in this situation is not easy as although blood transfusions improve some parameters in the short term, this is not a viable strategy for widespread use. Erythropoietin therapy requires further study, although it should be noted there is likely to be a degree of erythropoeitin resistance in stable and exacerbated COPD, likely related to systemic inflammation . Given its impact, more work is required to unravel the pathophysiology underlying anemia in COPD in order to provide an effective intervention.

Skeletal muscle dysfunction

Skeletal muscle dysfunction in COPD can have a direct impact on exercise capacity, fatigue and activity levels, which are likely to be associated with health-related quality of life. The prevalence of skeletal muscle weakness in COPD patients as tested by quadriceps strength is 32% . More than a quarter of GOLD stage I and II patients have skeletal muscle dysfunction, rising to 38% in GOLD stage IV. Quadriceps strength is related to fat-free mass index, Medical Research Council dyspnea score, BODE (BMI, airflow obstruction, dyspnea and exercise capacity) index and indeed mortality .

The pathophysiology of skeletal muscle weakness in COPD is likely to be multifactorial, but likely to include reduced activity leading to disuse atrophy, systemic corticosteroid therapy, inflammation leading to a cachexia syndrome, hormone imbalance, hypoxia and oxidative stress. It has been seen that there is a switch away from type I to type II muscle fibers, towards less endurance.

Assessing skeletal muscle dysfunction in routine clinical practice is not currently widespread due to equipment and time requirements. COPD patients with suspected or known skeletal dysfunction could preferentially be referred to a pulmonary rehabilitation program in order to attempt to reverse the changes. Neuromuscular stimulation of affected muscles may be a useful adjunct in future, although further work on this is required.

Low bone mineral density & fracture risk

The prevalence of low bone mineral density (BMD) is higher in COPD than control subjects at 40–70% depending on the study population, and is related to disease severity, CT-quantified emphysema score, arterial stiffness, systemic inflammatory markers, BMI and physical activity . Although low BMD is more common in female COPD patients, strikingly, males are also at high risk. This array of associations suggests multiple pathophysiological links between the two conditions, including excess proteolytic activity (Figure 2), systemic inflammation, less weight-bearing exercise, smoking, low sex hormones, vitamin D deficiency and systemic corticosteroid use.

It does not appear that inhaled corticosteroids play a major role in the progression of osteoporosis . Although themselves asymptomatic, the sequelae of osteoporosis and osteopenia in terms of fractures can have a profound impact on patients. Although fractures have a higher incidence in osteoporotic patients than those with osteopenia, the majority of low-impact fractures occur in people with osteopenia and therefore it may be prudent to intervene at less severe levels of bone density than is currently standard practice. Vertebral fractures are common in COPD and lead to significant decrements in lung function from extrathoracic restriction and pain.

Great efforts must be made to detect and treat low BMD in COPD patients in order to minimize fracture risk. Bone densitometry is widely available and should be employed to screen patients at risk of low BMD, current rates of detection and treatment of osteoporosis are low. Lehouck and colleagues have recently suggested a more aggressive approach to diagnosis and management of low BMD in COPD .

Depression

Depression is a common comorbidity of most symptomatic chronic diseases, although it has been suggested that patients with COPD are particularly susceptible to a reactive-type disorder. Although several studies have examined this issue, a large observational prospective analysis from the ECLIPSE study has recently been published. The authors showed around a quarter of COPD patients had depression as defined by the score on a validated questionnaire compared with 12% of control subjects . The diagnosis in this study was not clinically determined. As expected the prevalence of depression was higher as COPD became more severe, although scores were more closely related to health status and symptoms, than lung function . Depression scores also rise acutely during exacerbations and indeed frequent exacerbators have higher depression scores . It is widely acknowledged that depression is under-recognized in COPD and screening questionnaires may be a useful adjunct to a clinical diagnosis, upon which management should be based. Systemic inflammation, perhaps via TNF-α, and oxidative stress have been implicated in the pathophysiology of depression in COPD patients .

Pulmonary rehabilitation, pharmacological antidepressants and psychotherapeutic strategies may all be beneficial, but more work is required to optimize the management pathway of these individuals.

Obstructive sleep apnea

Although OSA is not thought to be more common in COPD than in the general population, it can have a profound impact on prognosis. When the two diseases coexist they have been termed overlap syndrome. COPD patients with OSA tend to have higher pulmonary artery pressures, more right heart failure , and more hypoxia and hypercapnia for a similar level of lung function.

Marin and colleagues have recently shown patients with overlap syndrome have increased hospital admission for COPD exacerbation and higher mortality than COPD patients without OSA. These findings are ameliorated by treatment with continuous positive airway pressure . The excess deaths in the overlap group were predominantly cardiovascular in nature. The mechanisms underlying this additive cardiovascular risk which is improved with continuous positive airway pressure requires further work.

Gastro-esophageal reflux disease

Although symptoms of gastroesophageal reflux disease (GERD) occur in up to 30–60% of COPD patients and are associated with more severe disease, many episodes of reflux are asymptomatic and are only detected by esophageal manometry. The relative risk of patients accruing a diagnosis of GERD is 1.46 in the year following COPD diagnosis .

The key underlying mechanism of GERD is transient relaxations of the lower esophageal sphincter allowing stomach contents to move into the esophagus and often as high as the larynx and mouth, particularly when intra-abdominal pressure is raised. There are reasons why reflux may be more prevalent in COPD, including a low lying diaphragm from hyperinflation, coughing and increased use of abdominal muscles for ventilation. Once liquid refluxate lies within the esophagus, increased extrinsic (intrathoracic) pressure that is evident in COPD may potentiate the movement of fluid against gravity towards the larynx. Given the anatomical arrangement and innervations of the human larynx, it is possible for small amounts of liquid refluxate to spill over into the airway where its constituents may cause an inflammatory response and/or potentially increase susceptibility to infection (Figure 3). Indeed, data from the ECLIPSE study identified a history of heartburn or reflux as an independent predictor of frequent exacerbator status . Prospectively identified exacerbation frequency was related to the frequency of reflux symptoms over a 6 month period . This link between reflux and COPD exacerbations is an intriguing one, requiring further investigation. It may indeed be possible that frequent exacerbations drive further GERD. There are several therapeutic options for GERD, none of which have yet been shown to be specifically useful in COPD, thus management should conform to standard practice.

Renal dysfunction

In 270 consecutive COPD patients admitted for an exacerbation, Antonelli Incalzi and colleagues found that 6% had chronic renal failure (CRF) (defined by an abnormal serum creatinine), they had a shorter survival time than those without CRF (0.8 vs 3.2 years; p = 0.002) . Some years later the same group assessed 365 COPD outpatients and assigned them to one of three groups; normal renal function, concealed CRF (normal creatinine with low estimated glomelular filtration rate) and overt CRF (abnormal serum creatinine). The prevalence of CRF was 43% compared with 23% in another group of hospital outpatients . This is of significance due to the potential for less effective clearing of inflammatory mediators and prothrombotic molecules, and increasing the risk for drug reactions. CRF should be screened for using estimated glomerular filtration rate calculated from a simple blood test, although there may not be a direct renal therapy applicable, there may be an underlying comorbidity such as hypertension or diabetes which could be managed more appropriately. CRF may also affect the ability to compensate for hypercapnic respiratory failure.

Expert commentary

Chronic obstructive pulmonary disease remains a challenging disease to optimally manage in individual patients, given its complexity and heterogeneity. Extra-pulmonary comorbidities, which often have pathophysiological links, can have a profound impact on morbidity and mortality. The prevalence of individual comorbidities are listed in Table 2. The majority of COPD patients have at least one important comorbidity. Understanding these relationships at every level from molecules to population epidemiology is key to enable future intervention and prevention of deleterious comorbidities in COPD. In particular, inflammation and oxidative stress require more accurate characterization in order to facilitate appropriate targeted therapy in future (Figure 4).

Cardiovascular and musculoskeletal conditions are among the most important comorbidities to recognize and manage in COPD patients, as interventions in these illnesses (such as aspirin, statins, bisphosphonates and exercise programs) are very effective. Increasing recognition and optimal management of comorbidities provides us with an opportunity to truly enhance the care of COPD patients.

Expanding horizons into the diagnosis and management of key comorbidities across existing boundaries represent an important challenge for healthcare professionals who manage COPD patients. Significant changes of healthcare organization and delivery may be required to deliver this.

Five-year view

Within the next 5 years we anticipate more rigorous systems of identifying and managing comorbidities in COPD come into widespread use. Methods of quantifying the burden of comorbidities should be part of a multidimensional assessment of global disease severity in COPD patients. This may prove challenging as each comorbidity may have its own degree of complexity and may vary in its impact in different populations in terms of age, gender, ethnicity and etiology. However, in the first instance, a specific COPD comorbidity index, along the lines of the Charlson score, should be developed and validated. It should be specific for those conditions relevant in COPD, and based on evidence of impact. This would be helpful not only for risk stratification but also for improved recognition, diagnosis and management. For example if osteoporosis is on a list of comorbidities in an index score, or in national guidelines, it is raised as a possibility in the mind of the clinician who is reminded that it is important to investigate for relevant risk factors. In this way, a potential future fracture may be prevented which is costly to the patient, carers and healthcare providers. Building on such an approach, we hope to see progress in the development of evidence-based advice for the investigation and management of specific comorbidities in patients with COPD.

We look forward to the outcome of studies of therapies indicated for other diseases (such as statins and β-blockers) having direct beneficial effects on COPD parameters. Likewise, novel therapies in COPD, in particular those which target acute and chronic inflammation, may also prove beneficial in the prevention and or management of comorbidities such as IHD and osteoporosis.

References

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Extrapulmonary comorbidities in chronic obstructive pulmonary disease: state of the art

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