Fig. 7.1
Potential pathways and mechanisms of tobacco smoke in the development of airway inflammation. Tobacco smoke activates macrophages and epithelial cells in the airways via the activation of Toll-like receptors (TLRs) and oxidative stress to cause the release of multiple chemotactic factors. Recruited neutrophils and monocytes, and T lymphocytes as well as structural cells release multiple inflammatory mediators. Some inflammatory and structural cells also release proteases leading to parenchymal destruction and mucus hypersecretion in the airways, and some release fibrogenic mediators leading to small airway fibrosis. Cytotoxic T lymphocytes (CTLs) may also be involved in alveolar wall destruction. Activation of the inflammasome may also be involved, and phagocytic dysfunction of alveolar macrophages may lead to bacterial colonization (Adapted from Barnes 2013 [4])
One of the classical hypotheses to explain the development of systemic inflammation in COPD is the “spillover” theory (Fig. 7.2) [13]. This concept suggests that the inflammatory reaction may initially be local, but thereafter, increased inflammatory mediators may spill over from the inflamed lungs into the circulation to cause systemic inflammation. Because plasma levels of TNF-α, soluble TNF receptor, IL-6, and IL-8 are elevated in patients with COPD [13, 14], an obvious explanation is that these mediators originate from the airways and accelerate subsequent immune reactions in the extrapulmonary organs. However, this concept remains unclear, as discussed below.
Fig. 7.2
“Spillover” hypothesis. Lung inflammation may cause a “spillover” of cytokines, such as (IL)-6, IL-1β, and tumor necrosis factor (TNF)-α, into the circulation to cause systemic inflammation and subsequent immune reactions within the extrapulmonary organs (Reproduced with permission of the European Respiratory Society ©: European Respiratory Journal May 2009, 33 (5) 1165–1185; DOI: 10.1183/09031936.00128008. This material has not been reviewed by European Respiratory Society prior to release; therefore the European Respiratory Society may not be responsible for any errors, omissions or inaccuracies, or for any consequences arising there from, in the content [13])
7.2.2 The Extrapulmonary Effects of Tobacco Smoke Exposure
Spillover is a clear-cut hypothesis; however, there are some inconsistent findings in previous studies. Wouters et al. reviewed research data from several sources, demonstrating no correlations in the levels of TNF-α, soluble TNF receptor, or IL-8 between sputum and plasma among COPD patients [14]. In addition, a recent study showed that the frequency of comorbid conditions, corresponding to the level of systemic inflammation, was not directly related to COPD severity [15]. In fact, patients with severe COPD demonstrating enhanced airway inflammation do not always develop systemic inflammation, and furthermore, patients with smoking-related cardiovascular disease do not always have COPD. Therefore, extrapulmonary comorbidities may involve an inflammatory process induced by exposure to tobacco smoke, which is independent from that of COPD. When a person inhales tobacco smoke, containing thousands of chemicals, free radicals, and ROS within its gases and particles, toxic substances deposit in the alveoli of the lungs and may rapidly diffuse into the systemic circulation. The toxicants may initially cause oxidative stress and immune responses in vascular endothelial cells and recruited inflammatory cells, similar to those in the airways (Fig. 7.1), and this effect may be further amplified leading to the systemic production of proinflammatory mediators to damage target organs.
The potential mechanisms underlying smoking-related cardiovascular disease are shown in Fig. 7.3. Oxidative stress, enhanced by free radicals and ROS generated from exogenous and endogenous sources, has been attributed a central role in the creation of atherothrombotic conditions, including endothelial dysfunction, inflammation in the vessel walls, a prothrombotic and antifibrinolytic milieu, and lipid peroxidation [16]. However, the causal relationship between airflow limitation and atherosclerosis remains equivocal. A recent clinical study demonstrated that both airflow limitation and endothelial dysfunction were associated with increased atherosclerosis, but were likely to be unrelated and mutually independent [17]. This may suggest that smoking-induced atherosclerosis is not easily explained with a simple linear pathway starting with smoking-induced airway inflammation and ending with the atherosclerotic disease.
Fig. 7.3
Potential pathways and mechanisms of tobacco smoke in the development of smoking-related cardiovascular disease. Oxidative stress, enhanced by free radicals and reactive oxygen species (ROS) generated from exogenous and endogenous sources, has been attributed a central role in the atherothrombotic conditions caused by tobacco smoke, which include endothelial dysfunction, inflammation in the vessel walls, a prothrombotic and antifibrinolytic milieu, and lipid peroxidation. The bold boxes and arrows in the flow diagram represent the probable central mechanisms in this complex pathophysiology. H2O2, hydrogen peroxide; METC, mitochondial electron transport chain; NADPH, nicotinamide adenine dinucleotide phosphate reduced form; NOS, nitric oxide synthase; ONOO−, peroxinitrite; O· 2 −, superoxide (Reproduced from Ambrose et al. 2004 [16])
Recent experimental studies have also demonstrated that tobacco smoke affects both insulin sensitivity and secretion. Inhaled nicotine has been shown to impair insulin signaling cascades and upregulate lipolysis within the adipose tissue through increased oxidative stress and to increase the levels of circulating free fatty acids in skeletal muscle and liver [18]. It has been also reported to activate mammalian target of rapamycin in skeletal muscle [19]; elevate the levels of circulating TNF-α, cortisol, and sex hormones; and decrease levels of adiponectin [20]. These findings may explain the relationship between nicotine and the impairment of insulin sensitivity. Additionally, tobacco smoke has been shown to suppress insulin secretion because of an alteration in pancreatic function [21]. All these results are consistent with the observation that chronic smokers are insulin resistant and at high risk for diabetes [22, 23].
The relationship between systemic inflammation and bone metabolism has also been characterized. IL-1, IL-6, and TNF-α, potential mediators for inflammation in the airways and extrapulmonary organs in COPD [13], are recognized as stimulators of bone resorption and inhibitors of bone formation [24]. This may correspond to the high prevalence of osteoporosis in patients with COPD.
7.2.3 Other Mechanisms Underlying Comorbidities
Because smoking is indicated as an age-accelerating factor, comorbidities have been associated with both long-term smoking and the consequent altered aging process [25]. However, among older smokers, not all subjects develop comorbidities or COPD. For example, a previous clinical study demonstrated that carotid intima-media thickness, a risk factor for cardiovascular diseases, was not significantly different between smoking and non-smoking control subjects, while it was significantly greater in smokers with airflow limitation than in control smokers without airflow limitation [26]. These data imply that, in addition to environmental factors, host susceptibility to smoke-induced inflammation in the airways and extrapulmonary organs may also be important in the development of COPD and comorbidities. Recent genome-wide association studies have identified several genetic loci responsible for the development of COPD, as discussed in the other chapters [27, 28]. The pathogenic role of these candidate genes in the susceptibility to systemic inflammation needs to be defined in future studies; however, genetic factors could be one possible explanation for a multi-comorbid condition in COPD.
The clinical symptoms and signs of COPD in themselves may be another important factor involved in the development of comorbidities. Feelings of breathlessness upon exertion gradually limit a patient’s physical activity, and finally the patient tends to become housebound and develops reduced amounts of vitamin D from the lack of sunlight. This may account for insulin resistance and loss of bone mass, leading to diabetes and osteoporosis. Limitation of the ADL may cause anxiety, depression, and cognitive disorder, and in some cases, the psychological stress may aggravate GERD symptoms by increasing acid production [29]. Furthermore, recent studies reported that percent emphysema was inversely associated with reduced right ventricular (RV) volume, RV mass, and cardiac output [30], and that pharmacological treatment of lung hyperinflation achieved beneficial effects on cardiac structural and functional alterations [31].
From a pharmacological point of view, COPD medications may be a possible risk factor for comorbidities. High-dose and long-term corticosteroid treatment is believed to cause a loss of bone density, and it may also cause peptic ulcer, occasionally associated with gastrointestinal bleeding and perforation. Theophylline, β-adrenergic agonists, and anticholinergics are known to reduce lower esophageal sphincter (LES) pressure, which may lead to gastroesophageal reflux. Theophylline has also been demonstrated to increase production of gastric acid. Treatments for other comorbidities, such as low-dose aspirin or oral anticoagulants for cardiovascular diseases, selective serotonin reuptake inhibitors for psychological problems, and bisphosphonates for osteoporosis, may worsen gastrointestinal symptoms [32, 33]. It is accepted that bronchodilators including β-adrenergic agonists and anticholinergic agents may be associated with an increase in cardiovascular risk. However, it does not necessarily mean that these medications cannot be used for the treatment of COPD. Rather, clinicians should bear the adverse effects of these medications in mind when providing all necessary treatments for both COPD and any comorbidities.
7.3 Etiology of Comorbidities in COPD
Comorbidities in COPD, with a prevalence of 5 % or greater, are presented in Fig. 7.4. Of these, anxiety and/or depression, heart failure, ischemic heart disease, pulmonary hypertension, metabolic syndrome, diabetes, osteoporosis, and GERD are considered particularly important [3]. A large cohort study reported that, compared with control subjects, COPD patients have a high risk of presenting with comorbidities. The odds ratios in COPD patients for the prevalence of chronic heart failure, angina, myocardial infarction, atrial fibrillation, hypertension, and diabetes compared with the control subjects were 8.48, 4.38, 4.42, 4.41, 1.76, and 1.51, respectively [34].
Fig. 7.4
Prevalence of comorbidities in patients with chronic obstructive pulmonary disease (COPD). a, comorbidities which result in a significant increase in the risk of mortality compared with COPD patients without the comorbidity; b, comorbidities with a significantly increased prevalence in COPD patients compared with the general population; AAA, abdominal aortic aneurysm; BPH, benign prostatic hypertrophy; COPD, chronic obstructive pulmonary disease; CVA, cerebrovascular accident; DVT, deep vein thrombosis; GERD, gastroesophageal reflux disease; PHT, pulmonary hypertension (Reproduced from Smith et al. 2014 [3])
With regard to mortality, COPD patients with comorbidities are believed to have a poor prognosis compared with those without comorbidities. Among various causes of death, cardiovascular disease and lung cancer are the two major contributors other than respiratory failure itself (Fig. 7.5) [35]. The proportion of cardiovascular mortality was reported to be 12–37 % of the total death in COPD [36], and the adjusted relative risks for cardiovascular death in COPD are 3.53 for chronic heart failure, 1.81 for myocardial infarction, and 1.25 for stroke, compared with those without COPD [34]. However, interestingly, in mild or moderate COPD, comorbidities such as cardiovascular disease and lung cancer are the main causes of death, while respiratory failure becomes the predominant cause in more advanced COPD [36].
Fig. 7.5
The primary cause of death in patients with chronic obstructive pulmonary disease (COPD). The number of deaths in each category is provided below the cause of death. CV, cardiovascular; SCD, sudden cardiac death; SD, sudden death (Reproduced from McGarvey et al. 2014 [35])
To gain a comprehensive understanding of COPD and its associated comorbidities, the “comorbidome,” proposed by Divo et al., is a useful concept. As shown in Fig. 7.6, it is a graphical representation, in which each comorbidity is plotted as a bubble that depicts two values, the prevalence and mortality of that comorbidity, through its size and location [37]. Although it remains contentious because patients at high risk for death were excluded in this study, the idea is simple and visually accessible, to allow us to easily recognize the multiplicity of comorbidities.
Fig. 7.6
The “comorbidome.” Comorbidities associated with chronic obstructive pulmonary disease (COPD), with more than 10 % prevalence, are plotted as bubbles. The diameter of each bubble reflects the prevalence of the disease. The distance to the center (death) is scaled using the inverse of the hazard ratio (HR) (1/HR). All bubbles (comorbidities) with a statistically significant increase in mortality are inside the dotted orbit (1/HR <1). A. fibrillation, atrial fibrillation/flutter; BPH, benign prostatic hypertrophy; CAD, coronary artery disease; CHF, congestive heart failure; CRF, chronic renal failure; CVA, cerebrovascular accident; DJD, degenerative joint disease; GERD, gastroesophageal reflux disease; OSA, obstructive sleep apnea; PAD, peripheral artery disease; pulmonary HTN + RHF, pulmonary hypertension and right heart failure (Reprinted with permission of the American Thoracic Society. Copyright © 2016 American Thoracic Society. Cite: Divo M, et al. /2012/ Comorbidities and risk of mortality in patients with chronic obstructive pulmonary disease. / Am J Respir Crit Care Med /186/155-61. The American Journal of Respiratory and Critical Care Medicine is an official journal of the American Thoracic Society [37])
It is interesting that most patients with COPD self-reported to have one or more comorbidities, and more than half of patients reported to have four or more comorbidities, even when their COPD was stable (Fig. 7.7) [38]. Additionally, the coexistence of multiple comorbidities, along with respiratory impairment, has been demonstrated to contribute to the risk of hospitalization and death (Fig. 7.8) [39]. These results imply that clinicians must pay attention to the entire spectrum of comorbidities associated with COPD, as well as respiratory symptoms.
Fig. 7.7
Number of objectively identified comorbidities in patients with chronic obstructive pulmonary disease (COPD) (Reprinted with permission of the American Thoracic Society. Copyright © 2016 American Thoracic Society. Cite: Vanfleteren LE, et al./2013/Clusters of comorbidities based on validated objective measurements and systemic inflammation in patients with chronic obstructive pulmonary disease./Am J Respir Crit Care Med /187/728-35. The American Journal of Respiratory and Critical Care Medicine is an official journal of the American Thoracic Society [38])
Fig. 7.8
The impact of comorbidities on all-cause mortality and time to first hospitalization in patients with chronic obstructive pulmonary disease (COPD). Cox proportional hazard models were used to predict all-cause death (a), and time to first hospitalization (b), within 5 years in patients with COPD. The subjects were classified according to their Global Initiative for Obstructive Lung Disease (GOLD) category and the presence of no (
), one (
), two (
), or three (
) comorbidities (diabetes, hypertension, or cardiovascular disease). The control group consisted of subjects with normal lung function for each comorbid disease. GOLD 3/4, forced expiratory volume in one second (FEV1)/forced vital capacity (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; GOLD 0, presence of respiratory symptoms in the absence of any lung function abnormality and no lung disease (Reproduced with permission of the European Respiratory Society ©: European Respiratory Journal Oct 2008, 32 (4) 962–969; DOI: 10.1183/09031936.00012408. This material has not been reviewed by European Respiratory Society prior to release; therefore the European Respiratory Society may not be responsible for any errors, omissions or inaccuracies, or for any consequences arising there from, in the content [39])
), one (), two (), or three () comorbidities (diabetes, hypertension, or cardiovascular disease). The control group consisted of subjects with normal lung function for each comorbid disease. GOLD 3/4, forced expiratory volume in one second (FEV1)/forced vital capacity (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; GOLD 0, presence of respiratory symptoms in the absence of any lung function abnormality and no lung disease (Reproduced with permission of the European Respiratory Society ©: European Respiratory Journal Oct 2008, 32 (4) 962–969; DOI: 10.1183/09031936.00012408. This material has not been reviewed by European Respiratory Society prior to release; therefore the European Respiratory Society may not be responsible for any errors, omissions or inaccuracies, or for any consequences arising there from, in the content [39])7.4 Comorbidities in COPD
As stated previously, and demonstrated in Fig. 7.7, almost all patients with COPD may have some kind of comorbid condition. Comorbidities have pivotal roles in causing poor health and a poor prognosis in COPD patients. It is therefore essential for clinicians to screen patients for the presence of these comorbidities and treat them comprehensively, in addition to treating their COPD. Below are outlines of the major extrapulmonary comorbidities in COPD. However, the presence of pulmonary comorbidities including lung cancer and pulmonary fibrosis also has a great impact on clinical outcomes in COPD and is discussed in the other chapters.
7.4.1 Cardiovascular Disease
Cardiovascular diseases, such as ischemic heart disease, hypertension, heart failure, atrial fibrillation, and cerebral vessel disease, are the major comorbidities in COPD [3, 39–41]. It is indicated that airflow limitation is associated with atherosclerotic plaque formation in the carotid artery and increased levels of coronary artery calcium [17], and tobacco smoke is an important risk factor for both atherosclerosis and COPD. Therefore, this shared factor is likely to contribute to the increased risk of cardiovascular comorbidities in patients with COPD. Moreover, from the evidence that carotid intima-media thickness is greater in smokers with airflow limitation than in those without airflow limitation [26], COPD patients may be particularly prone to atherosclerosis.
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