Abstract
Chronic obstructive pulmonary disease (COPD) is defined by fixed airflow limitation associated with an abnormal pulmonary and systemic inflammatory response of the lungs to cigarette smoke.
The systemic inflammation induced by smoking may also cause chronic heart failure, metabolic syndrome and other chronic diseases, which may contribute to the clinical manifestations and natural history of COPD. Thus COPD can no longer be considered a disease only of the lungs, as it is often associated with a wide variety of systemic consequences.
A better understanding of the origin and consequences of systemic inflammation, and of potential therapies, will most likely lead to better care of patients with COPD. Medical textbooks and clinical guidelines still largely ignore the fact that COPD seldom occurs in isolation.
As the diagnosis and assessment of severity of COPD may be greatly affected by the presence of comorbid conditions, the current authors believe that lung function measurement, noninvasive assessment of cardiovascular and metabolic functions, and circulating inflammatory markers (e.g. C-reactive protein) might help to better characterise these patients. Similarly, preventive and therapeutic interventions should address the patient in their complexity.
SERIES “COMPREHENSIVE MANAGEMENT OF END-STAGE COPD”
Edited by N. Ambrosino and R. Goldstein
Number 2 in this Series
Ageing is commonly characterised as a progressive, generalised impairment of function resulting in an increasing vulnerability to environmental challenge and a growing risk of disease. Ageing is highly complex, involving multiple mechanisms at different levels. Current theoretical understanding suggests that cells tend to accumulate damage as they age. Such damage is intrinsically random in nature, but its rate of accumulation is regulated by genetic mechanisms for maintenance and repair. As cell defects accumulate, the effects on the body as a whole are eventually revealed as age-related frailty, disability and disease 1, 2.
Therefore, ageing of the population increases the prevalence of chronic diseases, which represent a huge proportion of human illness. They include cardiovascular disease (30% of projected total worldwide deaths in 2005), cancer (13%), diabetes (2%) and chronic respiratory diseases (7%), mainly chronic obstructive pulmonary disease (COPD) 3.
COPD is a disease state characterised by poorly reversible airflow limitation that is usually progressive and associated with an abnormal inflammatory response of the lungs to noxious particles or gases, particularly cigarette smoke 4. COPD should be considered in any smoker aged >40 yrs with symptoms of cough, sputum production or dyspnoea, and spirometry should be used to evaluate the degree of airflow limitation 4. However, because there is increasing evidence that COPD is a more complex systemic disease than an airway and lung disease, a comprehensive approach including imaging 5, exercise tolerance and body mass index 6 may be required for an earlier diagnosis and better assessment of the disease.
Cigarette smoking is the major risk factor of COPD and is also one of the major risk factors of all chronic diseases and cancer 7, 8. Cigarette smoke causes lung and systemic inflammation, systemic oxidative stress, marked changes of vasomotor and endothelial function and enhanced circulating concentrations of several pro-coagulant factors 9–11. The systemic effects of smoking may significantly contribute not only to respiratory abnormalities, symptoms and functional impairment (e.g. exercise intolerance) associated with COPD 12–15 but also to its chronic comorbidities 12, 16–19. In particular, cachexia 20, skeletal muscle abnormalities 15, 21, 22, hypertension 23, 24, diabetes 25, coronary artery disease 26–28, heart failure 29, pulmonary infections 30–34, cancer 35, 36 and pulmonary vascular disease 37 are the most common comorbidities responsible for the clinical manifestations and natural history of COPD 17, 18. In addition to smoking, the other major risk factor for cardiovascular and other chronic comorbid conditions is obesity 38, 39. Although obesity by itself may profoundly affect lung function 40, its relationship with COPD has been poorly investigated and is still unclear 41. Smoking and obesity are the major risk factors for the complex chronic comorbidities seen throughout the world 42–44. Obese individuals who smoke have a markedly reduced life expectancy 38, 45. The two risk factors may interact synergistically, since both obesity and smoking are associated with insulin resistance, oxidative stress and increased concentrations of various (adipo)cytokines and inflammatory markers, all of which ultimately lead to endothelial dysfunction and cardiovascular diseases 46.
Comorbidities markedly affect health outcomes in COPD 16; in fact, patients with COPD mainly die of nonrespiratory diseases 47–50, such as cardiovascular diseases (∼25%), cancer (mainly lung cancer, 20–33%) and other causes (30%). Respiratory diseases, mainly respiratory failure due to COPD exacerbations, account for 4–35% of deaths, primarily in patients with severe COPD. The wide range of deaths attributable to respiratory diseases may be due to: different criteria used in different populations; the severity of COPD in the population examined 48, 50, 51; or to under-reporting of respiratory conditions on the death certificate 51, 52.
Considering that the pharmacological treatment of COPD to date is primarily symptomatic, a more comprehensive approach to comorbidities may provide an opportunity to modify the natural history of patients with COPD and to identify novel targets for treatment. This is particularly relevant for those conditions that appear more preventable and treatable than COPD, such as cardiovascular and metabolic disorders.
COMPLEX CHRONIC COMORBIDITIES
Chronic diseases, including cardiovascular disease, cancer, chronic respiratory diseases and metabolic syndrome (hypertension, diabetes, dyslipidaemia) 3, 43, are increasing in the developed countries and result in a substantial economic and social burden 3, 42, 43. The cost of individual chronic diseases increases exponentially in patients with two or more comorbid chronic diseases 53; almost half of all elderly people (≥65 yrs) have at least three chronic medical conditions, and one fifth have five or more 54. Patients with two or more chronic diseases account for only 26% of the population but for >50% of the overall costs 53.
The most frequent chronic diseases often develop together 13, 16, 24, 27, 48, 54–59. COPD is associated with chronic heart failure (CHF) in ≥20% of patients 29, 60; there is overwhelming evidence from large-scale epidemiological studies demonstrating that impaired forced expiratory volume in one second is a powerful marker of morbidity and mortality 61 and, particularly, of cardiovascular mortality 62. Interestingly, increased arterial stiffness is also related to the severity of airflow obstruction and may be a factor in the excess risk for cardiovascular disease in COPD 63. Patients with severe COPD have elevated circulating levels of C-reactive protein (CRP) 64. A working hypothesis to account for the high prevalence of left ventricular systolic dysfunction in patients with COPD is that low-grade systemic inflammation accelerates progression of coronary atherosclerosis, which ultimately results in ischemic cardiomyopathy. Such a hypothesis fits the clinical observation of a high incidence of left ventricular wall motion abnormalities noted in patients with COPD and left ventricular dysfunction 64.
Metabolic syndrome is a complex disorder and an emerging clinical challenge, recognised clinically by the findings of abdominal obesity, elevated triglycerides, atherogenic dyslipidaemia, elevated blood pressure, high blood glucose and/or insulin resistance 65. Metabolic syndrome is also associated with a pro-thrombotic state and a pro-inflammatory state. Central pathophysiological features of metabolic syndrome include: 1) insulin resistance; 2) atherogenic dyslipidaemia; 3) arterial hypertension, which occurs frequently in individuals with insulin resistance; 4) a pro-inflammatory state, with increases in acute-phase reactants (e.g. CRP); and 5) a pro-thrombotic state, with increases in plasminogen activator inhibitor and fibrinogen 65. Patients with COPD often have one or more component of the metabolic syndrome 66 and osteoporosis (≤70% of patients) which are at least, in part, independent of treatment with steroids and/or decreased physical activity 63, 67. Even when a specific single chronic comorbidity cannot be diagnosed according to the current criteria, COPD is often associated with a marker of chronic diseases, e.g. decreased tolerance to glucose, hypertension or decreased bone density 63, 68.
Type 2 diabetes is associated with hypertension in >70% of patients, and with cardiovascular diseases and obesity in >80% 69. Diabetes is independently associated with reduced lung function 70, 71, which, together with obesity, may further worsen the severity of COPD 41.
UNDERLYING MECHANISMS AND CONSEQUENCES FOR TREATMENT OF COMPLEX CHRONIC COMORBIDITIES
COPD can no longer be considered a disease only of the lungs 17, 18, 72. It is associated with a wide variety of systemic consequences, most notably systemic inflammation (fig. 1⇓). A better understanding of its origin, consequences and potential therapy will most likely prove to be of great relevance and lead to better care of patients with COPD. The origin of systemic inflammation in COPD is unresolved, although several potential mechanisms have been proposed 12.
The central role of inflammation in comorbidity is associated with chronic obstructive pulmonary disease (COPD). Inflammation appears to play a central role in the pathogenesis of COPD and other conditions that are increasingly being recognised as systemic inflammatory diseases. As part of the chronic inflammatory process, tumour necrosis factor (TNF)-α receptor polymorphisms are associated with increased severity of disease, possibly due to enhanced TNF-α effects. Also, C-reactive protein (CRP) levels can be increased directly by TNF-α and other cytokines. Elevated CRP and fibrinogen may be crucial in the pathogenesis of cardiovascular disease. Reactive oxygen species released as a result of COPD may enhance the likelihood of a patient developing cardiovascular disease, diabetes and osteoporosis. IL: interleukin; ?: unknown; +ve: positive.
Since smoking remains the major risk factor for the development of COPD and of the associated systemic inflammation 72, the study of the effects of smoking represents the best model for unravelling the underlying mechanisms of COPD and the consequences of systemic inflammation induced by smoking. In fact, cigarette smoke may cause systemic inflammation irrespective of COPD 73, and systemic inflammation in smokers may contribute significantly to the development of cardiovascular diseases, particularly atherosclerosis 74.
Smoking and acute exacerbations of COPD have a marked influence on redox status 75 by increasing levels of lipid peroxidation products and other markers 76. The increase in oxidative stress results in the inactivation of antiproteases, airspace epithelial damage, mucus hypersecretion, increased influx of neutrophils into lung tissue and the expression of pro-inflammatory mediators 77, 78. Inflammatory cells are also increased in peripheral blood, including neutrophils and lymphocytes 79. Furthermore, patients with COPD have increased numbers of neutrophils in the lungs, increased activation of neutrophils in peripheral blood and an increase in tumour necrosis factor (TNF)-α and soluble TNF receptor. Activated T-cells in emphysematous lungs predominantly express a T-helper cell type-1 phenotype and control the release of matrix metalloproteases via chemokines. Recent evidence, obtained through ex vivo experiments with T-cells from COPD patients, suggests that exposure to cigarette smoke induces secretion of proteolytic enzymes from cells of the innate immune system, which in turn liberate lung elastin fragments 80. In susceptible individuals, T- and B-cell-mediated immunity against elastin is initiated. Elastin is also abundant in tissues other than the lung, especially in arteries, arterioles and the skin; its fragments are chemotactic and cause pathology in mouse models of emphysema. These novel findings of anti-elastin autoimmunity in emphysema, together with earlier observations 81–84, suggest a broader, systemic autoimmune process involving the major elastin-bearing organs, such as the (coronary) vasculature and the skin.
To understand the relationship between pulmonary inflammation and systemic disease, common inflammatory pathways have been proposed 19. It is unclear why some patients with COPD have higher baseline concentrations of circulating inflammatory markers 85; whether this systemic inflammation is a primary or secondary phenomenon is a matter of debate. Some patients with COPD who exhibit increased resting energy expenditure and decreased fat-free mass have marked elevation of CRP and lipopolysaccharide-binding protein 86. Systemic inflammation may lead to a lack of response to nutritional supplementation 87, further contributing to the development of cachexia.
Systemic inflammation may also explain why patients with COPD have an increased risk of developing type 2 diabetes 88. Some aspects of inflammation can predict the development of diabetes and glucose disorders 89, 90, while fibrinogen, circulating white blood cell count and lower serum albumin predict the development of type 2 diabetes 89. Furthermore, patients with noninsulin-dependent diabetes mellitus have increased circulating levels of TNF-α, interleukin (IL)-6 and CRP 91, which are also risk factors for cardiovascular events in males and females 92, 93. Diabetes is independently associated with reduced lung function, which together with obesity could further worsen the severity of COPD 41. The complex interaction between smoking and obesity in the development of chronic comorbidities has been recently reviewed (fig. 2⇓) 46.
Schematic representation of how smoking might add to several mechanisms linking obesity to cardiovascular disease. Red arrows indicate an effect of smoking. HDL: high-density lipoprotein; TNF: tumour necrosis factor; ICAM: intercellular adhesion molecule; ROS: reactive oxygen species; IL: interleukin; CRP: C-reactive protein. Reproduced with permission from 46.
Patients with COPD have an increased risk of developing osteoporosis even in the absence of steroid use; vertebral fractures are present in ≤50% of steroid-naïve males with COPD 94. Post-menopausal osteoporosis is related to high serum levels of TNF-α and IL-6 95, and osteopenia found in COPD is also associated with an increase in circulating TNF-α 96. Increased levels of TNF-α (and IL-1) stimulate the differentiation of macrophages into osteoclasts via mesenchymal cells releasing receptor activator of nuclear factor-κB ligand, a member of the TNF-α superfamily 97.
The development of inflammatory processes associated with COPD is commonly believed to be initiated and maintained in the lung (parenchyma) 98 and to affect peripheral organs as the disease progresses. This concept is not proven and is probably rather naïvely related to the fact that the major risk factors for COPD enter the body by inhalation. To date, the limited data published on the contribution of the systemic circulation to the priming and activation of inflammatory cells in their transit through the pulmonary circulation 99, 100 have been negative, because the concentrations of inflammatory markers in induced sputum (presumably reflecting local inflammation) and plasma (reflecting systemic inflammation) in patients with moderate COPD are not correlated.
Alternatively, some of the nonpulmonary manifestations of COPD may occur early in the course of the disease and affect pulmonary inflammation. For example, inhibition of vascular endothelial growth factor (VEGF) receptors causes lung cell apoptosis and emphysema 101, 102. Furthermore, endothelial cell death and decreased expression of VEGF and the VEGF receptor KDR/FLK-1 occur in patients with smoking-induced emphysema 103. In summary, systemic oxidative stress 75 and the increased levels of pro-inflammatory cytokines could contribute to the pathogenesis of lung damage in COPD early in the course of the disease.
Tissue hypoxia is another mechanism that can contribute to systemic inflammation in COPD. In a recent clinical study 104 it was shown that TNF-α and receptor levels were significantly higher in patients with COPD, but were significantly correlated with the severity of arterial hypoxaemia. These results suggest that arterial hypoxaemia in COPD is associated with activation of the TNF-α system in vivo. If confirmed, this might indeed change the whole view on long-term oxygen therapy. Prolonged survival in patients receiving domiciliary oxygen therapy, as described many years ago 105, 106, might be attributable to an effect on systemic inflammation. This hypothesis could be tested in randomised trials.
Skeletal muscle itself can contribute to systemic inflammation. In particular, this has been demonstrated in patients with COPD during exercise 107, 108. Physical exercise specifically increases plasma TNF-α levels in COPD 109. TNF-α has a variety of effects that could lead to muscle wasting 110. TNF-α effects are mediated by the transcription factor nuclear factor (NF)-κB, which is normally inactive but can be activated by inflammatory cytokines such as TNF-α 96. Different mechanisms by which TNF-α could induce muscle loss have been described previously, including direct stimulation of protein loss, apoptosis of muscle cells and oxidative stress-induced alteration in TNF-α/NF-κB signalling 111. Inflammation and oxidative stress, characteristic of COPD 112, have synergistic effects on muscle breakdown 113.
Under conditions of nutritional imbalance, resting energy requirements are normally reduced 114. This is in contrast to the increased resting energy expenditure that is characteristic of some patients with COPD; the discrepancy is believed to be linked to systemic inflammation 86, 115. Increased oxygen consumption by respiratory muscles seems an incomplete explanation on its own 100, and as nutritional intake in stable disease is, on the whole, sufficient, generally accelerated loss of skeletal muscle in the context of a chronic inflammatory response is the most likely explanation 116. This loss of muscle is not specific to COPD but is generally found in states of cachexia with enhanced protein degradation 117 and poor responsiveness to nutritional interventions 118, 119; it also displays similarities to CHF, renal failure, AIDS and cancer.
Finally, bone marrow is an obvious site of production of systemic inflammation, although knowledge of its role in patients with COPD is sparse. Smoking causes leukocytosis with increased numbers of band cells, a higher content of myeloperoxidase and enhanced surface expression of l-selectin 73. Furthermore, these sequestrated polymorphonuclear leukocytes can be found in lung microvessels 120, supporting the concept that the bone marrow may directly contribute to smoking-induced lung inflammation.
MANAGEMENT OF COPD AS A COMPLEX DISEASE
Although textbooks 121 and guidelines have increasingly recognised the frequency and importance of comorbidities, particularly in the elderly, the fact that chronic diseases seldom occur in isolation is still largely ignore 4, 122, 123. Thus, clinicians treating chronic diseases lack definitions and a vocabulary to describe a syndrome that reflects real-life bedside medicine, not the medicines that have been taught 121. Recently, Fabbri and Rabe 124 suggested adding the term “chronic systemic inflammatory syndrome” to the diagnosis of COPD to reflect the complexity of the problem.
The diagnosis and assessment of severity of COPD may be greatly affected by the presence of a comorbid condition; therefore, lung function measurement, noninvasive assessment of left ventricular function (e.g. echocardiography and brain natriuretic peptide) and/or glycaemia, such as CRP serum levels, should be performed in these patients.
Considerations almost identical to those mentioned previously can obviously be applied to preventive and therapeutic interventions. Smoking prevention and cessation, weight control and diet, and exercise and rehabilitation all have the potential to beneficially affect all components of chronic disease.
Pharmacological treatment is more complex, as drugs are usually developed for single diseases or organs. However, glucose control with insulin or oral antidiabetic agents not only controls diabetes but also prevents systemic effects and comorbidities 123. Likewise, antihypertensive agents not only help control blood pressure but are also associated with dramatic prevention of coronary and cerebrovascular disease, with marked reduction of mortality 125. More recently, these agents have been found to have unexpected beneficial effects on COPD. Statins, which are used primarily as lipid-lowering agents in the treatment of metabolic syndrome, have potent anti-inflammatory properties that might positively affect comorbidities of metabolic syndrome, e.g. COPD, CHF and vascular diseases 126–128. However, on the negative side, β-blockers, which are considered to be life-saving drugs in CHF, might have some risks in COPD patients who have an asthmatic component 129. Furthermore, systemic steroids, which are required to treat COPD exacerbations 130, might negatively affect glucose control and cause osteoporosis and hypertension 131. Even drugs specifically developed and used to treat respiratory diseases, such as inhaled bronchodilators and steroids, may have significant beneficial effects on cardiovascular diseases 132, 133.
SINGLE-DISEASE VERSUS PATIENT-ORIENTED GUIDELINES FOR CHRONIC DISEASES
Clinical practice guidelines are being increasingly used as performance indicators, and have been shown to substantially improve the quality of clinical care. However, most guidelines ignore the fact that the majority of individuals with a chronic disease have one or more comorbidities.
COPD, CHF, peripheral artery disease, diabetes or nonlife-threatening cancer can have a major impact on individuals with a chronic disease, particularly the elderly 14. Therefore, it is evident that clinical practice guidelines, designed largely by specialty-dominated committees for managing single diseases, provide clinicians with little guidance in caring for patients with multiple chronic diseases. This lack of guidance frequently results in polypharmacia in these patients.
It is not only clinicians who will have to change their approach to treating chronic diseases; it is also the healthcare system in general that must rise to this major challenge.
Statement of interest
The study was supported by the Associazione per la Ricerca e la Cura dell'Asma (Padua, Italy) and the Consorzio Ferrara Ricerche, Associazione per lo Studio de tumouri e delle Malattie Polmonari.
Acknowledgments
The authors would like to thank M. McKenney (Menominee, MI, USA) for scientific assistance with the manuscript, and E. Veratelli (University of Modena and Reggio Emilia, Modena, Italy) for scientific secretarial assistance.
Footnotes
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Previous articles in this series: No. 1: Viegi G, Pistelli F, Sherrill DL, Maio S, Baldacci S, Carrozzi L. Definition, epidemiology and natural history of COPD. Eur Respir J 2007; 30: 993–1013.
- Received August 31, 2007.
- Accepted September 11, 2007.
- © ERS Journals Ltd
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