Chronic Obstructive Pulmonary Disease with Lung Cancer and/or Cardiovascular Disease

Transcription

1 Chronic Obstructive Pulmonary Disease with Lung Cancer and/or Cardiovascular Disease Roberto Rodríguez-Roisin 1 and Joan B. Soriano 2 1 Servei de Pneumologia (Institut del Tòrax), Hospital Clínic, Institut d Investigacions Biomédiques August Pi i Sunyer (IDIBAPS), Universitat de Barcelona, Barcelona, Spain; and 2 Program of Epidemiology and Clinical Research, Fundació Caubet-CIMERA Illes Balears, International Centre for Advanced Respiratory Medicine, and Ciber Enfermedades Respiratorias, Palma de Mallorca, Spain Chronic obstructive pulmonary disease (COPD) has been identified as an enormous growing worldwide health problem associated with long-term exposure to toxic gases and particles, most often related to cigarette smoking, heavily challenging our current millennium. The present article briefly reviews the evidence of the causes of death in COPD, while focusing on the impact of two of their most common and characteristic systemic effects, also named comorbidities namely, lung cancer and cardiovascular disease and drawing the attention to a new field of growing interest, namely the metabolic syndrome, and its potential interplay with the natural course of COPD. A comorbidity is defined as one or more distinct disorders (or diseases) in addition to COPD, regardless of whether this condition is or is not directly related to COPD, and irrespective of whether it is or is not part of the spectrum of the natural history of COPD. Keywords: airflow limitation; chronic systemic inflammatory disorder; comorbidities; obesity; systemic inflammation Over the past 10 years, a considerable effort has been made to increase awareness of all facets regarding chronic obstructive pulmonary disease (COPD). Several international initiatives such as the Global Initiative for Chronic Obstructive Lung Disease (GOLD) (1, 2), sponsored by public and scientific institutions all over the world, among other international contributions (including those of the American Thoracic Society [ATS], the European Respiratory Society [ERS] [3], and the Latin American Thoracic Association [ALAT] in conjunction with the Spanish Thoracic Society [SEPAR] [4]), and other national scientific societies (such as the National Institute for Clinical Excellence [NICE] [5]), have developed major concerted efforts along these premises. COPD has been identified as a rapidly growing worldwide health problem associated with long-term exposure to toxic gases and particles, most often related to cigarette smoking, heavily challenging our past and current millenniums. Greater public awareness of COPD is the main aim of all these initiatives to decrease both mortality and morbidity from COPD by providing to healthcare workers, healthcare authorities, and the general public specific recommendations on the most appropriate management and preventive strategies. GOLD has defined COPD 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 (Received in original form July 31, 2008; accepted in final form September 10, 2008) R.R.-R. is supported by the CibeRes (CB06/06), the Generalitat de Catalunya (2005SGR-00822), and a grant-in-aid by Esteve. Correspondence and requests for reprints should be addressed to R. Rodriguez- Roisin M.D., Servei de Pneumologia, Hospital Clínic, Villarroel, 170, Barcelona, Spain. rororo@clinic.ub.es Proc Am Thorac Soc Vol 5. pp , 2008 DOI: /pats TH Internet address: usually progressive and associated with an abnormal inflammatory response of the lung to noxious particles or gases. (2) This article reviews the available evidence on the causes of death in COPD, focusing on the impact of two of its most characteristic systemic effects (6) lung cancer and cardiovascular disease and draws attention to a new field of emerging interest: the metabolic syndrome, and its potential interplay with the natural history of COPD (7). MORTALITY COPD is a common, costly, and preventable disease that has substantial implications for the health of humanity. The term COPD is used in a variety of ways when it is judged to be a contributing factor to, but not the main cause of, death in death certificates, leading to misclassification and omission from medical records and life statistics. Therefore, mortality data from patients with COPD should always be interpreted with caution. In contrast to asthma, the diagnostic term COPD has not been widely used by physicians or other health professionals and is generally not recognized by the public. When questioned about their condition, most patients with COPD will say that they have asthma, chronic bronchitis, pulmonary emphysema, or that the disease is unrecognized. A prerequisite for diagnosis is the confirmation of airflow limitation by spirometry, preferably after bronchodilator (8). However, in many areas primary care physicians and practitioners rarely use routine spirometry to detect and confirm COPD in regular smokers or patients with respiratory symptoms (9). Worldwide, recent increases in COPD deaths are likely to continue. The Global Burden of Disease Study (10, 11) has projected COPD mortality rates from 1990 to 2020 and estimates that COPD will account for over 6 million deaths per year in 2020, which will move COPD from the sixth to the third leading cause of death worldwide over this period. COPD mortality trends generally track several decades behind smoking trends. Trends in age-standardized death rates for the six leading causes of death in the United States from 1970 to 2002 indicate that COPD mortality increased as compared with the decreased mortality from several of these chronic conditions over that period (12). A recent analysis of mortality trends in the United States from 1979 to 1993 showed that among 31 million death certificates, 8% had a diagnosis of obstructive lung disease (OLD). However, only 43% of the death certificates listing OLD had defined it as the primary underlying disease. Death rates for COPD in Canada, in both men and women, have also been increasing since In Europe, however, the trends are different, with decreasing mortality from COPD already being seen in many countries (13). In 1990, the WHO estimated the standardized mortality rate of COPD to be 50 per 100,000 in males and 20 per 100,000 in females in European countries. Thus, approximately 200,000 to 300,000 people die each year in Europe because of COPD. According to the WHO, in 1997, COPD was the cause of death in 4.1% of

2 Rodríguez-Roisin and Soriano: COPD, Lung Cancer, and Heart Disease 843 males and 2.4% of females in Europe. There has been a striking increase in the mortality trends for COPD among females (14). There is no obvious reason for the difference between trends in mortality rates over time in both North America and Europe, although presumably factors such as awareness, changing terminology, and diagnostic and potential sex biases contribute to these differences. Another plausible explanation for current increased mortality in women is the fact that the actual prevalence of smoking in the 1950s and 1960s was lower than in men.the overall mortality from COPD will probably also increase in Europe due to the increased proportion of females who smoke, as well as the aging of the population. The WHO has also made worldwide estimates of mortality rates for COPD. They estimated that age-specific mortality rates for COPD were considerably higher in China than in countries with established market economies. The death rates for COPD in China were also higher than in six other global health regions featuring countries with formerly socialist economies: Sub- Saharan Africa, India, Latin America and the Caribbean, the Middle East, and other Asian countries. In low-income and middle-income countries, the estimated age-stratified death rates for chronic diseases namely, cardiovascular disorders, cancer, chronic respiratory diseases, and diabetes in 2005 were 54% higher for men and 86% higher for women than those for the same respective sexes in high-income countries (15). In low-income and middle-income countries, the population growth and aging will lead to a substantial increased number of deaths for chronic diseases globally, with a projection of an 18% increase between 2006 and It is remarkable that over a short period of time there has been a substantial decline in death rates for the major causes of death in most European countries, but not for COPD. In contrast to cardiovascular mortality rates, it appears that COPD rates are relatively insensitive to intermittent or short-term smoking cessation (16, 17). COPD, THE SILENT KILLER To determine the specific cause of death in a patient with COPD is a challenge, even by experienced clinicians and when death occurs in in-patients. It is often agreed that patients die with COPD rather than of COPD. Perhaps the first comprehensive description on specific causes of death in COPD was conducted in the 1990s, when Zielinski and coworkers (18) from a panel established by the WHO reviewed deaths in a multicentric study of patients with COPD. At that time, despite the high global death toll already, little was known about the causes or circumstances of death in COPD. They collected data from 215 patients with severe COPD with chronic respiratory failure (Pa O2, 60 mm Hg) who died after treatment with long-term oxygen therapy. Three-quarters of patients died in the hospital. In this very sick group of patients with COPD, respiratory failure was the leading cause of death, but overall accounted for only a third of the total number of deaths. Cardiovascular causes, pulmonary infection, pulmonary embolism, lung cancer, and other cancers accounted for the remaining two-thirds of the deaths, reinforcing the likely importance of comorbidities in COPD-related mortality. Over the last 4 years, several reports, all with different designs and targets, investigated patients with COPD at diverse stages of severity and contributed with interesting, relevant data on all-cause mortality in COPD. Celli and colleagues (19) developed a multidimensional grading system to assess the respiratory and systemic components of COPD to better categorize and predict outcomes in these patients. They evaluated 207 patients and observed that the body-mass index (B), the degree of airflow obstruction (O), dyspnea (D), and exercise capacity (E, measured by the 6-minute-walking test) predicted the risk of death, and then used these four descriptors to construct the BODE index, a multidimensional 10-point scale in which higher scores indicate a higher risk of death. Afterward they prospectively validated this index in a population of 625 patients, with death from any cause and from respiratory causes as the outcome variables. There were 162 deaths (26%) over a median follow-up of 28 months (range, 4 68), of which the majority of patients (61%) died of respiratory failure, 14% died of myocardial infarction, 12% of lung cancer, and the remaining 13% of miscellaneous causes. While patients with higher BODE scores were at higher risk for death, the BODE index was better than the FEV 1 at predicting the risk of death from any cause and from respiratory causes among patients with COPD. The second study, by Anthonisen and coworkers (16), part of the original Lung Health Study (LHS) (20), was designed to target all-cause mortality benefit of smoking cessation and to assess the long-term effect on mortality of a randomly applied smoking cessation program. This was a multicentric, randomized clinical trial of smoking cessation, with a follow-up to 14.5 years, in which intervention participants were under the smoking interventional program and compared with a usual care cohort of subjects. All-cause mortality and mortality due to cardiovascular disease, lung cancer, and other respiratory disease was assessed in 5,887 middle-aged volunteers with asymptomatic airflow limitation. The intervention was a 10-week smoking cessation program that included a strong physician message and 12 group sessions using behavior modification and nicotine gum, plus either a short-acting anticholinergic bronchodilator or a placebo. At 5 years, 22% of intervention subjects had stopped smoking since study entry compared with 5% of usual care participants. After approximately 15 years of follow-up, 731 patients died of different causes. Lung cancer was the most common cause of death (33%), while coronary heart disease accounted for 77 deaths (11%) and cardiovascular disease, including coronary heart disease, accounted for 163 deaths (22%). One hundred fifty-four participants (21%) died of cancer of organs other than the lung. Deaths due to respiratory disease other than cancer were relatively uncommon (8%) (Figure 1). All-cause mortality was significantly lower in the intervention cohort than in the usual care group (9 per 1,000 person-years versus 10 per 1,000 person-years; P ). The hazard ratio for mortality in the usual care group compared with the special intervention group was 1.18 (95% confidence interval [CI], ). Differences in death rates for both lung cancer and cardiovascular disease were greater when death rates were analyzed by smoking habit. Mortality did not significantly differ Figure 1. Specific causes of death in approximately 6,000 participants, mostly with mild-to-moderate airflow limitation, from the Lung Health Study. (Data from Reference 16.)

3 844 PROCEEDINGS OF THE AMERICAN THORACIC SOCIETY VOL between the special intervention groups originally assigned to bronchodilator or placebo. The third study, known as the TORCH (Toward a Revoluion in COPD Health) trial (21), was a randomized, double-blind trial that compared a long-acting b-agonist (salmeterol) plus an inhaled glucococorticosteroid (fluticasone propionate) (combination therapy), with placebo, salmeterol alone, or fluticasone propionate alone for a period of 3 years. The primary outcome was death from any cause for the comparison between the combination inhaler and placebo; the frequency of exacerbations, health status, and spirometry were secondary variables. Out of a total of 6,112 individuals in the intervention arm, 875 died within 3 years after the start of the trial. All-cause mortality rates were similar in the four interventional arms. The hazard ratio for death in the combination-therapy subset, as compared with the placebo one, was 0.83 (95% CI, ; adjusted P ), and corresponded to a difference of 2.6% points or a relative reduction in the risk of death of 17.5%. Overall, 35% of the deaths were of cardiovascular causes, 27% were due to pulmonary problems, and 21% were due to cancer. Despite the different designs of these studies, and the different severity of airflow limitation in the participants of the three studies mentioned above to fulfill their specific goals, it is worth noting the close similarity of the results regarding causes of death in all of them, with cardiovascular disease and lung cancer heading up the list of mortality. Interestingly, the latter two causes of death are also envisaged as extrapulmonary or systemic manifestations of COPD, also named comorbidities. Perhaps, by pooling all this information together, it appears that the predominant causes of death in patients with COPD vary as a function of the underlying severity of airflow obstruction (22) (Figure 2). The lower the FEV 1, the more frequent is respiratory insufficiency as a cause of death in COPD. Alternatively, lung cancer is the most frequent cause of death in milder COPD, while its relative importance decreases with disease progression. Meanwhile, cardiovascular deaths appear to account for 20 to 25% of all causes of deaths throughout all COPD stages. It is worth noting the apparent paradox of the low percentage of total deaths at the most severe COPD stage, as it should be expected that as COPD becomes more severe, the grade of systemic inflammatory mediators is more elevated, hence possibly implying more intense systemic inflammation and more severe cardiovascular disease (23). This finding may simply indicate the inherent difficulties in accurately differentiating between various causes of death in COPD populations. COMORBIDITIES AND COPD There is no general consensus concerning the definition of comorbidity, and its definition is not universally accepted. Traditionally, a comorbid condition has been defined as a state or disease coexisting with the primary disease of interest, a definition that has been repeatedly modified or overlooked, as several coexisting diseases may be a consequence of the patients underlying COPD (24). For the purposes of this paper, we use as a definition of comorbidity the presence of one or more distinct disorders (or diseases) in addition to COPD, regardless of whether the comorbid conditions are or are not directly related to, or caused by COPD, and irrespective of whether they are or are not part of the spectrum of the natural history of COPD. Implicit in the approach to the definition of comorbidity is the assumption that the coexisting disease state is pathophysiologically related to the index disease or represents a disease-specific complication, although this only accounts for part of the comorbid conditions (25). Within this definition framework, cardiovascular disease and lung cancer are considered comorbidities of COPD. In the most recent COPD definition by GOLD (2) it is stated that:...symptoms, functional abnormalities and complications of COPD can partly be explained on the basis of this underlying inflammation of the lungs and the resulting pathology. These changes may also have significant extra-pulmonary or systemic consequences contributing to the severity in each individual patient... In COPD, the definition becomes even more controversial as these comorbid conditions are regular features of general practice, some being an indirect consequence of COPD and arising independently but more likely to occur when COPD is present (i.e., ischemic heart disease, lung carcinoma, and osteoporosis) (Table 1) (26). Other comorbidities may coexist with COPD because they become prevalent as part of the aging process, such as rheumatic disorders or diabetes mellitus, or due to smoking or other exposures. The management of comorbidities is difficult in the presence of COPD because all of them amplify the disability associated with COPD and can potentially complicate its management. Comorbid conditions in patients with COPD are very common; at least one comorbidity can be present in 84% of patients, and can influence the observed TABLE 1. PATHOGENIC CLASSIFICATION OF SYSTEMIC EFFECTS OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE Figure 2. Specific causes of death classified according to airflow limitation severity in patients with chronic obstructive pulmonary disease. (Adapted by permission from Reference 22.) EFRAM, BODE, ISOLDE and LHS-3 denote different clinical trials or studies. CVD 5 cardiovascular disease; EFRAM 5 Risk Factors of COPD Exacerbation Study; ISOLDE 5 Inhaled Steroids in Obstructive lung Disease in Europe; LHS 5 Lung Health Study; for other abbreviations, see text). Systemic inflammation Oxidative stress Activated inflammatory cells (neutrophils/lymphocytes) Increased plasma levels of cytokines and acute phase proteins Nutritional abnormalities and weight loss Increased resting energy expenditure Abnormal body composition Abnormal amino acid metabolism Skeletal muscle dysfunction Loss of muscle mass Abnormal structure/function Exercise limitation Other potential systemic effects Cardiovascular effects Nervous system effects Osteoskeletal effects Reprinted by permission from Reference 26.

4 Rodríguez-Roisin and Soriano: COPD, Lung Cancer, and Heart Disease 845 pattern of deterioration of health-related quality of life with worsening of disease (27). Furthermore, quality of life is moderately to strongly associated with worse COPD stage (27). However, evidence-based diagnostic and treatment guidelines overlook comorbid conditions (25). LUNG CANCER COPD is an independent risk factor for lung cancer, while chronic bronchitis and/or emphysema increase lung cancer incidence risk by two- to fivefold as compared with smokers with normal spirometry (28). There was a negative correlation between the degree of airflow limitation and lung cancer risk in a follow-up study over 22 years from 5,402 participants from the first National Health and Nutrition Examination Survey (NHANES I), which included a total of 113 cases of lung cancer (29). There is emerging evidence that chronic inflammation may play a significant role in the pathogenesis of lung cancer as a tumor promoter. This is supported by several reports showing that chronic inflammation has a relevant role in triggering cancer. Examples include inflammatory bowel disease and colon cancer, or chronic hepatic disorder including liver carcinoma. Cigarette smoke up-regulates experimentally the production of cytokines, such as interleukin (IL)-1b, and the Th-1 cytokines, which increase cyclooxygenase (COX)-2 enzymatic activity and can promote an inflammatory response through lymphocytes, resulting in an overproduction of cytokines, such as IL-6, IL-8, and IL- 10. Some of the latter mediators can inhibit apoptosis, interfere with cellular repair, and promote angiogenesis. All in all, chronic inflammation may play a pathogenic role in lung cancer by amplifying the initial mutagenic damage and enhancing both tumor growth and metastasis. IL-8, for example, has been shown to be pro-oncogenic, such as releasing BCL-2, but also suppresses oncogenes, such as p53, hence minimizing apoptosis while inducing cell transformation. These cytokines also create a proangiogenic milieu promoting tumor growth and have also been related potentially to the natural history of COPD. Similarly, there is a clear interaction between COPD and lung cancer irrespective of active smoking (30). After quitting smoking, lung cancer risk remains increased in patients with COPD, though this risk is superior in those who continue to smoke (31). Even in individuals who never smoked, a direct association is observed of lung cancer with decreasing lung function and COPD (32). It has been suggested that the link between FEV 1 decline and lung cancer is chronic airway inflammation, present in the airways of patients with COPD many years after smoking cessation (33 35). From a molecular viewpoint, activation of nuclear factor kappa B (NF-kB) transcription factor may have major relevance for cancer and COPD. Although the precise role of NF-kB in COPD remains unsettled, chronic airway inflammation in COPD has been associated with activation of NF-kB in alveolar macrophages and epithelial cells. Furthermore, it has been suggested that the synergistic effects of latent infection and cigarette smoking produce chronic airway inflammation through enhanced expression of cytokines and adhesion molecules, possibly through NF-kB mediated activation. Links between NF-kB and lung cancer have also been reported, including resistance to chemotherapy and regulation of pro-metastatic, pro-angiogenic, and anti-apoptotic genes (36). CARDIOVASCULAR DISEASE There is strong epidemiologic evidence to conclude that reduced FEV 1, independent of cigarette smoking, cholesterol and hypertension, is a marker for cardiovascular morbidity and mortality (22). The earliest reports come from the Framingham cohort studies more than 40 years ago, where cardiologists noted that forced spirometry was a better predictor of 10-year mortality, both cardiovascular and total, than any of the usual cardiovascular risk factors (37). Cardiovascular disease rates have been shown to be increased in patients with COPD. A recent retrospective cohort study in longitudinal health care databases of Saskatchewan, Canada (38), reported increased risks (odds ratios) of the following conditions when patients with COPD (n 5 11,493) were compared with matched population controls: arrhythmia 1.76, angina 1.61, acute myocardial infarction 1.61, congestive heart failure 3.84, and stroke Ischemic heart disease is characterized by atherosclerosis of coronary arteries. In these vessels there is endothelial dysfunction and an inflammatory process in the atheroma plaque with presence of macrophages, T cells, and increased proinflammatory cytokines and C-reactive protein (39). It is remarkable to observe the similarities of cardiac inflammation with lung inflammation. Cardiac failure has been found in about 20% of patients with COPD (40), and it has been related to possible coronary atherosclerosis. Often cardiac failure is difficult to diagnose in chronic respiratory patients due to the nonspecificity of symptoms. Rutten and colleagues (41) have suggested a score that combines clinical, electrocardiogram, and serum N-terminal fragment of brain-type natriuretic peptide (NTpro-BNP) to predict the probability to detect left ventricular failure. Moreover, the risk of hospitalization and mortality due to cardiovascular causes is increased in patients with COPD about 2.0- and 2.8-fold, respectively (42). In the Lung Health Study (20), cardiovascular causes accounted for 42% of first hospitalizations and 44% of second hospitalizations in these patients with relatively mild COPD, higher than for respiratory causes (14%). It is of note, however, that the underlying mechanisms linking COPD and cardiovascular disease are not fully understood. Cigarette smoking is a common risk factor of both diseases, but several pieces of evidence established that the association between COPD and cardiovascular diseases remains independent of established risk factors (43). Several investigators suggest the potential role of systemic inflammation in COPD to explain the increased incidence of cardiovascular morbidity (44). Both systemic inflammation and endothelial dysfunction are key mechanisms for atherosclerosis, and patients suffering from conditions associated with systemic inflammation should have an excess risk of cardiovascular morbidity and mortality (45). Given that systemic inflammation is a common feature in patients with COPD, even in mild-tomoderate stages, COPD may contribute to increased cardiovascular morbidity and mortality. Of vital importance to the clinical management of patients with COPD with comorbidities is the fact that some of the nonrespiratory therapies can modulate or modify COPD or worsen abruptly the stable condition of the disease, even mimicking a COPD exacerbation. Moreover, the use and abuse of respiratory medications can have interactions and potential contraindications in patients with COPD with coexisting cardiovascular or other conditions (Table 2) (22). CHRONIC SYSTEMIC INFLAMMATORY SYNDROME Fabbri and Rabe have provocatively proposed a more comprehensive approach to diagnosis, assessment of severity, and management of COPD and its comorbidities (7). They propose that in patients who develop clinical and functional COPD disturbances, the diagnostic approach to COPD should be linked to the search for signs of a more general disorder, to be named

5 846 PROCEEDINGS OF THE AMERICAN THORACIC SOCIETY VOL TABLE 2. POTENTIAL INTERACTIONS AND CONTRAINDICATIONS IN THE MANAGEMENT AND TREATMENT OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE Interactions of Comorbidity Treatment with COPD Beta-Blockers Hypnotics Statins Angiotensin converting enzyme (ACE) inhibitors and angiotensin receptor antagonists (ARA) Antibiotics Reprinted by permission from Reference 24. Interactions of COPD Treatments with Comorbidities Beta-agonists Anticholinergics Methylxanthines Glucocorticosteroids Pulmonary Rehabilitation chronic systemic inflammatory syndrome. The term chronic refers to the slow and progressive development of the underlying abnormalities, systemic to the fact that risk factors act directly or indirectly on all target organs simultaneously, inflammatory to the association of all components with inflammation, and syndrome to the association of several clinically recognizable clinical traits that generally arise together, so that the presence of one feature alerts the practitioner to the presence of the others. According to these investigators, the diagnosis of chronic systemic inflammatory syndrome could be established on the basis of at least three of the six following components: age older than 40 years; smoking for more than 10 pack-years; symptoms and abnormal lung function compatible with COPD; chronic heart failure; metabolic syndrome; and, increased C-reactive protein. The three cardinal criteria (COPD, chronic heart failure, and metabolic syndrome) have to be diagnosed according to current international guidelines (2, 46, 47) after thorough assessment of respiratory, heart, and metabolic functions. Other comorbidities, such as coronary and peripheral artery diseases, anemia, osteoporosis, and rheumatoid disorders, could be included either as additional comorbidities, as long-term complications of therapy, or as independent modifiers of severity of the chronic syndrome. Severity of the chronic systemic inflammatory syndrome should be assessed by combination of these six criteria. Indeed, the present approach of defining severity of COPD by spirometry has obvious limitations in the context of the coexistence of chronic heart failure, diabetes, or other chronic disease states. The key issue supporting the introduction of this new term of chronic systemic inflammatory syndrome is to highlight the relevance of common risk factors (e.g., smoking, obesity, hypertension) in the development not only of COPD, chronic heart failure, or metabolic syndrome, but also of systemic and complex abnormalities affecting other organs, in which smoking plays a major role or by interaction of major risk factors. The difficult interplay between smoking and obesity, the latter viewed by many experts as one of the most devastating outbreaks of our current century, in the development of chronic comorbidities has been raised over the last two years (48). Obesity increases the risk of cardiovascular disorders and reduces life expectancy. Adipose tissue releases a large battery of bioactive mediators, such as high-density lipoprotein, tumor necrosis factor, intercellular adhesion molecules, reactive oxygen species, IL, and C-reactive protein (48). Altogether these mediators influentially orchestrate body weight homeostasis; insulin resistance, the core trait of type 2 diabetes (49); and disturbances in lipids, blood pressure, coagulation, fibrinolysis, and systemic inflammation, with consequences on endothelial dysfunction and atheroseclerosis (50). These interactions are of particular interest and contrast with the finding that some patients with COPD, who have increased energy expenditure and reduced fat-free mass, associate high levels of C-reactive protein (51). Systemic inflammation may then lead to a lack of response to nutritional supplementation (52), hence contributing to underweight and cachexia (53). Such an implementation could be feasible. The proposal to search for the most frequent comorbid conditions of COPD may be of great help to remind to clinicians of the complexity of the effects of smoking and its interplay with COPD and comorbidities. Recently, the same authors have hypothesized on the mechanistic pathways, and even the inflammatory markers involved, linked with several COPD comorbidities in general, and with the metabolic syndrome in particular (54). CONCLUSIONS All in all, COPD is a common, costly, and preventable disease that has substantial implications for the health of human beings. Lung cancer and cardiovascular disease are common causes of death in the natural course of COPD, being influenced by the severity of airflow limitation. These causes of death are also viewed as comorbid conditions frequently coexisting with and deleteriously modulating COPD clinical evolution. The potential introduction of the new term chronic systemic inflammatory syndrome points to the relevance of common risk factors in the development not only of COPD, chronic heart failure, or metabolic syndrome, but also of complex systemic disturbances affecting other organs, all possibly reflecting the vital role played by systemic inflammation. The search for the most frequent comorbidities of COPD may be instrumental and of great help to improve our understanding of the complexities of the interplay between smoking habits, COPD, and comorbidities. This will ultimately improve our combat against COPD and its spectrum of major risk factors. Conflict of Interest Statement: R.R.-R. has participated as a lecturer and speaker in scientific meetings and courses under the sponsorship of Almirall, Boehringer Ingelheim (BI), Chiesi, GlaxoSmithKline (GSK), Kyorin, Novartis, and Pfizer. He has consulted with several pharmaceutical companies (Altana/Nycomed, BI, GSK, Novartis, and Pfizer). He serves on Advisory Boards for Almirall, BI, GSK, Novartis, Pfizer, and Procter & Gamble. He has been sponsored for several clinical trials by, and received laboratory research support from, Almirall, AstraZeneca, BI, GSK, Esteve, and Pfizer. J.B.S. has participated as a lecturer, and speaker in scientific meetings and courses under the sponsorship of Almirall, AstraZeneca, GSK, and Otsuka. References 1. Pauwels RA, Buist AS, Calverley PM, Jenkins CR, Hurd SS; GOLD Scientific Committee. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease. NHLBI/WHO Global Initiative for Chronic Obstructive Lung Disease (GOLD) Workshop summary. Am J Respir Crit Care Med 2001;163: Rabe KF, Hurd S, Anzueto A, Barnes PJ, Buist SA, Calverley P, Fukuchi Y, Jenkins C, Rodriguez-Roisin R, van Weel C, et al. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: GOLD Executive Summary. Am J Respir Crit Care Med 2007;176: Celli BR, MacNee W. Standards for the diagnosis and treatment of patients with COPD: a summary of the ATS/ERS position paper. Eur Respir J 2004;23: Peces-Barba G, Barberà JA, Agustí A, Casanova C, Casas A, Izquierdo JL, Jardim J, López Varela V, Monsó E, Montemayor T, et al. (Diagnosis and management of chronic obstructive pulmonary disease: joint guidelines of the Spanish Society of Pulmonology and Thoracic Surgery (SEPAR) and the Latin American Thoracic Society (ALAT)). Arch Bronconeumol 2008;44: [in Spanish] 5. National Institute for Clinical Excellence (NICE). Chronic obstructive pulmonary disease: national clinical guideline for management of chronic obstructive pulmonary disease in adults in primary and secondary care. Thorax 2004;59: Agusti A. Thomas A. Neff lecture. Chronic obstructive pulmonary disease: a systemic disease. Proc Am Thorac Soc 2006;3: Fabbri LM, Rabe KF. From COPD to chronic systemic inflammatory syndrome? Lancet 2007;370: Sterk PJ. Let s not forget: the GOLD criteria for COPD are based on post-bronchodilator FEV1. Eur Respir J 2004;23:

6 Rodríguez-Roisin and Soriano: COPD, Lung Cancer, and Heart Disease Rennard S, Decramer M, Calverley PM, Pride NB, Soriano JB, Vermeire PA, et al. Impact of COPD in North America and Europe in 2000: subjects perspective of Confronting COPD International Survey. Eur Respir J 2002;20: Lopez AD, Shibuya K, Rao C, Mathers CD, Hansell AL, Held LS, Schmid V, Buist S. Chronic obstructive pulmonary disease: current burden and future projections. Eur Respir J 2006;27: Murray CJ, Lopez AD. Global mortality, disability, and the contribution of risk factors: Global Burden of Disease Study. Lancet 1997;349: Jemal A, Ward E, Hao Y, Thun M. Trends in the leading causes of death in the United States, JAMA 2005;294: Chapman KR, Mannino DM, Soriano JB, Vermeire PA, Buist AS, Thun MJ, Connell C, Jemal A, Lee TA, Miravitlles M, et al. Epidemiology and costs of chronic obstructive pulmonary disease. Eur Respir J 2006; 27: Chapman KR. Chronic obstructive pulmonary disease: are women more susceptible than men? Clin Chest Med 2004;25: Abegunde DO, Mathers CD, Adam T, Ortegon M, Strong K. The burden and costs of chronic diseases in low-income and middleincome countries. Lancet 2007;370: Anthonisen NR, Skeans MA, Wise RA, Manfreda J, Kanner RE, Connett JE. The effects of a smoking cessation intervention on 14.5-year mortality: a randomized clinical trial. Ann Intern Med 2005;142: European Respiratory Society/European Lung Foundation. European Lung White Book. The first comprehensive survey on respiratory health in Europe,1sted.Sheffield,UK:EuropeanRespiratorySocietyJournals; Zielinski J, MacNee W, Wedzicha J, Ambrosino N, Braghiroli A, Dolensky J, Howard P, Gorzelak K, Lahdensuo A, Strom K, et al. Causes of death in patients with COPD and chronic respiratory failure. Monaldi Arch Chest Dis 1997;52: Celli BR, Cote CG, Marin JM, Casanova C, Montes de OM, Mendez RA, Pinto Plata V, Cabral HJ. The body-mass index, airflow obstruction, dyspnea, and exercise capacity index in chronic obstructive pulmonary disease. NEnglJMed2004;350: Anthonisen NR, Connett JE, Kiley JP, Altose MD, Bailey WC, Buist AS, Conway WA Jr, Enright PL, Kanner RE, O Hara P, et al. Effects of smoking intervention and the use of an inhaled anticholinergic bronchodilator on the rate of decline of FEV1. The Lung Health Study. JAMA 1994;272: Calverley PM, Anderson JA, Celli B, Ferguson GT, Jenkins C, Jones PW, Yates JC, Vestbo J; TORCH Investigators. Salmeterol and fluticasone propionate and survival in chronic obstructive pulmonary disease. N Engl J Med 2007;356: Sin DD, Anthonisen NR, Soriano JB, Agusti AG. Mortality in COPD: role of comorbidities. Eur Respir J 2006;28: Gan WQ, Man SF, Senthilselvan A, Sin DD. Association between chronic obstructive pulmonary disease and systemic inflammation: a systematic review and a meta-analysis. Thorax 2004;59: Soriano JB, Sauleda J. How the COPD patient should be assessed for comorbidities. In: Rennard SI, Rodríguez-Roisin R, Huchon G, Roche N, editors. Clinical management of chronic obstructive pulmonary disease, 2nd ed. New York: Informa Healthcare; pp van Weel C, Schellevis FG. Comorbidity and guidelines: conflicting interests. Lancet 2006;367: Agusti AGN, Noguera A, Sauleda J, Sala E, Pons J, Busquets X. Systemic effects of chronic obstructive pulmonary disease. Eur Respir J 2003;21: Ferrer M, Alonso J, Morera J, Marrades RM, Khalaf A, Aguar MC, Plaza V, Prieto L, Antó JM. Chronic obstructive pulmonary disease stage and health-related quality of life. The Quality of Life of Chronic Obstructive Pulmonary Disease Study Group. Ann Intern Med 1997; 127: Sherman CB. Health effects of cigarette smoking. Clin Chest Med 1991;12: Mannino DM, Aguayo SM, Petty TL, Redd SC. Low lung function and incident lung cancer in the United States: data from the First National Health and Nutrition Examination Survey follow-up. Arch Intern Med 2003;163: Jacobs DR Jr, Adachi H, Mulder I, Kromhout D, Menotti A, Nissinen A, Blackburn H. Cigarette smoking and mortality risk: twenty-fiveyear follow-up of the Seven Countries Study. Arch Intern Med 1999; 159: Pride NB, Soriano JB. Chronic obstructive pulmonary disease in the UK: trends in mortality, morbidity, and smoking. Curr Opin Pulm Med 2002;8: Turner MC, Chen Y, Krewski D, Calle EE, Thun MJ. Chronic obstructive pulmonarydiseaseisassociatedwithlungcancermortalityinaprospective study of never smokers. Am J Respir Crit Care Med 2007;176: Lapperre TS, Postma DS, Gosman MM, Snoeck-Stroband JB, ten Hacken NH, Hiemstra PS, Timens W, Sterck PJ, Mauad T. Relation between duration of smoking cessation and bronchial inflammation in COPD. Thorax 2006;61: Hogg JC, Chu F, Utokaparch S, Woods R, Elliott WM, Buzatu L, Cherniack RM, Rogers RM, Sciurba FC, Coxson HO, et al. The nature of small-airway obstruction in chronic obstructive pulmonary disease. N Engl J Med 2004;350: Brody JS, Spira A. Chronic obstructive pulmonary disease, inflammation, and lung cancer [State of the Art]. Proc Am Thorac Soc 2006;3: Dennis PA, Van WC, Gutkind JS, Kellar KJ, Vinson C, Mukhin AG, Spitz MR, Bailey-Wilson JE, Yeh GC, Anderson LM, et al. The biology of tobacco and nicotine: bench to bedside. Cancer Epidemiol Biomarkers Prev 2005;14: Ashley F, Kannel WB, Sorlie PD, Masson R. Pulmonary function: relation to aging, cigarette habit, and mortality. Ann Intern Med 1975;82: Curkendall SM, DeLuise C, Jones JK, Lanes S, Stang MR, Goehring E Jr, She D. Cardiovascular disease in patients with chronic obstructive pulmonary disease, Saskatchewan Canada cardiovascular disease in COPD patients. Ann Epidemiol 2006;16: Buffon A, Biasucci LM, Liuzzo G, D Onofrio G, Crea F, Maseri A. Widespread coronary inflammation in unstable angina. N Engl J Med 2002;347: Rutten FH, Cramer MJ, Lammers JW, Grobbee DE, Hoes AW. Heart failure and chronic obstructive pulmonary disease: an ignored combination? Eur J Heart Fail 2006;8: Rutten FH, Moons KG, Cramer MJ, Grobbee DE, Zuithoff NP, Lammers JW, et al. Recognising heart failure in elderly patients with stable chronic obstructive pulmonary disease in primary care: cross sectional diagnostic study. BMJ 2005;331: Huiart L, Ernst P, Suissa S. Cardiovascular morbidity and mortality in COPD. Chest 2005;128: Deyo RA, Cherkin DC, Ciol MA. Adapting a clinical comorbidity index for use with ICD-9-CM administrative databases. J Clin Epidemiol 1992;45: Sevenoaks MJ, Stockley RA. Chronic Obstructive Pulmonary Disease, inflammation and co-morbidity a common inflammatory phenotype? Respir Res 2006;7: Mannino DM, Watt G, Hole D, Gillis C, Hart C, McConnachie A, Davey Smith G, Upton M, Hawthorne V, Sin DD, et al. The natural history of chronic obstructive pulmonary disease. Eur Respir J 2006; 27: Swedberg K, Cleland J, Dargie H, Drexler H, Follath F, Komajda M, Tavazzi L, Smiseth OA. Guidelines for the diagnosis and treatment of chronic heart failure: executive summary (update 2005): The Task Force for the Diagnosis and Treatment of Chronic Heart Failure of the European Society of Cardiology. Eur Heart J 2005;26: Grundy SM, Cleeman JI, Daniels SR, Donato KA, Eckel RH, Franklin BA, et al. Diagnosis and management of the metabolic syndrome: an American Heart Association/National Heart, Lung, and Blood Institute Scientific Statement. Circulation 2005;112: Van Gaal LF, Mertens IL, De Block CE. Mechanisms linking obesity with cardiovascular disease. Nature 2006;444: Xu H, Barnes GT, Yang Q, Tan G, Yang D, Chou CJ, Sole J, Nichols A, Ross JS, Tartaglia LA, et al. Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance. JClinInvest 2003;112: Yudkin JS, Stehouwer CD, Emeis JJ, Coppack SW. C-reactive protein in healthy subjects: associations with obesity, insulin resistance, and endothelial dysfunction: a potential role for cytokines originating from adipose tissue? Arterioscler Thromb Vasc Biol 1999;19: Schols AM, Buurman WA, Staal van den Brekel AJ, Dentener MA, Wouters EF. Evidence for a relation between metabolic derangements and increased levels of inflammatory mediators in a subgroup of patients with chronic obstructive pulmonary disease. Thorax 1996;51: Creutzberg EC, Wouters EF, Vanderhoven-Augustin IM, Dentener MA, Schols AM. Disturbances in leptin metabolism are related to energy imbalance during acute exacerbations of chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2000;162: Schols AM, Wouters EF. Nutritional abnormalities and supplementation in chronic obstructive pulmonary disease. Clin Chest Med 2000;21: Fabbri LM, Luppi F, Beghe B, Rabe KF. Complex chronic comorbidities of COPD. Eur Respir J 2008;31: