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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
Correspondence and requests for reprints should be addressed to R. Rodriguez-Roisin M.D., Servei de Pneumologia, Hospital Clínic, Villarroel, 170, 08036-Barcelona, Spain. E-mail: rororo{at}clinic.ub.es
ABSTRACT
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.
Key Words: 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 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 1997. 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 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 2015.
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 (PaO2 < 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 FEV1 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 = 0.03). The hazard ratio for mortality in the usual care group compared with the special intervention group was 1.18 (95% confidence interval [CI], 1.02–1.37). 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 between the special intervention groups originally assigned to bronchodilator or placebo.
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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 FEV1, 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.
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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 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).
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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)-1β, 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 pro-angiogenic 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 FEV1 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-
B) transcription factor may have major relevance for cancer and COPD. Although the precise role of NF-B in COPD remains unsettled, chronic airway inflammation in COPD has been associated with activation of NF-B 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-B–mediated activation. Links between NF-B and lungcancer 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 FEV1, 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 = 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 1.11.
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-to-moderate 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).
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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 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.
FOOTNOTES
R.R.-R. is supported by the CibeRes (CB06/06), the Generalitat de Catalunya (2005SGR-00822), and a grant-in-aid by Esteve.
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.
(Received in original form July 31, 2008; accepted in final form September 10, 2008)
REFERENCES
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  R P Young, R Hopkins, and T E Eaton Potential benefits of statins on morbidity and mortality in chronic obstructive pulmonary disease: a review of the evidence Postgrad. Med. J., August 1, 2009; 85(1006): 414 - 421. [Abstract] [Full Text] [PDF]
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