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1 AstraZeneca R&D Lund, Lund, Sweden
Correspondence and requests for reprints should be addressed to Maria Gerhardsson de Verdier, M.D., AstraZeneca R&D Lund, S-221 87 Lund, Sweden. E-mail: maria.gerhardsson{at}astrazeneca.com
ABSTRACT
Tobacco use is the leading preventable cause of death and morbidity in the world. Chronic obstructive pulmonary disease (COPD), lung cancer, and cardiovascular disease (CVD) are the three major smoking-induced diseases that co-exist and can be detected at an early stage by screening, but are usually recognized in an advanced stage and treated as single entities. New epidemiologic data indicate a common origin of these diseases in susceptible individuals, and potential disease modification. Further exploration of a holistic concept of the Big Three smoking-induced diseases—COPD, lung cancer, and CVD—may be one way of reducing the burden of illness for individuals and society. This includes a reshift from reactivity to proactivity. Future treatment and management approaches should thus be focused on disease prevention. In this article, the Big Three concept is suggested, which aims for (1) identification of susceptible smokers; (2) screening for early diagnosis; (3) development of new treatment modalities that target shared disease mechanisms, thus having the potential to affect more than one of the comorbidities; and (4) increased awareness of these co-existing diseases and modification of current guidelines across specialties.
Key Words: the Big Three concept • chronic obstructive pulmonary disease • cardiovascular • lung cancer • inflammation
A NEW VIEW OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE
Although chronic obstructive pulmonary disease (COPD) represents an important and increasing burden throughout the world, it is underdiagnosed, undertreated, and underfunded when compared with other chronic diseases, such as cardiovascular disease (CVD) and lung cancer. Classically, COPD has been considered a respiratory condition, defined by lung function, mainly caused by tobacco smoking. However, during recent years epidemiologic studies have provided new information on the disease which has implications for patient care (1).
HERITABILITY IS IMPORTANT IN COPD
The role of smoking as a major determinant of COPD has been risen above any doubt. However, if everyone in the world had been smoking, COPD would have been considered to be a genetic disease, since only some smokers develop COPD (2). The smokers who develop COPD seem to be genetically more susceptible to the deleterious effects of cigarette smoke than smokers who do not develop COPD (e.g., the inflammatory response to tobacco smoke appears to be greater among people who are susceptible to developing COPD) (3, 4). In addition, dependence on tobacco is a complex behavior, with both genetic and environmental factors contributing to population variation. In a twin study of heritability for lifetime regular smoking, the estimates ranged from 46 to 57%, depending on sex (5). A recent study using the Swedish Twin Register explored to what extent genetic factors contribute to the development of chronic bronchitis, including emphysema, and whether the genetic influences are separate from those for smoking behavior. The analyses were based on smoking and symptoms data from 12,100 complete monozygotic and dizygotic pairs; the results showed that the heritability estimate for chronic bronchitis was 40%, and that only 14% of the genetic influences were shared with smoking (6). This is the first time that this association has been quantified, and it creates an opportunity to identify susceptible smokers.
COPD IS A SYNDROME RATHER THAN A DISEASE
Several recent epidemiologic studies have shown that comorbidities in patients with COPD have a larger impact on morbidity and mortality than COPD itself. Based on these data it has been suggested that COPD and all its comorbidities should come under a new umbrella term: "chronic systemic inflammatory syndrome" (7).
In the National Hospital Discharge Survey, around 47 million hospitalizations of patients with COPD were followed in the United States from 1979 to 2001; among these discharges, only 21% were made with COPD as the primary diagnosis, illustrating that COPD has important manifestations beyond the lungs, the so-called systemic effects (8). These include weight loss and nutritional abnormalities, skeletal-muscle dysfunction, CVD, cancer, diabetes/glucose intolerance, osteoporosis and fractures, depression, autoimmune disorders, cataracts, glaucoma, peptic ulcer, impotence, gastroesophageal reflux, and others (9–12). However, the two leading causes of morbidity and mortality in patients with COPD are CVD and lung cancer.
In a follow-up study of patients with mild to moderate COPD, which make up more than 80% of COPD cases in the community (13), lung cancer was the leading cause of mortality (33%) followed by CVD (22%), while only 8% of the patients died from respiratory failure (14). However, respiratory failure was the leading cause of mortality (35%) in a follow-up of patients with more severe COPD, for whom CVD accounted for 26% and cancer for 21% of all deaths (15). The long-term CVD survival is significantly reduced in patients with COPD compared with patients without comorbidities (16), and cardiovascular morbidity and mortality rates are about double in COPD cohorts compared with the general population (17, 18).
COPD is defined by a persistent airflow limitation. Forced expiratory volume in 1 second (FEV1) defines COPD severity and is a common primary endpoint in population-based studies evaluating COPD morbidity or mortality. Several epidemiologic studies have shown that reduced lung function in patients with COPD is associated with cardiovascular morbidity and mortality (11), and an increased risk of lung cancer (19). In addition, the prognosis of lung cancer seems to be worse in patients with COPD than in patients without COPD (20).
The high correlation between COPD, CVD, and lung cancer may be anticipated, since these three diseases share a common risk factor in cigarette smoking. However, the association between low lung function and increased risk for CVD and lung cancer still exists after control for smoking and also in those who never smoked, which indicates that there are other mechanisms involved beyond the direct effects of smoking (14, 19, 21–34).
LUNG FUNCTION IS A PREDICTOR FOR COPD, CVD, LUNG CANCER, AND ALL-CAUSE MORTALITY, INDEPENDENT OF SMOKING
Results from the Lung Health Study (LHS) showed that on average, for every 10% decrease in FEV1, all-cause mortality increased by 14%, cardiovascular mortality by 28%, and nonfatal coronary events by almost 20%, after adjustment for confounders such age, sex, smoking status, and treatment assignment (14). Similar findings were detected in a 26-year follow-up study of 1,223 healthy males, in which the relative risk of all-cause mortality increased by 10%, and of cardiovascular deaths by 7%, for each 10% decrease in FEV1% predicted, after adjustment for smoking habits, physical fitness, blood pressure, body mass index, and total cholesterol at baseline (21).
The relationship between reduced FEV1 and cardiovascular mortality was investigated in a longitudinal population-based study and a meta-analysis of the literature. The results showed that even a modest decline in FEV1 (from a mean of 109% of predicted to 88% of predicted) was associated with a fivefold increase in deaths from ischemic heart disease, independent of smoking, age, and other relevant covariates (22). A systematic review of population-based studies on the relationship between lung function and lung cancer produced several interesting observations (19). Reduced FEV1 increased the risk for lung cancer in the general population, independent of cigarette smoking history, and the risk appeared to be more amplified in women. This relationship was severity dependent, such that individuals with the worst lung function had the highest risk, whereas those with preserved lung function had the lowest risk. In addition, relatively small differences in FEV1 that are commonly considered within the normal range (for example, from 90% of predicted to 100% of predicted) increased the risk of lung cancer by 30 to 60% (19).
To eliminate confounding by smoking, the association between chronic bronchitis/emphysema and lung cancer mortality was examined in a U.S. prospective study of 448,600 lifelong nonsmokers who were cancer-free at baseline. Lung cancer mortality was significantly associated with emphysema but not with chronic bronchitis (23). Several other studies have detected an association between level of FEV1 and mortality in those who never smoked (24–27). Hole and coworkers found that the relationship between low FEV1 and increased mortality from all causes, ischemic heart disease, or respiratory disease also existed in the group that was free of symptoms, and also among lifelong nonsmokers (24). They estimated that FEV1 is second in importance to cigarette smoking as a predictor of subsequent all-cause mortality and is as important as cholesterol in predicting mortality from ischemic heart disease (24).
Furthermore, individuals with early-life lung impairment are also at higher risk of mortality, although the mechanisms that relate these conditions are unclear (28). A medical history of a respiratory disease in early life was associated with a 57% greater risk of overall respiratory disease mortality in adulthood, 38% higher risk of CVD mortality, and a more than twofold increase in COPD mortality (29).
Data from a Swedish cohort imply that the risk of CVD in those with reduced FEV1 is amplified by the presence of hypertension (30). Reduced FEV1 by itself was associated with only a 10% increase in the risk of cardiac events, defined as fatal or nonfatal myocardial infarction, but nearly tripled when subjects had both reduced FEV1 and coexisting hypertension at baseline assessment (30). Similarly, the incidence of stroke was nearly fourfold higher when subjects had both reduced FEV1 and hypertension, while reduced FEV1 by itself had no effect on the risk of stroke (30). Likewise, reduced FEV1 by itself was not significantly associated with coronary events, while individuals who had reduced FEV1 and evidence of significant ventricular dysrhythmia, experienced a twofold increase in the risk of coronary events, independent of other factors (31). Individuals who experience rapid decline in FEV1 are twice as likely to experience COPD-related hospitalizations and mortality (32). Cardiovascular events are also related to rapid decline in a study by Engström and colleagues (33), in which the cardiovascular event rate among smokers in the high, middle, and low thirds with regard to the decline in FEV1 was 56.0, 41.0, and 22.7 events per 1,000 person-years, respectively (P value = 0.01). The implications of the association between lung impairment and risk of CVD are that clinicians should consider spirometry in their patients with CVD or follow markers of systemic inflammation in patients with COPD to help assess or manage their CVD risk (34).
TOBACCO SMOKING TRIGGERS MECHANISMS THAT ARE AT PLAY EVEN AFTER SMOKING CESSATION
The only known intervention to reduce CVD and lung cancer risk in patients with COPD is smoking cessation, although the risk never returns to that of subjects without COPD (35). In contrast to CVD risk, which falls rapidly after smoking cessation, the risk for lung cancer falls much more slowly after smoking cessation. Moreover, for patients to experience the full benefits of smoking cessation on lung cancer risk, they must stop smoking completely. Intermittent quitters experience only trivial or no reductions in lung cancer risk. In the LHS study, sustained quitters experienced nearly a 60% reduction in the risk for lung cancer mortality. In contrast, intermittent quitters demonstrated a trivial (
16%) reduction in the risk. However, intermittent quitters experienced a more than 50% reduction in CVD mortality risk, and sustained quitters had an approximately 60% reduction in risk (35).
Smoking induces chronic inflammation of the airways and lung tissue, leading to airway remodeling and degradation of the lung tissue. It is unclear whether, once the inflammatory condition has been established in smokers, ex-smokers return to normal after smoking cessation or persist with inflammation similar to that of current smokers. Two published cross-sectional studies indicate that, if symptoms continue once they have developed, then inflammatory changes persist even after smoking cessation (36, 37). No reduction in airway inflammation was found in a study by Gamble and coworkers (38), in a population of ex-smokers compared with current smokers with similar lung function. The authors concluded that the characteristic inflammatory changes, although initially induced by smoking, are fundamental to the disease process rather than to smoking per se (38). Although the effects of smoking on inflammatory markers may persist for many years, a majority of the adverse health effects of smoking are reversible. Therefore, quitting smoking avoids much of the excess health-care risk associated.
WHAT ARE THE MECHANISMS LINKING COPD WITH CVD AND LUNG CANCER?
Tobacco smoke is a well-recognized stimulant of systemic and local inflammation, and the role of inflammation in the causal pathway for both lung cancer and COPD has been suggested (39). Cigarette smoke causes not only airway and lung inflammation but also systemic cellular and humoral inflammation, systemic oxidative stress, striking changes of vasomotor and endothelial function, and enhanced circulating concentrations of several procoagulant factors (11, 12, 40–42). These systemic effects of smoking could contribute substantially to the development not only of the airways and lung abnormalities characteristic of COPD, but also of chronic diseases such as CVD, metabolic disorders, and some cancers that are induced by smoking in combination with, or without, other risk factors such as obesity, hyperlipidemia, and increased blood pressure (43, 47). In lieu of the accumulating evidence implicating the role of inflammation in lung cancer pathogenesis (44, 45), it is plausible that chronic inflammation within the lung may result in repeated injury and repair that leads to a high rate of cell turnover, propagation of genetic errors, and ultimately, development of lung cancer (46).
In an article by van der Vaart and colleagues, the local and systemic effects of acute smoke exposure on oxidative stress and inflammatory mediators were reviewed (47), and the systemic effects of long-term smoking exposure in humans has also been reviewed (40). In particular, systemic oxidative stress, systemic inflammation, and the aspects of hemostatic and coagulation systems were discussed in relation to tobacco smoking (40). The conclusion was that the possible biological mechanisms responsible for the observed association of smoking with various diseases and global mortality are numerous and, in spite of many attempts to find causative relationships, are still unclear. A complicating factor is that COPD probably comprises several phenotypes with different pathophysiology (48). In addition, some mechanisms may be more important in the early stages of the disease, while others are more important in the later stages. This may explain some of the inconsistent results in the literature. Thus it is a great challenge to unravel exact pathways through which smoking affects human health.
IS SYSTEMIC INFLAMMATION A MECHANISM OF POTENTIAL FOR NEW TREATMENT FOR THE THREE MAJOR SMOKING-INDUCED DISEASES?
In the general population, a 1 g/L increase in plasma fibrinogen is associated with a 2.7-fold increase in mortality from coronary heart disease, 3.7-fold increase in COPD mortality, 2.3-fold increase in smoking-related cancer mortality, and 2.2-fold increase in all-cause mortality, highlighting the utility of this biomarker and the relevance of systemic inflammation in the health outcomes of individuals in the community (49). CRP levels, like fibrinogen, also predict CVD and all-cause morbidity and mortality in the general population (50). This relationship appears also to apply in patients with COPD. In LHS, a COPD-specific cohort, for instance, the risk of all-cause and CVD mortality over 7 years of follow-up increased as a function of CRP levels (51). A recent study suggests that heritability of lung function, as well as baseline C-reactive protein (CRP) levels, is at least partly controlled by the CRP gene, which supports a causal association between low-grade general inflammation and airway disease (52). It is widely accepted that lung inflammation plays a prominent role in COPD pathogenesis (53), and that systemic inflammation is present in COPD (54–56). However, the origin of systemic inflammation in COPD is unresolved, and it is unclear whether the systemic inflammation is driving the disease or vice versa.
Epidemiologic studies have presented unexpected effects of statins, angiotensin-converting enzyme inhibitors, or angiotensin receptor blockers and inhaled corticosteroids on COPD, CVD, and lung cancer. These studies may play a role in generating hypotheses about shared pathophysiology for these three diseases, but must be interpreted with caution since all epidemiologic studies include potential sources of error. To explore this further, other types of studies are needed, for example, clinical trials or mechanistic studies.
First, there has been growing interest in the antiinflammatory properties of the hydroxymethyl glutaryl CoA reductase inhibitor class of cholesterol-lowering agents (statins). Statins may also affect mortality from various diseases by their pleiotropic effects of antiinflammatory and antioxidative activities. Several recent observational studies have examined this prospect. Treatment with statins was associated with a 43% reduction in all-cause mortality in patients with COPD discharged from a Norwegian teaching hospital after an exacerbation. The combined treatment with statins and inhaled corticosteroids (ICS) compared with no such treatment was associated with a 61% reduction in all-cause mortality. The analyses were adjusted for sex, age, smoking, pulmonary function, and comorbidities (57). Similar findings were noted by an independent group in Japan (58). In a study on the administrative health data in Quebec, the combined use of statins and angiotensin-converting enzyme inhibitors or angiotensin receptor blockers was associated with a 34% reduction in hospitalization for COPD, a 61% reduction in myocardial infarction, and a 58% reduction in all-cause mortality (59). Another study addressed decline in pulmonary function in the elderly, and observed that in elderly statin users, a 10.9 ml/year decline in FEV1 occurred compared with a similarly aged group of non–statin users for whom FEV1 declined by 23.9 ml/year (60). Similar findings were detected in a Veterans Administration population in whom statins were associated with a slower decline in pulmonary function, in both smokers and former smokers, independent of the underlying lung disease (61). Blamoun and coworkers (62) used a retrospective design to assesses the rate of COPD exacerbation and intubations in patients taking statins. The statin group had fewer episodes of exacerbation and required intubation fewer times than the subjects not receiving statins (P < 0.0001 for both outcomes). A reduced risk of COPD death and a significantly reduced risk of influenza death among moderate-dose statin users has also been reported (63). Furthermore, a significant improvement in exercise tolerance, quality of life, and chemical markers in a homogenous group of patients with COPD was detected in a randomized controlled trial in which patients were treated with statins for 6 months (64). Statins also appear to be protective against the development of lung cancer. In patients enrolled in the Veterans Affairs (VA) Health Care System, statin use for greater than 6 months was associated with a risk reduction of lung cancer (65). Furthermore, the protective effect of a statin was seen across different age and racial groups and was irrespective of the presence of diabetes, smoking, or alcohol use (65).
Second, epidemiologic studies have shown benefical effects of ICS on CVD and lung cancer. In a study on the Saskatchewan (Canada) health services databases, low-dose ICS therapy has been associated with reduced risk of myocardial infarction, arrhythmias, and CVD mortality (66). Protected effects by ICS against ischemic cardiac events or cardiovascular death in patients with COPD have also been detected in other studies (67, 68). Parimon and coworkers (69) demonstrated a dose-dependent decrease in the risk of lung cancer associated with the use of ICS. Patients on 1.2 mg/day of beclomethasone or equivalent had a 61% reduction in the risk of lung cancer compared with patients who were not on any ICS (69). These data are also consistent with a pooled analysis of all large randomized controlled trials of ICS in COPD, which showed a 45% reduction in the risk for cancer with ICS (70).
THE BIG THREE CONCEPT—A WAY TO MAKE THE APPROACH TO COPD MORE EFFECTIVE?
Given the inadequacy of the single disease/single therapy concept in a world with limited healthcare resource, a concept like the Big Three may lead to better patient health care at similar or reduced costs. The Big Three Concept includes the following opportunities.
Identification of Smokers with High Susceptibility
Recent studies have shown that heritability plays an important role in COPD. Recognition of the addictive properties of cigarette smoking and genetic influences on COPD opens new opportunities to identify smokers with high susceptibility. These individuals will have a higher disease prevalence, which has implications for screening for early diagnosis. The proportion of those testing positive in a screening test who are true positive is called "predicted value," and depends on the prevalence of the disease, the sensitivity (probability that a sick individual will be classified as sick), and the specificity (probability that a healthy individual will be classified as healthy). Even for high values of the sensitivity and specificity, the predicted value is low when the prevalence is low. For example, if the sensitivity and specificity both are 99%, the predicted value is only 50% when the prevalence is 1%, but increases to 96% when the prevalence is 20% (71). The more susceptible smokers with a higher prevalence of COPD may thus be recommended screening for early diagnosis of COPD, CVD, and early-stage lung cancer.
Low-Dose Computed Tomography Screening of Smokers for Early Diagnoses of COPD, CVD, and Lung Cancer
Compared with older computed tomography (CT) scanners, newer systems have a greater spatial and temporal resolution, and can reconstruct images in any plane desired, as well as in three dimensions. Imaging of the lung with high-resolution CT provides a sensitive method to identify emphysema, and offers promise for quantifying airway remodeling (48). CT is also used to detect lung cancer, and currently, 50,000 high-risk smokers in the United States (72), and 16,000 smokers in Europe (73) are screened with low-dose CT, to identify early cases of lung cancer. CT can also estimate the amount of calcified and noncalcified plaque in coronary arteries; this information may help in predicting coronary events in patients at intermediate risk (74). CT may thus be considered for early diagnosis of COPD, lung cancer (75), and CVD in susceptible smokers. Another avenue is to identify biomarkers and genetic promoters to be used for early diagnosis.
New Treatment for Smokers and Ex-Smokers
New data imply that the three major smoking-induced diseases—COPD, CVD, and lung cancer—may share pathophysiology, and also that some mechanisms are still vivid after smoking cessation. More work needs to be focused on new approaches to drug discovery and findings of new mechanisms that are driving the different diseases, and these efforts must be coordinated across the different therapy areas. This may lead to future therapeutics that attack the shared mechanisms, and thus positively influence the outcome in all three diseases, in both smokers and ex-smokers.
Influence on Guidelines for Care of COPD, Lung Cancer, and Heart Patients
The current guidelines for COPD, CVD, and early-stage lung cancer, respectively, ignore the fact these smoking-induced diseases often share comorbidities. These guidelines should thus be modified to include integrated guidance about disease management for patients with multiple chronic diseases, and also emphasize the importance of an active search process and, eventually, adequate therapy for the optimal management of these diseases.
CONCLUSIONS
As the incidence of chronic illness explodes, and tobacco use is the leading preventable cause of death in the world (76), a holistic approach to the major smoking-induced diseases may be of real benefit to patients and society. COPD, CVD and lung cancer are the three major smoking-induced diseases, with a huge impact on hospitalization and mortality. Currently, they are managed as three singular and unconnected diseases, ignoring new data on common mechanisms. Future treatment guidelines in all three disease areas should encourage health care providers to identify susceptible smokers and screen for early diagnosis looking at the patient from a holistic perspective. Industry and society should co-operate to develop tools for early diagnosis as well as new treatments that target shared mechanisms. A multifaceted but holistic approach to the Big Three smoking-induced diseases should be taken to minimize the burden of illness for patients and society.
FOOTNOTES
Conflict of Interest Statement: M.G.d.V. is a full-time employee of AstraZeneca.
(Received in original form June 30, 2008; accepted in final form August 29, 2008)
REFERENCES
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