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1 Department of Pulmonary and Critical Care Medicine, Oregon Health and Science University, Portland, Oregon
Correspondence and requests for reprints should be addressed to A. Sonia Buist, M.D., Pulmonary & Critical Care Medicine, Oregon Health & Science University, Mail Code UHN 67, 3181 SW Sam Jackson Park Rd., Portland, OR 97239. E-mail: buists{at}ohsu.edu
ABSTRACT
The traditional approach to the diagnosis and management of chronic obstructive pulmonary disease (COPD), cardiovascular disease, and lung cancer has been to address each separately. Guidelines have documented the scientific basis for diagnosis and management, but have done little to explore the interconnections between them or to address comorbidity. The past few years have seen greater attention to the problem of chronic diseases and increased awareness of the impending crisis in health care as a result of the changing demographics of the world's population with a steady increase in life expectancy and a higher proportion living into the chronic disease age range. COPD presents a particular problem, as its mortality rate continues to climb steadily in most countries, particularly in women. The same is true for lung cancer. Cardiovascular disease mortality shows a different pattern, with deaths continuing to increase in developing countries but stabilizing or decreasing in resource-rich countries as aggressive strategies to diagnose and treat cardiovascular disease have been put into place. Predictions for 2020 from the Global Burden of Disease Study are that ischemic heart disease will stay the number one cause of death worldwide, COPD will go from sixth to third place, and lung cancer will go from tenth to fifth place. The purpose of this introduction is to set the stage for a review and discussion of the major comorbidities of COPD, heart disease, and lung cancer, to expand our understanding of the interrelationships among the "Big Three" diseases, causes of morbidity and mortality worldwide.
Key Words: COPD • comorbidities • risk factors
TRENDS IN CHRONIC OBSTRUCTIVE PULMONARY DISEASE MORTALITY
In the United States, chronic obstructive pulmonary disease (COPD) is the only one of the top six leading causes of death that is still increasing: heart disease, stroke, accidents, and diabetes mellitus have decreased steadily over the past 40 years, and cancer deaths are about constant (1). According to U.S. national statistics, deaths from coronary heart disease decreased by 59% and COPD deaths increased 163% during the period 1965 to 1998 (1). The striking feature of the increase in COPD deaths is that it was primarily driven by the huge increase in deaths in women (2, 3).
RISK FACTORS FOR COPD
The decrease in coronary heart disease deaths reported by Ford and coworkers (4) is encouraging and is viewed as a great public health success, but there has been uncertainty about the factors contributing to the decrease. Ford and coworkers (4) have shed some light on this important question by reporting on the IMPACT Study in the United States, performed between 1980 and 2000, that used a validated statistical model to look at the use and effectiveness of specific cardiac treatments and on changes in risk factors among U.S. adults 25 to 84 years of age. The investigators reported that half of the decline in U.S. coronary heart disease deaths in this 20-year period may be attributable to reductions in major risk factors and approximately half to evidence-based medical therapies. The pulmonary community needs to replicate studies like this. To do this, we need to fully understand why deaths from COPD are increasing so fast, and develop effective strategies to reverse the upward trend. We also need to sort out the misclassification problems that result in underreporting and potential overreporting of morbidity and mortality from COPD (5)
COPD is a classic gene–environment interaction disease (2). The risk factors are mostly understood, but there continues to be the misperception that smoking is the only important risk factor. Although there is no question that, worldwide, smoking is by far the most important risk factor, a very important driver of the striking rise in COPD morbidity and mortality that WHO predicts for the coming 20 years (6) is the aging of the world's population, with more living into the age range of highest susceptibility to COPD, especially in developing countries. When developing strategies to slow or reverse the increase in COPD deaths, it makes sense to address all of the risk factors.
COPD is the cumulative response of susceptible lungs to the total burden of inhaled particles and gases over a lifetime. Particles may come from active or passive smoking and occupational and environmental sources. This particulate burden is modified by the individual's nutrition, infections, socioeconomic status, and genes that may increase or decrease risk. How and when these risk factors operate and which genes are important is still unclear (2).
Tobacco continues to be the most important preventable cause of death worldwide. The recent WHO Report on the Global Tobacco Epidemic (7) predicts that tobacco will kill over 175 million people worldwide between now and 2030 (Figure 1). The majority of these deaths will occur in developing countries. Occupational exposures to particles and gases were thought to be contributory, rather than causal, but recent evidence from the third U.S. National Health and Nutrition Survey provides evidence that occupational exposures can be causal alone, especially in nonsmokers (8).
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LIFE COURSE PERSPECTIVE
It is an oversimplification to think of single risk factors for most chronic diseases. COPD is an excellent example. Although smoking is clearly the single most important risk factor globally, COPD is a result of the accumulation of molecular and cellular damage from conception on (9). In postnatal life, the damage is primarily from inhaled particles and gases. By constructing models of the life course of a disease, it may be possible to tease out the critical periods in life when the lungs are most vulnerable to damage and identify the biological and psychosocial exposures acting across the life course that may influence lung function. An example of this is that intrauterine influences, such as maternal smoking during gestation, have been shown to influence the way the lungs grow and develop in utero. Gestation is therefore a vulnerable stage in lung growth and development. Once vulnerable stages such as gestation have been identified, preventive strategies can be developed and focused on these periods. The key point here is that COPD should not be simply thought of as a disease of the sixth decade of life and older, but rather as a disease that may have its origins as early as gestation. This concept, together with the concept of expanding our thinking about risk factors, and the importance of co-morbidities that are associated with COPD, is central to a better understanding of COPD (10, 11). For this goal to be successful, it will be crucial to derive more information from longitudinal (cohort) studies as, presently, much of our information comes from cross-sectional studies. If medical and social interventions can be identified that reduce the rate of accumulation of damage, it may be possible to exploit the intrinsic malleability of the aging process (12).
COPD PREVALENCE
An important first step in developing a strategy for control of a disease is to estimate its prevalence and social and economic burden, and to explore variation in prevalence and risk factors across countries. The Burden of Obstructive Lung Disease (BOLD) Study was designed to accomplish this and has been performed to date in 15 countries (13, 14). The BOLD Study was originally developed so that uncertainties about the prevalence of COPD, stemming from differences in methods for estimating prevalence, could be resolved by using strictly standardized methods that could be used in countries at all levels of economic development (13). The standardized methods for BOLD have been published, as have several articles reporting outcome data, including the primary outcome paper that included data from 12 countries (14, 15). BOLD sites survey population-based samples of men and women aged 40 years and older.
Most previously reported studies of COPD prevalence have reported prevalence estimates by GOLD stages (GOLD). Halbert and colleagues (16, 17) summarized the data on COPD prevalence up to 2004. The later review (17) included a meta-analysis of prevalence estimates from 28 countries. The pooled prevalence of stage 1 and higher COPD from 26 studies with spirometric estimates was 9.2% (95% confidence interval [CI], 7.7–11.0). Restricting the estimates to GOLD Stage 2 to focus on clinically significant COPD reduced the pooled estimates to 5.5% (95% CI, 3.3–9). The authors suggested that the wide variation in estimates was likely a result of differences in methods, including selection of the studied population and response rates, methods for doing spirometry, and the equipment used.
Since there is considerable controversy about the importance of COPD GOLD stage 1, BOLD has chosen to focus on GOLD Stage 2 and higher, which is likely to be clinically significant disease. BOLD, reporting data from 12 sites in 12 countries (14), has shown that COPD is appreciably more common than was previously thought, with estimates for COPD Stage 2 and higher (postbronchodilator FEV1/FVC < 0.7 and FEV1 < 80% predicted) (NHANES) ranging from 6.8% in men aged 40 years and older in Uppsala, Sweden, to 22.2% in Cape Town, South Africa (Figure 2). For women, the range for GOLD Stage 2 was from 3.7% in Hannover, Germany, to 16.7% in Cape Town. As expected, smoking and age emerged as the most important risk factors. BOLD is presently looking at the impact of different lung function criteria for COPD on its prevalence to make the most accurate estimates possible for future health care planning.
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It has been the practice to develop single disease guidelines rather than emphasize the coexistence of many chronic diseases, and discuss how treatments for one may impact the others. COPD is a prime example, although the most recent global guidelines (2) stress the importance of the comorbidities of COPD. As an example, in 1999, 48% of Medicare beneficiaries in the United States aged 65 years and older had at least three chronic medical conditions, and 21% had five or more (18). These rates of chronic conditions are higher than those in a recent study from The Netherlands, which reported that 22% of adults aged 65 years and older seen in primary care had two chronic conditions and 17% had three or more (19). The exact number is less important than documenting the high frequency of chronic conditions in older adults (10, 11). Inevitably, the cost and complexity of care escalates with the number of comorbid conditions (18). Boyd and coworkers reviewed clinical practice guidelines for nine conditions (including COPD) and showed that most did not address comorbidity, quality of evidence or patient preferences (18). They presented a hypothetical 79-year-old woman with COPD, diabetes mellitus, osteoporosis, and hypertension who, according to clinical practice guidelines, should be prescribed 12 medications at a cost of $406 monthly in the United States.
Heart disease and lung cancer are two of the most common comorbidities of COPD. The link between these diseases is clearly smoking. Teo and colleagues reported results from the INTERHEART Study of tobacco use and acute myocardial infarction in 52 countries (20). Using a case control design with 27,089 participants, they assessed risk of current and former smoking, type of tobacco, dose, and exposure to secondhand smoke for acute myocardial infarction (MI). They reported that the odds ratio (OR) for current smoking and nonfatal MI was 2.95 (95% CI, 2.77–3.14), and that the risk increased 5.6% for every cigarette smoked. Also important, the OR for a nonfatal MI associated with former smoking fell to 1.87 (95% CI, 1.55–2.24) within 3 years of quitting smoking. Perhaps surprisingly, the investigators found that the risk for bidis (a cigarette substitute smoked in India) was the same as for cigarettes, and the risk for chewing was 2.23. Secondhand smoke also had an elevated risk (OR, 1.24–1.62) depending on the exposure. In this study, young male smokers had the highest population-attributable risk (58.3%) and older women had the lowest (6.2%).
As an example of failure to recognize comorbidities in patients with COPD, Rutten and coworkers, in the first study of its kind, reported on a survey of 405 patients aged 65 years and older in 51 primary care practices in The Netherlands (21). All of the patients underwent extensive diagnostic workup: 83 (20.5%) had unrecognized heart failure.
Lung cancer is the third of the "Big Three" diseases. It has long been recognized that the existence of COPD increases the risk for lung cancer (22–25) A recent metaanalysis (26) has taken this observation one step further by showing that four large population-based prospective studies using standardized methods found a strong inverse relationship between level of lung function and risk of lung cancer. The highest quintile of FEV1 had the lowest risk of lung cancer, and the lowest quintile had the highest risk (Figure 3). Also of great importance is the fact that for the same marginal decrease in FEV1, adjusted for smoking, women were two times more likely to develop lung cancer than men. This is a highly significant sex effect.
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Given the frequency with which older adults have more than one chronic health condition, guideline developers propose that it is no longer acceptable to focus on one disease without providing guidance to clinicians about how to assess and manage patients with multiple comorbid conditions (27). COPD coexists with many diseases that share tobacco smoking as a risk factor. The most common of these are heart disease and lung cancer. When looking at risk for these common conditions, it is important to take a broader view of the natural history of these conditions to identify critical points where intervention is most cost effective.
FOOTNOTES
Conflict of Interest Statement: A.S.B. has served on Advisory Boards for GlaxoSmithKline (GSK), ALTANA, Schering Plough, Merck, Novartis, Pfizer, and Sepracor. She donates most of her honoraria to the ATS, and has participated in COPD workshops funded by AstraZeneca and GSK. She is the Scientific Director for the Burden of Obstructive Lung Disease (BOLD) Initiative that receives unrestricted educational grants to the Kaiser Permanente Center for Health Research from GSK, Pfizer, Boehringer Ingelheim, AstraZeneca, ALTANA, Novartis, Merck, Chiesi, Schering Plough, and Sepracor.
(Received in original form May 28, 2008; accepted in final form July 14, 2008)
REFERENCES
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