Insights into COPD Comorbidities from the OLIN Study and Other Large Databases

In this Journal, Lindberg et al. describe the prevalence of comorbidities (non-pulmonary chronic illnesses and conditions) in a well-characterized cohort of 993 COPD cases and 993 age- and gender-matched controls without airflow obstruction. All were recruited as part of the OLIN (Obstructive Lung Disease in Northern Sweden) study, a large longitudinal project that has collected data on over 50,000 participants since 1985 (1). The strength of the OLIN project is that it is as close to a population-based cohort of COPD patients as you will find anywhere, so it reflects the clinical characteristics of COPD among persons in the general population, as opposed to COPD patients recruited for highly selected clinical trial populations that usually exclude comorbidities. Both cases and controls had spirometry and a detailed medical interview that included questions about specific chronic diseases and conditions. The COPD patients were stratified by GOLD-COPD severity classifications I-IV (mild through very severe), and the controls were stratified by those with normal lung function (N = 776) or those with restrictive lung function (N = 217). Among those with even mild COPD, increased prevalences of cardiovascular disease, intermittent claudication, and chronic rhinitis were found as compared to controls. The prevalence of comorbidities increased with COPD severity, and as expected, the adjusted odds ratios for most other smoking-related comorbidities were also substantially elevated. Interestingly, those with restrictive lung function, which is a population about which we have relatively little epidemiologic information, also had substantially increased comorbidities including diabetes, hyperlipidemia, and cardiovascular diseases.

As interest in the pathophysiology and treatment of COPD is increased, so too has interest in how to stratify the clinical characteristics of COPD patients so that we can identify the genetic factors that determine the response to airborne exposures, a process known as phenotyping. The traditional paradigm of stratifying COPD by the severity of airflow obstruction is useful and well validated, but it also has many notable limitations. It is not uncommon to find persons with severe airflow obstruction who are relatively asymptomatic, physically active, and otherwise healthy, and others with mild to moderate obstruction who are disabled by their pulmonary symptoms and chronic comorbidities. The ECLIPSE (Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints) study was designed to help re-examine some of the clinical manifestations and endpoints in COPD and identify their biological markers (2). Already the ECLIPSE study has helped to define the ‘frequent exacerbator’ phenotype, that is persons who have two or more COPD exacerbations within a year (3). As expected, frequent exacerbations increase with the severity of airflow obstruction (22%, 33%, and 47% among GOLD stage 2, 3, and 4, respectively). Prior to the ECLIPSE study, the conventional wisdom was that serious exacerbations did not begin until airflow obstruction was severe. Because stage 2 COPD patients are far more prevalent than stage 3 or 4, it is likely that most exacerbations in the general population occur among those with relatively moderate airflow obstruction. That in fact was observed in one hospital-based study in Spain, where 54% of patients hospitalized for the first time for an exacerbation of COPD had GOLD stage 1 or 2 at baseline (4). Large population based studies such as the OLIN project remind us that comorbidities are another way of stratifying COPD patients by phenotypes that might be useful for elucidating some of the genetic and inflammatory mechanisms of this disease. The OLIN project also illustrates that while studying patients with severe and very severe COPD is useful for proving treatment efficacy, most persons in the general population have mild to moderate disease.

Because many large epidemiologic studies are focused on the prevalence and risk factors of COPD, the problem of restrictive lung function has largely been ignored. The OLIN study illustrates that restrictive lung function is not uncommon (it was found in 22% of the ‘normal’ controls), and it identifies persons who are at risk for having serious comorbidities that are as prevalent as those found among persons with moderate COPD. A recent survival analysis of participants of the Third National Health and Nutrition Examination Survey (NHANES III), a cohort of 10,954 adults recruited between 1988 and 1994 from across the United States and who completed spirometry and a battery of questionnaires and tests, has also demonstrated that restrictive lung function is associated with a substantial increase in mortality (5). In the NHANES III, persons with restrictive impairment had an age-adjusted all-cause mortality rate more than double that of persons with normal lung function (15.6 versus 6.2 per 1000 person-years [p < 0.01]) but not as high as that of persons with moderate to severe COPD (20.2 per 1000 person-years). Those that have criticized the usefulness of lung function testing to screen for COPD have ignored the fact that lung function testing also identifies persons with restrictive lung impairment, a condition that is insidiously progressive, common, and associated with poor health status and poor long-term outcomes (6). Furthermore, many of the causes of restrictive disease (e.g., obesity, neuromuscular weakness, congestive heart failure) are treatable. Observations from longitudinal studies such as the OLIN project suggest that those of us interested in developing practical systems for identifying undiagnosed COPD patients in the general population need to remember that screening also identifies clinically important but undiagnosed restrictive lung function.

The results of OLIN project are consistent with cross-sectional surveys of comorbidities in COPD from large administrative databases. In a case-control analysis of patients enrolled in one large regional integrated health system, COPD patients were found to have substantially increased prevalence of and healthcare utilization for comorbidities in almost every chronic disease category (7). Not surprisingly much of this increase is for other conditions that are well known consequences of cigarette smoking, such as cardiovascular diseases and cancers. However, the OLIN study reveals that some conditions that pulmonologists may not realize are also associated with smoking, such as peptic ulcers and gastroesophageal reflux, are also substantially elevated in COPD (8). Healthcare utilization data have a lot of rich detail about comorbidities but not much detail about the clinical features of their COPD patients, whereas clinical studies such as the OLIN have much detail about their COPD patients but are not as sensitive or specific about their comorbidities due to their reliance on self-reported histories.

The OLIN results complement the findings of the Lung Health Study (LHS), which was a randomized clinical trial of smoking cessation and inhaled ipratropium therapy in 5887 smokers with mild to moderate COPD. After over 14.5 years of follow-up, lung cancer was the most common cause of death in the LHS (n = 240 [33% of all deaths]), followed by cardiovascular diseases (n = 163 [22%]) and cancer of organs other than the lungs (n = 154 [21%]), with respiratory non-cancer deaths relatively uncommon (n = 57 [7.8%]) (9). When LHS participants were stratified by their C-reactive protein (C-RP) levels at 5-years into the study, those in the highest quintile (mean C-RP 7.06 mg/l) had an adjusted risk of coronary heart disease deaths that was more than double that of those in the lowest quintile (mean C-RP 0.21) (10). In the OLIN COPD cohort, the increased prevalence of cardiovascular disease among those with mild COPD (47.7%) suggests that there are a substantial number in this cohort who already at risk of early death from heart disease. The majority of the increased cardiovascular disease cases in the OLIN COPD cohort were among men, and the majority of cardiovascular deaths in the LHS were also among men. Some believe that the LHS was a failure because of the low proportion of patients who were able to achieve complete abstinence from cigarettes. However, after 14.5 years, those who were randomized to the special smoking intervention group have significantly improved all-cause survival, largely due to the reduction in cardiovascular diseases (9).

Thomas S. Kuhn was a philosopher and scientist interested in the history of science and how scientific paradigms changed, and is credited for the concept of ‘paradigm shift’. Kuhn noted that as new observations and discoveries are made that are incongruent with old theories of how things work, the tension between these new discoveries and the inadequacies of the old paradigms often results in a tumultuous period of re-examination. “The proliferation of competing articulations, the willingness to try anything, the expression of explicit discontent, the recourse to philosophy and to debate over fundamentals, all these are symptoms of a transition from normal to extraordinary research.” (11) Interest in COPD has exploded over the last decade, and the quest for new knowledge in this area is forcing us to move beyond overly simplistic paradigms based only on the physiologic measure of airflow obstruction. Large studies such as the OLIN, ECLIPSE, NHANES III, and the LHS will continue to be invaluable resources for re-evaluating how we think about COPD patients, investigate the underlying disease mechanisms, and advance the treatment of this disease.