In this large study of chronic obstructive pulmonary disease (COPD) and lung cancer, we found that history of chronic bronchitis, emphysema, and COPD were associated with increased risk of lung cancer. The risk in patients with both chronic bronchitis and emphysema was similar to that in patients with only chronic bronchitis or emphysema. Previous asthma was associated with decreased risk of lung cancer in males. Additional adjustment for smoking beyond pack-years and smoking intensity did not materially change these results.
While there is strong and compelling evidence for associations between COPD and lung cancer 
, some have argued that this association may be largely due to smoking, even after adjustment 
. However, several lines of evidence suggest that the association between COPD and lung cancer may not be entirely due to smoking. Family history of chronic bronchitis and emphysema are associated with increased risk of lung cancer 
. In addition, COPD is associated with lung cancer in never-smokers 
. A recent study estimated that COPD accounts for 10% of lung cancer cases among never smokers and 12% among heavy smokers 
. We found that even restricted to adenocarcinoma, which is more common among non-smokers, particularly women 
, COPD remained strongly associated with lung cancer. In addition, the association between chronic bronchitis and lung cancer was stronger among smokers with lower pack-years, smoking intensity, and smoking duration. The stronger association among lighter smokers may suggest that chronic bronchitis and smoking share some molecular features, possibly involving inflammation. We can speculate that among lighter smokers both chronic bronchitis and smoking strongly contribute, while at heavier smoking levels some “saturation” occurs so that the contribution of chronic bronchitis to lung cancer appears less prominent. To fully evaluate these factors in concert with molecular and genetic markers (which for example, may assess inflammation and associated genes), larger studies in consortial settings will be required. Taken together, our data suggest that COPD contributes independently to lung cancer risk and are concordant with other evidence that some proportion of COPD cases develop lung cancer because of COPD itself, rather than because of its association with smoking. One potential mechanism is lung infections leading to inflammation, chronic immune stimulation 
, COPD exacerbation, and accelerated lung function decline 
. Although our data suggest that COPD may contribute independently to the risk of lung cancer, the proportion of never-smoking cases in EAGLE was small, underscoring the need for additional analyses among never smokers.
Previous studies have not found consistent patterns in the association of chronic bronchitis and emphysema with lung cancer by latency 
. Our finding that chronic bronchitis was most strongly associated with lung cancer among people who were diagnosed with chronic bronchitis more than 15 years prior to diagnosis of lung cancer is noteworthy because it rules out the possibility that the association with chronic bronchitis is due to reverse causality, i.e., the diagnosis of chronic bronchitis due to underlying lung cancer. Moreover, it suggests that chronic bronchitis may act in an early stage of lung carcinogenesis.
We found that asthma was associated with a decreased risk of lung cancer in males. While a previous meta-analysis found a modest increased risk for lung cancer associated with asthma, the magnitude of the risk ratios varied widely by study 
. Most previous studies of asthma and lung cancer did not account for negative confounding by chronic bronchitis and emphysema. Of two that did, one found an OR of 1.5 (95% CI
1.0–2.2) for asthma and risk of lung cancer after adjusting for chronic bronchitis and emphysema 
. This study was conducted in nonsmoking women, however, and is therefore not comparable to ours since we found an inverse association only among males. The other study was conducted in males and females and found an OR of 1.1 (95% CI
1.0–1.2) for asthma only and 0.73 (95% CI
0.65–0.83) for both asthma and hay fever and lung cancer mortality. Our results were unaffected by adjustment for additional smoking variables, including environmental tobacco smoke, and support several studies that found inverse associations with asthma, eczema, and hay fever 
. Although previous studies of the time from diagnosis of asthma to diagnosis of lung cancer have been inconsistent 
, we found that asthma was consistently inversely associated whether it was diagnosed within 5 years or more than 15 years prior to lung cancer.
Several potential explanations have been hypothesized for an inverse association between asthma and lung cancer 
. Asthmatics might avoid smoking and other deleterious exposures that could trigger their asthma symptoms. Avoidance of such exposures may subsequently decrease their risk of lung cancer. However, we carefully adjusted for smoking and saw no consistent trends for asthma by smoking status. Often asthmatics are administered allergy medications (antihistamines, decongestants, corticosteroids, bronchodilators, antibiotics, etc.) over long periods of time due to the chronic nature of asthma. Although the potential impact of these medications on lung carcinogenesis is unclear, antibiotics, for example, might eliminate lung pathogens postulated to increase risk of lung cancer, such as Chlamydia pneumonia 
. Finally, the “immunesurveillance hypothesis” suggests that asthma may stimulate the immune system such that it is better able to detect and destroy cancer cells 
. That the inverse association is limited to males may not be surprising since previous studies have found sex-specific differences in the prevalence and severity of asthma, possibly due to bronchial hyperresponsiveness, differential effects of tobacco, or hormone related differences 
. While we are unsure why we see inverse associations in males, verification and follow-up in other settings is desirable.
Our study has clear strengths. It is population-based and achieved a very high participation rate among both cases and controls. The study questionnaires were administered by interviewers who underwent centralized training, ensuring that important demographic and risk factor information (e.g., age, smoking) was obtained as accurately and completely as possible. In addition, quality control procedures were built into all facets of data collection and transfer 
These results must also be interpreted in the light of the study's limitations. Despite the large initial sample size, small numbers limited some sub-analyses (e.g., in never smokers). Given that previous lung disease exposure was ascertained through self-report, recall bias is possible. However, cases did not report all previous lung diseases at a consistently higher level than controls, as shown by the positive associations of chronic bronchitis and emphysema with lung cancer compared to the negative association for asthma. In addition, self report-based COPD was strongly associated spirometry-based COPD in a subset of cases with spirometry data, supporting a previous validation study that found self-reported COPD sufficiently robust for accurate estimation of relative risks 
. While the prevalence of COPD varies notably in the published literature, the prevalence of COPD in controls in EAGLE (6.9%) was similar to the pooled prevalence of COPD in Europe (7.4%) 
. In addition, the prevalence of asthma in EAGLE controls (4.7%) was similar to that reported in a general population study of northern and central Italy (3.3–5.5%) 
. This similarity suggests little potential for selection bias in EAGLE, consistent with the careful protocol for population control accrual in EAGLE. Although surveillance bias (i.e., increased lung cancer diagnosis in individuals with COPD due to increased medical investigations such as chest X-rays) is theoretically possible, the differences in the magnitude and direction of associations for chronic bronchitis and emphysema versus asthma and the stability or increased strength of the findings over time, as demonstrated through latency analysis, argue strongly against this interpretation. The consistency of our results with the previous COPD literature is a further indication of their validity.
In one of the largest studies of COPD and lung cancer to date, we verified the associations of chronic bronchitis, emphysema, and COPD with lung cancer. Our extensive analyses of these associations by smoking status suggest that a component of the associations is independent of smoking. This independent association of COPD with lung cancer risk could potentially arise from chronic inflammation. The inverse association with asthma is consistent with some previous observations, and its restriction to men might explain some of the inconsistency in the literature. Further investigations in studies powered to evaluate men and women separately are warranted.