The results of this study confirm that COPD is a highly heterogeneous disease [2, 3] and provide a number of observations that help to better delineate the complexity of the disease. Of particular clinical relevance is the observation that, within each GOLD stage (or BODE score) of disease severity, symptoms, exercise tolerance, the number of reported exacerbations and the prevalence of co-morbidities varied widely between patients, and that even in patients with severe airflow obstruction there were a substantial proportion of patients who did not complain of symptoms, report exacerbations or show impaired exercise tolerance. These observations highlight the fact that FEV1 does not capture the complexity of the disease and that clinical management of patients with COPD needs to consider such complexity rather than just spirometry alone. Other observations of interest are discussed below.
COPD is characterised by an accelerated rate of decline of FEV1 with age [1, 12]. According to this model, one might expect patients with severe COPD to be older. This was not the case in ECLIPSE. In fact, we did not find any relationship between age and FEV1. Several explanations can be conceived for this, apparently odd, observation. On the one hand, it should be explicitly acknowledged that ECLIPSE is not a population-based study. Hence, this observation can be due to sampling bias, as compared to the epidemiological studies where most of the conflicting data comes from . Thus, factors relating to subject recruitment into ECLIPSE may have resulted in similarly aged subjects regardless of severity being enrolled. On the other hand, the lack of relationship between age and severity of airflow limitation may also indicate that the ECLIPSE subjects had previously had a wide range of lung function decline, a possibility that would be perfectly in line with the accepted pathophysiological models of COPD [1, 12] because it would suggest that, similarly to what has been described in idiopathic pulmonary fibrosis  and has been suggested in COPD [14, 15], there are likely to be rapid and slow decliners among the population of COPD patients at large. This hypothesis will be tested directly in the three-year longitudinal portion of ECLIPSE.
Tobacco smoking is the main risk factor for COPD  but it is well established that not all smokers develop the disease as indicated by the identification of susceptible and non-susceptible smokers . We observed that, even among susceptible smokers (i.e. those smokers who have already developed COPD), the relationship between smoking exposure, as gauged by self-reported cigarette use, and airflow limitation is poor, albeit statistically significant (Figure 3, panel B). This suggests that 'susceptibility' is not a yes-no phenomenon. In fact, a range of 'susceptibility levels' was already suggested by Fletcher and Peto in 1977 , and has been more recently confirmed in the Framingham offspring cohort , potentially reflecting genetic differences or interactions with other risk factors, such as nutrition or infections. However, similarly to what we discussed above in relation to age, because ECLIPSE is not a population-based study, a potential sampling bias cannot be excluded. Likewise, smoking exposure was assessed by self-reported pack-years, which is known to be a very crude estimate of cumulative exposure to smoking.
Relief of symptoms and prevention of exacerbations are two of the main goals of COPD management . To achieve them, therapy in COPD is guided broadly by the severity of airflow limitation . We confirmed  that airflow limitation was poorly related to the degree of breathlessness, health status, 6MWD and number of exacerbations reported in the year before the study (Figure 4). Furthermore, as discussed above, within each category of airflow limitation, mMRC, SGRQ-C, 6MWD and the number of reported exacerbations varied widely. In fact, a substantial percentage of patients with severe airflow obstruction did not complain of symptoms, report exacerbations or show impaired exercise tolerance (Figure 4). These observations support the strategy suggested by the UK National Institute for Clinical Excellence (NICE) in that symptoms, exacerbations and co-morbidities must also be included in the assessment of the severity in any given patient, rather than just spirometry alone, because this is likely to offer a more appropriate way to direct therapy [18, 19].
We found that the frequency of reported exacerbations increased in parallel with airflow limitation but, interestingly, exacerbations were not reported by a substantial proportion of patients, including those with severe disease (Figure 4, panel C). Because this observation was based on patient recall, it may be subject to both selection and recall bias. Observations in relation to exacerbations, therefore, need to be confirmed prospectively during follow-up in ECLIPSE. If confirmed, a deeper understanding of why some patients with COPD develop exacerbations, which may represent a phenotype of COPD, whereas others do not (which may represent another one) despite a similar degree of airflow limitation may emerge. We could not confirm previous observations  that exacerbations of COPD were more prevalent among patients with chronic bronchitis, at each GOLD stage (Table 4). Yet, these are self-reported exacerbations over the previous year, and this may be subject to recall bias, so this finding will have to be confirmed or refuted during prospective follow up of these patients.
In keeping with previous results , we found that BMI and FFMI decreased progressively with increasing airflow limitation, particularly in females (Table 2). Likewise, our results also confirm that co-morbidities occur more frequently in patients with COPD than in controls . However, co-morbidities were largely independent of the degree of airflow limitation and occurred similarly in both moderate and severe disease. Because, ECLIPSE is not a population-based study, we cannot exclude some type of selection bias. However, the possibility that co-morbidities may occur early during the course of the disease raises important questions about their potential pathogenic mechanisms  and highlights the clinical importance of identifying (and treating) them if present early in the course of the disease. We also found that the extent of emphysema increased with GOLD stage, as did the proportion of COPD patients with bronchiectasis, although this proportion was small and lower than that reported previously .
We identified several, potentially relevant, gender differences. Interestingly, females had less smoking exposure for the same degree of airflow limitation (Table 2) or BODE score (Table 3), suggesting that women are more susceptible to tobacco smoke. This observation supports previous studies . Also in keeping with previous reports , we found that women reported more exacerbations than males for the same GOLD stage (Table 2). Finally, females with COPD appeared particularly susceptible to osteoporosis, inflammatory bowel disease, reflux and depression requiring treatment relative to males, but less so with respect to cardiovascular co-morbidity and diabetes (Table 2).
The main strength of our study is the large sample size of patients (and controls) included, as well as their careful clinical and functional characterisation thus allowing the study of relationships between clinical, functional, and radiological variables. The size of ECLIPSE permits more accurate estimates of the variance observed in a number of key parameters used to assess COPD patients. While ECLIPSE is not a population-based sample, recruitment was very similar to that in other clinical trials and variability between centres was minor (Figure 2). Thus, the data generated in ECLIPSE will be helpful in estimating sample sizes in future clinical studies. Our study, however, has some limitations. First, COPD patients were older than controls and had a history of more intense smoking exposure than the group of smokers with normal lung function. This may limit some of the comparisons between patients and controls, but it is not relevant for those analyses that include COPD patients only. Second, many patients were recruited from populations receiving care at the participating hospitals. Thus, the population studied here may not be a true reflection of the COPD patients regularly seen in primary care.