(2002) stratified by GOLD† and symptom‡ categories at SAPALDIA 1

(a) p,0.001; (b) p=0.083; (c) p=0.005; (d) p=0.159

Sensitivity analyses - results

In the weighted data analysis the associations between FEV1 decline, respiratory care utilisation, SF-36 summary scores and GOLD and symptom categories were robust and unchanged.

When subjects with physician-diagnosed asthma were included in the analysis, estimates of FEV1 decline for GOLD and symptom categories were close to those using the original cohort. Moreover, in this analysis the difference in FEV1 decline between asymptomatic and symptomatic subjects with stage 1 COPD was larger (−8 ml/year (95% CI −13 to −3)) than in the analysis excluding patients with asthma. The analysis centered on emergency room visits/hospitalizations for respiratory problems, as a specific respiratory care utilization outcome showed that asymptomatic subjects with stage 1 COPD had a similar rate of events to asymptomatic subjects with normal lung function (OR 0.83 (95% CI 0.19 to 3.71)). As expected, smoking persistence was associated with a faster decline in FEV₁ in subjects with stage 1 COPD than in persistent smokers with normal lung function. However, within persistent smokers with stage 1 COPD, the decline in FEV₁ was not significantly faster for symptomatic subjects than for asymptomatic subjects (data not shown). Subjects with stage 1 COPD who quit smoking had similar long-term outcomes to those with normal lung function who quit smoking. Finally, the interaction between the amount of smoking (pack years between SAPALDIA 1 and 2) and GOLD symptom categories added to the multivariate models for asymptomatic and symptomatic mild COPD subjects was not significant for decline in FEV1 (p=0.52), quality of life (PCS, p=0.23; MCS, p=0.68) and respiratory care use (p=0.19).

COMMENTS

In summary, this study found that the presence (or absence) of respiratory symptoms at baseline in adults with stage 1 COPD significantly modified long-term FEV1 decline, respiratory care utilization patterns and health-related quality of life scores. Symptomatic subjects with stage 1 COPD had long-term faster decline in lung function, increased

respiratory care utilization and lower health-related quality of life than asymptomatic subjects with normal lung function, whereas asymptomatic subjects with stage 1 COPD were similar to the reference group regarding these outcomes. In contrast, subjects with stages 2–4 COPD

Historically, accelerated decline in lung function has been recognized as a hallmark of COPD[10]. In the present study the net FEV₁ decline in subjects with stage 1 COPD, taken together, was faster than in subjects with normal lung function. However, we found that the decline in FEV1 within the subjects with stage 1 COPD was statistically different in relation to the absence or presence of respiratory symptoms. Those with stage 1 COPD and symptoms had a significantly faster decline in FEV1 than asymptomatic subjects with normal spirometry.

On the other hand, asymptomatic subjects labelled as stage 1 COPD had a trend towards a faster decline in FEV1 which was not statistically significant. Symptoms might be linked to a remodelling process of higher intensity in the airways and, as a consequence, may represent a prognostic marker of functional impairment[167]. We also found that the risk of stage 2AO elven years after inclusion was twice larger for those who had normal lung function and symptoms compared to those who were asymptomatic (OR 1.86 [CI95% 1.14-3.4]) . This hypothesis is consistent with the observation that chronic bronchitis without obstruction is a risk factor for developing COPD. For example, Lindberg reported a 2–3-fold increase in the cumulative 10-year incidence of COPD in the presence of respiratory symptoms [168]. This was also found by de Marco in a longitudinal population study where the risk of COPD was higher for those with persistent bronchitis symptoms than in asymptomatic subjects (relative risk 2.9 (95% CI 1.4 to 5.8)) [169]. However, to our knowledge, this is the first report to show that respiratory symptoms—as defined by chronic cough, phlegm or shortness of breath on walking—predict accelerated lung function decline and other clinically relevant outcomes in subjects with stage 1 COPD.

Symptomatic individuals with stage 1 COPD at SAPALDIA 1 were 1.6 times more likely to report respiratory care utilization, whereas those free of respiratory symptoms had similar rates to asymptomatic subjects with normal lung function. In the sensitivity analysis the results were unchanged when respiratory care utilization was strictly defined by emergency room visit or hospitalization for respiratory problems. The odds ratio of respiratory care utilization was also increased for symptomatic subjects with normal lung function. To date, no other population study has specifically reported long-term utilization of respiratory care in subjects with stage 1 COPD. The similar rate of respiratory care utilization for subjects with asymptomatic stage 1 COPD and those with normal lung function could be interpreted in several ways. Individuals labelled as stage 1 COPD may represent a normal variant of lung

that a larger cohort or a longer follow-up period than 11 years may have more power to observe differences in respiratory care utilization.

Individuals with stages 2–4 COPD at baseline had up to a six-fold higher risk of respiratory care utilization later. This is in line with the published literature. A case-control study showed that utilization of respiratory care was 12 times higher for those with physician-diagnosed COPD than for controls [170]. Similarly, a population study reported a 5–15-fold higher risk of hospitalization for subjects with stages 2–4 COPD [171]. In another cohort of patients with severe to very severe COPD, lower lung function and quality of life were independent

predictors of hospitalizations or emergency department visits [172].

In parallel with respiratory care utilization, asymptomatic subjects with stage 1 COPD and those with normal lung function had similar quality of life scores. These results are in line with a study by Antonelli-Incalzi who found that stage 1 COPD did not correspond to a meaningful alteration in quality of life [173].This study also suggested that the deterioration in the health status was possibly due to respiratory symptoms, which is also indicated by our results. Overall, symptomatic subjects with normal lung function, stage 1 or stages 2–4 COPD had significantly lower physical and mental health scores in the present cohort.

Quality of life in COPD has been mainly assessed in patients recruited from primary care clinics [174]. Compared with these studies, the physical and mental health scores of our subjects were higher, even for those with stages 2–4 COPD. This is not unexpected as our subjects were sampled from the general population and were not primarily identified as patients.

The strengths of our study are the size of the cohort, which is a representative sample of the Swiss population. For example, the SAPALDIA sample is comparable with other population studies in Europe and with the Swiss population in terms of BMI and smoking behaviour, thus supporting external validity [175]. The participation rate at follow-up was high. We were able to use detailed information on confounding factors such as lifetime smoking, nationality and education. Nevertheless, some residual confounding related to sociodemographic variables may still be present. Another strengtht of the study is the rigorous quality control of the spirometric records.

COPD. The potential of misclassification was recently evaluated at 27% by Johannessen et al in a population study in Norway using broncho-dilation and was higher for younger subjects and never-smokers [22].A Korean study reported a higher misclassification risk of 52%

[176].However, the effect of this potential misclassification is in part reduced in our study because, unlike the studies in Norway or Korea, we excluded patients with asthma. In addition, our subjects with modified stage 1 COPD were on average older than the reference group and were less likely to be never smokers. Another limitation may be the differential loss to follow-up. As in other cohort studies, subjects with a lower education level and worse lung function were more likely to be non-participants at follow-up. Such a bias would actually decrease the differences between the GOLD and symptom categories compared with the reference group. It should also be noted that, in our cohort, loss to follow-up in the stage 1 COPD category was similar to loss to follow-up in the reference group. In addition, the weighted sensitivity analyses showed that our results were only marginally affected by missing data.

Finally, we noted that the subgroup of subjects with stage 1 COPD who were persistent smokers between both surveys had an accelerated decline in FEV₁ with no significant difference between symptomatic and asymptomatic individuals. The presence or absence of symptoms might not therefore be such a strong determinant of FEV₁ decline in persistent smokers as it is in other subjects. However, a lack of power in these subgroup analyses requires caution. As a whole, our results indicate that different biological mechanisms may interact in symptomatic and asymptomatic subjects with mild COPD.

In summary, our results show that, in a population-based study, symptomatic and

asymptomatic adults with stage 1 COPD have different long-term decline in FEV₁, respiratory care utilization and quality of life scores. In addition, respiratory symptoms at baseline in subjects without GOLD-defined COPD are predictors of these outcomes. This suggests that population cross-sectional studies that are based only on spirometry may misestimate the prevalence of clinically relevant COPD. The risk of COPD misclassification is probably increased by the absence of bronchodilation to define airways obstruction. The heterogeneity of subjects with spirometry-defined stage 1 COPD should be addressed in future population studies in order to predict their long-term clinical outcomes and to estimate the public health

Because we used the fixed FEV1/FVC ratio as proposed by the GOLD guidelines instead of the lower limit of normal, our results were discussed. We re-analysed our dataset using the lower limit of normal definition for obstruction and found no relevant differences. This

analysis confirmed the important role of respiratory symptoms as predictors of long-term lung function decline in subjects with mild COPD. (see figure on page 108). [15]

Difference in adjusted* decline in forced expiratory volume in 1 s (FEV1; ml/year with 95% confidence interval) over 11 years in subjects with normal spirometry or mild obstruction, stratified at SAPALDIA 1 (1991) by GOLD and symptom categories or lower limit of normal (LLN) of FEV1 to forced vital capacity (FEV1/FVC) ratio (Source

Bridevaux et al, thorax 2008)[15]

In 2009, De Marco et al repeated the design of our study using the European Community Respiratory health Survey (ECRHS), which included more than 5000 subjects form 25 centres in Europe [33]. He tested whether subjects with FEV1/FVC ratio below the lower limit of normal (LLN-COPD) who reported respiratory symptoms or who were smokers had worse long term respiratory outcomes compared to normal subjects.

In line with our report, De Marco found that asymptomatic subjects with LLN-COPD had

*Adjusted FEV1 decline (top) and adjusted hospitalization rate ratios (bottom) for respiratory causes according to the presence LLN-COPD and respiratory symptoms at baseline (European Community Respiratory Health Survey 1) Reference category:

asymptomatic subjects with normal lung function.

*adjusted for length of follow-up, sex, age, body mass index (BMI), educational level, and

smoking habits at baseline by a two-level linear regression model (top). * Adjusted for sex, age, BMI, educational level, and smoking habits at baseline by a two-level Poisson regression (from De Marco et al

However De Marco et al also described that the pulmonary function decline was fastest among symptomatic smokers with LLN-COPD, reporting an interaction between respiratory symptoms, smoking behavior and FEV1 decline.

In summary, the long-term outcome of subjects with mild COPD is dependent on the presence of respiratory symptoms or smoking. The definition of airway obstruction itself (LLN vs

These two studies underline that even mild form of COPD should be considered when measuring prevalence. However, relying only on spirometry to measure population prevalence will bias the true burden of COPD.

CONCLUSIONS

THIS THESIS summarizes some aspects of COPD epidemiology in 2011. Prevalence of COPD is increasing worldwide. Even mild COPD is associated with worse outcomes when present in smokers or symptomatic subjects. In Switzerland, prevalence of moderate or severe COPD is lower than elsewhere. Beyond smoking, which is decreasing in developed countries, novel risk factors have been documented. In developing countries, biomass exposure probably constitutes the most important risk factor for COPD in women. In developed countries, the role of environmental risk factors such as air pollution or occupational exposure is to be considered. But, air pollution slowly decreased and heavy industries and mining activities are outsourced in developing countries. Risk factors such as asthma or bronchial

hyper-responsivness do play a role. Both may be considered as the results of interaction between genes and environment.

Future epidemiological studies will focus on COPD in non smokers. On one hand, to identify environmental exposure amenable to reduction is a primary goal of public health oriented research. On the other hand, to identify protective factors, such as nutrition or physical activities is as important. Genetic epidemiology will help to a better understanding of the causes of COPD, once the biological role of candidate genes is discovered. Individuals with

―at risk‖ genetic traits might be better informed and avoid exposure to the environmental factors interacting with the trait.

ACKNOWLEDGEMENTS

HIS WORK could not have been done without the help and support of the following people:

Professor Thierry Rochat, head of the pulmonary division and principal investigator of SAPALDIA provided invaluable advices and support.

Bernard Burnand & Jacques Cornuz at the University of Lausanne, who opened my eyes to clinical epidemiology guided me during my first years in the field. Both converted the mind of the young physicians we were to an evidence based approach of medical care.

Jean-William Fitting at the University of Lausanne who taught me the interpretation of lung function tests.

Steve Fihn, David Au and Vincent Fan at the University of Washington in Seattle who taught me the basics of biostatistics, medical writing and were models of clinical researchers

Professor Jacobus Lubsen provided advices and encouragements when they were needed.

Isabelle Peytremann-Bridevaux whose encouragement and patience helped me so much.

All my colleagues at the Pulmonary Division with special thought for Jean-Paul Janssens and Margaret Gerbase.

Laurent Kaiser & John-David Aubert for their useful professional and personal advices.

This thesis is dedicated to my wife, Isabelle, my parents Georges & Pierina, my godfather André, my children Julie & Louis and all the patients suffering with COPD.

T

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