Prevalence of stage 0
The prevalence of individuals with stage 0 in our study was 2.2% in men and 2.4% in women. In the Copenhagen City Heart study the prevalence was slightly higher; criteria for GOLD Stage 0 were met in 5.8% of the total adult population and in 7.2% of smokers [
4]. In the National Health and Nutrition Examination Study (NHANES) study [
14] the prevalence of respiratory symptoms among individuals with normal pulmonary function was substantially higher (approximately 13%). This is probably mostly dependent on different selection criteria due to variation in the definition of stage 0. Vestbo and coworkers limited the selection of individuals to those with symptoms of chronic bronchitis but included all individuals without airflow limitation irrespective of the level of FEV
1. On the other hand the NHANES study had higher prevalence rates probably due to a broader definition of the respiratory symptoms [
14]. In our study a specific definition of symptoms of chronic bronchitis was used and we only selected individuals with normal pulmonary function, both with respect to FEV
1 and the FEV
1/FVC ratio. Consequently the prevalence of stage 0 was lower in our study than in the NHANES [
14] and the Copenhagen City Heart study [
4].
Mortality risks associated with symptoms of chronic bronchitis
Among male smokers of our study, the HR of total mortality in GOLD stage 0 was strongly significant irrespective of whether we used "ever" or "recent" symptoms of chronic bronchitis" to define stage 0. The HR:s were of a similar magnitude as for stage 2. Among men with GOLD stage 1 in men and among women with stage 2 in women, increased HR:s were noticed in smokers who reported symptoms of chronic bronchitis, implying that respiratory symptoms might be important for an adverse prognosis. However, in GOLD stage 3 we were not able to show an additive risk associated with symptoms of chronic bronchitis possibly due to low statistical power.
Similar results have previously been demonstrated in some studies. In the Copenhagen City Heart study, chronic mucus hypersecretion was associated with an increased risk of all cause mortality statistically significant in men only (relative risk: 1.3 in men and 1.1 in women) [
7]. There was no interaction between the effect of chronic mucus hypersecretion and FEV
1 percent predicted with regard to total mortality which is in agreement with our results. However, also in the same study, regarding obstructive lung disease mortality, the effect of chronic mucus hyper-secretion varied with the level of ventilatory function, being weak in individuals with normal ventilatory function but more pronounced in individuals with reduced ventilatory function. This interaction was statistically significant [
7]. Furthermore, another study using the Copenhagen City Heart study population showed that chronic mucus hyper-secretion was associated with later hospitalization due to COPD, relative risks were 2.4 (1.3 to 4.5) for men and 2.6 (1.2 to 5.3) for women [
16].
In contrast, in the National Health and Nutrition Examination Study (NHANES) the presence of respiratory symptoms was not associated with an increased mortality risk in subjects with normal lung function [
14]. The relative risk (1.2) was elevated but not statistically significant probably due to the fact that a much wider definition of respiratory symptoms was used which included as well individuals with wheeze and a diagnosis of asthma. In our study based on a similar number of deaths, but also on a more specific definition of respiratory symptoms (symptoms of chronic bronchitis) a HR of 1.6 was statistically significant among smoking men.
Occupational studies have shown results in agreement with our study. In a population of 1061 men working in the Paris area and followed for 22 years, chronic phlegm production was significantly associated with mortality: Relative risk 1.35; (p less than 0.01) [
6]. In a group of gold miners, chronic mucus hyper-secretion was not related to COPD mortality, but related to mortality in ischemic heart disease and other causes after adjustment for tobacco and dust exposure [
17].
On the contrary, in another occupational cohort of 2,718 British men examined between 1954 and 1961, and followed for 20 to 25 years, the risk of death from COPD was correlated with the initial degree of air-flow obstruction. Among men with similar initial air-flow obstruction, age-specific COPD death rates were not significantly related to initial mucus hypersecretion [
18].
The explanation for the relation between chronic productive cough and future mortality risk is still unclear. Previously, in the classic study by Fletcher and coworkers, conducted in a cohort of working men in London, chronic phlegm production was unrelated to the development of airway obstruction and regarded as a less important condition [
19]. Furthermore, the presence of stage 0 at baseline was not a meaningful predictor for the subsequent development of COPD in later stages after 5 and 15 years follow-up in a Danish prospective population based study [
4].
Thus it seems that the symptoms of chronic bronchitis do not affect the FEV
1 decline and development of COPD to the same extent that it affects all-cause and obstructive lung disease mortality and risk of COPD hospitalization. An explanation could be that symptoms of chronic bronchitis may be an independent pulmonary disorder associated with inflammatory and/or infectious exacerbations [
20] and possibly also with the development of other diseases such as lung cancer [
15] and thus not specifically associated with COPD development and progression. We were able to analyse cause specific mortality in GOLD stage 0 in male smokers. Our findings of significantly increased HR for lung cancer, all cancers, and other diseases in individuals of stage 0 support this view.
Mortality risks in stages 1–4
GOLD stage 1 in our study, as well as in the NHANES study [
14], conveyed only a slight increase in total mortality risk of borderline significance, even lower than found for GOLD stage 0. Among former smokers there was a tendency towards a decreased risk. Thus among individuals who quit smoking when still in GOLD stage 1, the future mortality risk will be normal. In GOLD stages 2 to 4 our findings of increased mortality HR are in agreement with other previously conducted studies, as they actually reflect a successive reduction in FEV
1 [
21‐
23]. Mortality risks were also increased among never smokers, and these results are entirely in line with other studies [
24]. The NHANES study showed increased mortality risks associated with moderate to severe COPD, among smokers and former smokers of approximately the same magnitude as we report [
14].