Discussion
The main finding of our study is that reduced DLCO is present in more than a quarter of current smokers without airflow limitation, being associated with lower spirometric parameters, as well as reduced exercise tolerance and less daily physical activity. Furthermore, a reduced FVC and increased exhaled CO have been identified as independent predictors of reduced DLCO in smokers without airflow limitation.
As previous methodological comments, it is worth mentioning that the procedure followed for study subject selection generated a sample with a prevalence of current and former smokers that are the same as in the general population of our country (22% and 25%, respectively).32 In fact, to our knowledge, this is the first article that shows a population approach to the evaluation of DLCO with simultaneous measurements of low dose CT scan in smokers without airflow limitation.
The population prevalence of DLCO below the LLN identified in our study in current and former smokers (19.8%) is consistent with the 17% previously described in active smokers selected from advertisements to assess lung health10 and 24% identified in a retrospective analysis of a lung function database.33 In addition, our data confirm the relationship of DLCO with some previously identified variables, such as male gender or spirometric parameters.34–36 However, the sample analysed has not identified a relationship between DLCO and the presence of chronic respiratory symptoms. This finding is also consistent with a small study of 58 smokers without airflow limitation, in which subjects who reported non-specific respiratory problems, chronic bronchitis or wheezing had lower spirometric parameters, but no differences were found in DLCO or with the single-breath nitrogen method, suggesting that symptoms are more related to physiological changes in the central airways than in the peripheral airways.37
Although some previous studies have described a weak relationship between the DLCO of heavy smokers (>20 pack-years) and lung attenuation,6 38 they included a notable percentage of patients with airflow limitation. Thus, in a subsample of smokers or former smokers from the GenKOLS study, DLCO was related to the percentage of low-attenuation areas and to the standardised airway wall thickness only in patients with COPD, while in subjects without airflow limitation the same relationship was not significant.39 Similarly, in 38 former smokers without airflow limitation, no differences in low-attenuation areas or bronchial wall thickness were identified between those with normal or low DLCO.40 This suggests that, in early phases of smoking-induced lung damage, the decrease in DLCO is not attributable to emphysema-like changes. As DLCO decreases in a wide variety of pathologic conditions, including reduction in alveolar surface area, decreased perfusion, even ventilation or inflammation or fibrosis of the alveolar wall impairing alveolar diffusion,5 impaired gas exchange may not necessarily reflect early emphysema, since it may be due to other smoking-related changes, including altered membrane diffusion or pulmonary vascular changes.41 The contribution of peripheral airways to DLCO reduction has been suggested in never-smokers from the COPDGene cohort, in which small airway dysfunction correlated significantly with lower DLCO among both non-obstructed and GOLD 1–2 subjects.42 This might justify that, in our smoker subjects, FVC was retained as an independent predictor of low DLCO, instead of FEV1, since the former better represents the contribution of the whole bronchial tree, including its most distal portions.
In this study, the other risk factor independently associated with the presence of reduced DLCO was increased exhaled CO. The DLCO correction for exhaled CO suggests that its contribution does not seem to be exclusively dependent on CO backpressure, so it is interesting to consider that exhaled CO is a recognised indicator of oxidative stress,43 one of the main causes of endothelial damage. This possibility is reinforced by the identification in smokers with reduced DLCO of low levels of albumin, a negative acute-phase reactant with anti-inflammatory and antioxidant properties.44 Indeed, it has been suggested that albumin level may be a marker of susceptibility to the oxidative response resulting from smoking, while albuminuria should be a non-invasive marker of arterial stiffness.45 Although merely speculative, these findings are in agreement with some current evidence suggesting that peripheral airway destruction might be initiated, in part, by early smoking-induced damage to the pulmonary vascular endothelium mediated by plasma endothelial microparticles with apoptotic features, which are elevated in smokers with normal spirometry and reduced DLCO.46 It is particularly attractive to consider that, in the absence of lung parenchymal damage, DLCO provides a window into the microvasculature of smoker subjects. Thus, the lower DLCO of smokers probably reflects the presence of greater ventilation-perfusion inequalities, lower carbon dioxide elimination efficiency and, consequently, greater ventilatory stimulation,47 which, in turn, would justify the higher degree of dyspnoea reported by our smokers with reduced DLCO. This basic physiological proposal is in line with studies about exercise response in smokers at risk of COPD, in which exercise dyspnoea is mainly explained by increased inspiratory neural drive.47 Furthermore, this could also explain their lower exercise tolerance, consistently with the previous description of a correlation between low DLCO and reduced 6 min walk distance in former smokers with normal chest CT scans and spirometry.40 However, since the EPISCAN study protocol did not include the determination of functional residual capacity or inspiratory capacity, it is not possible to completely rule out the existence of a certain degree of hyperinflation not detected by lung imaging tests, which is a main determinant of exercise tolerance in patients with airflow limitation.48
Finally, one last aspect of our study to highlight is the larger diameter of the PA found in smokers with reduced DLCO compared with those with normal DLCO. Although this difference does not lead to significant differences in the PA enlargement between the two smoker subgroups or in the relationship between the diameter of the PA and the ascending aorta, which is the most consistent indicator of pulmonary hypertension,49 they might also reflect an early impact of smoking on the pulmonary vascular bed. In this regard, it is interesting to note that cigarette smoking has recently been shown to contribute to pulmonary arterial remodelling through several hypoxia-independent pathways that promote K+channel dysregulation in the absence of clinically established COPD.50
Our study has several limitations that are worth discussing. First, the cross-sectional design does not allow for cause-and-effect relationships to be established, although the data reveal that reduced DLCO is associated with differences in dyspnoea level, exercise tolerance and PA diameter. Second, the sample size may be limiting for some subanalyses, despite providing a representative sample of smokers at the population level and achieving statistical significance in most comparisons. Third, other spirometric parameters suggestive of peripheral airway disease have not been evaluated, such as the FEV3/FEV6 ratio, whose decrease is highly prevalent in smokers with preserved pulmonary function but impaired indices of physical function and quality of life.51 52 And fourth, the EPISCAN II study did also not include specific measurements of small airway function or pulmonary microcirculation to allow for the specific assessment of their relationship with a reduced DLCO.
In conclusion, this study shows that reduced DLCO is a frequent finding among smokers without airflow limitation and is associated with a limited exercise tolerance and reduced daily physical activity, as well as a larger PA diameter. These findings, together with increased exhaled CO and reduced plasma albumin, in the absence of differences in the lung parenchyma attenuation, allow us to speculate that, in these subjects, DLCO may be a surrogate marker of smoking-induced early vascular lung damage.