Our analysis of HRCT scans from this large cohort shows that interstitial lung abnormalities are present in approximately 8% of smokers. The findings also show that interstitial lung abnormalities are associated with both reduced total lung capacity and a lesser amount of emphysema in smokers, and the magnitude of these reductions is greatest among those with COPD. We found that smokers with interstitial lung abnormalities have reduced total lung capacity (the extent of which varies according to the subtype of interstitial lung abnormality) and are at an increased risk for a restrictive lung deficit. Although reductions in total lung capacity are expected in established clinical interstitial lung disease,17
our data provide a quantitative estimate of the degree to which interstitial lung abnormalities are associated with reductions in total lung capacity.
A major finding of our analyses is the inverse association between interstitial lung abnormalities and the severity of COPD or of emphysema (particularly among participants with COPD). We considered the possibility that interstitial lung abnormalities would result in an erroneous underestimation of the amount of emphysema by increasing the overall lung density defined by Hounsfield-unit thresholds. Several lines of evidence suggest that a density shift in the distribution of Hounsfield units is unlikely to explain our findings. First, the associations we found between emphysema and interstitial lung abnormalities were not most prominent in the lower lobes, where more interstitial abnormalities are expected (see the Supplementary Appendix
). Second, the reductions in emphysema noted in participants with interstitial lung abnormalities were paired with the physiological consequences of reduced emphysema (e.g., additional reductions in total lung capacity). Third, we noted inverse associations between the presence of interstitial lung abnormalities and clinically diagnosable COPD, a variable that is independent of the measurement of emphysema with the use of HRCT.
Our findings are consistent with, and add weight to, previous studies showing that cigarette smoking is associated with both spirometric restriction18
and areas of high attenuation on HRCT.3
Since emphysema and interstitial lung abnormalities have opposing effects on lung volume, our findings suggest that HRCT may provide important diagnostic information in smokers whose total lung capacity is unexpectedly “normal.” We speculate that this could be clinically important to physicians who may think that a patient who does not have symptoms or characteristic abnormalities on lung-function tests is disease-free, when in fact the patient could be affected by two of the consequences of smoking — emphysema and interstitial lung abnormalities.
It is possible that a number of smokers with interstitial lung abnormalities have clinically diagnosable respiratory bronchiolitis, a well-described interstitial lung disease that is related to smoking and associated with ground-glass opacities and centrilobular nodules,19,20
or smoking-related interstitial fibrosis,21
a less well-defined entity with features overlapping those of usual interstitial pneumonia and emphysema.22
However, among the participants in the COPDGene Study with interstitial lung abnormalities, 81% (157) had specific radiographic features and reductions in lung volumes that are not typical of respiratory bronchiolitis.9
As mentioned previously, expected reductions in lung volumes among patients with smoking-related interstitial lung abnormalities could be masked by concomitant emphysema.
Our study has several limitations. First, we recognize that congestive heart failure, compression artifacts from bullous emphysema, and atelectasis could mimic the changes on chest HRCT that we have defined as interstitial lung abnormalities. However, in a prior study that excluded participants with heart failure (defined by a physician’s diagnosis), a similar association between interstitial lung abnormalities and cigarette smoking was noted.3
In addition, a strong inverse association between emphysema and interstitial lung abnormalities suggests that compression artifacts associated with bullous emphysema are an unlikely explanation for our findings. Moreover, our study shows similar associations with total lung capacity and lung volume at relaxed exhalation, which suggests that our findings are probably not the result of differences in inspiratory effort (or atelectasis). Second, although our measurements of total lung capacity were obtained by means of HRCT, not body plethysmography, previous studies have consistently reported very high degrees of correlation between these measurements (r2
and recent data suggest that plethysmography may be a less accurate measurement of total lung capacity than radiographic measurement in patients with COPD.25
Third, since our population includes smokers with an oversampling of participants with COPD, caution should be exercised in extrapolating our findings to general population samples.
We have found that as compared with smokers without interstitial lung abnormalities, smokers with interstitial abnormalities on HRCT, particularly smokers with COPD, have a reduced total lung capacity and a lesser amount of emphysema. Longitudinal follow-up studies of persons with interstitial lung abnormalities will be required to determine whether these radiographic abnormalities, and the associated reductions in lung volumes, are transient or stable, or whether they will progress to clinically significant disease.