In this study we determined the performance characteristics of standard PFTs in discriminating emphysema in a well-defined cohort of current and former smokers. We further evaluated the correlations between airway wall thickness, airflow obstruction, and emphysema in the same population. We found that airflow obstruction, as defined by an FEV1
/FVC < 70%, was 79% sensitive and 75% specific in discriminating significant emphysema. Combining FEV1
/FVC < 70% with FEV1
< LLN increased the sensitivity of emphysema detection to 80% but reduced specificity to 63%, while other combinations of PFTs decreased specificity further, and failed to improve predictive values. Measurement of lung volumes, specifically TLC, was the only method found to meet criteria for a definitive test, i.e.
, a test in which a positive result would rule-in the presence of emphysema. However, an abnormally high TLC, in the absence of airflow obstruction, occurred rarely in our population, and therefore does not appear to have a practical application in clinical setting for detecting emphysema. Conversely, a reduced diffusion capacity was found to be quite sensitive for emphysema, however, this test is very non-specific as evidenced by a low LR+ < 1. Further current smokers had significantly reduced DLCO when compared to former smokers with the same degree of emphysema. This finding is consistent with the previously tested hypothesis that active smoking acutely reduces DLCO independent of emphysema by decreasing subjects’ lung capillary blood volume [46
We show here that measurement of the FEV1
/FVC ratio from simple spirometry demonstrated the best combination of sensitivity and specificity for discriminating emphysema and spirometry could be performed readily in clinics [15
]. In a subset of subjects with less severe emphysema (LAA 7–23%), increased airway thickness was associated with airflow obstruction, suggesting that an increase in airway wall thickness significantly contributed to airflow obstruction. Further, the failure of emphysema severity to correlate with airway wall thickness in this subset suggests that airway disease and anatomical emphysema from smoking, at least in part, may represent distinct pathophysiological processes.
Our findings are of clinical importance to the study of COPD for many reasons. Currently, the exact prevalence of emphysema in smokers is unknown and we show here that, consistent with prior studies, emphysema remains an under diagnosed medical condition [47
]. Further spirometry based classification of ever-smokers with smoking-related lung disease may fail to include those with emphysema who do not show reduced FEV1
. Our findings here, together with those of others [48
], highlight the importance of additional diagnostic tests that could provide an accurate estimate of concurrent emphysema in ever smokers. We show here that while standard pulmonary function tests correlate well with airway wall thickening, they fail to identify a substantial number of ever smokers with emphysema. These findings have important implications for the design of future clinical studies that should consider a better phenotypic classification of ever-smokers with radiographic assessment of emphysema.
Individuals with distinct patterns of anatomical emphysema may present with different degrees of pulmonary function abnormalities [50
]. In this study we found no correlation between airway wall thickness and severity of emphysema, with the caveat that we did not measure the transpulmonary pressure to control for the elastic recoil pressure. Our findings thus represent an in vivo
demonstration of the dissociation between airflow limitation, airway wall thickness and anatomical emphysema in smokers and suggest that the pathological processes underlying airway obstruction and emphysema are likely distinct. With a growing number of interventions and treatments targeted to patients specifically with emphysema [51
], and our current findings that more advanced emphysema (LAA > 23%) is always associated with airflow obstruction, it is of increasing clinical importance that these patients are identified properly at an earlier stage of their disease.
Our findings underscore the need to develop improved diagnostic and prognostic methods for evaluating ever smokers who will eventually develop irreversible lung parenchymal disease. Chest CT evaluation is clearly the standard for detecting early emphysema in vivo
, but is limited by cost and the long-term consequences of exposure to ionizing radiation [53
]. Improved diagnostic methods are essential for answering critical questions regarding the natural history of smoking-related lung disease, specifically regarding the relationship of obstructive to destructive lung diseases and whether these processes represent inexorably progressive or self-limited conditions. A proposed strategy in the evaluation of ever smokers may be to measure full pulmonary function tests, including spirometry and lung volumes, and diffusion capacity; if spirometry is normal but hyperinflation, air trapping, or reduced gas exchange are noted, a CT should be considered to evaluate for isolated emphysema. Detection of emphysema without airflow obstruction may also provide an explanation of symptoms such as dyspnea or exercise intolerance in ever smokers with normal spirometry, who might otherwise be identified as normal. Future studies are necessary to identify emphysema at an early-stage, and smokers who are at risk of developing lung disease where intervention may be more efficacious. In summary, our data supports the notion that emphysema is a pathologic process that occurs in a substantial proportion of smokers independent of airflow obstruction, and thus highlighting the need for a modern approach to the evaluation of this large population of patients.