Ventilation heterogeneity in smokers: role of unequal lung expansion and peripheral lung structure

Smoking-induced ventilation heterogeneity measured at the mouth via established washout indices (lung clearance index LCI and alveolar mixing efficiency AME) potentially results from unequal expansion, which can be quantified by CT, and structural changes down to the lung periphery, characterized by CT parametric response mapping indices (PRMfSAD,PRMEmph). By combining CT imaging and N2 washout tests in smokers, we specifically examined the roles of unequal lung expansion and of peripheral structure. We first extracted 3D maps of local lung expansion from registered inspiratory/expiratory CT images in 50 smokers (GOLD 0-IV) to compute for each smoker, the theoretical N2 washout concentration curve solely attributable to unequal local expansion. By a head-on comparison with washout N2 concentrations measured at the mouth in the same smokers supine, we observed that (a) LCI increased from 4.8+0.2(SD) to 6.6+0.8(SD) due to unequal lung expansion alone, and further increased to 9.0+1.5(SD) independent of local expansion, (b) AME decreased (from 100% by definition) to 95+2(SD)% due to unequal expansion alone, and further decreased to 75+7(SD)% independent of local expansion. In a multiple regression between the washout indices and CT derived PRMfSAD and PRMEmph, LCI was related to PRMfSAD (r=+0.58; P<0.001) while AME was related to both PRMfSAD (rpartial=-0.44; P=0.002) and PRMEmph (rpartial=-0.31;P=0.033), in line with AME being dominated by alterations in peripheral structure. We conclude that smokers showing an increased LCI without corresponding AME decrease are predominantly affected by unequal lung expansion, whereas an AME decrease with a commensurate LCI increase indicates a smoking-induced alteration of peripheral structure.