Proposal and Validation of the Minimum Clinically Important Difference in Emphysema Progression

The severity of emphysema may be measured by lung density on computed tomography (CT) scanning, and in alpha-1 antitrypsin deficiency (AATD) this measure has been used as the primary outcome in trials of disease-modifying therapy, namely augmentation. However, the minimum clinically important difference (MCID) in lung density change is not known; this study aimed to derive and validate MCIDs for density values in AATD.

The distribution method and anchoring density against forced expiratory volume in 1 second (FEV₁) were used to derive mean and 95% confidence intervals for the MCID. Data from systematic reviews of CT density measurement and therapy for AATD obtained both absolute and annual changes in lung density. Using the range of potential MCID generated by these methods, a value was chosen for validation against mortality, lung function, and health status in the Birmingham, United Kingdom AATD cohort, using regression to adjust for confounders.

Anchor and distribution methods generated a probable MCID of -1.87 g/L/year (range -1.53 to -2.20). The greatest differences between groups were found at the -2.2g/L/year with a greater FEV₁ decline in individuals with greater lung loss. Absolute lung density change had a probable MCID of -2.04g/L (range -1.83 to -2.30), and there was a difference in lung function (p<0.001) and mortality; where individuals whose absolute lung loss of more than -2.04g/L had a greater risk of death (p<0.05).

From initial evidence, we have shown absolute lung density change as a potential outcome for emphysema modifying therapies in AATD rather than annual density change, with an MCID of -2.04g/L.