Lung Function Variability in Alpha-1 Antitrypsin Deficiency: Implications for Clinical Trials

Alpha-1 antitrypsin deficiency (AATD) has considerable interindividual variability in lung disease progression. Pulmonary impairment is often measured by forced expiratory volume in one second (FEV1) and diffusing capacity of the lung for carbon monoxide (DLCO). This study aimed to quantify within-person variability in pulmonary function test (PFT) measures and identify baseline factors associated with variability.

Adult participants with AATD enrolled in the National Heart, Lung, and Blood Institute (NHLBI) Registry (1989-1992) were eligible for inclusion in this analysis if they had three serial PFTs and severe genetic deficiency. PFT variability was evaluated using linear mixed-effects models (LMM) with maximum likelihood estimation. Intra-subject variability was assessed through residual analyses. Baseline predictors, including age, sex, augmentation therapy, liver disease, and FEV1% predicted, were examined as fixed effects.

The analytic FEV1 cohort (n = 832) had a mean age of 46.3 ± 10.1 years, 44.4% were female, and 99% were white. Over a mean of 4.4 ± 1.4 years of follow-up, participants completed an average of 5.7 ± 2.0 spirometry tests. FEV1 varied by more than 10% of baseline in 82% of participants and by more than 20% in 55%. DLCO varied by more than 10% in 91% and by more than 20% in 43% of participants.

Substantial individual variability in FEV1 and DLCO was observed in this large AATD cohort. These findings suggest that FEV1 and DLCO are unreliable as clinical trial or stopping rule endpoints in AATD.