Exploring the optimum approach to the use of CT densitometry in a randomised placebo-controlled study of augmentation therapy in alpha 1-antitrypsin deficiency

Abstract

Background: Computed tomography (CT) lung densitometry has been demonstrated to be the most sensitive and specific outcome measure for the assessment of emphysema-modifying therapy, but the optimum densitometric index has yet to be determined and targeted sampling may be more sensitive than whole lung assessment. The EXAcerbations and CT scan as Lung Endpoints (EXACTLE) trial aimed to clarify the optimum approach to the use of CT densitometry data for the assessment of alpha 1-antitrypsin (AAT) augmentation therapy on the progression of emphysema in AAT deficiency (AATD).

Methods: Patients with AATD (n = 77) were randomised to weekly infusions of 60 mg/kg human AAT (Prolastin) or placebo over 2 to 2.5 years. Lung volume was included as a covariate in an endpoint analysis and a comparison was made of different CT densitometric indices (15th percentile lung density [PD15], mean lung density [MLD] and voxel index at a threshold of -910 [VI-910] and -950 [VI-950] Hounsfield Units) obtained from whole lung scans at baseline and at 24 to 30 months. Targeted regional sampling was compared with whole lung assessment.

Results: Whole lung analysis of the total change (baseline to last CT scan) compared with placebo indicated a concordant trend that was suggestive of a treatment effect for all densitometric indices (MLD [1.402 g/L, p = 0.204]; VI-910 [-0.611, p = 0.389]; VI-950 [-0.432, p = 0.452]) and that was significant using PD15 (1.472 g/L, p = 0.049). Assessment of the progression of emphysema in the apical, middle and basal regions of the lung by measurement with PD15 showed that this treatment effect was more evident when the basal third was sampled (1.722 g/L, p = 0.040). A comparison between different densitometric indices indicated that the influence of inspiratory variability between scans was greatest for PD15, but when adjustment for lung volume was made this index was the most sensitive measure of emphysema progression.

Conclusion: PD15 is the most sensitive index of emphysema progression and of treatment modification. Targeted sampling may be more sensitive than whole lung analysis.

Trial registration: Registered in ClinicalTrials.gov as 'Antitrypsin (AAT) to Treat Emphysema in AAT-Deficient Patients'; ClinicalTrials.gov Identifier: NCT00263887.

Figures

Figure 1

Voxel frequency distribution histogram indicating the appearance in normal lung and in emphysema, and the derivation of the densitometric indices that were used in the current study. 15th percentile point is defined as the cut-off value, in Hounsfield Units (HU), below which are distributed the 15% of voxels with the lowest density. (This index may be converted to the 15th percentile lung density (PD15) in g/L by the addition of 1000.) The voxel index at a threshold of -950HU (VI-950) is shown and is defined as the percentage of voxels with a value less than -950HU. The mean lung density is defined as the mean value (in g/L) of all voxels distributed within the lung histogram.

Figure 2

Changes in PD15 (g/L) in whole lung and in basal, middle and apical regions in patients treated with Prolastin versus placebo (mITT population).