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


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


BACKGROUND
Registered in ClinicalTrials.gov as 'Antitrypsin (AAT) to Treat Emphysema in AAT-Deficient Patients'; ClinicalTrials.gov Identifier: NCT00263887.
Parr
David G
DG
Department of Respiratory Medicine, University Hospitals of Coventry and Warwickshire, Clifford Bridge Road, Coventry CV22DX, UK. david.parr@uhcw.nhs.uk
Dirksen
Asger
A
Piitulainen
Eeva
E
Deng
Chunqin
C
Wencker
Marion
M
Stockley
Robert A
RA
D015502:Absorptiometry, Photon / Q000379:methods*; D005060:Europe; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D015990:Placebo Effect; D011379:Prognosis; D011656:Pulmonary Emphysema / Q000000981:diagnostic imaging* / Q000188:drug therapy* / Q000209:etiology; D011785:Quality Assurance, Health Care; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity; D014057:Tomography, X-Ray Computed / Q000379:methods*; D016896:Treatment Outcome; D014361:Trypsin Inhibitors / Q000008:administration & dosage; D000515:alpha 1-Antitrypsin / Q000008:administration & dosage*; D019896:alpha 1-Antitrypsin Deficiency / Q000150:complications / Q000000981:diagnostic imaging* / Q000188:drug therapy*
D014361:Trypsin Inhibitors; D000515:alpha 1-Antitrypsin
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