Professional Documents
Culture Documents
Purpose: To evaluate quantitative air trapping measurements in children with mild cystic fibrosis
(CF) lung disease during a 1-year, double-blind, placebo-controlled, recombinant human deoxyri-
bonuclease (rhDNase) [dornase alfa] intervention trial and compare results from quantitative air
trapping with those from spirometry or visually scored high-resolution CT (HRCT) scans of the
chest.
Materials and methods: Twenty-five children with CF randomized to either daily rhDNase or
placebo aerosol were evaluated at baseline, and at 3 months and 12 months by spirometer-
triggered HRCT and spirometry. Outcome variables were percentage of predicted FVC, FEV1,
and forced expiratory flow, midexpiratory phase (FEF25–75%); total and subcomponent visual
HRCT scores; and quantitative air trapping measurements derived from chest HRCT images.
Results: At baseline, there were no statistical differences between groups in any of the variables
used as an outcome. After 3 months of treatment, both groups had improvements in percentage
of predicted FEV1 and FEF25–75%, and total HRCT visual scores. In contrast, the rhDNase group
had a 13% decrease in quantitative air trapping from baseline (severe air trapping [A3]),
compared to an increase of 48% in the placebo group (p ⴝ 0.023). After 12 months, both groups
had declines in percentage of predicted FVC and FEV1, but the rhDNase group retained
improvements in percentage of predicted FEF25–75% and quantitative air trapping. The mucus
plugging and total HRCT visual scores were also improved in the rhDNase group after 12 months
of treatment, with and without significant differences between groups (p ⴝ 0.026 and p ⴝ 0.676).
Quantitative air trapping (A3) remained improved in the rhDNase group (ⴚ 15.4%) and worsened
in the placebo group (ⴙ 61.3%) with nearly significant differences noted between groups
(p ⴝ 0.053) after 12 months of treatment.
Conclusions: Quantitative air trapping is a more consistent sensitive outcome measure than either
spirometry or total HRCT scores, and can discriminate differences in treatment effects in
children with minimal CF lung disease. (CHEST 2005; 128:2327–2335)
Key words: cystic fibrosis; dornase alfa; high-resolution CT; mucus plugging; quantitative air trapping
Abbreviations: A1 ⫽ mild, moderate, and severe air trapping; A2 ⫽ moderate and severe air trapping; A3 ⫽ severe air
trapping; CF ⫽ cystic fibrosis; FEF25–75% ⫽ forced expiratory flow, midexpiratory phase; HRCT ⫽ high-resolution CT;
HU ⫽ Hounsfield unit; PFT ⫽ pulmonary function test; rhDNase ⫽ recombinant human deoxyribonuclease (dornase
alfa)
T hein cystic
predominant cause of morbidity and mortality
fibrosis (CF) lung disease is progressive
lar wall thickening, and bronchial/bronchiolar airway
dilatation.3–14 Using spirometer-triggered HRCT im-
obstructive lung disease resulting from reduced mu- aging and an automated approach for quantifying air
cociliary clearance, airway obstruction, recurrent en- trapping defects, we previously demonstrated in-
dobronchial infections, and persistent inflammation creased quantitative air trapping in children with
and destruction of the airways. Early manifestations mild CF lung disease compared to age-matched
of CF lung disease include submucosal gland hyper- normal children.9 Unlike percentage of predicted
trophy, inspissated airway mucus, inflammatory in- FEV1 and forced expiratory flow, midexpiratory
filtrates, and bronchiectasis.1,2 High-resolution CT phase (FEF25–75%), which did not discriminate sta-
(HRCT) in infants and children with early and/or tistical differences between these groups, the quan-
mild CF lung disease has demonstrated evidence of titative air trapping measures clearly showed robust
peripheral regional air trapping, bronchial/bronchio- differences between groups with p values ⬍ 0.001.
*From the Departments of Pediatrics (Pulmonary) [Drs. Robin- HRCT Scoring and HRCT Image Analysis
son, Bhise, Sheikh, and Moss], and Radiology (Nuclear Medi-
cine) [Drs. Goris and Zhu], Stanford University Medical Center, Total (global) and component HRCT scores were determined
Palo Alto; and Department of Statistics (Ms. Chen), Stanford for each CT scan utilizing a scoring system similar to that of
University, Stanford, CA. Brody et al,6 with different scoring components and different
Dr. Robinson received a research grant from Genentech, Inc. of rating criteria.15 A total (global) score was calculated as the sum
$3,700.00 representing the cost of pharmacist set-up and inven-
tory activities associated with Pulmozyme and placebo medica- of the seven component scores of extent and severity of bronchi-
tion for this study. ectasis, extent and severity of bronchial wall thickening, and
Dr. Moss has received research grants from Genentech, Inc. for extent of mucus plugging, atelectasis/consolidation, and air trap-
studies related to Pulmozyme since 1993. ping. Each component feature was scored individually from 1 to
This study was funded by the Cystic Fibrosis Foundation and 4 in each lobe (with the lingula considered as a separate lobe) at
Genentech, Inc. each of the six image levels. A score of 4 for each component
Manuscript received November 26, 2004; revision accepted April would yield a total possible score of 168. The HRCT scans were
29, 2005. independently assessed by three radiologists, and the average of
Reproduction of this article is prohibited without written permission the three readers was utilized for analysis. To evaluate regional
from the American College of Chest Physicians (www.chestjournal.
org/misc/reprints.shtml). air trapping, chest HRCT images were postprocessed utilizing an
Correspondence to: Terry E. Robinson, MD, Pediatric Pulmonary automated approach for lung segmentation and subsequent air
Division, Stanford University Medical Center, 701 Welch Rd, trapping defect determination as described.9 In short, air trap-
Whelan Building, #3328, Palo Alto, CA 94305-5786; e-mail: ping was based on the density distribution of individual voxel
ter@stanford.edu densities (in Hounsfield units [HUs]) within the segmented lung
Figure 1. Example of the processing of slice No. 5 in a typical CF case. In the first column of the first
row (top), the inspiratory HRCT slice is shown next to the segmented lung at the same level. The
negative values are the median 90th percentile in HUs, a measure of CT density. In row 2 (center), the
slice image at near residual volume is in the first column, next to the segmented expiratory lung. In row
3 (bottom), the segmented expiratory lung is seen with three defects—A1, A2, and A3—in overlay in
white. The positive numbers are the percentage of voxels included in the defects. The negative values
are the HUs of the thresholds. The third image in the first row (top right) is the combined inspiratory
and expiratory histograms at that level. In row 2 (center, right), a composite of the expiratory slice with
the three defects (A1, A2, and A3) are presented in shades of gray.
Table 2—Percentage Change in PFT Results, HRCT Scores, and Air Trapping After 3 Months and 12 Months of
Treatment in CF Patients Randomized to rhDNase and Placebo Groups*
3 mo 12 mo
1 year demonstrated significant differences between numbers evaluated at 12 months similar to 3-month
groups, with a continued decline in the dornase alfa testing, the quantitative air trapping measures would
group compared to an increase in the placebo group. have demonstrated significant differences between
However, this discrimination only occurred at 1 year groups after 12 months of treatment as well. This
and not at 3 months. Overall, much more consistent suggests that quantitative CT air trapping measure-
differences between groups at 3 months and 12 ments better discriminate differences in treatment
months were demonstrated in the quantitative air effects in children with minimal CF lung disease
trapping measurements compared to spirometry or (baseline FEV1 ⱖ 70%).
visual HRCT scores. This was especially true for the In this study, there was a marked difference
quantitative A2 and A3, which demonstrated signifi- between the results of the visual HRCT air trapping
cant differences between groups after 3 months of scores and the quantitative air trapping measures (A1
treatment and nearly statistical differences between to A3). In contrast to all HRCT scoring components
groups after 12 months of intervention. It is sus- in Table 2 and quantitative air trapping measures
pected that if there had been comparable subject that improved in the dornase alfa group with treat-