Chest
Volume 140, Issue 1, July 2011, Pages 178-185
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Original Research
Cystic Fibrosis
Bronchiectasis and Pulmonary Exacerbations in Children and Young Adults With Cystic Fibrosis

https://doi.org/10.1378/chest.10-1152Get rights and content

Objective

Respiratory tract exacerbation rate (RTE-R) is a key clinical efficacy end point in cystic fibrosis (CF) trials. Chest CT scanning holds great potential as a surrogate end point. Evidence supporting the ability of CT scan scores to predict RTE-R is an important step in validating CT scanning as a surrogate end point. The objective of this study was to investigate the association between CT scan scores and RTE-R in a cohort of pediatric patients with CF.

Methods

A retrospective review of data from pediatric patients with CF included chest CT scans, spirometry, and 2 years follow-up. RTE-R was defined as the number of IV antibiotics courses per year. CT scans were scored with the Brody-II system, assessing bronchiectasis, airway wall thickening, mucus, and opacities.

Results

One hundred fifteen patients contributed 170 CT scans. Median age and FEV1 at first CT scan were 12 years (range, 5–20 years) and 90% predicted (range, 23% predicted-132% predicted), respectively. Analyzing exacerbation counts using Poisson regression models, bronchiectasis score and FEV1 both were found to be strong independent predictors of RTE-R in the subsequent 2 years. For the bronchiectasis score categorized in quartiles, RTE-R increased by factors of 1.8 (95% CI, 0.6–6.1; P = .31), 5.5 (95% CI, 1.9-15.4; P = .001), and 10.6 (95% CI, 3.8–29.4; P < .001), respectively, for each quartile compared with the quartile with the best (ie, lowest) scores. Similarly, time to first respiratory tract exacerbation was significantly associated with quartiles of both bronchiectasis score and FEV1.

Conclusions

The CT scan bronchiectasis score is strongly associated with RTE-R in pediatric patients with CF, providing an important piece of evidence in the validation of CT scans as an end point for CF clinical trials.

Section snippets

Study Population

This institutional review board-approved, retrospective, single-center study used clinical data from patients with CF who were followed at the Sophia Children's Hospital Cystic Fibrosis Clinic in Rotterdam, The Netherlands. Inclusion criteria were: (1) confirmed CF diagnosis, (2) one or more routine biannual chest CT scans performed between March 2002 and March 2006 while clinically stable (CT scans performed for acute respiratory deterioration were not included in the current analysis), (3) at

Results

We identified 156 patients who had at least one chest CT scan during the study period. From this cohort, 41 patients were excluded for reasons outlined in Figure 1. Thus, 115 patients were included in the current analyses, with 55 contributing two scans and 60 contributing one scan for a total of 170 scans. Total person-years of follow-up was 335. The mean ± SD follow-up period was 23.6 ± 2.2 months after each CT scan. Spirometry was performed on the same day as CT scanning for 149 of 170

Discussion

The US Food and Drug Administration defines a surrogate end point as “a laboratory measurement or physical sign that is used in therapeutic trials as a substitute for a clinically meaningful endpoint that is a direct measure of how a patient feels, functions, or survives.”20 Surrogate end points, such as CT scan scores, generally are used as a substitute for true clinical efficacy measures, such as RTEs, when the clinical benefit may not be detectable in trials of reasonable cost, duration, or

Acknowledgments

Author contributions: Dr Loeve: contributed to the study design, CT scan scoring, statistical analysis, and writing of the manuscript.

Dr Gerbrands: contributed to the data collection, CT scan scoring, and critical reading of the manuscript.

Dr Hop: contributed to the study design, statistical analysis, and writing of the manuscript.

Dr Hartmann: contributed to the study design and critical reading of the manuscript.

Dr Rosenfeld: contributed to the study design and writing of the manuscript.

Dr

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    Funding/Support: This study was supported by grants from the Sophia Cystic Fibrosis Research Fund, the Dutch Cystic Fibrosis Foundation, the Italian Cystic Fibrosis Fund, and the Cystic Fibrosis Foundation.

    Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (http://www.chestpubs.org/site/misc/reprints.xhtml).

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