Chest
Volume 153, Issue 2, February 2018, Pages 395-403
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Original Research: Genetic and Developmental Disorders
CORK Study in Cystic Fibrosis: Sustained Improvements in Ultra-Low-Dose Chest CT Scores After CFTR Modulation With Ivacaftor

https://doi.org/10.1016/j.chest.2017.10.005Get rights and content

Background

Ivacaftor produces significant clinical benefit in patients with cystic fibrosis (CF) with the G551D mutation. Prevalence of this mutation at the Cork CF Centre is 23%. This study assessed the impact of cystic fibrosis transmembrane conductance regulator modulation on multiple modalities of patient assessment.

Methods

Thirty-three patients with the G551D mutation were assessed at baseline and prospectively every 3 months for 1 year after initiation of ivacaftor. Change in ultra-low-dose chest CT scans, blood inflammatory mediators, and the sputum microbiome were assessed.

Results

Significant improvements in FEV1, BMI, and sweat chloride levels were observed post-ivacaftor treatment. Improvement in ultra-low-dose CT imaging scores were observed after treatment, with significant mean reductions in total Bhalla score (P < .01), peribronchial thickening (P = .035), and extent of mucous plugging (P < .001). Reductions in circulating inflammatory markers, including interleukin (IL)-1β, IL-6, and IL-8 were demonstrated. There was a 30% reduction in the relative abundance of Pseudomonas species and an increase in the relative abundance of bacteria associated with more stable community structures. Posttreatment community richness increased significantly (P = .03).

Conclusions

Early and sustained improvements on ultra-low-dose CT scores suggest it may be a useful method of evaluating treatment response. It paralleled improvement in symptoms, circulating inflammatory markers, and changes in the lung microbiota.

Section snippets

Methods

All patients with CF aged 6 years or older with at least one copy of the G551D mutation attending Cork CF Centre began ivacaftor treatment after March 2013 and were followed prospectively for a mean follow-up of 12 months. The prevalence of the G551D mutation at Cork CF Centre is 23%, with 51 of 220 patients carrying at least one copy of the G551D mutation. Thirty-three patients with the G551D mutation consented to participate. Eight children were too young to receive ivacaftor, six patients

Clinical Findings

Twenty adults and 13 pediatric patients participated. Table 1 summarizes baseline characteristics. The mean age of the cohort was 21.6 years, and 70% were male participants. The mean baseline FEV1 % predicted was 75.21% (SD, 20.7). The mean baseline sweat chloride level was 101 mmol/L (SD, 14.7). The majority of patients (85%) had the F508del mutation as a second mutation. One patient was homozygous for the G551D mutation. All other patients had a class I or II mutation as the second mutation.

Discussion

This is the first study to use ultra-low-dose chest CT scanning (mean dose, 0.08 mSv per scan) to serially examine the ivacaftor response over a 1-year period, allowing an assessment of the key mechanisms underlying clinical response and assessing its utility in a clinical setting to monitor CFTR modulatory therapy response. Significant improvements in ultra-low-dose chest CT scans were observed early, after 3 months of treatment, with further improvements noted after 1 year of therapy. The

Conclusions

This study demonstrates sustained improvement after ivacaftor treatment across multiple modalities of assessment, including multiple clinical parameters, ultra-low-dose chest CT imaging, blood inflammatory markers, and the lung microbiome. It suggests the potential utility of ultra-low-dose chest CT imaging as an approach for assessing treatment response.

Acknowledgments

Author contributions: N. J. R., F. S., J. A. E., M. M. M., and B. J. P. contributed to study design. N. J. R., G. G. E., M. T., D. Mooney, D. Mullane, M. C., G. O., D. M. M., O. J. O., C. A. S., M. M. T., J. A. E., M. M. M., J. S. E., and B. J. P. contributed to data acquisition, analysis, and interpretation. All authors contributed to drafting the work and final approval.

Financial/nonfinancial disclosures: The authors have reported to CHEST the folllwing: J. S. E. reports grants, personal

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    FUNDING/SUPPORT: This work received funding from the European Commission for CFMATTERS [Grant agreement 603038].

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