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Restoring Cystic Fibrosis Transmembrane Conductance Regulator Function Reduces Airway Bacteria and Inflammation in People with Cystic Fibrosis and Chronic Lung Infections

Hisert, Katherine B. and Heltshe, Sonya L. and Pope, Christopher and Jorth, Peter and Wu, Xia and Edwards, Rachael M. and Radey, Matthew and Accurso, Frank J. and Wolter, Daniel J. and Cooke, Gordon and Adam, Ryan J. and Carter, Suzanne and Grogan, Brenda and Launspach, Jan L. and Donnelly, Seamas C. and Gallagher, Charles and Bruce, James E. and Stoltz, David and Welsh, Michael J. and Hoffman, Lucas R. and McKone, Edward F. and Singh, Pradeep K. (2017) Restoring Cystic Fibrosis Transmembrane Conductance Regulator Function Reduces Airway Bacteria and Inflammation in People with Cystic Fibrosis and Chronic Lung Infections. American Journal of Respiratory and Critical Care Medicine, 195 (12). pp. 1617-1628. ISSN 1073-449X.

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Rationale: Previous work indicates that ivacaftor improves cystic fibrosis transmembrane conductance regulator (CFTR) activity and lung function in people with cystic fibrosis and G551D-CFTR mutations but does not reduce density of bacteria or markers of inflammation in the airway. These findings raise the possibility that infection and inflammation may progress independently of CFTR activity once cystic fibrosis lung disease is established. Objectives: To better understand the relationship between CFTR activity, airway microbiology and inflammation, and lung function in subjects with cystic fibrosis and chronic airway infections. Methods: We studied 12 subjects with G551D-CFTR mutations and chronic airway infections before and after ivacaftor. We measured lung function, sputum bacterial content, and inflammation, and obtained chest computed tomography scans. Measurements and Main Results: Ivacaftor produced rapid decreases in sputum Pseudomonas aeruginosa density that began within 48 hours and continued in the first year of treatment. However, no subject eradicated their infecting P. aeruginosa strain, and after the first year P. aeruginosa densities rebounded. Sputum total bacterial concentrations also decreased, but less than P. aeruginosa. Sputum inflammatory measures decreased significantly in the first week of treatment and continued to decline over 2 years. Computed tomography scans obtained before and 1 year after ivacaftor treatment revealed that ivacaftor decreased airway mucous plugging. Conclusions: Ivacaftor caused marked reductions in sputum P. aeruginosa density and airway inflammation and produced modest improvements in radiographic lung disease in subjects with G551D-CFTR mutations. However, P. aeruginosa airway infection persisted. Thus, measures that control infection may be required to realize the full benefits of CFTR-targeting treatments.

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Jorth, Peter0000-0002-0981-740X
Alternate Title:Restoring CFTR Function Reduces Airway Bacteria and Inflammation in People With Cystic Fibrosis and Chronic Lung Infections
Additional Information:© 2017 American Thoracic Society. Received: September 28, 2016; Accepted: February 15, 2017; Published Online: February 21, 2017. Supported by an investigator-initiated award from Vertex, Inc., National Institutes of Health grants R01AI101307 and K24HL102246 (P.K.S.), European Commission Seventh Framework Program Project 603038 CFMatters (P.K.S.), the Cystic Fibrosis Foundation (K.B.H., P.J., and P.K.S.), and the Burroughs Wellcome Fund (P.K.S.). Author Contributions: Concept and design, K.B.H., S.L.H., X.W., J.E.B., D.A.S., M.J.W., L.R.H., E.F.M., and P.K.S. Acquisition of data, analysis, and interpretation, K.B.H., S.L.H., C.P., P.J., F.J.A., X.W., M.R., R.M.E., D.J.W., R.J.A., G.C., S.C., B.G., J.L.L., S.C.D., C.G.G., J.E.B., D.A.S., M.J.W., L.R.H., E.F.M., and P.K.S. Drafting the manuscript, K.B.H., S.L.H., M.R., D.A.S., M.J.W., L.R.H., E.F.M., and P.K.S. All authors revised the manuscript critically.
Funding AgencyGrant Number
European Commission603038 CFMatters
Cystic Fibrosis FoundationUNSPECIFIED
Burroughs Wellcome FundUNSPECIFIED
Subject Keywords:Cystic Fibrosis; Pseudomonas aeruginosa; Ivacaftor; Inflammation
Issue or Number:12
Record Number:CaltechAUTHORS:20170227-074612083
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Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:74533
Deposited By: Tony Diaz
Deposited On:27 Feb 2017 18:45
Last Modified:09 Mar 2020 13:18

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