Katherine B. Hisert, Sonya L. Heltshe, Christopher Pope, Peter Jorth, Xia Wu, Rachael M. Edwards, Matthew Radey, Frank J. Accurso, Daniel J. Wolter, Gordon Cooke, Ryan J. Adam, Suzanne Carter, Brenda Grogan, Janice L. Launspach, Seamas C. Donnelly, Charles G. Gallagher, James E. Bruce, David A. Stoltz, Michael J. Welsh, Lucas R. Hoffman, Edward F. McKone, Pradeep K. Singh

Previous work indicates that ivacaftor improves CFTR activity and lung function in people with cystic fibrosis (CF) 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 CF lung disease is established. To better understand the relationship between CFTR activity, airway microbiology and inflammation, and lung function in subjects with CF and chronic airway infections. We studied twelve 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 (CT) scans. Ivacaftor produced rapid decreases in sputum P. 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 two years. CT scans obtained before and 1 year after ivacaftor treatment revealed that ivacaftor decreased airway mucous plugging. 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.