Title | Restoring Cystic Fibrosis Transmembrane Conductance Regulator Function Reduces Airway Bacteria and Inflammation in People with Cystic Fibrosis and Chronic Lung Infections. |
Publication Type | Journal Article |
Year of Publication | 2017 |
Authors | Hisert KB, Heltshe SL, Pope C, Jorth P, Wu X, Edwards RM, Radey M, Accurso FJ, Wolter DJ, Cooke G, Adam RJ, Carter S, Grogan B, Launspach JL, Donnelly SC, Gallagher CG, Bruce JE, Stoltz DA, Welsh MJ, Hoffman LR, McKone EF, Singh PK |
Journal | Am J Respir Crit Care Med |
Volume | 195 |
Issue | 12 |
Pagination | 1617-1628 |
Date Published | 2017 06 15 |
ISSN | 1535-4970 |
Keywords | Adult, Aminophenols, Chloride Channel Agonists, Cystic Fibrosis, Cystic Fibrosis Transmembrane Conductance Regulator, Female, Humans, Inflammation, Lung, Male, Quinolones, Respiratory Tract Infections, Sputum, Tomography, X-Ray Computed |
Abstract | 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. |
DOI | 10.1164/rccm.201609-1954OC |
Alternate Journal | Am. J. Respir. Crit. Care Med. |
PubMed ID | 28222269 |
PubMed Central ID | PMC5476912 |
Grant List | K24 HL102246 / HL / NHLBI NIH HHS / United States P01 HL091842 / HL / NHLBI NIH HHS / United States P01 HL051670 / HL / NHLBI NIH HHS / United States P30 ES005605 / ES / NIEHS NIH HHS / United States T32 HL007638 / HL / NHLBI NIH HHS / United States P30 DK089507 / DK / NIDDK NIH HHS / United States R01 AI101307 / AI / NIAID NIH HHS / United States P30 DK054759 / DK / NIDDK NIH HHS / United States |
Submitted by kej2006 on June 6, 2018 - 4:11pm