Changes in Airway Microbiome and Inflammation with Ivacaftor Treatment in Patients with Cystic Fibrosis and the G551D Mutation.

RATIONALE Modulation of the cystic fibrosis transmembrane conductance regulator (CFTR) protein improves clinical outcomes in patients with cystic fibrosis (CF) and specific CFTR genetic mutations. It remains unclear how improving CFTR function modifies existing airway infection and inflammation. OBJECTIVE To compare sputum microbiome and markers of inflammation before and after 6 months of ivacaftor treatment Methods: The study included 31 people with CF, ages 10 and older, with at least one G551D CFTR allele and an FEV1 ≥ 40% predicted who were enrolled in the G551D Observational (GOAL) study. Sputum samples were collected either by induction (n = 14) or by spontaneous expectoration (n = 17) before and 6 months after initiation of ivacaftor. Changes in bacterial community indices by sequencing of 16S rRNA amplicons, total and specific bacterial load, and a panel of proteases, antiproteases, and inflammatory cytokines were determined. RESULTS The cohort that spontaneously expectorated sputum had a lower FEV1, higher proportion with Pseudomonas aeruginosa infection, and higher concentrations of sputum inflammatory markers compared with the cohort that provided sputum by induction. While the overall cohort experienced significant improvements in FEV1 and reductions in sweat chloride, no significant changes in bacterial diversity, specific bacterial pathogens, or markers of inflammation were observed in these subjects. Neither total bacterial load nor presence of Pseudomonas changed significantly between paired samples with ivacaftor treatment. Younger patients experienced more shifts in their microbial communities than older patients. CONCLUSIONS In this multicenter cohort, six months of ivacaftor treatment were not associated with significant changes in airway microbial communities or measures of inflammation. These data suggest that concomitant antimicrobial and anti-inflammatory treatments will still be needed to manage airway disease in CF patients treated with highly effective CFTR modulator therapy, especially in older patients with more advanced disease.

[1]  T. Kotsimbos,et al.  Antibiotic exposure and interpersonal variance mask the effect of ivacaftor on respiratory microbiota composition. , 2018, Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society.

[2]  W. T. Harris,et al.  Airway microbiota across age and disease spectrum in cystic fibrosis , 2017, European Respiratory Journal.

[3]  L. Hoffman,et al.  Restoring Cystic Fibrosis Transmembrane Conductance Regulator Function Reduces Airway Bacteria and Inflammation in People with Cystic Fibrosis and Chronic Lung Infections , 2017, American journal of respiratory and critical care medicine.

[4]  F. Accurso,et al.  Use of ibuprofen to assess inflammatory biomarkers in induced sputum: Implications for clinical trials in cystic fibrosis. , 2015, Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society.

[5]  J. Mounier,et al.  Impact of the CFTR-Potentiator Ivacaftor on Airway Microbiota in Cystic Fibrosis Patients Carrying A G551D Mutation , 2015, PloS one.

[6]  B. Ramsey,et al.  Pseudomonas aeruginosa in cystic fibrosis patients with G551D-CFTR treated with ivacaftor. , 2015, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[7]  J. Harris,et al.  Assessment of airway microbiota and inflammation in cystic fibrosis using multiple sampling methods. , 2015, Annals of the American Thoracic Society.

[8]  Umer Khan,et al.  Clinical mechanism of the cystic fibrosis transmembrane conductance regulator potentiator ivacaftor in G551D-mediated cystic fibrosis. , 2014, American journal of respiratory and critical care medicine.

[9]  Daniel N. Frank,et al.  Explicet: graphical user interface software for metadata-driven management, analysis and visualization of microbiome data , 2013, Bioinform..

[10]  J. Mainz,et al.  Efficacy and safety of ivacaftor in patients aged 6 to 11 years with cystic fibrosis with a G551D mutation. , 2013, American journal of respiratory and critical care medicine.

[11]  Leah M. Feazel,et al.  Sex Differences in the Gut Microbiome Drive Hormone-Dependent Regulation of Autoimmunity , 2013, Science.

[12]  S. Sagel,et al.  Sputum biomarkers of inflammation and lung function decline in children with cystic fibrosis. , 2012, American journal of respiratory and critical care medicine.

[13]  S. Willsie.  A CFTR Potentiator in Patients with Cystic Fibrosis and the G551D Mutation , 2012 .

[14]  Matthias Griese,et al.  A CFTR potentiator in patients with cystic fibrosis and the G551D mutation. , 2011, The New England journal of medicine.

[15]  J. Harris,et al.  Reliability of Quantitative Real-Time PCR for Bacterial Detection in Cystic Fibrosis Airway Specimens , 2010, PloS one.

[16]  M. Conese,et al.  Validation of an automated sensitive immunoassay for quantitation of cytokines in the sputum of cystic fibrosis patients , 2007, Clinical chemistry and laboratory medicine.

[17]  T. Asahara,et al.  Sensitive Quantitative Detection of Commensal Bacteria by rRNA-Targeted Reverse Transcription-PCR , 2006, Applied and Environmental Microbiology.

[18]  Neil Hunter,et al.  Determination of bacterial load by real-time PCR using a broad-range (universal) probe and primers set. , 2002, Microbiology.

[19]  F. Accurso,et al.  Airway inflammation in children with cystic fibrosis and healthy children assessed by sputum induction. , 2001, American journal of respiratory and critical care medicine.