Long-term effect of CFTR modulator therapy on airway nitric oxide

The fraction of exhaled nitric oxide (FeNO) is generally lower in individuals with cystic fibrosis (CF), compared to healthy controls. Two recent studies reported that the CFTR potentiator ivacaftor, resulted in an increase in FeNO after 4 weeks therapy [1, 2], suggesting that changes in FeNO have the potential to serve as biomarker of restored CFTR function. However, it is currently unknown whether ivacaftor results in a sustained increases in FeNO and whether combination therapy of ivacaftor with the CFTR corrector lumacaftor, also leads to changes in FeNO. Therefore, the objective of this research was to document long-term effects of ivacaftor and lumacaftor-ivacaftor therapy on FeNO in treated CF patients. The two prospective observational studies were approved by the local institutional review boards (Hospital for Sick Children's REB #1000036224 and #1000057599, St. Michael's Hospital REB #13-089). Patients were included if they had a confirmed diagnosis of CF and were eligible for treatment with either therapy. FeNO was measured before, and 1, 3, 6, 12 and 24 months after initiation of therapy during regular outpatient visits. Sputum samples were collected in the ivacaftor cohort. The non-liquid phase (mucus plugs) of the sputum was processed by adding 0.1% dithiothreitol in Dulbecco's phosphate-buffered saline (4:1, vol:wt), and the clear supernatant of the cell suspension was separated from the cells by centrifugation [3, 4]. No protease inhibitors were added. Samples were stored at −80C before analysis of L-arginine metabolism using liquid chromatography-mass spectrometry (LC-MS), as reported [5]. NO metabolites nitrate and nitrite were measured in sputum by Griess reagent [6] and myeloperoxidase (MPO) by ELISA (R&D Systems, Inc., Minneapolis, MN). Changes in outcomes between visits were assessed using paired t-tests and Wilcoxon sign-rank tests for skewed distributions, and correlations with the Pearson's correlation coefficient. Footnotes This manuscript has recently been accepted for publication in the European Respiratory Journal . It is published here in its accepted form prior to copyediting and typesetting by our production team. After these production processes are complete and the authors have approved the resulting proofs, the article will move to the latest issue of the ERJ online. Please open or download the PDF to view this article. Conflict of interest: Dr. Grasemann reports grants from Vertex Pharmaceutical, during the conduct of the study. Conflict of interest: Ms. Klingel has nothing to disclose. Conflict of interest: Dr. Avolio has nothing to disclose. Conflict of interest: Dr. Prentice has nothing to disclose. Conflict of interest: Dr. Tullis reports grants and personal fees from Vertex Pharmaceuticals, during the conduct of the study; grants and personal fees from Proteostasis, outside the submitted work. Conflict of interest: Dr. Ratjen reports grants and personal fees from Vertex, personal fees from Novartis, personal fees from Bayer, personal fees from Roche, personal fees from Genetech, outside the submitted work. Conflict of interest: Tanja Gonska received funding from Vertex pharmaceutical incl for parts of the ivacaftor observational study.