Ivacaftor Reduces Inflammatory Mediators in Upper Airway Lining Fluid From Cystic Fibrosis Patients With a G551D Mutation: Serial Non-Invasive Home-Based Collection of Upper Airway Lining Fluid

Abstract

In cystic fibrosis (CF) therapy, the recent approval of CF-transmembrane conductance regulator (CFTR) channel modulators is considered to be the major breakthrough. However, the current first-line approach based mainly on pulmonary function to measure effects of the novel therapy, tested by forced expiratory volumes in one second (FEV1), provides restricted sensitivity to detect early structural damages. Accordingly, there is a need for new sensitive surrogate parameters. Most interestingly, these should quantify inflammation that precedes a decline of pulmonary function. We present a novel method assessing inflammatory markers in the upper airways’ epithelial lining fluid (ELF) obtained by nasal lavage (NL). In contrast to broncho-alveolar lavage, ELF sampling by NL is an attractive method due to its limited invasiveness which allows repeated analyses, even performed in a home-based setting. In a longitudinal cohort study (ClinicalTrials.gov, Identifier: NCT02311140), we assessed changes of inflammatory mediators in 259 serially obtained nasal lavages taken up to every second day before and during therapy with ivacaftor from ten CF patients carrying a G551D mutation. Patients were trained to sample NL-fluid at home, to immediately freeze and transfer chilled secretions to centers. Neutrophil Elastase, Interleukins IL-1β, IL-6 and IL-8 in NL were quantified. During 8-12 weeks of ivacaftor-treatment, median values of IL-1β and IL-6 significantly declined 2.29-fold (2.97→1.30 pg/mL), and 1.13-fold (6.48→5.72 pg/mL), respectively. In parallel, sweat tests and pulmonary function improved considerably. This is the first study assessing changes of airway inflammation on a day-to-day basis in CF patients receiving a newly administered CFTR-modulator therapy. It proves a decline of airway inflammation during ivacaftor-therapy.

Detection of cytokines in nasal lavage samples of patients with cystic fibrosis: comparison of two different cytokine detection assays

“…(IL-8) and 4.3 pg/ml (IL-1β) [ 8 ]. Similar concentrations were also measured by Mainz et al using Milliplex® in NL samples [ 19 ]. These results are comparable to our values.…”

Impact of Airway Inflammation on the Efficacy of CFTR Modulators

“…However, the G551D CF subjects continued to have persistent Pseudomonas aeruginosa infections [68]. In a longitudinal cohort study with ten G551D CF patients, results from inflammatory mediators in nasal lavages indicated that the levels of IL-1β and IL-6 declined during 12 weeks after initiation of ivacaftor treatment, whereas IL-8 levels were decreased only up to 8 weeks of treatment [69]. Another recent study evaluated several clinical outcomes, including pro-inflammatory cytokines in 12 years and older F508del homozygous patients before and 8-16 weeks after initiation of therapy with lumacaftor and ivacaftor [70].…”

Regulatory T cell enhancement in adults with cystic fibrosis receiving Elexacaftor/Tezacaftor/Ivacaftor therapy

“…Current evidence on the potential anti-inflammatory effects of CFTR modulators is limited and is predominantly based on studies investigating the effects of mono- (ivacaftor) or dual combination (ivacaftor/lumacaftor, ivacaftor/tezacaftor) CFTR modulators ( 12 , 13 ). Decreased sputum levels of IL-8 and IL-1β, and decreased serum levels of tumor necrosis factor (TNF) and IL-1β have been reported in PwCF receiving ivacaftor or ivacaftor/tezacaftor, respectively ( 14 – 16 ). However, these studies involve only a small number of participants and conflicting data exist ( 17 ).…”