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.

Keywords: CFTR; cystic fibrosis; cytokines; inflammation; modulation; nasal lavage; sampling.

Conflict of interest statement

JGM reports grants and JGM and HE report speaker/board honoraria from Vertex, outside the submitted work. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Copyright © 2021 Mainz, Arnold, Wittstock, Hipler, Lehmann, Zagoya, Duckstein, Ellemunter and Hentschel.

Figures

Figure 1

(A–C) Method to sample NL-fluid rinsing 10 mL of isotonic saline through each nasal side while closing the soft palate. (D, E) home-based aliquotation into disposed reaction tubes, containing 15 µL of protease inhibitor, before freezing.

Figure 2

Changes in cytokines in nasal lavage after initiation of ivacaftor therapy (day 0) in two representative CF patients with a G551D mutation. (A) female, age: 27 years, follow up: 5.7 months. (B) male, age: 32 years, follow up: 5.8 months, values shown are relative changes to median of 5 [both (A, B)] measurements prior to ivacaftor. NE, neutrophil elastase; IL, interleukin.

Figure 3

Percentage changes of patients’ inflammation markers levels (dots) and their overall time trends as obtained from linear mixed-effects models. (A) An overall decreasing trend for IL-1β is observed (solid line) over the whole 12-week time period (slope: -0.19 ± 0.09 pg/mL week, p = 0.042 and intercept 2.95 ± 0.49 pg/mL, p < 0.001). (B) An overall decreasing trend (solid line) was observed for IL-8 (slope: -11.48 ± 5.86 pg/mL week, p = 0.049 and intercept 189.76 ± 32.20 pg/mL, p < 0.001). Notice that for clarity, 16 data points surpassing the 100% level in (A) and 5 data points surpassing the 200% level in (B) are not shown.

Figure 4

(A–C) Cumulative changes of inflammatory cytokines during the novel ivacaftor-therapy (regarding each periods of 4 weeks during treatment).

Figure 5

(A) Changes in sweat chloride prior to and during ivacaftor therapy (p = 0.008). Baseline mean: 96.31 ± 14.34 (median: 92.50, IQR=24.38) mmol/L. Mean after three months of therapy initiation: 40.10 ± 13.85 (median: 46.50, IQR=25.10) mmol/L. (B) Changes in FEV1 prior and during ivacaftor therapy (p=0.016). Baseline mean: 99.7 ± 20.3% predicted, (median: 103.6% predicted, IQR=20.4% predicted). Mean after three months of therapy initiation: 107.6 ± 21.4%pred (median: 109.6% predicted, IQR=18.4% predicted).