Dynamic perfluorinated gas MRI reveals abnormal ventilation despite normal FEV1 in cystic fibrosis.

We hypothesized that dynamic perfluorinated gas MRI would sensitively detect mild cystic fibrosis (CF) lung disease. This cross-sectional study enrolled 20 healthy volunteers and 24 stable subjects with CF, including a subgroup of subjects with normal forced expiratory volume in the first second (FEV1; >80% predicted, n = 9). Dynamic fluorine-19-enhanced MRI (19F MRI) were acquired during sequential breath holds while breathing perfluoropropane (PFP) and during gas wash-out. Outcomes included the fraction of lung without significant ventilation (ventilation defect percent, VDP) and time constants that described PFP wash-in and wash-out kinetics. VDP values (mean ± SD) of healthy controls (3.87% ± 2.7%) were statistically different from moderate CF subjects (19.5% ± 15.5%, P = 0.001) but not from mild CF subjects (10.4% ± 9.9%, P = 0.24). In contrast, the fractional lung volume with slow gas wash-out was elevated both in subjects with mild (9.61% ± 4.87%; P = 0.0066) and moderate CF (16.01% ± 5.01%; P = 0.0002) when compared with healthy controls (3.84% ± 2.16%) and distinguished mild from moderate CF (P = 0.006). 19F MRI detected significant ventilation abnormalities in subjects with CF. The ability of gas wash-out kinetics to distinguish between healthy and mild CF lung disease subjects makes 19F MRI a potentially valuable method for the characterization of early lung disease in CF. This study has been registered at ClinicalTrials.gov (NCT03489590).

Hypertonic saline has a prolonged effect on mucociliary clearance in adults with cystic fibrosis.

BACKGROUND: Inhaled hypertonic saline (HS) has been shown to increase mucociliary clearance (MCC) and improve clinical outcomes in adults and adolescents with cystic fibrosis (CF). However, in younger children with CF, a large study failed to demonstrate clinical benefits. This discrepancy could reflect pharmacodynamic differences in the MCC response to HS in different populations. We previously demonstrated the absence of a sustained effect of HS on MCC in healthy adults and in this study sought to characterize the durability of the MCC response to HS in adults with CF. METHODS: At two study sites, MCC was measured in CF adults using gamma scintigraphy during three separate visits: at baseline, 15 min, and 4 h after a single dose of HS (7% NaCl, 4 mL). Particle clearance rates at these visits were used to assess the durability of the MCC response to HS. RESULTS: The average 90-minute clearance rate measured 4 h after HS was significantly increased (21.81% ±â€¯12.8) when compared to baseline (13.77% ±â€¯8.7, p = .048) and showed no apparent slowing relative to the rate measured 15 min after HS. While not all subjects responded to HS, the acute response strongly predicted the sustained effect in these subjects (r = 0.896, p < .0001). CONCLUSIONS: These results suggest that, in contrast to healthy adults, a single dose of HS has a prolonged effect on MCC in adults with CF, which lasts at least 4 h. This may explain its clinical efficacy in this population.

Ivacaftor withdrawal syndrome in cystic fibrosis patients with the G551D mutation.

Ivacaftor use can lead to dramatic health improvements in cystic fibrosis (CF) patients with gating mutations. Here, we report five instances of dramatic clinical decline following withdrawal of ivacaftor in three individuals with the G551D-CFTR mutation. In each case, the patient's lung function and symptoms rapidly deteriorated after cessation of treatment. Awareness of this phenomenon should inform both clinical practices as well as the design of future clinical trials of highly active CFTR modulators.

CFTR Modulator Therapies for Cystic Fibrosis.

The cloning of cystic fibrosis transmembrane conductance regulator (CFTR) set into motion a cascade of discoveries that have helped to reveal the underlying pathophysiologic basis of cystic fibrosis (CF). This discovery and the knowledge that followed have also provided the opportunity to target this basic defect, with the hope of reversing or preventing the serious clinical consequences that result from absent CFTR function. With the recent approval of 2 therapies that directly modulate CFTR function in more than half of the CF population, we are now at the beginning of a pathway to providing increasingly effective therapies that have the potential to provide a fundamental change in the outcome of most patients with CF.