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

Abstract

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).

Keywords: Diagnostic imaging; Pulmonology.

Conflict of interest statement

Conflict of interest: RCB is the Chairman of the Board of Parion Sciences. Parion Sciences is a privately held UNC spin-out company focused on developing therapies for CF. RCB reports having equity in Parion Sciences and receiving monetary compensation as board chair. BJS holds patents assigned to Duke related to the 19F imaging technology. HCC holds patents assigned to Duke related to the 19F imaging technology. (Patent nos. 13/577926, 2011218194, 2793101, 2011800194020, 11745148.4, and PCTUS11025011.)

Figures

Figure 1. Consort diagram detailing reasons for subject exclusion from analysis.

Figure 2. Ventilation Kinetics Analysis.

(A and B) Histograms of wash-in (A) and wash-out (B) time constants for healthy controls, mild CF subjects, and moderate CF subjects. (C–F) Scatter and box plots (median ± 95% CI) demonstrating FLV of fast wash-in (C), fast wash-out (D), slow wash-in (E), and slow washout (F). ANOVA. Tukey’s honest significance test (HSD) was performed for multiple between-group comparisons. Slow emptying fraction: healthy vs. mild CF, P = 0.007; mild CF vs. mod CF, P = 0.006. Fast emptying fraction: healthy vs. mild CF, P = 0.04; mild vs. moderate CF, P = 0.13).

Figure 3. Representative color-coded heatmaps of τ2, demonstrating distribution of voxels with prolonged gas wash-out.

The x and y axes are marked in centimeters. (A) Healthy control. (B) Mild CF. (C) Moderate CF.

Figure 4. Correlations of VDP and FLV with FEV1.

Scatterplot demonstrating the correlation (via Spearman rank-order correlation) of VDP with FEV1 (A) and FEF25–75 (B) in CF subjects. (A) FEV1 correlation coefficient, –0.703; P = 0.001. (B) FEF25–75 correlation coefficient, –0.686; P = 0.0015. C and D demonstrate correlation of FLV with slow τ2 with FEV1 and FEF25–75, respectively. (C) FEV1 correlation coefficient, –0.686; P = 0.0015. (D) FEF25–75 correlation coefficient, –0.763; P < 0.0001.

Figure 5. Example 4D 19F image set for a healthy control, mild CF subject, and moderate CF subject with lung contours.

All image sets are 3D so acquisition over time results in a 4D data set. Steady state image for VDP calculation is defined as the fifth wash-in image. Images in sequence: 1H GRE, first wash-in, fifth wash-in, first wash-out, final wash-out. Signal/noise ratio (SNR) for first wash-in in mild CF subject was 8.342 ± 3.078, compared with SNR of 15.562 ± 4.073 for fifth wash-in image.