c) longitudinal tracking
To assess the differences in the longitudinal course of LCI between Spiroware 3.2.1 and 3.3.1, we reanalyzed 796 measurements from 72 children with CF (Table 1). Without adjustment for risk factors, LCI increase was comparable in both settings, however less pronounced in Spiroware 3.3.1 (0.16 LCI units/year (95% CI 0.08; 0.24) vs. 0.30 LCI units/year (95% CI 0.21; 0.38) in Spiroware 3.2.1). The pattern of increase in LCI was similar in both settings, remaining stable during preschool years and school-age and then starting to increase in adolescence (Figure 3 and Supplemental Table 2). Similar to our previous findings, Aspergillus and P. aeruginosa colonization, severe exacerbations, and experiencing ABPA during the study period remained individually associated with a steeper increase in LCI also in Spiroware 3.3.1, even though with a smaller magnitude (Supplemental Table 3). The effect on covariates associated with acute changes in LCI (acute exacerbations, CF-related diabetes, BMI z-score) remained similar for both Spiroware settings (Supplemental Table 4). With adjustment for previously defined risk factors (sex, BMI, PsA- and Aspergillus-colonization, CF-related diabetes, acute and severe exacerbations) the pattern of increase in LCI was similar for both Spiroware settings, again, less pronounced for 3.3.1 (0.08 LCI units/year (95% CI 0.01; 0.14) (Spiroware 3.3.1) vs. 0.19 LCI units/year (95% CI 0.12; 0.27) in Spiroware 3.2.1) (Supplemental Figure 4).
d) Response to intervention To characterize differences in the response to intervention with double or triple modulator therapy between Spiroware 3.2.1 and 3.3.1, we reanalyzed 212 visits from 28 patients (Table 1) and compared mean LCI values at baseline, under double, under triple, and combined therapy. There was a statistically significant improvement (reduction) in LCI in all three treatment groups when compared to baseline in both Spiroware algorithms (Figure 4). In Spiroware 3.2.1, within-group mean (95% CI) absolute change from baseline was -1.7 LCI units (-2.8 to -0.5, p=0.012) under double therapy, -1.7 LCI units (-2.5 to -0.9; p≤0.001) under triple therapy, and -2.5 LCI units (-4.1 to -1.0; p=0.007) under combined modulator therapy (Figure 4 and supplemental Table 5). In Spiroware 3.3.1, LCI was substantially lower but the change from baseline remained statistically significant in all groups (within-group mean (95% CI) absolute change from baseline was -1.5 LCI units (-2.5 to -0.4, p=0.013) under double therapy, -1.3 LCI units (-1.9 to -0.7; p≤0.001) under triple therapy, and -1.7 LCI units (-2.9 to -0.5; p=0.014) under combined modulator therapy). Overall, within-group mean values differed substantially between Spiroware 3.2.1 and 3.3.1 (mean (95% CI) difference between software versions over all groups was -1.5 (-2.0 to -1.1) LCI units).
Discussion