Figures
- FIGURE 1
Longitudinal time trends of clinical outcomes before and after cystic fibrosis transmembrane conductance regulator (CFTR) modulator initiation. Estimated longitudinal trends of per cent predicted forced expiratory volume in 1 s (FEV1 % pred), body mass index (BMI), BMI Z-score and annual intravenous (i.v.) antibiotic treatment duration. Time ranges from −7 years before to +3 years after CFTR modulator initiation, with time=0 (baseline) defined by the start date of CFTR modulator treatment. Dashed lines represent 95% confidence intervals, which are also given in parentheses. a) Mean FEV1 decline before CFTR modulator treatment was −1.36% pred per year (95% CI: −1.55– −1.17%), which changed by 0.88% pred per year (95% CI: 0.35–1.39%, p=0.001) after CFTR modulator initiation (table 2). The calculated FEV1 decline after modulator initiation (−0.48% pred per year, 95% CI: −0.99–0.01%) was added to the figure to illustrate the difference in FEV1 decline before and after CFTR modulator initiation. b) In adults ≥19 years, BMI gradually increased over time by 0.08 kg·m−2 per year (95% CI: 0.04–0.12 kg·m−2) before CFTR modulator treatment. This annual BMI trend did not significantly change (change: 0.10 kg·m−2 per year (95% CI: −0.01–0.21 kg·m−2, p=0.079)) in the years after modulator initiation (table 3). The calculated BMI after modulator initiation (0.18 kg·m−2 per year, 95% CI: 0.07–0.29 kg·m−2) was added to the figure to illustrate the difference in BMI before and after CFTR modulator initiation. c) In children <19 years, BMI Z-score initially decreased over time before CFTR modulator initiation, by a mean of −0.08 per year (95% CI: −0.10– −0.05). This annual trend significantly changed into an increasing trend (change: 0.14 per year (95% CI: 0.06–0.22, p<0.001)) in the years after CFTR modulator initiation (table 4). The calculated BMI Z-score after modulator initiation (0.06 per year, 95% CI: 0.03–0.14) was added to the figure to illustrate the difference in BMI Z-score before and after CFTR modulator initiation. d) The mean annual duration of i.v. antibiotic treatment (in days) increased by 16% (IRR: 1.16, 95% CI: 1.07–1.26, p<0.001) in the years preceding CFTR modulator treatment. In the year of CFTR modulator initiation, a drop in the mean duration of i.v. antibiotics was observed, leading to a three-times lower (IRR 0.28, 95% CI: 0.19–0.40, p<0.001) duration of i.v. antibiotic treatment compared to the years before CFTR modulator initiation. In the years after CFTR modulator initiation, the mean annual duration of i.v. treatment did not significantly change (change in IRR: 1.19, 95% CI: 0.94–1.50, p=0.153; table 5). The calculated IRR after modulator initiation (IRR: 1.84, 95% CI: 1.10–1.72) was added to the figure to illustrate the trend after CFTR modulator initiation.
Tables
- TABLE 1
Baseline characteristics (n=401)
CFTR modulator treatment, n (%) Lumacaftor/ivacaftor (LUM/IVA) 401 (100) Transition to tezacaftor/ivacaftor (TEZ/IVA) 208 (51.9) Time (years) to transition from LUM/IVA to TEZ/IVA, mean±sd 2.0±0.6 Death, n (%) 2 (0.5) Lung transplantation, n (%) 11 (2.7) Sex, n (%) Male 233 (58.1) Female 168 (41.9) Age (years), median (IQR) 24.5 (18.0–31.5) Age 12–18 years, n (%) 116 (28.9) Age >18 years, n (%) 285 (71.1) Missing, n (%) 0 FEV1 % pred, mean±sd 70.5±23.4 FEV1 <40% pred, n (%) 51 (12.7) FEV1 40–70% pred, n (%) 128 (31.9) FEV1 70–90% pred, n (%) 129 (32.2) FEV1 ≥90% pred, n (%) 90 (22.4) Missing, n (%) 3 (0.8) BMI adults (kg·m−2) ≥19 years, mean±sd 21.4±2.5 Missing, n (%) 5 (1.8) BMI Z-score children 12–19 years, mean±sd −0.5±0.8 Missing, n (%) 0 Received intravenous antibiotic treatment, n (%) Yes 149 (37.3) No 201 (50.0) Missing 51 (12.7) Duration of intravenous antibiotic treatments in days, median (IQR) 23 (17–42) Pseudomonas aeruginosa sputum culture status, n (%) Positive 179 (44.6) Negative 209 52.2) Missing 13 (3.2) Staphylococcus aureus sputum culture status, n (%) Positive 196 (48.9) Negative 192 (47.9) Missing 13 (3.2) Cystic fibrosis-related diabetes, n (%) Yes 156 (38.9) No 234 (58.4) Missing 11 (2.7) Cystic fibrosis-related liver disease, n (%) Yes 89 (22.2) No 255 (63.6) Missing 57 (14.2) Definitions: age was calculated at the date of CFTR modulator initiation (baseline). FEV1 % pred, BMI, BMI Z-score, number and duration of received intravenous antibiotic treatment, Pseudomonas aeruginosa and Staphylococcus aureus sputum culture status, CF-related diabetes and CF-related liver disease status reported at the last annual measurement preceding CFTR modulator initiation. The median duration of intravenous treatments was calculated for the 149 participants who received intravenous antibiotics in the last year prior to CFTR modulator initiation. BMI: body mass index. CFTR: cystic fibrosis transmembrane conductance regulator; FEV1 % pred: % predicted forced expiratory volume in 1 s; IQR: interquartile range.
- TABLE 2
Bayesian linear mixed effects model estimates of per cent predicted forced expiratory volume in 1 s (FEV1 % pred) (n=401, years of observation=3844)
Unadjusted coefficient 95% CI p-value Adjusted coefficient# 95% CI p-value Intercept 69.09 66.78–71.39 <0.001 70.97 68.52–73.42 <0.001 Time −1.35 −1.54 – −1.15 <0.001* −1.36 −1.55 – −1.17 <0.001* CFTR modulator 1.51 0.49–2.48 0.002* 1.51 0.56–2.46 0.002* Time : CFTR modulator 0.86 0.31–1.41 0.002* 0.88 0.35–1.39 0.001* Interpretation: the intercept represents the mean FEV1 % pred of the study population at the time of CFTR modulator initiation (baseline). The coefficient of time (in years) reflects the mean annual FEV1 % pred decline in the years before CFTR modulator initiation. The coefficient CFTR modulator indicates the acute change in mean FEV1 % pred after CFTR modulator initiation, whereas time : CFTR modulator represents the change in annual FEV1 % pred decline in the years after CFTR modulator initiation compared to the years before. CFTR: cystic fibrosis transmembrane conductance regulator. #: coefficients were adjusted for the main effects of sex, age at baseline and the interaction effect of age at baseline with time; *: significance level p<0.05.
- TABLE 3
Bayesian linear mixed effects model estimates of body mass index (BMI) in adults ≥19 years (n=312, years of observation=2317)
Unadjusted coefficient 95% CI p-value Adjusted coefficient# 95% CI p-value Intercept 21.40 21.12–21.67 <0.001 21.37 21.00–21.74 <0.001 Time 0.06 0.03–0.31 <0.001* 0.08 0.04–0.12 <0.001* CFTR modulator 0.14 −0.02–0.31 0.086 0.14 −0.03–0.31 0.097 Time : CFTR modulator 0.06 −0.03–0.15 0.217 0.10 −0.01–0.21 0.079 Interpretation: the intercept represents the mean BMI at the time of CFTR modulator initiation (baseline) in adults of 19 years and older. The coefficient of time indicates the mean annual change in BMI in the years before modulator initiation. The coefficient of CFTR modulator reflects the acute change in BMI after modulator initiation, whereas time : CFTR modulator represents the change in annual BMI in the years after CFTR modulator initiation compared to the years before. CFTR: cystic fibrosis transmembrane conductance regulator. #: coefficients were adjusted for the main effects of sex, age at baseline, the interaction effect of age at baseline with time and the interaction effect of age at baseline with time and CFTR modulator treatment; *: significance level p<0.05.
- TABLE 4
Bayesian linear mixed effects model estimates of BMI Z-score in children <19 years (n=225, years of observation=1552)
Unadjusted coefficient 95% CI p-value Adjusted coefficient# 95% CI p-value Intercept −0.60 −0.73 – −0.47 <0.001 −0.85 −1.08 – −0.62 <0.001 Time −0.06 −0.09 – −0.05 <0.001* −0.08 −0.11 – −0.05 <0.001* CFTR modulator 0.003 −0.15–0.15 0.959 0.05 −0.10–0.19 0.537 Time : CFTR modulator 0.13 0.05–0.21 0.002* 0.14 0.06–0.22 <0.001* Interpretation: the intercept represents the mean BMI Z-score at the time of CFTR modulator initiation (baseline) in children under 19 years (according to World Health Organization growth reference standards). The coefficient of time indicates the mean annual change in BMI Z-score in the years before modulator initiation. The coefficient of CFTR modulator reflects the acute change in BMI Z-score after modulator initiation, whereas time : CFTR modulator represents the change in annual BMI Z-score in the years after CFTR modulator initiation compared to the years before. BMI: body mass index. CFTR: cystic fibrosis transmembrane conductance regulator. #: coefficients were adjusted for the main effects of sex, age at baseline, the interaction effect of sex with time and the interaction effect of age at baseline with time; *: significance level p<0.05.
- TABLE 5
Negative binomial mixed effects model estimates of the duration of intravenous (i.v.) antibiotic treatment (n=364, years of observation=2805)
Unadjusted coefficient IRR 95% CI (IRR) p-value Adjusted coefficient# IRR 95% CI (IRR) p-value Intercept 1.76 5.83 3.97–8.56 <0.001 1.48 4.38 2.82–6.79 <0.001 Time 0.15 1.16 1.07–1.26 <0.001* 0.15 1.16 1.07–1.26 <0.001* CFTR modulator −1.28 0.28 0.19–0.40 <0.001* −1.28 0.28 0.19–0.40 <0.001* Time : CFTR modulator 0.16 1.18 0.93–1.49 0.170 0.17 1.19 0.94–1.50 0.153 Interpretation: coefficients are on the log-scale. Incidence rate ratios (IRRs) are transformed back to the original scale. The IRR of the intercept represents the mean duration of received i.v. antibiotics (in days) of the study population at the time of CFTR modulator initiation (baseline). The IRR of time shows the relative annual change in the duration of i.v. antibiotics before CFTR modulator treatment. The IRR of CFTR modulator reflects the acute change in the duration of i.v. antibiotics in the first year after CFTR modulator initiation, whereas time : CFTR modulator treatment indicates the relative change of i.v. antibiotic treatment in the years after modulator initiation compared to the annual trend before CFTR modulator use. CFTR: cystic fibrosis transmembrane conductance regulator. #: coefficients and IRRs were adjusted for sex and age at baseline; *: significance level p<0.05.
Supplementary Material
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Supplementary material 00204-2022.SUPPLEMENT
Supplementary tables and figure legends 00204-2022.SUPPLEMENTARY_TABLES
FIGURE S1 Comparison of longitudinal ppFEV1 trends before and after CFTR modulator initiation in subgroups with baseline ppFEV1 <40%, between 40-90% and ≥90%. 00204-2022.FIGURES1
FIGURE S2 Comparison of longitudinal BMI and BMI Z-score trends before and after CFTR modulator initiation in subgroup with baseline ppFEV1 between 40-90%. 00204-2022.FIGURES2
FIGURE S3 Comparison of longitudinal trends in IV antibiotic treatment duration before and after CFTR modulator initiation in subgroups with baseline ppFEV1 <40%, between 40-90% and ≥90%. 00204-2022.FIGURES3
