
==== Front
Eur Respir J
Eur Respir J
ERJ
erj
The European Respiratory Journal
0903-1936
1399-3003
European Respiratory Society

38901883
10.1183/13993003.00004-2024
ERJ-00004-2024
Version of Record
Original Research Articles
Cystic Fibrosis
3
Impact of elexacaftor/tezacaftor/ivacaftor therapy on lung clearance index and magnetic resonance imaging in children with cystic fibrosis and one or two F508del alleles
Impact of ETI in children with CF and 1 or 2 F508del alleles
https://orcid.org/0000-0001-6941-8315
Stahl Mirjam 12314
Dohna Martha 414
https://orcid.org/0000-0002-1666-8924
Graeber Simon Y. 12314
https://orcid.org/0000-0002-3941-8944
Sommerburg Olaf 5614
Renz Diane M. 4
Pallenberg Sophia T. 78
Voskrebenzev Andreas 4
https://orcid.org/0000-0003-2680-3541
Schütz Katharina 78
Hansen Gesine 789
Doellinger Felix 10
Steinke Eva 123
https://orcid.org/0000-0001-9090-7869
Thee Stephanie 123
https://orcid.org/0000-0002-1535-8852
Röhmel Jobst 123
Barth Sandra 1112
Rückes-Nilges Claudia 1112
Berges Julian 56
Hämmerling Susanne 5
https://orcid.org/0000-0001-6962-037X
Wielpütz Mark O. 613
Naehrlich Lutz 111215
Vogel-Claussen Jens 4815
https://orcid.org/0000-0002-2566-8758
Tümmler Burkhard 7815
https://orcid.org/0000-0002-4057-2199
Mall Marcus A. 12315
https://orcid.org/0000-0002-9582-1025
Dittrich Anna-Maria 7815
1 Department of Pediatric Respiratory Medicine, Immunology and Critical Care Medicine, and Cystic Fibrosis Center, Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
2 Berlin Institute of Health (BIH) at Charité – Universitätsmedizin Berlin, Berlin, Germany
3 German Center for Lung Research (DZL), Associated Partner Site, Berlin, Germany
4 Department for Radiology, Hannover Medical School, Hannover, Germany
5 Division of Pediatric Pulmonology and Allergy, and Cystic Fibrosis Center, Department of Pediatrics, University of Heidelberg, Heidelberg, Germany
6 Translational Lung Research Center Heidelberg (TLRC), German Center for Lung Research (DZL), University of Heidelberg, Heidelberg, Germany
7 Department for Pediatric Pneumology, Allergology and Neonatology, Hannover Medical School, Hannover, Germany
8 German Center for Lung Research, Biomedical Research in Endstage and Obstructive Lung Disease (BREATH), Hannover Medical School, Hannover, Germany
9 Cluster of Excellence RESIST (EXC 2155), German Research Foundation (DFG), Hannover Medical School, Hannover, Germany
10 Department of Radiology, Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
11 Department of Pediatrics, Justus Liebig University Giessen, Giessen, Germany
12 Universities of Giessen and Marburg Lung Center (UGMLC), German Center for Lung Research (DZL), Giessen, Germany
13 Department of Diagnostic and Interventional Radiology, University of Heidelberg, Heidelberg, Germany
14 M. Stahl, M. Dohna, S.Y. Graeber and O. Sommerburg contributed equally as first authors
15 L. Naehrlich, J. Vogel-Claussen, B. Tümmler, M.A. Mall and A-M. Dittrich contributed equally as senior authors
Corresponding author: Mirjam Stahl (mirjam.stahl@charite.de)
9 2024
05 9 2024
64 3 240000401 1 2024
28 5 2024
Copyright ©The authors 2024.
2024
https://creativecommons.org/licenses/by-nc/4.0/ This version is distributed under the terms of the Creative Commons Attribution Non-Commercial Licence 4.0. For commercial reproduction rights and permissions contact permissions@ersnet.org
Extract

Clinical trials of the triple combination cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapy elexacaftor/tezacaftor/ivacaftor (ETI) demonstrated unprecedented clinical benefits including improvements in lung function, respiratory symptoms and nutritional outcomes in patients with cystic fibrosis (CF) aged ≥2 years with at least one copy of the F508del allele [1–11]. Despite the emergence of highly effective CFTR modulator therapy, chronic progressive lung disease remains the main cause of morbidity and mortality in patients with CF; however, early intervention with CFTR-directed therapeutics in children with CF now provides an opportunity to delay or even prevent irreversible lung damage. Because of the limited sensitivity of percentage predicted forced expiratory volume in 1 s (FEV1) to capture response to therapy in CF children with preserved spirometry [12, 13], more sensitive outcome measures such as multiple-breath washout (MBW) and lung imaging by computed tomography (CT) and magnetic resonance imaging (MRI) have been established [14–25]. A number of studies demonstrated that the LCI derived from MBW is sensitive to detect response to therapeutic interventions including CFTR modulators in children with CF with normal spirometry [9–15, 18].

Graphical abstract

Overview of the study. LCI: lung clearance index; N2: nitrogen; MRI: magnetic resonance imaging.

Background

We recently demonstrated that elexacaftor/tezacaftor/ivacaftor (ETI) improves the lung clearance index (LCI) and abnormalities in lung morphology detected by magnetic resonance imaging (MRI) in adolescent and adult patients with cystic fibrosis (CF). However, real-world data on the effect of ETI on these sensitive outcomes of lung structure and function in school-age children with CF have not been reported. The aim of this study was therefore to examine the effect of ETI on the LCI and the lung MRI score in children aged 6–11 years with CF and one or two F508del alleles.

Methods

This prospective, observational, multicentre, post-approval study assessed the longitudinal LCI up to 12 months and the lung MRI score before and 3 months after initiation of ETI.

Results

A total of 107 children with CF including 40 heterozygous for F508del and a minimal function mutation (F/MF) and 67 homozygous for F508del (F/F) were enrolled in this study. Treatment with ETI improved the median (interquartile range (IQR)) LCI in F/MF (−1.0 (−2.0– −0.1); p<0.01) and F/F children (−0.8 (−1.9– −0.2); p<0.001) from 3 months onwards. Further, ETI improved the median (IQR) MRI global score in F/MF (−4.0 (−9.0–0.0); p<0.01) and F/F children (−3.5 (−7.3– −0.8); p<0.001).

Conclusions

ETI improves early abnormalities in lung ventilation and morphology in school-age children with CF and at least one F508del allele in a real-world setting. Our results support early initiation of ETI to reduce or even prevent lung disease progression in school-age children with CF.

Shareable abstract

LCI and MRI detect rapid and sustained improvement of CF lung disease in school-aged children following initiation of ETI https://bit.ly/3wR4LWj

German Federal Ministry of Education and Research 82DZL002A1 82DZL004B1 82DZL005B1 82DZL009B1 Deutsche Forschungsgemeinschaft http://dx.doi.org/10.13039/501100001659 CRC 1449 – 431232613 Z02 STA 1685/1-1 Vertex Pharmaceuticals Incorporated IIS-2018-107555
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pmcIntroduction

Clinical trials of the triple combination cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapy elexacaftor/tezacaftor/ivacaftor (ETI) demonstrated unprecedented clinical benefits including improvements in lung function, respiratory symptoms and nutritional outcomes in patients with cystic fibrosis (CF) aged ≥2 years with at least one copy of the F508del allele [1–11]. Despite the emergence of highly effective CFTR modulator therapy, chronic progressive lung disease remains the main cause of morbidity and mortality in patients with CF; however, early intervention with CFTR-directed therapeutics in children with CF now provides an opportunity to delay or even prevent irreversible lung damage. Because of the limited sensitivity of percentage predicted forced expiratory volume in 1 s (FEV1) to capture response to therapy in CF children with preserved spirometry [12, 13], more sensitive outcome measures such as multiple-breath washout (MBW) and lung imaging by computed tomography (CT) and magnetic resonance imaging (MRI) have been established [14–25]. A number of studies demonstrated that the LCI derived from MBW is sensitive to detect response to therapeutic interventions including CFTR modulators in children with CF with normal spirometry [9–15, 18]. Further, MRI was shown to detect the extent, progression and response to therapy of key features of early CF lung disease, such as airway mucus plugging, wall thickening/bronchiectasis and impaired lung perfusion, thereby providing additional information on the nature and spatial distribution of abnormalities in the lungs of children with CF [16, 17, 20, 25–33]. In a post-approval observational study, we recently demonstrated that ETI restores CFTR function in the airway and intestinal epithelium to ∼40–50% of that observed in healthy people [34], and that this level of rescue of CFTR activity is associated with improvements in the LCI and the MRI score in adolescent and adult CF patients with at least one F508del allele and chronic lung disease [35]. These findings are in line with results from two other real-world studies in adolescent and adult patients, demonstrating improvements in lung function by means of FEV1 % pred and LCI, and in structural lung disease by CT [6, 36]. However, effects of ETI on lung disease severity and progression, as determined by these sensitive outcome measures, have not been studied in a real-world setting in school-age children with mild lung disease and preserved spirometry.

The aim of this study was therefore to assess the effect of ETI on the longitudinal LCI and the lung MRI score in school-age children with CF and one or two F508del alleles in a real-world setting. Further, we sought to determine the relationship between changes in the LCI and the MRI score in response to ETI therapy. To achieve these goals, we performed a prospective, multicentre, observational study in 107 children aged 6–11 years with CF compound heterozygous for F508del and a minimal function mutation (F/MF) or homozygous for F508del (F/F), and investigated MBW at baseline and at quarterly visits up to 12 months, as well as lung MRI at baseline and after 3 months following initiation of ETI therapy.

Methods

Study design and participants

This prospective observational post-approval multicentre study (Modulate-CF; ClinicalTrials.gov: NCT04732910) was conducted at four CF centres of the German Center for Lung Research (DZL) following approval by the ethics committee of Charité – Universitätsmedizin Berlin (EA2/220/18) and all participating institutions. Patients were eligible to participate after written informed consent if they were 6–11 years old, had at least one F508del allele (F/MF or F/F) and had no prior exposure to ETI. Exclusion criteria were an acute respiratory infection or pulmonary exacerbation at baseline and a history of solid organ transplantation. Spirometry, anthropometry and the LCI were assessed at baseline and quarterly up to 12 months after initiation of therapy with the weight-adapted approved dose of elexacaftor and tezacaftor every 24 h in combination with ivacaftor every 12 h (figure 1). Sweat chloride concentration (SCC) and MRI score were assessed at baseline and 3 months after initiation of therapy.

FIGURE 1 Flowchart of recruited patients with cystic fibrosis, heterozygous for F508del and a minimal function mutation (F/MF) or homozygous for F508del (F/F). CFTRm: cystic fibrosis transmembrane conductance regulator modulator; ETI: elexacaftor/tezacaftor/ivacaftor; MBW: multiple-breath washout; MRI: magnetic resonance imaging.

Multiple-breath washout

MBW testing was performed with the Exhalyzer D system (Eco Medics, Dürnten, Switzerland) and 100% oxygen was used to wash out resident nitrogen (N2) from the lungs with a mouthpiece as interface [20]. All measurements were performed at each study site and evaluated centrally using Spiroware 3.3.1 (Eco Medics) [37–39]. The upper limit of normal (ULN) for the LCI was determined as 7.1 [40]. Quality control measures included performance of MBW by European Cystic Fibrosis Society Clinical Trial Network (ECFS-CTN)-certified operators at all sites according to a Standard Operating Procedure. The LCI was determined from washout curves with no evidence of leak, sighs, hiccoughing or swallowing and with functional residual capacity measurements that differed <10% from the lower value obtained from the other curves within the set. The LCI was determined from a minimum of two acceptable washout curves that reached end of test and started from an acceptable baseline N2 level (return to baseline concentration).

Morpho-functional chest MRI

A standardised MRI protocol was used on a 1.5 T MRI scanner (Magnetom Avanto, Magnetom Aera; Siemens Healthineers, Erlangen, Germany) to acquire T1- and T2-weighted sequences at baseline and 3 months after initiation of therapy (median (interquartile range (IQR)) time between start of ETI and follow-up MRI was 3.6 (2.4–6.0) months; the minimum time allowed between start of ETI and follow-up MRI was 4 weeks). Images were assessed for abnormalities in lung morphology and perfusion using a dedicated morpho-functional MRI score as previously described [41]. In this MRI score, structural findings are assessed by the MRI morphology score that comprises subscores for 1) bronchial wall abnormalities (wall thickening and/or bronchiectasis), 2) mucus plugging, 3) abscesses and/or sacculations, 4) consolidations and 5) special findings such as pleural effusion. The extent of these structural findings, as well as changes in lung perfusion, are rated in each lobe (right upper lobe, right middle lobe, right lower lobe, left upper lobe, lingula and left lower lobe) as 0 (no abnormality), 1 (<50% of the lobe involved) or 2 (≥50% of the lobe involved), resulting in a range of the MRI global score from 0 (normal) to 72 (severely abnormal), with each score of ≥1 being rated as abnormal [25, 41]. MRI analysis and scoring was performed by three raters blinded to clinical data and time-points of MRI assessments, one designated senior observer and two further radiologists with high experience in thoracic MRI. All readers evaluated all MR images in a random, anonymised order.

Statistical analysis

We analysed all data with SPSS Statistics version 29 (IBM, Armonk, NY, USA) and Prism version 9.0.1 (GraphPad, San Diego, CA, USA). Data are presented as median (IQR). Comparison of the proportion of LCI values below the ULN was performed using the Chi-squared test. Two-point comparisons were assessed using the Mann–Whitney U-test, longitudinal courses of the LCI, FEV1 % pred and body mass index (BMI) z-score across multiple time-points using a mixed effects model. Spearman correlation coefficients (r) were calculated to describe the relationship between changes in the LCI and FEV1 % pred or MRI score. By convention, an r-value of 0.0–0.2 was regarded as negligible, 0.2–0.4 as weak, 0.4–0.7 as moderate, 0.7–0.9 as strong and 0.9–1.0 as very strong correlation [42]. Correction for multiple comparisons was performed using the Benjamini–Hochberg procedure. p<0.05 was accepted to indicate statistical significance.

Results

Characteristics of the study population

In total, 107 children with CF aged 6–11 years were enrolled to assess anthropometry, spirometry, SCC, the LCI and the lung MRI score at baseline and after initiation of ETI (figure 1). 40 F/MF and 66 F/F patients had repeated MBW measurements, and a representative subgroup of 19 F/MF as well as 34 F/F patients had paired lung MRI studies at baseline and on ETI (figure 1 and supplementary table S1). CFTR genotypes of patients compound heterozygous for F508del are provided in supplementary table S2. At baseline, all F/MF children were naïve to CFTR modulator treatment, while out of the 67 F/F children, four had no CFTR modulator treatment and 63 were treated with a dual CFTR modulator (lumacaftor/ivacaftor: n=58; tezacaftor/ivacaftor: n=5) at baseline (figure 1). Demographics and clinical characteristics of all children at baseline are summarised in table 1. In F/MF children as well as in F/F children, treatment with ETI led to improvements in SCC and FEV1 % pred at 3 months, with a stable course in spirometry thereafter (figure 2a, b, d and e and supplementary tables S3–S5). In F/MF children, there was no association between baseline FEV1 % pred and the change in FEV1 % pred, whereas in F/F children, a lower baseline FEV1 % pred was associated with a larger increase after start of ETI (r= −0.443, p<0.05) (data not shown). Throughout the 12-month follow-up period, the BMI z-score increased in F/MF children but not in F/F children with CF (figure 2c and f and supplementary table S6).

FIGURE 2 Effects of elexacaftor/tezacaftor/ivacaftor (ETI) on sweat chloride concentration (SCC), forced expiratory volume in 1 s (FEV1) % pred and body mass index (BMI) z-score in children with cystic fibrosis with at least one F508del allele. Paired determinations of SCC and quarterly assessments of FEV1 % pred and BMI were performed. Investigation of a–c) children heterozygous for F508del and a minimal function mutation (F/MF) (n=40) and d–f) children homozygous for F508del (F/F) (n=67). a, d) Dots represent individual values of children at both time-points, dotted horizontal lines represent the 25th and the 75th percentiles, and solid horizontal lines represent the group median. ***: p<0.001 compared with baseline. b, c, e, f) Data are shown as median and error bars represent the median absolute deviation of the respective group. *: p<0.05; ***: p<0.001 for the longitudinal course throughout the whole study period.

TABLE 1 Clinical characteristics of patients with cystic fibrosis at baseline

	F/MF children	F/F children	
Patients	40	67	
Age (years)	9.3 (7.4–10.8)	8.1 (6.5–10.5)	
Female	19 (47.5)	35 (52.5)	
Pancreatic insufficiency	38 (95.0)	66 (98.5)+	
No CFTR modulator	40 (100.0)	4 (6.0)***	
LUM/IVA therapy	0 (0.0)	58 (86.6)***	
TEZ/IVA therapy	0 (0.0)	5 (7.5)***	
Sweat chloride (mmol·L−1)#	101.0 (92.5–111.5)	78.5 (69.8–97.0)***	
FEV1 % pred¶	91.5 (80.6–98.7)	93.8 (79.0–100.1)	
MEF25 % pred¶	80.0 (56.5–103.4)	79.5 (53.0–103.0)	
BMI z-score	−0.6 (−1.2– −0.1)	−0.2 (−0.7–0.3)*	
Data are presented as n, median (interquartile range) or n (%). F/MF: F508del/minimal function mutation; F/F: F508del/F508del; LUM/IVA: lumacaftor/ivacaftor; TEZ/IVA: tezacaftor/ivacaftor; FEV1: forced expiratory volume in 1 s; MEF25: mid-expiratory flow at 25% of vital capacity; BMI: body mass index. #: available in 37 F/MF and 54 F/F children; ¶: available in 40 F/MF and 63 F/F children; +: one child was pancreatic insufficient at birth but developed pancreatic sufficiency following early treatment with LUM/IVA. *: p<0.05; ***: p<0.001 versus F/MF group.

ETI improves LCI in CF children with at least one F508del allele

To determine longitudinal effects on the LCI in school-age children with CF, we performed MBW measurements at baseline and quarterly after initiation of ETI for 12 months. In F/MF children, the median (IQR) LCI was elevated at baseline (7.3 (6.8–8.1)), decreased after 3 months on ETI to 6.6 (6.3–7.1) and remained in the normal range thereafter with a change of −1.0 (−2.0– −0.1) (−13.7%; p<0.01) at 12 months compared to baseline (figure 3a and supplementary table S7). In F/F children, the median (IQR) baseline LCI was normal (7.1 (6.5–8.9)), was reduced after 3 months on ETI to 6.5 (6.2–7.3) and remained in the normal range thereafter with a change of −0.8 (−1.9– −0.2) (−11.3%; p<0.001) at 12 months compared to baseline (figure 3b and supplementary table S7). The percentage of children with an LCI below the ULN at baseline was 40.5% in the F/MF group and 48.5% in the F/F group. This proportion increased to 77.4% after 3 months of ETI therapy in F/MF children with a further increase to 86.4% after 12 months (supplementary table S7). In F/F children, the proportion with a normal LCI increased to 66.1% after 3 months of ETI and remained at that level up to 12 months (supplementary table S7). In both genotype groups, the baseline LCI showed an inverse correlation with the change in the LCI after initiation of ETI (F/MF, r= −0.925; F/F, r= −0.686; both p<0.001) (data not shown). In F/F children with a baseline FEV1 <80% predicted, the median change in the LCI after initiation of ETI was higher than in F/F children with a baseline FEV1 ≥80% predicted (−2.4 (−3.4– −1.1) versus −0.6 (−0.9– −0.2); p<0.05) (data not shown). In the F/MF group, there was a trend towards a larger improvement in the LCI in children with a baseline FEV1 <80% predicted compared to those with a baseline FEV1 ≥80% predicted (−3.2 (−5.5– −1.3) versus −0.7 (−1.7–0.0); p=0.053) (data not shown).

FIGURE 3 Effects of elexacaftor/tezacaftor/ivacaftor (ETI) on the lung clearance index (LCI) in children with cystic fibrosis with at least one F508del allele. Quarterly assessment of the LCI from baseline up to 12 months after initiation of ETI therapy in a) children compound heterozygous for F508del and a minimal function mutation (F/MF) and b) children homozygous for F508del (F/F). Data are shown as median and error bars represent the median absolute deviation of the respective group. ***: p<0.001 for the longitudinal course throughout the whole study period.

Effect of ETI on the lung MRI score in CF children with at least one F508del allele

To determine effects of ETI on lung morphology and perfusion in school-age children with CF, we performed lung MRI at baseline and 3 months after initiation of therapy. In F/MF children, baseline studies showed a median (IQR) MRI global score of 18.0 (10.0–26.0) (figures 4a and 5a). The MRI morphology score was 12.0 (8.0–18.0) (figure 5b) and the MRI perfusion score was 5.0 (2.0–8.0) (figure 5c). ETI reduced the MRI global score in F/MF patients by 4.0 (−9.0–0.0) (p<0.01) (figures 4a and 5a and supplementary table S8), reflecting a relative decline of 22.2%. The MRI morphology score was reduced by 4.0 (−5.0– −2.0) (p<0.001) (figure 5b and supplementary table S8), reflecting a relative decline of 33.3%. The MRI perfusion score showed a trend towards reduction. Reductions of the MRI morphology score were mainly attributable to a decrease in the MRI mucus subscore that was reduced by 1.0 (−4.0–1.0) (p<0.05) (figure 4a and 5e and supplementary table S8) and the MRI wall thickening/bronchiectasis subscore that was reduced by 1.0 (−2.0–0.0) (p<0.01) (figure 5d and supplementary table S8). In F/F patients, baseline studies showed an MRI global score of 13.0 (9.8–16.0) (figures 4b and 5a), an MRI morphology score of 8.5 (6.0–12.3) (figure 5a) and an MRI perfusion score of 4.5 (3.0–6.3) (figure 5c). Treatment of F/F children with ETI led to a reduction of the MRI global score by 3.5 (−7.3– −0.8) (p<0.001) (figure 5a and supplementary table S8), reflecting a relative decline of 39.9%, and in the MRI morphology score by 3.0 (−6.0–0.0) (p<0.001) (figure 5b and supplementary table S8), reflecting a relative decline of 26.9%. The MRI perfusion score was reduced by 2.0 (−4.0–0.0) (p<0.001), reflecting a relative decline of 44.4% (figure 5c and supplementary table S8). The MRI wall thickening/bronchiectasis subscore was reduced by 1.0 (−2.0–0.0) (p<0.01) (figure 5d and supplementary table S8) and the MRI mucus subscore was reduced by 1.0 (−3.0–0.0) (p<0.01) (figure 5e and supplementary table S8). There were no differences between F/MF and F/F children regarding baseline or follow-up on ETI for any of the MRI (sub)scores (supplementary table S8).

FIGURE 4 Examples of structural changes and abnormal perfusion in cystic fibrosis lung disease and their response to elexacaftor/tezacaftor/ivacaftor (ETI) detected by magnetic resonance imaging (MRI). a, b) Representative MRI studies of a) a child compound heterozygous for F508del and a minimal function mutation (F/MF) and b) a child homozygous for F508del (F/F) at baseline and 3 months after initiation of ETI. The initial MRI studies revealed contrast-enhancing airway wall thickening (black arrows) and mucus plugging with high signal intensity on T2-weighted sequences (white arrows) of upper and lower lung lobes. Peripheral consolidations together with pleural enhancement were present in the middle lobe and lingula in F/F (black arrowheads). Wedge-shaped perfusion abnormalities were identified on the subtracted perfusion map (white arrowheads). After initiation of ETI, airway wall thickening and enhancement, mucus plugging and consolidations were substantially reduced. Most perfusion defects resolved and a more homogeneous perfusion was restored.

FIGURE 5 Effects of elexacaftor/tezacaftor/ivacaftor on abnormalities in lung morphology and perfusion detected by magnetic resonance imaging (MRI) in children with cystic fibrosis with at least one F508del allele. Paired studies of lung MRI at baseline and 3 months after initiation of ETI therapy in children heterozygous for F508del and a minimal function mutation (F/MF) and children homozygous for F508del (F/F). Summary of a) the MRI global score (F/MF, n=19; F/F, n=30), representing the sum of b) the MRI morphology score (F/MF, n=19; F/F, n=34) and c) the MRI perfusion score (F/MF, n=19; F/F, n=30). Summary of d) the MRI wall thickening/bronchiectasis subscore (F/MF, n=19; F/F, n=34) and e) the MRI mucus plugging subscore (F/MF, n=19; F/F, n=34) that contribute to the MRI morphology score. Bars represent the group median and error bars represent 25th and 75th percentile. *: p<0.05; **: p<0.01; ***: p<0.001 compared with baseline.

Relationship between changes in LCI, FEV1 % pred and lung MRI score in response to ETI in CF children with at least one F508del allele

Finally, we determined the relationship between changes in the LCI, FEV1 % pred and MRI score in response to 3 months of ETI therapy across all CF children included in our study. Changes in the LCI correlated with changes in FEV1 % pred (r= −0.550, p<0.001) with a concordance in improvement in both outcome measures of 77.1% (figure 6a). Despite a concordance of 65.9%, changes in the LCI did not correlate with changes in the MRI global score. Changes in the LCI were weakly correlated with changes in the MRI morphology score and MRI mucus plugging subscore, but did not correlate with the MRI perfusion score and MRI wall thickening/bronchiectasis subscore (figure 6b–f).

FIGURE 6 Relationship between changes in the lung clearance index (LCI), percent predicted forced expiratory volume in 1 s (FEV1) and lung magnetic resonance imaging (MRI) scores in response to 3 months of elexacaftor/tezacaftor/ivacaftor therapy in children with cystic fibrosis with at least one F508del allele. a) Relationship between absolute change of the LCI and absolute change of FEV1 % pred (n=83). b–f) Relationship between absolute change of the LCI and b) absolute change in the MRI global (n=41), c) morphology (n=45) and d) perfusion (n=41) scores, as well as e) MRI wall thickening/bronchiectasis (n=45) and f) mucus (n=45) subscores. Closed circles indicate individual patients compound heterozygous for F508del and a minimal function mutation (F/MF). Open circles represent individual patients homozygous for F508del (F/F). Solid lines represent simple linear regression for the whole study population (r=Spearman correlation coefficient). Dashed lines indicate zero change.

Discussion

This is the first study that determined the effects of triple combination CFTR modulator therapy with ETI on ventilation inhomogeneity assessed by the longitudinal LCI, and lung morphology and perfusion assessed by lung MRI, in school-age children with CF and at least one F508del allele in a real-world setting. Improvements in the key clinical outcomes FEV1 % pred and BMI, as well as SCC, observed after initiation of ETI therapy in this post-approval study in 107 children with a broad range of lung disease severity (FEV1 at baseline 41.5–118.9% predicted) were comparable to the results obtained in controlled clinical trials [9–11]. We found that initiation of ETI leads to a substantial and sustained improvement of the LCI that was comparable in F/MF and F/F school-age children with CF (figure 3). In addition, we show that ETI leads to substantial improvements of the MRI global and morphology scores in CF children of that age group (figures 4 and 5). These improvements were predominantly driven by a decrease in the MRI morphology subscores for mucus plugging and wall thickening/bronchiectasis (figure 5 and supplementary table S8). Overall, we observed a moderate correlation between improvements in the LCI and FEV1 % pred, and weak correlations between changes in the LCI and changes in the MRI morphology score and the MRI mucus subscore in response to ETI (figure 6). Taken together, our results provide novel insights into the effects of ETI on abnormal lung ventilation, morphology and perfusion in school-age children with CF.

The LCI has been used successfully as an outcome measure in clinical trials of paediatric CF patients with preserved spirometry, where it was found to be more sensitive than FEV1 % pred to detect response to therapeutic interventions including CFTR modulators [10–14, 18]; however, longitudinal effects of ETI on the LCI in children with CF in a real-world setting have not been reported. Previous real-world observational studies in adolescent and adult CF patients demonstrated that initiation of ETI therapy leads to a rapid and sustained improvement in the LCI for up to 12 months of therapy [35, 36, 43]. In this study, we demonstrate an improvement in the LCI in F/MF and F/F school-age children following initiation of ETI therapy (figure 3), resulting in considerable fractions of F/MF (86%) and F/F patients (63%) that achieved LCI values below the ULN at 12 months of therapy (figure 3 and supplementary table S7). Of note, additional benefits of ETI were also evident by improvement of the LCI in F/F patients that were treated with lumacaftor/ivacaftor or tezacaftor/ivacaftor at baseline (supplementary table S7). Compared to previous observational studies in adolescent and adult patients [35, 36], the children in this study had substantially milder lung disease and more participants had LCI values below the ULN at baseline, highlighting the potential of ETI to improve the LCI in school-age children with early lung disease. The absolute and relative change in the LCI in our real-world study is somewhat lower than in the open-label and placebo controlled clinical trials in the same age group, where the LCI improved between 1.7 and 2.3 units, reflecting ∼20% improvement from their baseline level [9–11]. We speculate that several factors may contribute to this difference. First, our study population included a substantial number of children with LCI values below the ULN at baseline, whereas all children included in the clinical trials had an elevated LCI at baseline [9–11]. Further, our LCI data were derived in the most recent software version, correcting for a sensor cross-talk error in the Exhalyzer D MBW device that was shown to overestimate the LCI [39, 40, 44, 45]. Therefore, our absolute LCI values are lower with a lower variance (supplementary table S7) and less room for improvement. Collectively, our results demonstrate effective improvement of ventilation homogeneity by ETI in school-age children with at least one F508del allele in the real-world setting and underscore the importance of enhanced improvement of CFTR function to achieve optimal benefit on the longitudinal course of lung disease.

Previously, we found that proton MRI is sensitive to detect response to ETI therapy in adolescent and adult CF patients with one or two F508del alleles and chronic lung disease with a substantial reduction in mucus plugging and airway wall thickening that was also observed in CT studies [35, 36]. In our present study in school-age children with CF, the improvement of the MRI global score in patients with at least one F508del allele by ETI (figures 4 and 5 and supplementary table S8) was comparable to those seen in older populations [35]. In contrast to the LCI (figure 3 and supplementary table S7), the MRI global score remained elevated in all but one patient, indicating enhanced sensitivity of MRI to detect persistent abnormalities like structural changes of the airways in the CF lung. In previous studies in children with CF, mucus plugging and wall thickening/bronchiectasis were the main contributors to the MRI morphology score [20, 21, 25, 32, 37]. The findings of our study in both genotype groups are in line with these results (figure 5 and supplementary table S8). Mucus plugging and, to a lesser extent, wall thickening were improved following initiation of ETI (figures 4 and 5), comparable with the results of previous studies in older patients with CF using either chest MRI or CT studies [35, 36, 46]. Due to its lower spatial resolution, MRI is less sensitive than CT to discriminate between peribronchial thickening and bronchiectasis [41]. Therefore, we speculate that the improvement in the MRI subscore for wall thickening/bronchiectasis observed with ETI in our present study in school-age children and our previous study in adolescents and adults with CF [35] may be attributed to improved peribronchial thickening associated with potentially reversible airway inflammation. Consistent with this notion, recent studies in adolescent and adult patients with CF showed substantially reduced airway inflammation and infection after initiation of ETI [47–49]. Similar to our previous findings in adolescents and adult CF patients [35], we found that initiation of ETI largely reduces the MRI mucus subscore and to some extent airway wall thickening/bronchiectasis, but not lung perfusion defects in school-age children with CF (figures 4 and 5). Taken together, our MRI data support that ETI is highly effective in reducing mucus plugging and potentially inflammatory changes of airway walls in school-age children with CF and at least one F508del allele.

Our study also provides initial information on the relationship between improvements in response to ETI therapy detected by the LCI, FEV1 % pred and MRI score in school-age children with CF. Changes in the LCI correlated with changes in FEV1 % pred in school-age children with CF with a good concordance (figure 6). In addition, we found a good concordance between improvements in the LCI and the MRI global and morphology scores (figure 6). Despite this good concordance, changes in the LCI correlated only weakly with changes in the MRI morphology score and the MRI mucus subscore, and there was no correlation between changes in the LCI and the MRI global and perfusion scores (figure 6). This lack of correlation may be explained by the large variability of lung disease at baseline, treatment responses and sample size of children who underwent both MBW and MRI assessments at the same time-point. Overall, these results are in line with findings in adolescent and adult CF patients [35]. Furthermore, these findings also suggest that MBW and MRI may provide complementary information on different aspects of disease manifestation, progression and resolution in response to therapy, a notion supported by previous studies using these two outcome measures to analyse changes from baseline to pulmonary exacerbations [16, 20]. This is also supported by the fact that MRI detected persisting morphological abnormalities in all but one child included in our study, whereas most children had an LCI in the normal range on ETI therapy.

This post-approval study has limitations. First, we were not able to perform paired LCI and MRI measurements in all patients in this real-world study because of coronavirus disease 2019 pandemic-related restrictions. Second, while the LCI was studied longitudinally over a period of 12 months, MRI studies were limited to a single follow-up at 3 months after initiation of ETI. It will therefore be important to obtain longer term follow-up data for both the LCI and MRI to elucidate the longitudinal relationship between changes captured by these different outcome measures in response to highly effective CFTR modulator therapy to estimate their impact on disease progression over time [50, 51]. Further, it will be important to determine the relationship between improvements of the LCI and MRI as quantitative outcome measures and clinical symptoms including pulmonary exacerbations, as well as patient-reported outcome measures such as quality of life.

In summary, our study demonstrates that initiation of triple combination CFTR modulator therapy with ETI leads to rapid and sustained improvements in lung ventilation and morphological changes including mucus plugging and airway wall thickening, as determined by MBW and MRI in children with CF aged 6–11 years with at least one F508del allele. Our real-world data therefore support initiation of ETI therapy in school-age children with CF with preserved spirometry to reduce lung disease progression for optimal long-term benefit. However, whereas most school-age children with CF achieved a normal LCI, morphological abnormalities were not normalised, suggesting that ETI may not completely reverse structural lung disease in this age group and providing a rationale for earlier treatment and/or developing additional therapeutic strategies.

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Acknowledgements

We thank the patients with CF and their families for their participation in this study. We thank Azadeh Bagheri-Pothoff and Julia Westhoff (Justus Liebig University Giessen, Giessen, Germany); Leonie Busack, Bent Rasmus Fuhlrott, Florian Sören Gerts, Tina Büttner, Ellen Julia Halver, Neila Marie Holzing, Christiane Labitzke, Linus Piehler, Alexandra Schnorr, Janette Tattersall-Wong, Lara Toursakissian and Niklas Ziegahn (Charité – Universitätsmedizin Berlin, Berlin, Germany); Sibylle Junge, Rebecca Minso, Astrid Demus, Simon Grewendorf, Melanie Pfeifer, Frank Schröder and Sven Thiele (Hannover Medical School, Hannover, Germany); and all CF physicians and study teams for assistance in patient recruitment and study conduct.

Ethics statement: This prospective observational post-approval multicentre study (Modulate-CF) was conducted at four CF centres of the German Center for Lung Research (DZL) following approval by the ethics committee of Charité – Universitätsmedizin Berlin (EA2/220/18) and all participating institutions. Written informed consent was obtained from patients.

This article has an editorial commentary: https://doi.org/10.1183/13993003.01178-2024

This study is registered at ClinicalTrials.gov with identifier number NCT04732910.

Author contributions: Conception and design of the study: M. Stahl, S.Y. Graeber, L. Naehrlich, J. Vogel-Claussen, B. Tümmler, M.A. Mall and A-M. Dittrich. Acquisition, analysis and interpretation of data: M. Stahl, S.Y. Graeber, M. Dohna, O. Sommerburg, D.M. Renz, S.T. Pallenberg, A. Voskrebenzev, K. Schütz, G. Hansen, F. Doellinger, E. Steinke, S. Thee, J. Röhmel, S. Barth, C. Rückes-Nilges, J. Berges, S. Hämmerling, M.O. Wielpütz, L. Naehrlich, J. Vogel-Claussen, B. Tümmler, M.A. Mall and A-M. Dittrich. First drafting of manuscript: M. Stahl, M.D., S.Y. Graeber, O. Sommerburg, L. Naehrlich, J. Vogel-Claussen, B. Tümmler, M.A. Mall and A-M. Dittrich. Critical revisions for important intellectual content: M. Stahl, S.Y. Graeber, M. Dohna, O. Sommerburg, D.M. Renz, S.T. Pallenberg, A. Voskrebenzev, K. Schütz, G. Hansen, F. Doellinger, E. Steinke, S. Thee, J. Röhmel, S. Barth, C. Rückes-Nilges, J. Berges, S. Hämmerling, M.O. Wielpütz, L. Naehrlich, J. Vogel-Claussen, B. Tümmler, M.A. Mall and A-M. Dittrich.

Conflicts of interest: M. Stahl, S.Y. Graeber and S. Thee are participants of the Berlin Institute of Health (BIH)-Charité Clinician Scientist Program, and J. Röhmel is participant of the Case Analysis and Decision Support (CADS) program funded by Charité – Universitätsmedizin Berlin and the BIH. M. Stahl reports an Independent Research Innovation Award and honoraria for lectures and participation in advisory boards, all by Vertex Pharmaceuticals Incorporated, outside of the submitted work; she is Chairman of the German CF Research Council (FGM), Treasurer of the German Society of Paediatric Pulmonology (GPP) and was Secretary of the Group CF of the Paediatric Assembly of the ERS. M. Dohna is a participant of the Ellen-Schmidt Habilitationsförderung funded by the Hannover Medical School. S.Y. Graeber reports grants from the German CF Foundation and Vertex Pharmaceuticals Incorporated, and honoraria from Chiesi GmbH and Vertex Pharmaceuticals Incorporated for lectures and participation in advisory boards, outside of the submitted work. O. Sommerburg reports grants and honoraria from Vertex Pharmaceuticals Incorporated for lectures, outside of the submitted work. S.T. Pallenberg is a member of the Else-Kröner Forschungskolleg TITUS. A. Voskrebenzev reports a grant and honoraria for lectures from Siemens Healthineers, outside of the submitted work, holds a patent for a method of quantitative magnetic resonance lung imaging (Voskrebenzev, Gutberlet, Vogel-Claussen; number EP3107066, US-2016-0367200-Al 22.12.2016), and is a stockholder and CEO of BioVisioneers GmbH. K. Schütz reports payments for attending meetings and/or travel from Vertex Pharmaceuticals Incorporated, outside of the submitted work. G. Hansen reports receipt of consultation fees from Sanofi GmbH, outside of the submitted work. F. Doellinger reports payment or honoraria for lectures, presentations, manuscript writing or educational events from Bayer, Bayer Vital, Berlin-Chemie Menarini, Boehringer Ingelheim and Chiesi GmbH, payment for expert testimony from Calyx, and support for attending meetings from Bayer. E. Steinke reports grants from Berlin Institute of Health at Charité Berlin, and payment or honoraria for lectures, presentations, manuscript writing or educational events from Vertex Pharmaceuticals Incorporated. S. Thee reports honoraria for lectures and payment for attending meetings and/or travel from Vertex Pharmaceuticals Incorporated and Viatris, outside of the submitted work. J. Röhmel reports honoraria for lectures from Vertex Pharmaceuticals Incorporated, outside the submitted work; additionally, he is work package leader in BEAT-PCD (ERS-CRC). M.O. Wielpütz reports a grant from Vertex Pharmaceuticals Incorporated, and receipt of consulting fees and honoraria for lectures from Vertex Pharmaceuticals Incorporated and Boehringer Ingelheim, outside of the submitted work. L. Naehrlich reports receipt of fees for a data quality project of the German CF Registry. He is the medical lead of the German CF Registry, the pharmacovigilance study manager of the European Cystic Fibrosis Society Patient Registry and part of the Trial Steering Committee for CF STORM. He also reports grants from the German Center for Lung Research, Vertex Pharmaceuticals and Mukoviszidose Institute, and receipt of medical writing services from Articulate Science. J. Vogel-Claussen reports grants from BMBF, Siemens Healthineers, AstraZeneca, Boehringer Ingelheim and GSK, royalties or licenses from Siemens Healthineers, receipt of consulting fees from AstraZeneca, honoraria for lectures from Siemens Healthineers, AstraZeneca, Boehringer Ingelheim, GSK, Roche, Coreline Soft and Bayer, payments for attending meetings and/or travel from Vertex Pharmaceuticals Incorporated, Bayer, GSK and AstraZeneca, and holds a patent for a method of quantitative magnetic resonance lung imaging (Voskrebenzev, Gutberlet, Vogel-Claussen; number EP3107066, US-2016-0367200-Al 22.12.2016). B. Tümmler reports support for the present study from Bundesministerium für Forschung und Technologie, grants from the German Research Foundation (DFG; CRC 900; Excellence cluster “RESIST”), consultancy fees from Helmholtz Institut für Infektionsforschung, payment or honoraria for lectures, presentations, manuscript writing or educational events from Vertex Pharmaceutical (Germany) Incorporated, participation on a data and safety monitoring board or advisory board with Vertex Pharmaceuticals Incorporated, and leadership roles with Christiane Herzog Stiftung and the Microbiome/Metagenome Group of the German Center for Lung Research (DZL). M.A. Mall reports grants from the German Research Foundation (DFG; SFB-TR 84, and project 450557679) and the German Innovation Fund (01NVF19008), outside of the submitted work. Additionally, he reports receipt of consulting fees from AbbVie, Antabio, Arrowhead, Boehringer Ingelheim, Enterprise Therapeutics, Kither Biotec, Prieris, Recode, Santhera, Splisense and Vertex Pharmaceuticals Incorporated, of honoraria for lectures from Vertex Pharmaceuticals Incorporated and participation in advisory boards from AbbVie, Antabio, Arrowhead, Boehringer Ingelheim, Enterprise Therapeutics, Kither Biotec, Pari and Vertex Pharmaceuticals Incorporated, and of payment for travel from Vertex Pharmaceuticals Incorporated and Boehringer Ingelheim, all outside of the submitted work. He is a Fellow of ERS (FERS). A-M. Dittrich reports support for the present study from the German Center for Lung Research (DZL), Vertex Pharmaceuticals Incorporated and European Cystic Fibrosis Society Clinical Trial Network (ECFS-CTN), grants from Vertex Pharmaceuticals Incorporated, ECFS-CTN, DFG and Christiane Herzog Stiftung, consultancy fees from the c4c consortium, GSK and European Cystic Fibrosis Society. The remaining authors have no potential conflicts of interest to disclose.

Support statement: This study was supported by an independent medical grant from Vertex Pharmaceuticals Incorporated (IIS-2018-107555), the German Federal Ministry of Education and Research (82DZL009B1, 82DZL002A1, 82DZL005B1, 82DZL004B1) and the German Research Foundation (STA 1685/1-1 and CRC 1449–431232613 Z02). The funders had no role in the design, management, data collection, analyses or interpretation of the data, or in the writing of the manuscript or the decision to submit for publication. Funding information for this article has been deposited with the Crossref Funder Registry.
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