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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., Competing Interests: 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., (Copyright ©The authors 2024.)

Background: Pseudomonas aeruginosa (Pa) continues to affect disease progression in cystic fibrosis (CF). However, the best eradication regimen remains unclear. This work compares three different antibiotic eradication regimens in pediatric CF: an administration according to a standard-operating procedure (SOP) order vs. administration outside of this order (ooSOP)., Methods: This observational study includes all CF patients<18 years who received one of three Pa eradication treatments in the past eight years at our center: 1) inhaled high-dose tobramycin (Hi-TOBI), 2) inhaled colistin+oral ciprofloxacin (COL/Cip), 3) inhaled low-dose tobramycin+4 intravenous 14-day Pa active antibiotic treatments (lo-Tobra/IV). We compared eradication rates of the three treatment regimens performed according to the SOP-based order vs. ooSOP. Logistic regression analysis was performed to identify risk factors for eradication failure., Results: Performed according to SOP order, Hi-TOBI showed the greatest efficacy, followed by lo-Tobra/IV and finally COL/Cip, while ooSOP lo-Tobra/IV was most successful, followed by COL/Cip and Hi-TOBI. Previous Pa-infections and Pa-therapies along with age at CF diagnosis were risk factors for eradication failure., Conclusion: Antibiotic treatment in SOP-based pre-defined order leads to significantly better eradication rates than individual modifications of the order of administration. A short course of inhalational high-dose Tobramycin is most successful at the first attempt. Prolonged antibiotic therapy seems to improve eradication after failed initial attempts., Competing Interests: The authors declare that they have no conflict of interest., (Thieme. All rights reserved.)

Background: Newborn screening (NBS) has been shown to improve cystic fibrosis (CF) disease course and has been widely implemented worldwide. This monocentric study compared children diagnosed by NBS vs. a cohort preceding the implementation of NBS in Germany in 2016 to evaluate ascribed benefits of NBS., Methods: We compared all children with confirmed CF diagnosis (n=19, "NBS group") out of all children presenting with positive NBS at our center after implementation of NBS (n=100) to children diagnosed with CF at our center within 4 years before NBS implementation (n=29, "pre-NBS group") for outcomes of anthropometry, gastrointestinal and pulmonary disease manifestations and respiratory microbiology., Results: Children diagnosed by NBS had a lower incidence of initial difficulty to thrive (15 vs. 41%) and showed higher mean z-scores for Body-Mass-Index (BMI), weight and length at diagnosis and during study period. Children in the pre-NBS group displayed higher proportions of oxygen-dependent pulmonary exacerbations (10 vs. 0%). They show a significantly lower amount of normal bacterial flora (p=0.005) along with a significantly higher number of throat swab cultures positive for Pseudomonas aeruginosa (p=0.0154) in the first year of life. Yet, pulmonary imaging did not reveal less pulmonary morbidity in the NBS group., Conclusions: Our results confirm that NBS for CF leads to earlier diagnosis and improves nutritional outcomes in early childhood. Although trajectories of structural lung damage at early age were unaffected by NBS, NBS positive CF patients at preschool age displayed less pulmonary exacerbations and pathological bacteria in throat swabs., Competing Interests: The authors declare that they have no conflict of interest., (Thieme. All rights reserved.)

Introduction: Triple-combination cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapy with elexacaftor/tezacaftor/ivacaftor (ETI) was introduced in August 2020 in Germany for people with CF (pwCF) =12 years (yrs.) of age and in June 2021 for pwCF =6 yrs of age. In this single-center study, we analyzed longitudinal data on the percent-predicted forced expiratory volume (ppFEV1) and body-mass-index (BMI) for 12 months (mo.) after initiation of ETI by linear mixed models and regression analyses to identify age- and severity-dependent determinants of response to ETI. Methods: We obtained data on 42 children =6-11 yrs, 41 adolescents =12-17 yrs, and 143 adults by spirometry and anthropometry prior to ETI, and 3 and 12 mo. after ETI initiation. Data were stratified by the age group and further sub-divided into age-specific ppFEV1 impairment. To achieve this, the age strata were divided into three groups, each according to their baseline ppFEV1: lowest 25%, middle 50%, and top 25% of ppFEV1. Results: Adolescents and children with more severe lung disease prior to ETI (within the lowest 25% of age-specific ppFEV1) showed higher improvements in lung function than adults in this severity group (+18.5 vs. +7.5; p = 0.002 after 3 mo. and +13.8 vs. +7.2; p = 0.012 after 12 mo. of ETI therapy for =12-17 years and +19.8 vs. +7.5; p = 0.007 after 3 mo. for children =6-11 yrs). In all age groups, participants with more severe lung disease showed higher BMI gains than those with medium or good lung function (within the middle 50% or top 25% of agespecific ppFEV1). Regression analyses identified age as a predictive factor for FEV1 increase at 3 mo. after ETI initiation, and age and ppFEV1 at ETI initiation as predictive factors for FEV1 increase 12 mo. after ETI initiation. Discussion: We report initial data, which suggest that clinical response toward ETI depends on age and lung disease severity prior to ETI initiation, which argue for early initiation of ETI. [ABSTRACT FROM AUTHOR]

For sensitive diagnosis and monitoring of pulmonary disease, ionizing radiationfree imaging methods are of great importance. A noncontrast and free‐breathing proton magnetic resonance imaging (MRI) technique for assessment of pulmonary perfusion is phase‐resolved functional lung (PREFUL) MRI. Since there is no validation of PREFUL MRI across different centers and scanners, the purpose of this study was to compare perfusion‐weighted PREFUL MRI with the well‐established dynamic contrast‐enhanced (DCE) MRI across two centers on scanners from two different vendors. Sixteen patients with cystic fibrosis (CF) (Center 1: 10 patients; Center 2: 6 patients) underwent PREFUL and DCE MRI at 1.5T in the same imaging session. Normalized perfusion‐weighted values and perfusion defect percentage (QDP) values were calculated for the whole lung and three central slices (dorsal, central, ventral of the carina). Obtained parameters were compared using Pearson correlation, Spearman correlation, Bland–Altman analysis, Wilcoxon signed‐rank test, and Wilcoxon rank‐sum test. Moderate‐tostrong correlations between normalized perfusion‐weighted PREFUL and DCE values were found (posterior slice: r = 0.69, p < 0.01). Spatial overlap of PREFUL and DCE QDP maps showed an agreement of 79.4% for the whole lung. Further, spatial overlap values of Center 1 were not significantly different to those of Center 2 for the three central slices (p > 0.07). The feasibility of PREFUL MRI across two different centers and two different vendors was shown in patients with CF and obtained results were in agreement with DCE MRI. [ABSTRACT FROM AUTHOR]