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Background: Non-invasive and sensitive clinical endpoints are needed to monitor onset and progression of early lung disease in children with cystic fibrosis (CF). We compared lung clearance index (LCI), FEV 1 , functional and structural lung magnetic resonance imaging (MRI) outcomes in Swiss children with CF diagnosed following newborn screening., Methods: Lung function (LCI, FEV 1 ) and unsedated functional and structural lung MRI was performed in 79 clinically stable children with CF (3 - 8 years) and 75 age-matched healthy controls. Clinical information was collected throughout childhood., Results: LCI, ventilation and perfusion defects, and structural MRI scores were significantly higher in children with CF compared with controls, but FEV 1 was not different between groups. Lung MRI outcomes correlated significantly with LCI (morphology score (r = 0.56, p < 0.001); ventilation defects (r = 0.43, p = 0.001); perfusion defects (r = 0.64, p < 0.001), but not with FEV 1 . Lung MRI outcomes were more sensitive to detect impairments in children with CF (abnormal ventilation and perfusion outcomes in 47 %, morphology score in 30 %) compared with lung function (abnormal LCI in 21 % and FEV 1 in 4.8 %). Pulmonary exacerbations, respiratory hospitalizations, and increase in patient-reported cough was associated with higher LCI and higher structural and functional MRI outcomes., Conclusions: The LCI and lung MRI outcomes non-invasively detect even mild early lung disease in young children with CF diagnosed following newborn screening. Pulmonary exacerbations and early respiratory symptoms were risk factors for structural and functional impairment in childhood., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Prof. P. Latzin reports the followind COIs: - Grants from Vertex and OM Pharma paid to the institution - Participation on data safety monitoring boards or advisory boards of Polyphor, Santhera DMC, Vertex, OM Pharma, Vifor, Sanofi Aventis - Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: Vertex, Vifor, OM Pharma Jakob Usemann reports: Grants from - Swiss lung foundation - Palatin Foundation, Basel, Switzerland Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: - Vertex - Zurich Lung foundation Support for attending meetings and/or travel from Vertex Kathryn Ramsey reports: Support for the present manuscript form: -Swiss National Science Foundation Ambizione Research Grant (168173), paid to the institution Leadership or fiduciary role in other board, society, committee or advocacy group, unpaid Global Lung Initiative MBW Task Force Elisabeth Kieninger reports: Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: Sanofi-Aventis., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Multiple-breath washout (MBW) is a sensitive method for assessing lung volumes and ventilation inhomogeneity in infants, but remains prone to artefacts (e.g., sighs). There is a lack of tools for systematic retrospective analysis of existing datasets, and unlike N 2 -MBW in older children, there are few specific quality control (QC) criteria for artefacts in infant SF 6 -MBW., Aim: We aimed to develop a computer-based tool for systematic evaluation of visual QC criteria of SF 6 -MBW measurements and to investigate interrater agreement and effects on MBW outcomes among three independent examiners., Methods: We developed a software package for visualization of raw Spiroware (Eco Medics AG, Switzerland) and signal processed WBreath (ndd Medizintechnik AG, Switzerland) SF 6 -MBW signal traces. Interrater agreement among three independent examiners (two experienced, one novice) who systematically reviewed 400 MBW trials for visual artefacts and the decision to accept/reject the washin and washout were assessed., Results: Our tool visualizes MBW signals and provides the user with (i) display options (e.g., zoom), (ii) options for a systematic QC assessment [e.g., decision to accept or reject, identification of artefacts (leak, sigh, irregular breathing pattern, breath hold), and comments], and (iii) additional information (e.g., automatic identification of sighs). Reviewer agreement was good using pre-defined QC criteria (κ 0.637-0.725). Differences in the decision to accept/reject had no substantial effect on MBW outcomes., Conclusion: Our visual quality control tool supports a systematic retrospective analysis of existing data sets. Based on predefined QC criteria, even inexperienced users can achieve comparable MBW results., Competing Interests: M-AO, FW, and PL are in regular contact with manufacturers of MBW devices (ndd Medizintechnik AG, Zurich, Switzerland and Eco Medics AG, Duernten, Switzerland), all outside of this work. PL: personal fees from Vertex, Novartis, Roche, Polyphor, Vifor, Gilead, Schwabe, Zambon, Santhera, grants from Vertex, all outside this work. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest, (© 2024 Oestreich, Doswald, Salem, Künstle, Wyler, Frauchiger, Kentgens, Latzin and Yammine.)

Background: With improvement in supportive therapies and the introduction of cystic fibrosis transmembrane conductance regulator (CFTR)-modulator treatment in patients with cystic fibrosis (CF), milder disease courses are expected. Therefore, sensitive parameters are needed to monitor disease course and effects of CFTR-modulators. Functional lung MRI using matrix-pencil decomposition (MP-MRI) is a promising tool for assessing ventilation and perfusion quantitatively. This study aimed to assess the treatment effect of elexacaftor/tezacaftor/ivacaftor combination regimen (ELX/TEZ/IVA) on measures of structural and functional lung abnormalities., Methods: 24 children with CF underwent lung function tests (multiple breath washout, spirometry), functional and structural MRI twice (one year apart) before and once after at least two weeks (mean 4.7 ± 2.6 months) on ELX/TEZ/IVA. Main outcomes were changes (Δ) upon ELX/TEZ/IVA in lung function, defect percentage of ventilation (VDP) and perfusion (QDP), defect distribution index of ventilation and perfusion (DDI V, DDI Q ), and Eichinger score. Statistical analyses were performed using paired t-tests and multilevel regression models with bootstrapping., Results: We observed a significant improvement in lung function, structural and functional MRI parameters upon ELX/TEZ/IVA treatment (mean; 95%-CI): ΔLCI 2.5 (TO) -0.84 (-1.62 to -0.06); ΔFEV 1 (z-score) 1.05 (0.56 to 1.55); ΔVDP (% of impairment) -6.00 (-8.44 to -3.55); ΔQDP (% of impairment) -3.90 (-5.90 to -1.90); ΔDDI V -1.38 (-2.22 to -0.53); ΔDDI Q -0.31 (-0.73 to 0.12); ΔEichinger score -3.89 (-5.05 to -2.72)., Conclusions: Besides lung function tests, functional and structural MRI is a suitable tool to monitor treatment response of ELX/TEZ/IVA therapy, and seems promising as outcome marker in the future., (Copyright © 2022. Published by Elsevier B.V.)

Background: Nitrogen multiple breath washout (N2MBW) is a lung function test increasingly used in small airway diseases. Quality criteria have not yet been globally implemented and time-consuming retrospective overreading is necessary. Little data has been published on children with recurrent wheeze or asthma from multicentered studies., Methods: Children with wheeze or asthma and healthy controls were included in the longitudinal All Age Asthma Cohort (ALLIANCE). To assess ventilation inhomogeneity, N2MBW tests were performed in five centers from 2013 until 2020. All N2MBW tests were centrally overread by one center. Multiple washout procedures (trials) at the visit concluded to one test occasion. Tests were accepted if trials were technically sound (started correctly, terminated correctly, no leak, regular breathing pattern) and repeatable within one test occasion. Signal misalignment was retrospectively corrected. Factors that may impact test quality were analyzed, such as experience level., Results: N2MBW tests of n=561 participants were analyzed leading to n=949 (68.3%) valid tests of n=1,390 in total. Inter-center test acceptability ranged from 27.6% to 77.8%. End-of-test criterion and leak were identified to be the most common reasons for rejection. Data loss and uncorrectable signal misalignment led to rejection of 58% of trials in one center. In preschool children, significant improvement of test acceptability was found longitudinally (χ2(8)=18.6; p=0.02)., Conclusion: N2MBW is feasible in a multicenter asthma study in children. However, the quality of this time-consuming procedure is dependent on experience level of staff in preschool children and still requires retrospective overreading for all age groups., Competing Interests: TB reports grants from National Pandemic Cohort Network (NAPKON), funded by Network University Medicine (NUM)(BMBF grant number 01KX2021), during the conduct of the study; personal fees from AstraZeneca, personal fees from Novartis, personal fees from Pfizer, personal fees from GlaxoSmithKline, personal fees from BoeringerIngelheim, personal fees from Chiesi, personal fees from Merck, grants from German Center For Lung Research, outside the submitted work.EVM reports personal fees from Pharmaventures, personal fees from OM Pharma S. A., personal fees from Springer-Verlag GmbH, personal fees from Elsevier GmbH and Elsevier Ltd., personal fees from Peptinnovate Ltd., personal fees from Turun Yliopisto, personal fees from Tampereen Yliopisto, personal fees from Helsingin Yliopisto, personal fees from European Respiratory Society, personal fees from Deutsche Pharmazeutische Gesellschaft e. V., personal fees from Massachusetts Medical Society, personal fees from Chinese University of Hongkong, personal fees from European Commission, personal fees from Böhringer Ingelheim International GmbH, personal fees from Universiteit Utrecht, Faculteit Diergeneeskunde, personal fees from Universität Salzburg, personal fees from Georg Thieme Verlag, personal fees from Japanese Society of Pediatric Allergy and Clinical Immunology (JSPACI), Klinikum Rechts der Isar München, University of Colorado, Paul-Martini-Stiftung, Astra Zeneca, Imperial College London, Children´s Hospital Research Institute of Manitoba, Kompetenzzentrum für Ernährung (Kern), OM Pharma S.A., Swedish Pediatric Society for Allergy and Lung Medicine, Chinese College of Allergy and Asthma (CCAA), ALK-Abello Arzneimittel GmbH, Abbott Laboratories, Deutscher Apotheker Verlag GmbH & Co. KG, Chinese University of Hongkong, European Commission, HiPP GmbH & Co KG, OM Pharma S.A., Astra Zeneca MVK received consulting fees and/or payment or honoraria for lectures, presentations, speakers bureaus from Allergopharma GmbH, ALK-Abello, Chiesi GmbH, Infectopharm GmbH, Novartis Pharma GmbH, Sanofi Aventis GmbH, Vertex GmbH.The other authors have no conflict of interest to declare., (Thieme. All rights reserved.)

Rationale: The lung clearance index (LCI) is increasingly being used in the clinical surveillance of patients with cystic fibrosis (CF). However, there are limited data on long-term variability and physiologically relevant changes in LCI during routine clinical surveillance., Objectives: To evaluate the long-term variability of LCI and propose a threshold for a physiologically relevant change., Methods: In children aged 4-18 years with CF, LCI was measured every 3 months as part of routine clinical surveillance during 2011-2020 in two centers. The variability of LCI during periods of clinical stability was assessed using mixed-effects models and was used to identify thresholds for physiologically relevant changes., Results: Repeated LCI measurements of acceptable quality (N = 858) were available in 100 patients with CF; for 74 patients, 399 visits at clinical stability were available. The variability of repeated LCI measurements over time expressed as the coefficient of variation (CV%) was 7.4%. The upper limit of normal (ULN) for relative changes in LCI between visits was 19%., Conclusion: We report the variability of LCI in children and adolescents with CF during routine clinical surveillance. According to our data, a change in LCI beyond 19% may be considered physiologically relevant. These findings will help guide clinical decisions according to LCI changes., (© 2022 Wiley Periodicals LLC.)

Background: Accurate breath detection is essential for the computation of outcomes in the multiple-breath washout (MBW) technique. This is particularly important in young children, where irregular breathing is common, and the designation of inspirations and expirations can be challenging., Aim: To investigate differences between a commercial and a novel breath-detection algorithm and to characterize effects on MBW outcomes in children., Methods: We replicated the signal processing and algorithms used in Spiroware software (v3.3.1, Eco Medics AG). We developed a novel breath detection algorithm (custom) and compared it to Spiroware using 2,455 nitrogen (N2) and 325 sulfur hexafluoride (SF6) trials collected in infants, children, and adolescents., Results: In 83% of N2 and 32% of SF6 trials, the Spiroware breath detection algorithm rejected breaths and did not use them for the calculation of MBW outcomes. Our custom breath detection algorithm determines inspirations and expirations based on flow reversal and corresponding CO2 elevations, and uses all breaths for data analysis. In trials with regular tidal breathing, there were no differences in outcomes between algorithms. However, in 10% of pre-school children tests the number of breaths detected differed by more than 10% and the commercial algorithm underestimated the lung clearance index by up to 21%., Conclusion: Accurate breath detection is challenging in young children. As the MBW technique relies on the cumulative analysis of all washout breaths, the rejection of breaths should be limited. We provide an improved algorithm that accurately detects breaths based on both flow reversal and CO2 concentration., Competing Interests: All authors are in regular contact with ndd Medizintechnik AG (Zurich, Switzerland) and Eco Medics AG (Duernten, Switzerland). The authors contacted both companies in the process of this study to obtain further information on current breath detection algorithms and to present results. There were no changes to the manuscript by either company. Florian Wyler was hired from July to August 2022 to work on an unrelated project for ndd Medizintechnik AG. The authors declare no conflict of interest. This does not alter our adherence to PLOS ONE policies on sharing data and materials. Prof. Latzin: personal fees from Vertex, Novartis, Roche, Polyphor, Vifor, Gilead, Schwabe, Zambon, Santhera, grants from Vertex, all outside this work. All other authors declare no conflicts of interest.

Background: The recently described sensor-crosstalk error in the multiple-breath washout (MBW) device Exhalyzer D (Eco Medics AG) could highly influence clinimetric properties and the current interpretation of MBW results. This study reanalyzes MBW data from clinical routine in the corrected software version Spiroware® 3.3.1 and evaluates the effect on outcomes., Methods: We included nitrogen-MBW data from healthy children and children with cystic fibrosis (CF) from previously published trials and ongoing cohort studies. We specifically compared lung clearance index (LCI) analyzed in Spiroware 3.2.1 and 3.3.1 with regard to (i) feasibility, (ii) repeatability, and (iii) validity as outcome parameters in children with CF., Results: (i) All previously collected measurements could be reanalyzed and resulted in unchanged feasibility in Spiroware 3.3.1. (ii) Short- and midterm repeatability of LCI was similar in both software versions. (iii) Clinical validity of LCI remained similar in Spiroware 3.3.1; however, this resulted in lower values. Discrimination between health and disease was comparable between both software versions. The increase in LCI over time was less pronounced with 0.16 LCI units/year (95% confidence interval [CI] 0.08; 0.24) versus 0.30 LCI units/year (95% CI 0.21; 0.38) in 3.2.1. Response to intervention in children receiving CF transmembrane conductance-modulator therapy resulted in a comparable improvement in LCI, in both Spiroware versions., Conclusion: Our study confirms that clinimetric properties of LCI remain unaffected after correction for the cross-sensitivity error in Spiroware software., (© 2022 The Authors. Pediatric Pulmonology published by Wiley Periodicals LLC.)

Background: Volumetric capnography (VCap) is a simpler alternative to multiple-breath washout (MBW) to detect ventilation inhomogeneity in patients with cystic fibrosis (CF). However, its diagnostic performance is influenced by breathing dynamics. We introduce two novel VCap indices, the capnographic inhomogeneity indices (CIIs), that may overcome this limitation and explore their diagnostic characteristics in a cohort of CF patients., Methods: We analysed 320 N 2 -MBW trials from 50 CF patients and 65 controls (age 4-18 years) and calculated classical VCap indices, such as slope III (SIII) and the capnographic index (KPIv). We introduced novel CIIs based on a theoretical lung model and assessed their diagnostic performance compared to classical VCap indices and the lung clearance index (LCI)., Results: Both CIIs were significantly higher in CF patients compared with controls (mean±sd CII 1 5.9±1.4% versus 5.1±1.0%, p=0.002; CII 2 7.7±1.8% versus 6.8±1.4%, p=0.002) and presented strong correlation with LCI (CII 1 r 2 =0.47 and CII 2 r 2 =0.44 in CF patients). Classical VCap indices showed inferior discriminative ability (SIII 2.3±1.0%/L versus 1.9±0.7%/L, p=0.013; KPIv 3.9±1.3% versus 3.5±1.2%, p=0.071), while the correlation with LCI was weak (SIII r 2 =0.03; KPIv r 2 =0.08 in CF patients). CIIs showed lower intra-subject inter-trial variability, calculated as coefficient of variation for three and relative difference for two trials, than classical VCap indices, but higher than LCI (CII 1 11.1±8.2% and CII 2 11.0±8.0% versus SIII 16.3±13.5%; KPIv 15.9±12.8%; LCI 5.9%±4.2%)., Conclusion: CIIs detect ventilation inhomogeneity better than classical VCap indices and correlate well with LCI. However, further studies on their diagnostic performance and clinical utility are required., Competing Interests: Conflicts of interest: S. Fouzas has nothing to disclose. Conflicts of interest: A-C. Kentgens repots no other conflicts of interest. Conflicts of interest: O. Lagiou has nothing to disclose. Conflicts of interest: B.S. Frauchiger has nothing to disclose. Conflicts of interest: F. Wyler has nothing to disclose. Conflicts of interest: I. Theodorakopoulos has nothing to disclose. Conflicts of interest: S. Yammine repots no other conflicts of interest. Conflicts of interest: P. Latzin reports grants from Vertex and Vifor paid to his institution, personal fees and honoraria paid to his institution from Vertex, Vifor and OM Pharma, fees for participation on a data safety monitoring or advisory board from Santhera (DMC), and personal fees paid to his institution from Polyphor, Vertex, OM pharma and Vifor, all outside the submitted work. Support statement: The work was supported by Swiss National Science Foundation Grants (Yammine 179905 and Latzin 182719). A-C. Kentgens is a recipient of the Swiss Government Excellence Scholarship from The Swiss Confederation. Funding information for this article has been deposited with the Crossref Funder Registry., (Copyright ©The authors 2022.)

Nitrogen multiple-breath washout is an established technique to assess functional residual capacity and ventilation inhomogeneity in the lung. Accurate measurement of gas concentrations is essential for the appropriate calculation of clinical outcomes. We investigated the accuracy of oxygen and carbon dioxide gas sensor measurements used for the indirect calculation of nitrogen concentration in a commercial multiple-breath washout device (Exhalyzer D, Eco Medics AG, Duernten, Switzerland) and its impact on functional residual capacity and lung clearance index. High-precision calibration gas mixtures and mass spectrometry were used to evaluate sensor output. We assessed the impact of corrected signal processing on multiple-breath washout outcomes in a data set of healthy children and children with cystic fibrosis using custom analysis software. We found inadequate correction for the cross sensitivity of the oxygen and carbon dioxide sensors in the Exhalyzer D device. This results in an overestimation of expired nitrogen concentration and consequently, multiple-breath washout outcomes. Breath-by-breath correction of this error reduced the mean (SD) cumulative expired volume by 19.6% (5.0%), functional residual capacity by 8.9% (2.2%), and lung clearance index by 11.9% (4.0%). It also substantially reduced the level of the tissue nitrogen signal at the end of measurements. Inadequate correction for cross sensitivity in the oxygen and carbon dioxide gas sensors of the Exhalyzer D device leads to an overestimation of functional residual capacity and lung clearance index. Correction of this error is possible and could be applied by reanalyzing the measurements in an updated software version. NEW & NOTEWORTHY We investigated the sensor accuracy of a prominent nitrogen multiple-breath washout (N 2 MBW) device (Eco Medics AG, Duernten, Switzerland) as a possible cause of lack of comparability between outcomes of different MBW devices and methods. We identified an error in the nitrogen concentration calculation of this device, which results in a 10%-15% overestimation of primary outcomes, functional residual capacity, and lung clearance index. It also leads to a significant overestimation of nitrogen back-diffusion into the lungs.

Background: Although the lung clearance index (LCI) is a sensitive marker of small airway disease in individuals with cystic fibrosis (CF), less is known about longitudinal changes in LCI during routine clinical surveillance. Here, our objectives were to describe the longitudinal course of LCI in children with CF during routine clinical surveillance and assess influencing factors., Methods: Children with CF aged 3-18 years performed LCI measurements every 3 months as part of routine clinical care between 2011 and 2018. We recorded clinical data at every visit. We used a multilevel mixed effect model to determine changes in LCI over time and identify clinical factors that influence LCI course., Results: We collected LCI measurements from 1204 visits (3603 trials) in 78 participants, of which 907 visits had acceptable LCI data. The average unadjusted increase in LCI for the entire population was 0.29 (95% CI 0.20-0.38) LCI units·year -1 . The increase in LCI was more pronounced in adolescence (0.41 (95% CI 0.27-0.54) LCI units·year -1 ). Colonisation with either Pseudomonas aeruginosa or Aspergillus fumigatus , pulmonary exacerbations, CF-related diabetes and bronchopulmonary aspergillosis were associated with a higher increase in LCI over time. Adjusting for clinical risk factors reduced the increase in LCI over time to 0.24 (95% CI 0.16-0.33) LCI units·year -1 ., Conclusions: LCI measured during routine clinical surveillance is associated with underlying disease progression in children with CF. An increased change in LCI over time should prompt further diagnostic intervention., Competing Interests: Conflict of interest: B.S. Frauchiger has nothing to disclose. Conflict of interest: S. Binggeli has nothing to disclose. Conflict of interest: S. Yammine reports grants from Swiss National Science Foundation, outside the submitted work. Conflict of interest: B. Spycher reports grants from Swiss National Science Foundation and Swiss Cancer League, outside the submitted work. Conflict of interest: L. Krüger has nothing to disclose. Conflict of interest: K.A. Ramsey reports grants from Swiss National Science Foundation, outside the submitted work. Conflict of interest: P. Latzin reports grants from Vertex, during the conduct of the study; personal fees from Vertex, Novartis, Roche, Polyphor, Vifor, Gilead, Schwabe, Zambon and Santhera, grants from Vertex, outside the submitted work., (Copyright ©ERS 2021. For reproduction rights and permissions contact permissions@ersnet.org.)

Background: Multiple breath washout (MBW) is increasingly used in the clinical assessment of patients with cystic fibrosis (CF). Guidelines for MBW quality control (QC) were developed primarily for retrospective assessment and central overreading. We assessed whether real-time QC of MBW data during the measurement improves test acceptability in the clinical setting., Methods: We implemented standardized real-time QC and reporting of MBW data at the time of the measurement in the clinical pediatric lung function laboratory in Bern, Switzerland, in children with CF aged 4-18 years. We assessed MBW test acceptability before (31 tests; 89 trials) and after (32 tests; 96 trials) implementation of real-time QC and compared agreement between reviewers. Further, we assessed the implementation of real-time QC at a secondary center in Zurich, Switzerland., Results: Before the implementation of real-time QC in Bern, only 58% of clinical MBW tests were deemed acceptable following retrospective QC by an experienced reviewer. After the implementation of real-time QC, MBW test acceptability improved to 75% in Bern. In Zurich, after the implementation of real-time QC, test acceptability improved from 38% to 70%. Further, the agreement between MBW operators and an experienced reviewer for test acceptability was 84% in Bern and 93% in Zurich., Conclusion: Real-time QC of MBW data at the time of measurement is feasible in the clinical setting and results in improved test acceptability., (© 2020 Wiley Periodicals LLC.)