Search

Background: Respiratory tract infections (RTIs) drive lung function decline in children with cystic fibrosis (CF). While the respiratory microbiota is clearly associated with RTI pathogenesis in infants without CF, data on infants with CF is scarce. We compared nasal microbiota development between infants with CF and controls and assessed associations between early-life nasal microbiota, RTIs, and antibiotic treatment in infants with CF., Methods: We included 50 infants with CF and 30 controls from two prospective birth cohorts followed throughout the first year of life. We collected 1511 biweekly nasal swabs and analyzed the microbiota after amplifying the V3-V4 region of the 16S rRNA gene. We conducted structured weekly interviews to assess respiratory symptoms and antibiotic treatment. We calculated generalized additive mixed models and permutational analysis of variance., Results: Here, we show that the nasal microbiota is already altered before the first RTI or antibiotic treatment in infants with CF. Microbiota diversity differs between infants with CF and controls following RTIs and/or antibiotic treatment. CF infants with lower α-diversity have a higher number of subsequent RTIs., Conclusions: Early nasal microbiota alterations may reflect predisposition or predispose to RTIs in infants with CF, and further change after RTIs and antibiotic treatment. This highlights the potential of targeting the nasal microbiota in CF-related RTI management, while also questioning current practices in the era of novel modulator therapies., Competing Interests: Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Objective. Sulfur hexafluoride (SF 6 ) multiple-breath washout (MBW) assesses ventilation inhomogeneity, as an early marker of obstructive respiratory diseases. Primary outcomes are customarily washout-derived, and it is unclear whether the preceding SF 6 -washin can provide similar estimates. We aimed to assess comparability of primary SF 6 -MBW outcomes between washin and washout phases of infant SF 6 -MBW data measured with the WBreath (ndd Medizintechnik AG, Zurich, Switzerland) and Spiroware (Eco Medics AG, Duernten, Switzerland) MBW-setups, respectively. Approach. We assessed mean relative differences in lung clearance index (LCI) and functional residual capacity (FRC) between the washin and washout of existing SF 6 -MBW data from healthy infants and infants with cystic fibrosis (CF). We assessed whether these differences exceeded the mean relative within-test between-trial differences of washout-derived outcomes, which can be attributed to natural variability. We also explored non-physiological factors using a pediatric lung simulator. Main results. LCI and FRC from washin and washout were not comparable, for both setups. The mean difference (SD) in LCI between washin and washout was 2.3(10.8)% for WBreath and -9.7(8.0)% for Spiroware, while in FRC it was -4.7(8.4)% for WBreath and -2.3(9.7)% for Spiroware. These differences exceeded the within-test between-trial differences in washout-derived outcomes. Outcomes from washin and washout were also not comparable in a pediatric lung simulator. Significance. Outcomes of the washin and washout were not comparable due to an interplay of physiological and non-physiological factors, and cannot be used interchangeably., (© 2024 Institute of Physics and Engineering in Medicine. All rights, including for text and data mining, AI training, and similar technologies, are reserved.)

Background: Host and environment early-life risk factors are associated with progression of wheezing symptoms over time; however, their individual contribution is relatively small. We hypothesised that the dynamic interactions of these factors with an infant's developing respiratory system are the dominant factor for subsequent wheeze and asthma., Methods: In this dynamic network analysis we used data from term healthy infants from the Basel-Bern Infant Lung Development (BILD) cohort (435 neonates aged 0-4 weeks recruited in Switzerland between Jan 1, 1999, and Dec 31, 2012) and replicated the findings in the Protection Against Allergy Study in Rural Environments (PASTURE) cohort (498 infants aged 0-12 months recruited in Germany, Switzerland, Austria, France, and Finland between Jan 1, 2002, and Oct 31, 2006). BILD exclusion criteria for the current study were prematurity (<37 weeks), major birth defects, perinatal disease of the neonate, and incomplete follow-up period. PASTURE exclusion criteria were women younger than 18 years, a multiple pregnancy, the sibling of a child was already included in the study, the family intended to move away from the area where the study was conducted, and the family had no telephone connection. Outcome groups were subsequent wheeze, asthma, and healthy. The first outcome was defined as ever wheezed between the age of 2 years and 6 years. Week-by-week correlations of the determining factors with cumulative symptom scores (CSS) were calculated from weeks 2 to 52 (BILD) and weeks 8 to 52 (PASTURE). The complex dynamic interaction between the determining factors and the CSS was assessed via dynamic host-environment correlation network, quantified by a simple descriptor: trajectory function G(t). Wheeze outcomes at age 2-6 years were compared in 335 infants from BILD and 437 infants from PASTURE, and asthma outcomes were analysed at age 6 years in a merged cohort of 783 infants., Findings: CSS was significantly different for wheeze and asthma outcomes and became increasingly important during infancy in direct comparison with all determining factors. Weekly symptoms were tracked for groups of infants, showing a non-linear increase with time. Using logistic regression classification, G(t) distinguished between the healthy group and wheeze or asthma groups (area under the curve>0·97, p<0·0001; sensitivity analysis confirmed significant CSS association with wheeze [BILD p=0·0002 and PASTURE p=0·068]) and G(t) was also able to distinguish between the farming and non-farming exposure groups (p<0·0001)., Interpretation: Similarly to other risk factors, CSS had weak sensitivity and specificity to identify risks at the individual level. At group level however, the dynamic host-environment correlation network properties (G(t)) showed excellent discriminative ability for identifying groups of infants with subsequent wheeze and asthma. Results from this study are consistent with the 2018 Lancet Commission on asthma, which emphasised the importance of dynamic interactions between risk factors during development and not the risk factors per se., Funding: The Swiss National Science Foundation, the Kühne Foundation, the EFRAIM study EU research grant, the FORALLVENT study EU research grant, and the Leibniz Prize., Competing Interests: Declaration of interests PL reports board membership, funding grants, and speaking and lecture fees from Vertex and OM Pharma; speaking and lecture fees from Vifor Pharma Switzerland; and board membership with Polyphor, Santhera Pharmaceuticals Schweiz, Allecra Therapeutics, and Sanofi. AD-C reports consulting fees from Sanofi, Stallergens, ALK, and Aimmune Therapeutics; speaking fees and meeting attendance costs from Novartis and ALK; stock or stock options with Essilor Luxottica; a grant from Novartis and ARAIRLOR for asthma and cough research; received a grant from Don du Souffle, Fondation du Souffle, and ARAIRLOR for the PASTURE research; and received a contract with the French public agency ANSES. AMK reports that payments were made to their institution from the Juho Vanio Foundation, the Päiwikki and Sakari Sohlberg Foundation, the Finnish Cultural Foundation, the Academy of Finland, and the Finnish Institute for Health and Welfare. RL reports a research grant from the Kühne Foundation; and advisory board and lecture fees from ALK, Pfizer, Milupia, VIFOR, and Sanofi. BS reports research grants from Deutsche Forschungsgemeinschaft and consulting fees from GSK, Novartis, and Sanofi. EvM reports funding grants from the PASTURE study, the EFRAIM study, the FORALLVENT study, and the Leibniz Prize; research grants from the German Federal Ministry of Education and Research, the Bavarian State Ministry of Health and Care, OM Pharma, and the European Research Council; royalties or licences from Elsevier, Georg Thieme Verlag, Springer-Verlag, and Springer Nature Group; consulting fees from the Chinese University of Hong Kong, the European Commission, AstraZeneca, Imperial College London, and OM Pharma; lecture, speaker, or educational fees from ALK-Abello Arzneimittel, Japanese Society of Pediatric Allergy and Clinical Immunology, Klinikum Rechts der Isar, University of Colorado, Paul-Martini-Stiftung, AstraZeneca, Imperial College London, Children's Hospital Research Institute of Manitoba Kompetenzzentrum für Ernährung (Kern), OM Pharma, Swedish Pediatric Society for Allergy and Lung Medicine, Chinese College of Allergy and Asthma, Abbott Laboratories, Deutscher Apotheker Verlag, Socieded Chilena de Enfermedades Respiratorias, Japanese Society of Allergology,British Society for Asthma and Clinical Immunology, American Academy of Allergy, Asthma & Immunology, and the European Respiratory Society (ERS); meeting attendance support from Deutsches Zentrum für Lungenforschung, Fraunhofer ITEM Hannover, MCCA Institut für Immunologie Uni Wien, Karl-Landsteiner Privatuniversität für Gesundheitswissenschaften, Swiss Institute of Allergy and Asthma Research, Davos (Associated Institute of the University of Zurich), Medizinische Hochschule Hannover, Natasha Allergy Research Foundation, Deutsche Forschungsgemeinschaft, Gordon Research Conferences, Socieded Chilena de Enfermedades Respiratorias, Arla, Universität Leiden,OM Pharma, American Academy of Allergy, Asthma & Clinical Immunology, Deutsche Forschungsgemeinschaft, ERS, Deutsche Gesellschaft für Kinder- und Jugendmedizin, World Allergy Organization, and European Parliament; has a patent pending (PCT/EP2019/085016) for barn dust extract for the prevention and treatment of diseases; has royalties paid to ProtectImmun for a patent (EP2361632 for specific environmental bacteria for the protection from and/or the treatment of allergic, chronic inflammatory and/or autoimmune disorders, granted on March 19, 2014); has patents licensed to ProtectImmun (EP1411977 for composition containing bacterial antigens used for the prophylaxis and the treatment of allergic diseases, granted on April 18, 2007; EP1637147 for stable dust extract for allergy protection granted on Dec 10, 2008; and EP1964570 for pharmaceutical compound to protect against allergies and inflammatory diseases, granted on Nov 21, 2012); has a patent (EP21189353.2) for proteins identified from barn dust extract for the prevention and treatment of diseases; has a patent (PCT/US2021/016918) for therapeutic fractions and proteins from asthma-protective farm dust; has a patent (EP21189353.2) for proteins identified from barn dust extract for the prevention and treatment of diseases; and is a member of the EXPANSE (funded by European Commission) Scientific Advisory Board, the BEAMS External Scientific Advisory Board, the Editorial Board of The Journal of Allergy and Clinical Immunology: In Practice, the Scientific Advisory Board of the Children's Respiratory and Environmental Workgroup, the International Scientific & Societal Advisory Board of Utrecht Life Sciences University of Utrecht, the External Review Panel of the Faculty of Veterinary Science (University of Utrecht), the Selection Committee for the Gottfried Wilhelm Leibniz Programme, the International Advisory Board of Asthma UK Centre for Applied Research, the International Advisory Board of The Lancet Respiratory Medicine, the Scientific Advisory Board of the Canadian Healthy Infant Longitudinal Development study (McMaster University, Hamilton, Canada), the Asthma UK Centre for Applied Research, the Pediatric Scientific Advisory Board Iceland, and the Abbott Allergy Risk Reduction Advisory Board. All other authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background: Preterm infants are susceptible to oxidative stress and prone to respiratory diseases. Autophagy is an important defense mechanism against oxidative-stress-induced cell damage and involved in lung development and respiratory morbidity. We hypothesized that autophagy marker levels differ between preterm and term infants., Methods: In the prospective Basel-Bern Infant Lung Development (BILD) birth cohort we compared cord blood levels of macroautophagy (Beclin-1, LC3B), selective autophagy (p62) and regulation of autophagy (SIRT1) in 64 preterm and 453 term infants., Results: Beclin-1 and LC3B did not differ between preterm and term infants. However, p62 was higher (0.37, 95% confidence interval (CI) 0.05;0.69 in log2-transformed level, p = 0.025, p adj  = 0.050) and SIRT1 lower in preterm infants (-0.55, 95% CI -0.78;-0.31 in log2-transformed level, p adj  < 0.001). Furthermore, p62 decreased (p adj -value for smoothing function was 0.018) and SIRT1 increased (0.10, 95% CI 0.07;0.13 in log2-transformed level, p adj  < 0.001) with increasing gestational age., Conclusion: Our findings suggest differential levels of key autophagy markers between preterm and term infants. This adds to the knowledge of the sparsely studied field of autophagy mechanisms in preterm infants and might be linked to impaired oxidative stress response, preterm birth, impaired lung development and higher susceptibility to respiratory morbidity in preterm infants., Impact: To the best of our knowledge, this is the first study to investigate autophagy marker levels between human preterm and term infants in a large population-based sample in cord blood plasma This study demonstrates differential levels of key autophagy markers in preterm compared to term infants and an association with gestational age This may be linked to impaired oxidative stress response or developmental aspects and provide bases for future studies investigating the association with respiratory morbidity., (© 2024. The Author(s).)

Introduction: Respiratory pathogens are frequently isolated from airway samples in primary ciliary dyskinesia (PCD) patients. Few studies have investigated associations between these pathogens and lung function, with current management based on evidence from cystic fibrosis. We investigated the association between commonly isolated respiratory pathogens and lung function in PCD patients., Methods: Using a cross-sectional design, we prospectively collected clinical and concurrent microbiology data from 408 participants with probable or confirmed PCD, aged ≥5 years, from 12 countries. We used Global Lung Function Initiative 2012 references to calculate forced expiratory volume in 1 s (FEV 1 ) z-scores. For 351 patients (86%) with complete data, we assessed the association of the four most frequently isolated pathogens with lung function by fitting multilevel linear models with country as random intercept, adjusted for age at diagnosis, age at lung function, use of antibiotic prophylaxis and body mass index z-scores., Results: Individuals with Pseudomonas aeruginosa growth in culture had significantly lower FEV 1 z-scores (β= -0.87, 95% CI -1.40- -0.34), adjusted for presence of Haemophilus influenzae , methicillin-sensitive Staphylococcus aureus and Streptococcus pneumoniae , and for covariates. When stratified by age, associations remained strong for adults but not for children. Results were similar when ciliary defects by transmission electron microscopy were included in the models and when restricting analysis to only confirmed PCD cases., Conclusions: We found that P. aeruginosa was associated with worse lung function in individuals with PCD, particularly adults. These findings suggest that it is prudent to aim for P. aeruginosa eradication in the first instance, and to treat exacerbations promptly in colonised patients., Competing Interests: Conflict of interest: M. Boon declares receiving grants or contracts from the Fund Alphonse and Jean Forton, managed by the King Baudouin Foundation, and by the Belgian Cystic Fibrosis Association (number 2020-J1810150-217926); and payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing or educational events from Vertex. Conflict of interest: S.B. Carr declares receiving payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing or educational events from Chiesi Pharmaceuticals, and participation on a Data Safety Monitoring Board or Advisory Board for Vertex Pharmaceuticals. Conflict of interest: S. Dillenhöfer declares receiving support for attending meetings and/or travel from Vertex (Advance Program 2022). Conflict of interest: B. Karadag declares receiving payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing or educational events from VEM Ilac, Abdi Ibrahim and OMRON, and participating on a Data Safety Monitoring Board or Advisory Board for Abdi Ibrahim. Conflict of interest: C. Koerner-Rettberg declares receiving speaker honoraria from Berlin Chemie, and advisory board participation and being a member of the medical board of the German PCD patient organisation. Conflict of interest: V. Martinu declares having received grants or contracts from Ministry of Health of the Czech Republic (grant number NV19-07-00210) and participation on an advisory board for indication of tobramycin in noncystic fibrosis bronchiectasis for Chiesi, and receiving payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing or educational events from Chiesi Pharmaceuticals. Conflict of interest: A. Moreno-Galdó declares receiving personal payment for lectures from AstraZeneca, Sanofi-Pasteur and Janssen, receiving support for attending meetings or travel from Sanofi-Pasteur and Vivisol, participation on a Data Safety Monitoring Board or Advisory Board for AstraZeneca and Sanofi-Pasteur, and is President of the Spanish Society of Pediatric Pulmonology. Conflict of interest: U. Ozcelik is Head of the Turkish Respiratory Disease and Cystic Fibrosis Society (unpaid). Conflict of interest: P. Pohunek declares receiving payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing or educational events from GlaxoSmithKline, AstraZeneca and Chiesi, and consulting fees, support for attending meetings and/or travel, and participation on a Data Safety Monitoring Board or Advisory Board from AstraZeneca and GlaxoSmithKline. Conflict of interest: J. Raidt declares receiving the following funds: DFG CRU326 RA3522/1. Conflict of interest: P. Latzin declares receiving grants or contracts from Vertex and OM Pharma, payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing or educational events from Vertex, Vifor and OM Pharma, and participating on a Data Safety Monitoring Board or Advisory Board for the following: Polyphor, Santhera (DMC), Vertex, OM Pharma, Vifor, Allecra and Sanofi Aventis. Conflict of interest: J.S. Lucas declares receiving support for the present manuscript (funds the clinical investigations (spirometry, microbiology)) from NHS England, to the institution; and grants or contracts from COST ACTION to fund the BEATPCD COST Action BM1407, which funded the network that undertook this work, and the institution managed the funding. Conflict of interest: The other authors have nothing to disclose., (Copyright ©The authors 2024.)

Background: Multiple breath washout is a lung function test based on tidal breathing that assesses lung volume and ventilation distribution. The aim of this analysis was to use the Global Lung Function Initiative methodology to develop all-age reference equations for the multiple breath washout indices lung clearance index (LCI) and functional residual capacity (FRC)., Methods: Multiple breath washout data from healthy individuals were collated from sites. Data were re-analysed using the latest software versions. Reference equations were derived using the lambda-mu-sigma (LMS) method using the generalised additive models of location shape and scale programme in R. The impact of equipment type, inert tracer gas, and equipment dead space volume on the derived reference ranges were investigated., Results: Data from 23 sites (n=3647 test occasions) were submitted. Reference equations were derived from 1581 unique observations from participants between the ages of 2 and 81 years. Equipment type, inert tracer gas, and equipment dead space volume did not significantly affect the prediction equations for either LCI or FRC. Reference equations for LCI include age as the only predictor, whereas sex-specific reference equations for FRC included height and age., Conclusions: Global Lung Function Initiative reference equations for multiple breath washout variables provide a standard for reporting and interpretation of LCI and FRC., (Copyright ©The authors 2024. For reproduction rights and permissions contact permissions@ersnet.org.)

Purpose: To introduce and evaluate TrueLung, an automated pipeline for computation and analysis of free-breathing and contrast-agent free pulmonary functional magnetic resonance imaging., Materials and Methods: Two-dimensional time-resolved ultra-fast balanced steady-state free precession acquisitions were transferred to TrueLung, which included image quality checks, image registration, and computation of perfusion and ventilation maps with matrix pencil decomposition. Neural network whole-lung and lobar segmentations allowed quantification of impaired relative perfusion (R Q ) and fractional ventilation (R FV ). TrueLung delivered functional maps and quantitative outcomes, reported for clinicians in concise documents. We evaluated the pipeline using 1.5T data from 75 children with cystic fibrosis by assessing the feasibility of functional MR imaging, average scan time, and the robustness of the functional outcomes. Whole-lung and lobar segmentations were manually refined when necessary, and the impact on R Q and R FV was quantified., Results: Functional imaging was feasible in all included CF children without any dropouts. On average, 7.9 ± 1.8 (mean±SD) coronal slice positions per patient were acquired, resulting in a mean scan time of 6min 20s per patient. The whole pipeline required 20min processing time per subject. TrueLung delivered the functional maps of all the subjects for radiological assessment. Quality controlling maps and segmentations lasted 1min 12s per patient. The automated segmentations and quantification of whole-lung defects were satisfying in 88% of patients (97% of slices) and the lobar quantification in 73% (93% of slices). The segmentations refinements required 16s per patient for the whole-lung, and 2min 10s for the lobe masks. The relative differences in R FV and R Q between fully-automated and manually refined data were 0.7% (1.2%) and 2.0% (2.9%) for whole-lung quantification (median, [third quartile]), and excluding two outliers, 1.7% (3.9%) and 1.2% (3.8%) for the lobes, indicating the refinements could be potentially omitted in several patients., Conclusions: TrueLung quickly delivers functional maps and quantitative outcomes in an objective and standardized way, suitable for radiological and pneumological assessment with minimal manual input. TrueLung can be used for clinical research in cystic fibrosis and might be applied across various lung diseases., (Copyright © 2024 The Author(s). Published by Elsevier GmbH.. All rights reserved.)

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: Current knowledge suggests that the gene region containing MUC5B and TOLLIP plays a role in airway defence and airway inflammation, and hence respiratory disease. It is also known that exposure to air pollution increases susceptibility to respiratory disease. We aimed to study whether the effect of air pollutants on the immune response and respiratory symptoms in infants may be modified by polymorphisms in MUC5B and TOLLIP genes., Methods: 359 healthy term infants from the prospective Basel-Bern Infant Lung Development (BILD) birth cohort were included in the study. The main outcome was the score of weekly assessed respiratory symptoms in the first year of life. Using the candidate gene approach, we selected 10 single nucleotide polymorphisms (SNPs) from the MUC5B and TOLLIP regions. Nitrogen dioxide (NO 2 ) and particulate matter ≤10 μm in aerodynamic diameter (PM 10 ) exposure was estimated on a weekly basis. We used generalised additive mixed models adjusted for known covariates. To validate our results in vitro, cells from a lung epithelial cell line were downregulated in TOLLIP expression and exposed to diesel particulate matter (DPM) and polyinosinic-polycytidylic acid., Results: Significant interaction was observed between modelled air pollution (weekly NO 2 exposure) and 5 SNPs within MUC5B and TOLLIP genes regarding respiratory symptoms as outcome: E.g., infants carrying minor alleles of rs5744034, rs3793965 and rs3750920 (all TOLLIP) had an increased risk of respiratory symptoms with increasing NO 2 exposure. In vitro experiments showed that cells downregulated for TOLLIP react differently to environmental pollutant exposure with DPM and viral stimulation., Conclusion: Our findings suggest that the effect of air pollution on respiratory symptoms in infancy may be influenced by the genotype of specific SNPs from the MUC5B and TOLLIP regions. For validation of the findings, we provided in vitro evidence for the interaction of TOLLIP with air pollution., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Urs Frey reports financial support was provided by Swiss National Science Foundation. Celine Ruettimann reports a relationship with Freie Akademische Gesellschaft Basel that includes: funding grants. Philipp Latzin reports a relationship with Vertex that includes: board membership, funding grants, and speaking and lecture fees. Philipp Latzin reports a relationship with Vifor Pharma Switzerland SA that includes: speaking and lecture fees. Philipp Latzin reports a relationship with OM Pharma Ltd that includes: board membership, funding grants, and speaking and lecture fees. Philipp Latzin reports a relationship with Polyphor Ltd that includes: board membership. Philipp Latzin reports a relationship with Santhera Pharmaceuticals Schweiz AG that includes: board membership. Philipp Latzin reports a relationship with Allecra Therapeutics that includes: board membership. Philipp Latzin reports a relationship with Sanofi that includes: board membership. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Biallelic ATP-binding cassette subfamily A member 3 (ABCA3) variants can cause interstitial lung disease in children and adults, for which no proven treatments exist. Recent in vitro evidence suggested that cyclosporine A (CsA) could correct some ABCA3 variants, however for other variants this is unknown and no data in patients exist., Methods: We retrieved the clinical data of two children aged 2 and 4 years carrying homozygous ABCA3 variants (G210C and Q1045R, respectively) and empiric CsA treatment from the Kids Lung Register database. In vitro experiments functionally characterized the two variants and explored the effects of CsA alone or combined with hydroxychloroquine (HCQ) in a human alveolar epithelial cell line (A549) derived from adenocarcinoma cells., Results: Six weeks following the introduction of CsA, both children required a reduced O 2 flow supply, which then remained stable on CsA. Later, when CsA was discontinued, the clinical status of the children remained unchanged. Of note, the children simultaneously received prednisolone, azithromycin, and HCQ. In vitro, both ABCA3 variants demonstrated defective lysosomal colocalization and impaired ABCA3 + vesicle size, with proteolytic cleavage impairment only in Q1045R. CsA alone corrected the trafficking impairment and ABCA3 + vesicle size of both variants with a variant-specific effect on phosphatidylcholine recycling in G210C. CsA combined with HCQ were additive for improving trafficking of ABCA3 in G210C, but not in Q1045R., Conclusions: CsA treatment might be helpful for certain patients with ABCA3 deficiency, however, currently strong clinical supporting evidence is lacking. Appropriate trials are necessary to overcome this unmet need., (© 2024 The Author(s). Pediatric Pulmonology published by Wiley Periodicals LLC.)

Introduction: Major methodological issues with the existing algorithm (WBreath) used for the analysis of speed-of-sound-based infant sulfur hexafluoride (SF 6 ) multiple-breath washout (MBW) measurements lead to implausible results and complicate the comparison between different age groups and centers., Methods: We developed OASIS-a novel algorithm to analyze speed-of-sound-based infant SF 6 MBW measurements. This algorithm uses known context of the measurements to replace the dependence of WBreath on model input parameters. We validated the functional residual capacity (FRC) measurement accuracy of this new algorithm in vitro, and investigated its use in existing infant MBW data sets from different infant cohorts from Switzerland and South Africa., Results: In vitro, OASIS managed to outperform WBreath at FRC measurement accuracy, lowering mean (SD) absolute error from 5.1 (3.2) % to 2.1 (1.6) % across volumes relevant for the infant age range, in variable temperature, respiratory rate, tidal volume and ventilation inhomogeneity conditions. We showed that changes in the input parameters to WBreath had a major impact on MBW results, a methodological drawback which does not exist in the new algorithm. OASIS produced more plausible results than WBreath in longitudinal tracking of lung clearance index (LCI), provided improved measurement stability in LCI over time, and improved comparability between centers., Discussion: This new algorithm represents a meaningful advance in obtaining results from a legacy system of lung function measurement by allowing a single method to analyze measurements from different age groups and centers., (© 2024 The Author(s). Pediatric Pulmonology published by Wiley Periodicals LLC.)

Background: The adverse effects of high air pollution levels on childhood lung function are well-known. Limited evidence exists on the effects of moderate exposure levels during early life on childhood lung function. We investigated the association of exposure to moderate air pollution during pregnancy, infancy, and preschool time with lung function at school age in a Swiss population-based study., Methods: Fine-scale spatiotemporal model estimates of particulate matter with a diameter <2.5 µm (PM 2.5 ) and nitrogen dioxide (NO 2 ) were linked with residential address histories. We compared air pollution exposures within different time windows (whole pregnancy, first, second, and third trimester of pregnancy, first year of life, preschool age) with forced expiratory volume in 1 s (FEV 1 ) and forced vital capacity (FVC) measured cross-sectionally using linear regression models adjusted for potential confounders., Results: We included 2182 children, ages 6-17 years. Prenatal air pollution exposure was associated with reduced lung function at school age. In children aged 12 years, per 10 µg·m -3 increase in PM 2.5 during pregnancy, FEV 1 was 55 mL lower (95% CI -84 to -25 mL) and FVC 62 mL lower (95% CI -96 to -28 mL). Associations were age-dependent since they were stronger in younger and weaker in older children. PM 2.5 exposure after birth was not associated with reduced lung function. There was no association between NO 2 exposure and lung function., Conclusion: In utero lung development is most sensitive to air pollution exposure, since even modest PM 2.5 exposure during the prenatal time was associated with reduced lung function, most prominent in younger children., (© 2024 The Author(s). Pediatric Pulmonology published by Wiley Periodicals LLC.)

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.)

Competing Interests: We declare no competing interests.

Objectives: In patients with congenital diaphragmatic hernia (CDH) the exact functional outcome of the affected lung side is still unknown, mainly due to the lack of spatially resolved diagnostic tools. Functional matrix-pencil decomposition (MP-) lung MRI fills this gap as it measures side-specific ventilation and perfusion. We aimed to assess the overall and side-specific pulmonary long-term outcomes of patients with CDH using lung function tests and MP-MRI., Methods: Thirteen school-aged children with CDH (seven with small and six with large defect-sized CDH, defined as > 50% of the chest wall circumference being devoid of diaphragm tissue) and thirteen healthy matched controls underwent spirometry, multiple-breath washout, and MP-MRI. The main outcomes were forced expiratory volume in 1 second (FEV 1 ), lung clearance index (LCI 2.5 ), ventilation defect percentage (VDP), and perfusion defect percentage (QDP)., Results: Patients with a large CDH showed significantly reduced overall lung function compared to healthy controls (mean difference [95%-CI adjusted ]: FEV 1 (z-score) -4.26 [-5.61, -2.92], FVC (z-score) -3.97 [-5.68, -2.26], LCI 2.5 (TO) 1.12 [0.47, 1.76], VDP (%) 8.59 [3.58, 13.60], QDP (%) 17.22 [13.16, 21.27]) and to patients with a small CDH. Side-specific examination by MP-MRI revealed particularly reduced ipsilateral ventilation and perfusion in patients with a large CDH (mean difference to contralateral side [95%-CI adjusted ]: VDP (%) 14.80 [10.50, 19.00], QDP (%) 23.50 [1.75, 45.20])., Conclusions: Data indicate impaired overall lung function with particular limitation of the ipsilateral side in patients with a large CDH. MP-MRI is a promising tool to provide valuable side-specific functional information in the follow-up of patients with CDH., Clinical Relevance Statement: In patients with congenital diaphragmatic hernia, easily applicable MP-MRI allows specific examination of the lung side affected by the hernia and provides valuable information on ventilation and perfusion with implications for clinical practice, making it a promising tool for routine follow-up., Key Points: • Functional matrix pencil decomposition (MP) MRI data from a small sample indicate reduced ipsilateral pulmonary ventilation and perfusion in children with large congenital diaphragmatic hernia (CDH). • Easily applicable pencil decomposition MRI provides valuable side-specific diagnostic information on lung ventilation and perfusion. This is a clear advantage over conventional lung function tests, helping to comprehensively follow up patients with congenital diaphragmatic hernia and monitor therapy effects., (© 2023. The Author(s).)

Background: Methods used to assess ventilation heterogeneity through inert gas washout have been standardised and showed high sensitivity in diagnosing many respiratory diseases. We hypothesised that nitrogen single or multiple breath washout tests, respectively nitrogen single breath washout (N 2 SBW) and nitrogen multiple breath washout (N 2 MBW), may be pathological in patients with clinical suspicion of asthma but normal spirometry. Our aim was to assess whether N 2 SBW and N 2 MBW are associated with methacholine challenge test (MCT) results in this population. We also postulated that an alteration in S III at N 2 SBW could be detected before the 20% fall of forced expiratory volume in the first second (FEV 1 ) in MCT., Study Design and Methods: This prospective, observational, single-centre study included patients with suspicion of asthma with normal spirometry. Patients completed questionnaires on symptoms and health-related quality-of-life and underwent the following lung function tests: N 2 SBW (S III ), N 2 MBW (Lung clearance index (LCI), S cond , S acin ), MCT (FEV 1 and sGeff) as well as N 2 SBW between each methacholine dose., Results: 182 patients were screened and 106 were included in the study, with mean age of 41.8±14 years. The majority were never-smokers (58%) and women (61%). MCT was abnormal in 48% of participants, N 2 SBW was pathological in 10.6% at baseline and N 2 MBW abnormality ranged widely (LCI 81%, S cond 18%, S acin 43%). The dose response rate of the MCT showed weak to moderate correlation with the subsequent N 2 SBW measurements during the provocation phases (ρ 0.34-0.50) but no correlation with N 2 MBW., Conclusions: Both MCT and N 2 washout tests are frequently pathological in patients with suspicion of asthma with normal spirometry. The weak association and lack of concordance across the tests highlight that they reflect different but not interchangeable pathological pathways of the disease., Competing Interests: Competing interests: DS (second author) is currently employed at Tillotts Pharma AG, however, during the period of the study was an employee of the University Hospital of Basel. AMD has received a grant from University Hospital Basel, PL has a grant/contract to Vertex and OM Pharma. DS (last author) reports grants from Astra-Zeneca AG, Curetis AG, BostonScientific, Novartis AG, GSK AG, Roche AG, Zambon, Pfizer, Schwabe Pharma AG, Vifor AG. Other authors have no conflict of interest to declare., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Good data quality is essential when rare disease registries are used as a data source for pharmacovigilance studies. This study investigated data quality of the Swiss cystic fibrosis (CF) registry in the frame of a European Cystic Fibrosis Society Patient Registry (ECFSPR) project aiming to implement measures to increase data reliability for registry-based research., Methods: All 20 pediatric and adult Swiss CF centers participated in a data quality audit between 2018 and 2020, and in a re-audit in 2022. Accuracy, consistency and completeness of variables and definitions were evaluated, and missing source data and informed consents (ICs) were assessed., Results: The first audit included 601 out of 997 Swiss people with CF (60.3 %). Data quality, as defined by data correctness ≥95 %, was high for most of the variables. Inconsistencies of specific variables were observed because of an incorrect application of the variable definition. The proportion of missing data was low with <5 % for almost all variables. A considerable number of missing source data occurred for CFTR variants. Availability of ICs varied largely between centers (10 centers had >5 % of missing documents). After providing feedback to the centers, availability of genetic source data and ICs improved., Conclusions: Data audits demonstrated an overall good data quality in the Swiss CF registry. Specific measures such as support of the participating sites, training of data managers and centralized data collection should be implemented in rare disease registries to optimize data quality and provide robust data for registry-based scientific research., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Kathleen Jahn, Andreas Jung, Philipp Latzin, Alexander Moeller, Christian Murer, Lutz Naehrlich, Alain Sauty and Jakob Usemann have received honoraria from Vertex Pharmaceuticals. Andreas Jung has received consulting fees and honoraria from EffRx Pharmaceuticals and Viatris. Philipp Latzin has received honoraria from CSL Vifor., (Copyright © 2023. Published by Elsevier B.V.)

We assessed human metapneumovirus infections in children hospitalized between 2011 and 2023 and compared the strongest pre- and postpandemic seasons. After the COVID-19 pandemic, we observed offseason cases and loss of the alternating pattern of the human metapneumovirus season magnitude. Incidence rate ratio of 0- to 11-month-old versus 12- to 23-month-old children was 2.1 (95% CI: 1.0-4.8) before and 1.3 (95% CI: 0.6-2.9) after the pandemic., Competing Interests: R.S., V.M., I.K., and C.A. have no conflicts of interest to disclose. P.L. reports grants from Vertex and OM Pharma paid to the institution; personal payments or honoraria from Vertex, Vifor and OM Pharma; all outside the submitted work. P.A. reports honoraria from Sanofi paid to the institution outside the submitted work., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

Multiple-breath washout (MBW) is an established technique to assess functional residual capacity (FRC) and ventilation inhomogeneity in the lung. Indirect calculation of nitrogen concentration requires accurate measurement of gas concentrations. To investigate the accuracy of the CO 2 concentration and molar mass (MM) values used for the indirect calculation of nitrogen concentration in a commercial MBW device [EasyOne Pro LAB (EOPL), ndd Medizintechnik AG, Switzerland] and its impact on outcomes. We used high-precision gas mixtures to evaluate CO 2 and MM sensor output in vivo and in vitro. We developed updated algorithms to correct observed errors and assessed the impact on MBW outcomes and FRC measurement accuracy compared with body plethysmography. The respiratory exchange ratio (RER)-based adjustment of the measured CO 2 signal used in the EOPL led to an overestimated CO 2 signal (range -0.1% to 1.0%). In addition, an uncorrected dependence on humidity was identified. These combined effects resulted in an overestimation of expired nitrogen concentrations (range -0.7% to 2.6%), and consequently MBW outcomes. Corrected algorithms reduced the mean (SD) cumulative expired volume by 15.8% (9.7%), FRC by 6.6% (3.0%), and lung clearance index by 9.9% (7.6%). Differences in FRC between the EOPL and body plethysmography further increased. Inadequate signal correction causes RER- and humidity-dependent expired nitrogen concentration errors and overestimation of test outcomes. Updated algorithms reduce average signal error, however, RER values far from the population average still cause measurement errors. Despite improved signal accuracy, the updated algorithm increased the difference in FRC between the EOPL and body plethysmography. NEW & NOTEWORTHY We investigated the accuracy of the molar mass (MM) and CO 2 sensors of a commercial multiple-breath washout device (ndd Medizintechnik AG, Switzerland). We identified humidity and respiratory exchange ratio-dependent errors that in most measurements resulted in an overestimation of expired nitrogen concentrations, and consequently, MBW results. Functional residual capacity and lung clearance index decreased by 6.6% and 9.9%, respectively. Despite improved signal accuracy, the difference in FRC between the EOPL and body plethysmography increased.

Childhood, adolescent, and young adult (CAYA) cancer survivors are at risk of pulmonary dysfunction. Current follow-up care guidelines are discordant. Therefore, the International Late Effects of Childhood Cancer Guideline Harmonization Group established and convened a panel of 33 experts to develop evidence-based surveillance guidelines. We critically reviewed available evidence regarding risk factors for pulmonary dysfunction, types of pulmonary function testing, and timings of surveillance, then we formulated our recommendations. We recommend that CAYA cancer survivors and healthcare providers are aware of reduced pulmonary function risks and pay vigilant attention to potential symptoms of pulmonary dysfunction, especially among survivors treated with allogeneic haematopoietic stem cell transplantation, thoracic radiotherapy, and thoracic surgery. Based on existing limited evidence and current lack of interventions, our panel recommends pulmonary function testing only for symptomatic survivors. Since scarce existing evidence informs our recommendation, we highlight the need for prospective collaborative studies to address pulmonary function knowledge gaps among CAYA cancer survivors., Competing Interests: -AC Dietz is employed by and has equity in Shape Therapeutics, Inc. and was employed by and has equity in bluebird bio, Inc., neither of which provided financial support or oversight of this work.-AB received fees for lectures and/or boards from Astra-Zeneca, Novartis, Enanta paid to her institution as well as travel grants from Boehringer and Astra-Zeneca.-CEK received grants from the Swiss National Science Foundation-MO received research support from the Swiss Pediatric Oncology Society (SPOG)-DJW received grants/contracts from Vertex pharmaceuticals, Cystic Fibrosis Foundation Therapeutic Development Network, payment or honoraria for lectures/presentations by Cystic Fibrosis Foundation and American Board of Pediatrics-GS and RK received support for the present manuscript by Bernische Krebsliga and Lungenliga Bern-LSC received support from University of Alabama for COG Survivorship guidelines, royalties or licenses from Springer and Wolters Kluwer, payment or honoraria for lectures/presentations from the American Society for Hematology and the University of Miami, travel support from the First International Pediatric Cardio-oncology meeting, and participates on the Data Safety Monitoring Board or Advisory Board of the NCI PDQ-MG received a grant from the Swiss National Science Foundation, support for attending meetings and/or travel from the European Respiratory Society, has a leadership role in the BEAT-PCD ERS clinical research collaboration-NW received general research support from CANSEARCH Research Foundation, payment/honoraria and support to attend an international meeting from Swedish Orphan Biovitrum (SOBI), participates on a Data Safety Monitoring Board or Advisory Board from SOBI-PL received grants/contracts from Vertex and OM Pharma, payments or honoraria for lectures/presentations by Vertex, Vifor and OM Pharma, participates on a Data Safety Monitoring Board or Advisory Board from Polyphor, Santhera, Vertex, OM Pharma, Vifor, Sanofi Aventis-UH received a grant and support for attending meetings from the German Childhood Cancer Foundation,, (© 2024 Published by Elsevier Ltd.)

Background: The early life origins of chronic pulmonary diseases are thought to arise in peripheral small airways. Predictors of ventilation inhomogeneity, a proxy of peripheral airway function, are understudied in schoolchildren., Research Question: Is the double-tracer gas single-breath washout (DTG-SBW) measurement feasible in a pediatric field study setting? What are the predictors of the DTG-SBW-derived ventilation inhomogeneity estimate in unselected schoolchildren?, Study Design and Methods: In this prospective cross-sectional field study, a mobile lung function testing unit visited participating schools in Switzerland. We applied DTG-SBW, fraction of exhaled nitric oxide (Feno), and spirometry measurements. The DTG-SBW is based on tidal inhalation of helium and sulfur-hexafluoride, and the phase III slope (SIII He-SF6 ) is derived. We assessed feasibility, repeatability, and associations of SIII He-SF6 with the potential predictors of anthropometrics, presence of wheeze (ie, parental report of one or more episode of wheeze in the prior year), Feno, FEV 1 , and FEV 1 /FVC., Results: In 1,782 children, 5,223 DTG-SBW trials were obtained. The DTG-SBW was acceptable in 1,449 children (81.3%); the coefficient of variation was 39.8%. SIII He-SF6 was independently but weakly positively associated with age and BMI. In 276 children (21.2%), wheeze was reported. SIII He-SF6 was higher by 0.049 g.mol.L -1 in children with wheeze compared with those without and remained associated with wheeze after adjusting for age and BMI in a multivariable linear regression model. SIII He-SF6 was not associated with Feno, FEV 1 , and FEV 1 /FVC., Interpretation: The DTG-SBW is feasible in a pediatric field study setting. On the population level, age, body composition, and wheeze are independent predictors of peripheral airway function in unselected schoolchildren. The variation of the DTG-SBW possibly constrains its current applicability on the individual level., Trial Registration: ClinicalTrials.gov; No.: NCT03659838; URL: www., Clinicaltrials: gov., Competing Interests: Financial/Nonfinancial Disclosures The authors have reported to CHEST the following: A.-C. K. is recipient of a Swiss Excellence Grant from the Swiss government. J. M. K. reports funding for this work from a grant from the KinderInsel Bern Foundation. J. U. reports receiving grants or contracts from the Swiss Lung Foundation, Palatin Foundation, University of Basel, and Swiss Cancer League; and payment or honoraria for lectures, presentations, speaker bureaus, manuscript writing, or educational events received from Vertex and the Zürich Lung Foundation, outside the submitted work. P. L. reports receiving grants or contracts from Vertex and OM Pharma paid to the institution; personal payment or honoraria and payments or honoraria for lectures, presentations, speaker bureaus, manuscript writing, or educational events received from Vertex, Vifor, and OM Pharma; personal fees and fees paid to the institution for participation on a data safety monitoring or advisory board for Polyphor, Vertex, OM Pharma, and Vifor; and personal fees for participation on data safety monitoring or advisory board for Santhera (DMC) and Sanofi Aventis. A. M. reports receiving consulting fees from Vertex Pharmaceuticals and Vifor Pharma; payments or honoraria for lectures, presentations, speaker bureaus, manuscript writing, or educational events received from Vertex Pharmaceuticals and Vifor Pharma; participation on a data safety monitoring or advisory board for Vertex Pharmaceuticals; leadership or fiduciary roles in other boards, societies, committees, or advocacy groups, paid or unpaid, held for European Respiratory Society Assembly 7, Swiss Society of Pulmonology Board, Swiss Society of Pediatric Pulmonology Board, Swiss Working Group for Cystic Fibrosis, and Swiss Society for Sleep Research, Sleep Medicine and Chronobiology; and receipt of medical writing from Vertex Pharmaceuticals, with all disclosures made outside the submitted work. F. S. reports support of this manuscript from the Medical University of Graz for the processing charges; grants or contracts from the Medical University of Graz and Lungen Liga Bern paid to the institution; personal payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Novartis Pharma Switzerland, Vertex Pharmaceuticals Switzerland, and Vertex Pharmaceuticals Austria; and nonfinancial support from EcoMedics AG, Dürnten, Switzerland and Chiesi Pharmaceuticals Austria, outside the submitted work. None declared (R. M., E. S. L. P., C. E. K.)., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Importance: The usage of 16S rRNA gene sequencing has become the state-of-the-art method for the characterization of the microbiota in health and respiratory disease. The method is reliable for low biomass samples due to prior amplification of the 16S rRNA gene but has limitations as species and certainly strain identification is not possible. However, the usage of metagenomic tools for the analyses of microbiome data from low biomass samples is not straight forward, and careful optimization is needed. In this work, we show that by validating StrainPhlAn 3 results with the data from bacterial cultures, the strain-level tracking of the respiratory microbiome is feasible despite the high content of host DNA being present when parameters are carefully optimized to fit low biomass microbiomes. This work further proposes that strain retention analyses are feasible, at least for more abundant species. This will help to better understand the longitudinal dynamics of the upper respiratory microbiome during health and disease., Competing Interests: L.S., S.K., and O.S. are employees of Société des Produits Nestlé (SPN). P.L. reports grants (from Vertex and OM Pharma), lecture fees (from Vertex, Vifor, and OM Pharma), and participation on data and safety monitoring boards or advisory boards (for Polyphor, Santhera, Vertex, OM Pharma, Vifor, and Sanofi Avenits), outside the submitted work. M.H. reports a grant (from Pfizer) and participation on advisory boards (for Pfizer and MSD), outside the submitted work.

Introduction: Distinguishing phenotypes among children with cough helps understand underlying causes. Using a statistical data-driven approach, we aimed to identify and validate cough phenotypes based on measurable traits, physician diagnoses, and prognosis., Methods: We used data from the Swiss Paediatric Airway Cohort and included 531 children aged 5-16 years seen in outpatient clinics since 2017. We included children with any parent-reported cough (i.e. cough without a cold, cough at night, cough more than other children, or cough longer than 4 weeks) without current wheeze. We applied latent class analysis to identify phenotypes using nine symptoms and characteristics and selected the best model using the Akaike information criterion. We assigned children to the most likely phenotype and compared the resulting groups for parental atopy history, comorbidities, spirometry, fractional exhaled nitric oxide (FeNO), skin prick tests and specific IgE, physician diagnoses, and 1-year prognosis., Results: We identified four cough phenotypes: non-specific cough (26%); non-allergic infectious and night cough with snoring and otitis (4%); chronic allergic dry night cough with snoring (9%); and allergic non-infectious cough with rhino-conjunctivitis (61%). Children with the allergic phenotype often had family or personal history of atopy and asthma diagnosis. FeNO was highest for the allergic phenotype [median 17.9 parts per billion (ppb)] and lowest for the non-allergic infectious phenotype [median 7.0 parts per billion (ppb)]. Positive allergy test results differed across phenotypes (p < .001) and were most common among the allergic (70%) and least common among the non-specific cough (31%) phenotypes. Subsequent wheeze was more common among the allergic than the non-specific phenotype., Conclusion: We identified four clinically relevant cough phenotypes with different prognoses. Although we excluded children with current wheeze, most children with cough belonged to allergy-related phenotypes., (© 2023 John Wiley & Sons Ltd.)

Objectives: Population-based studies of children with dry night cough alone compared with those who also wheeze are few and inconclusive. We compared how children with dry night cough differ from those who wheeze., Methods: LuftiBus in the school is a population-based study of schoolchildren conducted between 2013 and 2016 in Zurich, Switzerland. We divided children into four mutually exclusive groups based on reported dry night cough (henceforth referred as "cough") and wheeze and compared parent-reported symptoms, comorbidities, exposures, FeNO, spirometry, and healthcare use and treatment., Results: Among 3457 schoolchildren aged 6-17 years, 294 (9%) reported "cough," 181 (5%) reported "wheeze," 100 (3%) reported "wheeze and cough," and 2882 (83%) were "asymptomatic." Adjusting for confounders in a multinomial regression, children with "cough" reported more frequent colds, rhinitis, and snoring than "asymptomatic" children; children with "wheeze" or "wheeze and cough" more often reported hay fever, eczema, and parental histories of asthma. FeNO and spirometry were similar among "asymptomatic" and children with "cough," while children with "wheeze" or "wheeze and cough" had higher FeNO and evidence of bronchial obstruction. Children with "cough" used healthcare less often than those with "wheeze," and they attended mainly primary care. Twenty-two children (7% of those with "cough") reported a physician diagnosis of asthma and used inhalers. These had similar characteristics as children with wheeze., Conclusion: Our representative population-based study confirms that children with dry night cough without wheeze clearly differed from those with wheeze. This suggests asthma is unlikely, and they should be investigated for alternative aetiologies, particularly upper airway disease., (© 2023 The Authors. Pediatric Pulmonology published by Wiley Periodicals LLC.)

Background: The effects of prenatal antibiotic exposure on respiratory morbidity in infancy and the involved mechanisms are still poorly understood. We aimed to examine whether prenatal antibiotic exposure in the third trimester is associated with nasal microbiome and respiratory morbidity in infancy and at school age, and whether this association with respiratory morbidity is mediated by the nasal microbiome., Methods: We performed 16S ribosomal RNA gene sequencing (regions V3-V4) on nasal swabs obtained from 296 healthy term infants from the prospective Basel-Bern birth cohort (BILD) at age 4-6 weeks. Information about antibiotic exposure was derived from birth records and standardised interviews. Respiratory symptoms were assessed by weekly telephone interviews in the first year of life and a clinical visit at age 6 years. Structural equation modelling was used to test direct and indirect associations accounting for known risk factors., Results: α-Diversity indices were lower in infants with antibiotic exposure compared to nonexposed infants ( e.g. Shannon index p-value 0.006). Prenatal antibiotic exposure was also associated with a higher risk of any, as well as severe, respiratory symptoms in the first year of life (risk ratio 1.38, 95% CI 1.03-1.84; adjusted p-value (p adj )=0.032 and risk ratio 1.75, 95% CI 1.02-2.97; p adj =0.041, respectively), but not with wheeze or atopy in childhood. However, we found no indirect mediating effect of nasal microbiome explaining these clinical symptoms., Conclusion: Prenatal antibiotic exposure was associated with lower diversity of nasal microbiome in infancy and, independently of microbiome, with respiratory morbidity in infancy, but not with symptoms later in life., Competing Interests: Conflict of interest: C. Rüttimann is partially funded by the Freie Akademische Gesellschaft Basel. The other authors declare no conflict of interest., (Copyright ©The authors 2023.)

Background: Inhalation of hypertonic saline (HS) is standard of care in patients with cystic fibrosis (CF). However, it is unclear if adding salbutamol has-besides bronchodilation-further benefits, for example, on the mucociliary clearance. We assessed this in vitro by measuring the ciliary beating frequency (CBF) and the mucociliary transport rate (MCT) in nasal epithelial cells (NECs) of healthy volunteers and patients with CF. Aims: To investigate the effect of HS, salbutamol, and its combination on (muco)ciliary activity of NECs in vitro , and to assess potential differences between healthy controls and patients with CF. Methods: NECs obtained from 10 healthy volunteers and 5 patients with CF were differentiated at the air-liquid interface and aerosolized with 0.9% isotonic saline ([IS] control), 6% HS, 0.06% salbutamol, or combined HS and salbutamol. CBF and MCT were monitored over 48-72 hours. Results: In NECs of healthy controls, the absolute CBF increase was comparable for all substances, but CBF dynamics were different: HS increased CBF slowly and its effect lasted for an extended period, salbutamol and IS increased CBF rapidly and the effect subsided similarly fast, and HS and salbutamol resulted in a rapid and long-lasting CBF increase. Results for CF cells were comparable, but less pronounced. Similar to CBF, MCT increased after the application of all the tested substances. Conclusion: CBF and MCT of NECs of healthy participants and CBF of patients with CF increased upon treatment with aerosolized IS, HS, salbutamol, or HS and salbutamol, showing a relevant effect for all tested substances. The difference in the CBF dynamics can be explained by the fact that the properties of the mucus are changed differently by different saline concentrations.

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.)

Lung function testing and lung imaging are commonly used techniques to monitor respiratory diseases, such as cystic fibrosis (CF). The nitrogen (N 2 ) multiple-breath washout technique (MBW) has been shown to detect ventilation inhomogeneity in CF, but the underlying pathophysiological processes that are altered are often unclear. Dynamic oxygen-enhanced magnetic resonance imaging (OE-MRI) could potentially be performed simultaneously with MBW because both techniques require breathing of 100% oxygen (O 2 ) and may allow for visualisation of alterations underlying impaired MBW outcomes. However, simultaneous MBW and OE-MRI has never been assessed, potentially as it requires a magnetic resonance (MR) compatible MBW equipment. In this pilot study, we assessed whether MBW and OE-MRI can be performed simultaneously using a commercial MBW device that has been modified to be MR-compatible. We performed simultaneous measurements in five healthy volunteers aged 25-35 years. We obtained O 2 and N 2 concentrations from both techniques, and generated O 2 wash-in time constant and N 2 washout maps from OE-MRI data. We obtained good quality simultaneous measurements in two healthy volunteers due to technical challenges related to the MBW equipment and poor tolerance. Oxygen and N 2 concentrations from both techniques, as well as O 2 wash-in time constant maps and N 2 washout maps could be obtained, suggesting that simultaneous measurements may have the potential to allow for comparison and visualization of regional differences in ventilation underlying impaired MBW outcomes. Simultaneous MBW and OE-MRI measurements can be performed with a modified MBW device and may help to understand MBW outcomes, but the measurements are challenging and have poor feasibility., Competing Interests: Conflict of interest statement Eco Medics AG (Duernten, Switzerland) produced the customized MBW setup and a research version of their commercial software Spiroware 3.3. A.C. Kentgens is recipient of a Swiss Government Excellence Scholarship from the Swiss Confederation, Federal Department of Economic Affairs, Education and Research (EAER). F. Santini reports research grants from the Swiss National Science Foundation and consulting fees of Hoffmann – La Roche paid to the institution. P. Latzin reports grants from Vertex and OM Pharma paid to the institution; personal payments or honoraria from Vertex, Vifor and OM Pharma; payments or honoraria from Vertex, Vifor and OM Pharma paid to the institution; personal fees for participation on a Data Safety Monitoring Board or Advisory Board from Polyphor, Santhera (DMC), Vertex, OM pharma, Vifor and Sanofi Aventis; and fees for participation on a Data Safety Monitoring Board or Advisory Board from Polyphor, Vertex, OM pharma and Vifor paid to the institution, all outside the submitted work. K.A. Ramsey reports a grant from Vertex paid to the institution. Otherwise, all other authors report no other competing interests., (Copyright © 2023 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Background: Sinonasal symptoms are a common feature of primary ciliary dyskinesia (PCD); however, literature about their severity and frequency, particularly during the life course, is scarce. Using baseline data from the Ear, nose and throat (ENT) Prospective International Cohort of PCD patients, we describe sinonasal disease in PCD., Methods: We included participants who had a routine sinonasal examination during which they completed a symptoms questionnaire. We compared frequency of reported symptoms and examination findings among children and adults, and identified characteristics potentially associated with higher risk of sinonasal disease using ordinal regression., Results: 12 centres contributed 384 participants; median age was 16 years (IQR 9-22), and 54% were male. Chronic nasal problems were the most common feature, reported by 341 (89%). More adults (33; 24%) than children (10; 4%) described hyposmia. Quality of life was moderately affected by rhinosinusitis among 136 participants with completed SNOT-22 questionnaires (median score 31; IQR 23-45). Examinations revealed nasal polyps among 51 of 345 participants (15%) and hypertrophic inferior nasal turbinates among 127 of 341 participants (37%). Facial pain was detected in 50 of 342 participants (15%). Nasal polyps, hypertrophic turbinates, deviated septum and facial pain were found more commonly in adults than children. The only characteristic associated with higher risk of sinonasal disease was age 10 years and older., Conclusions: Based on our findings, regular sinonasal examinations are relevant for patients with PCD of all ages. There is a need for improved management of sinonasal disease supported by evidence-based guidelines., Competing Interests: Conflict of interest: P. Latzin received grants or honoraria for participation in data safety monitoring boards or advisory boards from Vertex, Vifor, OM Pharma, Polyphor, Santhera (DMC) and Sanofi Aventis within the last 36 months. J. Roehmel received grants and clinical study remuneration from Vertex, INSMED, Medical Research Council/UK, BMBF and Mukoviszidose Institut. All other authors have nothing to declare., (Copyright ©The authors 2023.)

Nasal nitric oxide (nNO) is extremely low in most people with primary ciliary dyskinesia (PCD) and its measurement is an important contributor to making the diagnosis. Existing guidelines and technical standards focus on nNO measurements in older, cooperative children using chemiluminescence analysers. However, measurements of nNO in pre-school-age children (age 2-5 years) may facilitate early diagnosis and electrochemical rather than chemiluminescence analysers are widely used. Pre-schoolers often need different methods to be employed when measuring nNO. Hence, a European Respiratory Society Task Force has developed this technical standard as the first step towards standardising sampling, analysis and reporting of nNO measured as part of the diagnostic testing for PCD in all age groups, including pre-school-age children. Furthermore, we considered both chemiluminescence and electrochemical analysers that are in use worldwide. There was a paucity of quality evidence for electrochemical analysers and sampling methods used in young children, and the Task Force proposes future research priorities to allow updates of this technical standard., Competing Interests: Conflict of interest: N. Beydon reports educational writing payments as a member of the HERMES examination committee for paediatric respiratory medicine of the European Respiratory Society, and a leadership role as Chair of Group 07.01 of the European Respiratory Society (Paediatric respiratory physiology and sleep), outside the submitted work. P. Latzin reports grants from Vertex and OM Pharma, lecture honoraria from Vertex, Vifor and OM Pharma, and advisory board participation from Polyphor, Santhera (DMC), Vertex, Vifor, OM Pharma and Sanofi Aventis, outside the submitted work. S.D. Davis reports grants from the National Institutes of Health/National Heart, Lung, and Blood Institute, to support the present manuscript, and consulting fees from Parion Sciences and ReCode Therapeutics, and advisory board participation for the PCD Foundation, outside the submitted work. T. Ferkol reports grants from the National Institutes of Health (HL096458) to support the present manuscript, and grants from the National Institutes of Health (HL116211, HL125241, AI146999), National Health and Medical Research Council (NHMRC1043768) and Parion Sciences, advisory board participation for the PCD Foundation, Parion Sciences and Translate Bio, and is past president and executive board member of the American Thoracic Society, outside the submitted work. J.S. Lucas reports grants from AAIR Charity and NIHR Research for patient benefit, and consulting fees from Translate Bio, outside the submitted work. All other authors have nothing to disclose., (Copyright ©The authors 2023. For reproduction rights and permissions contact permissions@ersnet.org.)

Background: Epidemiological studies use different questions to assess recurrent cough in children. In two independent population-based studies, we assessed how prevalence estimates of cough vary depending on the questions parents are asked about their child's cough and how answers to the different questions overlap., Methods: We analysed cross-sectional data from two population-based studies on respiratory health: LuftiBus in the School (LUIS), conducted in 2013-2016 among 6- to 17-year-school children in the Canton of Zurich, Switzerland, and the 1998 Leicester Respiratory Cohort (LRC) study, UK where we used data from 6- to 8-year-old children from the 2003 follow-up survey. Both studies used parental questionnaires that included the same three questions on the child's cough, namely cough without a cold, dry cough at night and coughing more than others. We assessed how the prevalence of cough varied depending on the question and how answers to the different questions on cough overlapped. We also assessed how results were influenced by age, sex, presence of wheeze and parental education., Results: We included 3457 children aged 6-17 years from LUIS and 2100 children aged 6-8 years from LRC. All respiratory outcomes - cough, wheeze and physician-diagnosed asthma - were reported twice as often in the LRC as in LUIS. We found large differences in the prevalence of parent-reported cough between the three cough questions. In LUIS, 880 (25%) parents reported cough without a cold, 394 (11%) dry night cough, and 159 (5%) reported that their child coughed more than other children. In the LRC, these numbers were 1003 (48%), 527 (25%) and 227 (11%). There was only partial overlap of answers, with 89 (3%) answering yes to all questions in LUIS and 168 (8%) in LRC. Prevalence of all types of cough and overlap between the cough questions was higher in children with current wheeze., Conclusion: In both population-based studies prevalence estimates of cough depended strongly on the question used to assess cough with only partial overlap of responses to different questions. Epidemiological studies on cough can only be compared if they used exactly the same questions for cough.

Purpose: The aim of this study was to identify the monogenic cause of pulmonary arterial hypertension (PAH), a multifactorial and often fatal disease, in 2 unrelated consanguine families., Methods: We performed exome sequencing and validated variant pathogenicity by whole-blood RNA and protein expression analysis in both families. Further RNA sequencing of preserved lung tissue was performed to investigate the consequences on selected genes that are involved in angiogenesis, proliferation, and apoptosis., Results: We identified 2 rare biallelic variants in CAPNS1 , encoding the regulatory subunit of calpain. The variants cosegregated with PAH in the families. Both variants lead to loss of function (LoF), which is demonstrated by aberrant splicing resulting in the complete absence of the CAPNS1 protein in affected patients. No other LoF CAPNS1 variant was identified in the genome data of more than 1000 patients with unresolved PAH., Conclusion: The calpain holoenzyme was previously linked to pulmonary vascular development and progression of PAH in patients. We demonstrated that biallelic LoF variants in CAPNS1 can cause idiopathic PAH by the complete absence of CAPNS1 protein. Screening of this gene in patients who are affected by PAH, especially with suspected autosomal recessive inheritance, should be considered., Competing Interests: The authors declare no conflicts of interest., (© 2023 The Authors.)

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: Pollen exposure is associated with respiratory symptoms in children and adults. However, the association of pollen exposure with respiratory symptoms during infancy, a particularly vulnerable period, remains unclear. We examined whether pollen exposure is associated with respiratory symptoms in infants and whether maternal atopy, infant's sex or air pollution modifies this association., Methods: We investigated 14,874 observations from 401 healthy infants of a prospective birth cohort. The association between pollen exposure and respiratory symptoms, assessed in weekly telephone interviews, was evaluated using generalized additive mixed models (GAMMs). Effect modification by maternal atopy, infant's sex, and air pollution (NO 2 , PM 2.5 ) was assessed with interaction terms., Results: Per infant, 37 ± 2 (mean ± SD) respiratory symptom scores were assessed during the analysis period (January through September). Pollen exposure was associated with increased respiratory symptoms during the daytime (RR [95% CI] per 10% pollen/m 3 : combined 1.006 [1.002, 1.009]; tree 1.005 [1.002, 1.008]; grass 1.009 [1.000, 1.23]) and nighttime (combined 1.003 [0.999, 1.007]; tree 1.003 [0.999, 1.007]; grass 1.014 [1.004, 1.024]). While there was no effect modification by maternal atopy and infant's sex, a complex crossover interaction between combined pollen and PM 2.5 was found (p-value 0.003)., Conclusion: Even as early as during the first year of life, pollen exposure was associated with an increased risk of respiratory symptoms, independent of maternal atopy and infant's sex. Because infancy is a particularly vulnerable period for lung development, the identified adverse effect of pollen exposure may be relevant for the evolvement of chronic childhood asthma., (© 2022 The Authors. Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Rationale: Fetal growth restriction (FGR) and resulting low birth weight are risk factors for impaired lung development. However, both are often correlated with other factors, especially prematurity. Therefore, the question whether lung function changes in individuals with FGR are driven by gestational age, fetal growth, or both often remains unanswered. Objectives: To examine the association of birth weight with lung function in monochorionic twins with selective FGR in one twin. Methods: We included 20 monochorionic twin pairs with selective FGR and subsequent discordant birth weight with a minimum age of 6 years. In this unique case-control design, the smaller twin represents the case and the cotwin the almost identical counterpart. They performed spirometry and underwent body plethysmography, multiple-breath washout, and magnetic resonance imaging (MRI). We compared lung function and MRI outcomes between the smaller twins and their cotwins by paired t tests, and we used mixed linear models to assess the association between birth weight and outcomes. Results: Mean study age was 18.4 years (range, 7.5-29.4), and mean difference in birth weight within the twin pairs was 575 g (range, 270-1,130). The mean difference of forced expiratory volume in 1 second z -score was -0.64 (95% confidence interval [CI], -0.98 to -0.30), and -0.55 (95% CI, -0.92 to -0.18) of forced vital capacity z -score between the smaller twins and their cotwins. Both were associated with birth weight: per 500 g of birth weight, forced expiratory volume in 1 second z -score increased by 0.50 (95% CI, 0.35-0.65; P  < 0.001) and forced vital capacity z -score increased by 0.44 (95% CI, 0.31-0.57; P  < 0.001). S acin from multiple-breath washout, as a marker for ventilation inhomogeneity of acinar airways, was elevated in the smaller twins and was associated with low birth weight. There was no difference for MRI outcomes. The results remained similar after adjustment for study height. Conclusions: Low birth weight was associated with reduced large and small airway function independent of gestational age and body growth. Our findings suggest that intrauterine impairment of lung development induced by FGR has significant consequences on lung function until early adulthood.

Primary ciliary dyskinesia (PCD) presents with symptoms early in life and the disease course may be progressive, but longitudinal data on lung function are scarce. This multinational cohort study describes lung function trajectories in children, adolescents and young adults with PCD. We analysed data from 486 patients with repeated lung function measurements obtained between the age of 6 and 24 years from the International PCD Cohort and calculated z-scores for forced expiratory volume in 1 s (FEV 1 ), forced vital capacity (FVC) and FEV 1 /FVC ratio using the Global Lung Function Initiative 2012 references. We described baseline lung function and change of lung function over time and described their associations with possible determinants in mixed-effects linear regression models. Overall, FEV 1 , FVC and FEV 1 /FVC z-scores declined over time (average crude annual FEV 1 decline was -0.07 z-scores), but not at the same rate for all patients. FEV 1 z-scores improved over time in 21% of patients, remained stable in 40% and declined in 39%. Low body mass index was associated with poor baseline lung function and with further decline. Results differed by country and ultrastructural defect, but we found no evidence of differences by sex, calendar year of diagnosis, age at diagnosis, diagnostic certainty or laterality defect. Our study shows that on average lung function in PCD declines throughout the entire period of lung growth, from childhood to young adult age, even among patients treated in specialised centres. It is essential to develop strategies to reverse this tendency and improve prognosis., Competing Interests: Conflict of interest: P. Latzin reports grants from Vertex and Vifor, payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Vertex, Vifor and OM Pharma, and participation on a data safety monitoring board or advisory board for Polyphor, Santhera (DMC), Vertex, OM Pharma and Vifor. M.R. Loebinger reports consultancy fees from Insmed, AstraZeneca and Grifols, and payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Insmed and Grifols. The remaining authors disclose no potential conflicts of interest., (Copyright ©The authors 2022.)

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: Pneumococcal carriage has often been studied from a serotype perspective; however, little is known about the strain-specific carriage and inter-strain interactions. Here, we examined the strain-level carriage and co-colonization dynamics of Streptococcus pneumoniae in a Swiss birth cohort by PacBio single-molecule real-time (SMRT) sequencing of the plyNCR marker., Methods: A total of 872 nasal swab (NS) samples were included from 47 healthy infants during the first year of life. Pneumococcal carriage was determined based on the quantitative real-time polymerase chain reaction (qPCR) targeting the lytA gene. The plyNCR marker was amplified from 214 samples having lytA-based carriage for pneumococcal strain resolution. Amplicons were sequenced using SMRT technology, and sequences were analyzed with the DADA2 pipeline. In addition, pneumococcal serotypes were determined using conventional, multiplex PCR (cPCR)., Results: PCR-based plyNCR amplification demonstrated a 94.2% sensitivity and 100% specificity for Streptococcus pneumoniae if compared to lytA qPCR. The overall carriage prevalence was 63.8%, and pneumococcal co-colonization (≥ 2 plyNCR amplicon sequence variants (ASVs)) was detected in 38/213 (17.8%) sequenced samples with the relative proportion of the least abundant strain(s) ranging from 1.1 to 48.8% (median, 17.2%; IQR, 5.8-33.4%). The median age to first acquisition was 147 days, and having ≥ 2 siblings increased the risk of acquisition., Conclusion: The plyNCR amplicon sequencing is species-specific and enables pneumococcal strain resolution. We therefore recommend its application for longitudinal strain-level carriage studies of Streptococcus pneumoniae. Video Abstract., (© 2022. The Author(s).)

In contrast to molecular changes associated with increased inflammatory responses, little is known about intracellular counter-regulatory mechanisms that control signaling cascades associated with functional responses of neutrophils. Active RHO GTPases are typically considered as effector proteins that elicit cellular responses. Strikingly, we show here that RHOH, although being constitutively GTP-bound, limits neutrophil degranulation and the formation of neutrophil extracellular traps (NETs). Mechanistically, RHOH is induced under inflammatory conditions and binds to non-muscle myosin heavy chain IIA (NMHC IIA) in activated neutrophils in order to inhibit the transport of mitochondria and granules along actin filaments, which is partially reverted upon disruption of the interaction with NMHC IIA by introducing a mutation in RhoH at lysine 34 (RhoHK34A). In parallel, RHOH inhibits actin polymerization presumably by modulating RAC1 activity. In vivo studies using Rhoh-/- mice, demonstrate an increased antibacterial defense capability against Escherichia coli (E. coli). Collectively, our data reveal a previously undefined role of RHOH as a molecular brake for actomyosin-mediated neutrophil effector functions, which represents an intracellular regulatory axis involved in controlling the strength of an antibacterial inflammatory response., Competing Interests: The authors have declared that no competing interests exist.

Aims of the Study: We know little about the level of physical activity, respiratory physiotherapy practices and nutritional status of people with primary ciliary dyskinesia (PCD), although these are important aspects of patients with chronic respiratory disease. We assessed physical activity, respiratory physiotherapy practices and nutritional status among people with primary ciliary dyskinesia in Switzerland, investigated how these vary by age and identified factors associated with regular physical activity., Methods: We sent a postal questionnaire survey to people with primary ciliary dyskinesia enrolled in the Swiss PCD registry (CH-PCD), based on the standardised FOLLOW-PCD patient questionnaire. We collected information about physical activity, physiotherapy, respiratory symptoms and nutritional status. We calculated the metabolic equivalent (MET) to better reflect the intensity of the reported physical activities. To assess nutritional status, we extracted information from CH-PCD and calculated participants' body mass index (BMI)., Results: Of the 86 questionnaires we sent, 74 (86% response rate) were returned from 24 children and 50 adults. The median age at survey completion was 23 years (IQR [interquartile range] 15-51), and 51% were female. Among all 74 participants, 48 (65%) performed sports regularly. Children were vigorously active (median MET 9.1; IQR 7.9-9.6) and adults were moderately active (median MET 5.5; IQR 4.3-6.9). Fifty-nine participants (80%) reported performing some type of respiratory physiotherapy. However, only 30% of adults saw a professional physiotherapist, compared with 75% of children. Half of the participants had normal BMI; one child (4%) and two adults (4%) were underweight. People who were regularly physically active reported seeing a physiotherapist more often., Conclusions: Our study is the first to provide patient-reported data about physical activity, respiratory physiotherapy and nutrition among people with primary ciliary dyskinesia. Our results highlight that professional respiratory physiotherapy, exercise recommendations and nutritional advice are often not implemented in the care of people with primary ciliary dyskinesia in Switzerland. Multidisciplinary care in specialised centres by teams including physiotherapists and nutrition consultants could improve the quality of life of people with primary ciliary dyskinesia.

Purpose: To introduce a widely applicable workflow for pulmonary lobe segmentation of MR images using a recurrent neural network (RNN) trained with chest CT datasets. The feasibility is demonstrated for 2D coronal ultrafast balanced SSFP (ufSSFP) MRI., Methods: Lung lobes of 250 publicly accessible CT datasets of adults were segmented with an open-source CT-specific algorithm. To match 2D ufSSFP MRI data of pediatric patients, both CT data and segmentations were translated into pseudo-MR images that were masked to suppress anatomy outside the lung. Network-1 was trained with pseudo-MR images and lobe segmentations and then applied to 1000 masked ufSSFP images to predict lobe segmentations. These outputs were directly used as targets to train Network-2 and Network-3 with non-masked ufSSFP data as inputs, as well as an additional whole-lung mask as input for Network-2. Network predictions were compared to reference manual lobe segmentations of ufSSFP data in 20 pediatric cystic fibrosis patients. Manual lobe segmentations were performed by splitting available whole-lung segmentations into lobes., Results: Network-1 was able to segment the lobes of ufSSFP images, and Network-2 and Network-3 further increased segmentation accuracy and robustness. The average all-lobe Dice similarity coefficients were 95.0 ± 2.8 (mean ± pooled SD [%]) and 96.4 ± 2.5, 93.0 ± 2.0; and the average median Hausdorff distances were 6.1 ± 0.9 (mean ± SD [mm]), 5.3 ± 1.1, 7.1 ± 1.3 for Network-1, Network-2, and Network-3, respectively., Conclusion: Recurrent neural network lung lobe segmentation of 2D ufSSFP imaging is feasible, in good agreement with manual segmentations. The proposed workflow might provide access to automated lobe segmentations for various lung MRI examinations and quantitative analyses., (© 2022 The Authors. Magnetic Resonance in Medicine published by Wiley Periodicals LLC on behalf of International Society for Magnetic Resonance in Medicine.)

Background: The management of asymptomatic congenital lung malformations is debated. Particularly, there is a lack of information regarding long-term growth and development of the remaining lung in children following lung resection for congenital lung malformations. In addition to conventional pulmonary function tests, we used novel functional magnetic resonance imaging (MRI) methods to measure perfusion and ventilation., Objective: To assess functionality of the remaining lung expanded into the thoracic cavity after resection of congenital lung malformations., Materials and Methods: A prospective, cross-sectional pilot study in five children who had surgery for congenital lung malformations during infancy. Participants had structural and functional MRI as well as spirometry, body plethysmography and multiple breath washout at school age., Results: Structural MRI showed an expansion of the remaining lung in all cases. Fractional ventilation and relative perfusion of the expanded lung were locally decreased in functional MRI. In all other parts of the lungs, fractional ventilation and relative perfusion were normal in all children. There was an association between overall impairment of perfusion and elevated lung clearance index. The results of spirometry and body plethysmography varied between patients, including normal lung function, restriction and obstruction., Conclusion: Fractional ventilation and relative perfusion maps from functional MRI specifically locate impairment of the remaining lung after lung resection. These changes are not captured by conventional measures such as structural MRI and standard pulmonary function tests. Therefore, following lung resection for congenital lung malformation, children should be investigated more systematically with functional lung MRI., (© 2022. The Author(s).)