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This is the third paper in the series providing updated information and recommendations for people with cystic fibrosis transmembrane conductance regulator (CFTR)-related disorder (CFTR-RD). This paper covers the individual disorders, including the established conditions - congenital absence of the vas deferens (CAVD), diffuse bronchiectasis and chronic or acute recurrent pancreatitis - and also other conditions which might be considered a CFTR-RD, including allergic bronchopulmonary aspergillosis, chronic rhinosinusitis, primary sclerosing cholangitis and aquagenic wrinkling. The CFTR functional and genetic evidence in support of the condition being a CFTR-RD are discussed and guidance for reaching the diagnosis, including alternative conditions to consider and management recommendations, is provided. Gaps in our knowledge, particularly of the emerging conditions, and future areas of research, including the role of CFTR modulators, are highlighted., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: NJS reports consulting fees and/or honoraria from Vertex, Chiesi, Gilead and Menarini. KDB reports consulting fees and/or honoraria from Vertex, ELoxx, Splisense and Arcturus. JGM reports honoraria from Vertex, Chiesi, Abbvie and Viatris. PGM reports consulting fees and/or honoraria from Vertex, AstraZenica, Limbic and MedEd. CS reports consulting fees and/or honoraria from Vertex, Chiesi, TFF and Pfizer. JC reports consulting fees for Astrazeneca, Boehringer Ingelheim, Grifols, Gilead sciences, Insmed, Genentech, Glaxosmithkline, Antabio, Zambon and Trudell. OCY reports consulting fees and honoraria from Vertex. DGD reports consulting fees and/or honoraria from Chiesi, Insmed and Vertex. DP reports payments for educational talks. DVD reports consulting fees for Arcturus, Arrevus, BiomX, Clarametyx, CFF, Enbiotix, Microbion, Pyros, Respirion and Zambon. ISG reports honoraria from Vertex. KWS, FB, VV, EDW, MW, EB, DD, PE, EG, GH, AK, DN, JAN, CR, IS, MDW report no personal fees/honoraria, (Copyright © 2024. Published by Elsevier B.V.)

Background: The pneumococcal antibody response after vaccination with unconjugated pneumococcal vaccine can be evaluated as part of the diagnostic work-up of children with recurrent respiratory tract infections to detect an underlying polysaccharide antibody deficiency. Little is known about the prevalence of polysaccharide antibody deficiency in this population and its therapeutic consequences., Objectives: This study aimed to investigate the prevalence of polysaccharide antibody deficiency in children with recurrent respiratory tract infections and to correlate polysaccharide responsiveness with clinical severity. In addition, we aimed to evaluate differences in the immunoglobulin (Ig)G2/IgG ratio, IgA level, and age in relation to the number of deficient serotype-specific antibody responses., Methods: Polysaccharide antibody titers for pneumococcal serotypes 8, 9N, and 15B; clinical characteristics; and immunoglobulin levels of 103 children with recurrent respiratory tract infections were retrospectively assessed. American Academy of Allergy, Asthma, and Immunology guidelines were used for the interpretation of the polysaccharide antibody response., Results: Overall, 28 children (27.2 %) were diagnosed with polysaccharide antibody deficiency. No correlation was found between the number of deficient serotype-specific antibody responses and clinical severity. The study participants with a normal response to all three serotypes had a higher IgG2/IgG ratio than those with one or more deficient responses (p < 0.003). No significant correlation between IgA levels and polysaccharide responsiveness was found. The median age of children with normal polysaccharide responsiveness for the three tested serotypes was higher than that of children with a deficient response to one or more serotypes (p < 0.0025)., Conclusion: For a large group of children (18.4 %) with recurrent respiratory tract infections, an underlying mechanism for their susceptibility was defined thanks to diagnostic unconjugated pneumococcal polysaccharide vaccination. Further research is needed to formulate age-specific normal values for polysaccharide responsiveness and to investigate the usefulness of the IgG2/IgG ratio in determining the need for diagnostic unconjugated pneumococcal polysaccharide vaccination., Competing Interests: Declaration of competing interest None., (Copyright © 2024 French Society of Pediatrics. Published by Elsevier Masson SAS. All rights reserved.)

Background: The forskolin-induced swelling (FIS) assay measures CFTR function on patient-derived intestinal organoids (PDIOs) and may guide treatment selection for individuals with Cystic Fibrosis (CF). The aim of this study is to demonstrate the repeatability and reproducibility of the FIS assay following a detailed Standard Operating Procedure (SOP), thus advancing the validation of the assay for precision medicine (theranostic) applications., Methods: Over a 2-year period, FIS responses to CFTR modulators were measured in four European labs. PDIOs from six subjects with CF carrying different CFTR genotypes were used to assess the repeatability and reproducibility across the dynamic range of the assay., Results: Technical, intra-assay repeatability was high (Lin's concordance correlation coefficient (CCC) 0.95-0.98). Experimental, within-subject repeatability was also high within each lab (CCCs all >0.9). Longer-term repeatability (>1 year) showed more variability (CCCs from 0.67 to 0.95). The reproducibility between labs was also high (CCC ranging from 0.92 to 0.97). Exploratory analysis also found that between-lab percentage of agreement of dichotomized CFTR modulator outcomes for predefined FIS thresholds ranged between 78 and 100 %., Conclusions: The observed repeatability and reproducibility of the FIS assay within and across different labs is high and support the use of FIS as biomarker of CFTR function in the presence or absence of CFTR modulators., Competing Interests: Declaration of competing interest The authors 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 Author(s). Published by Elsevier B.V. All rights reserved.)

After three publications defining an updated guidance on the diagnostic criteria for people with cystic fibrosis transmembrane conductance regulator (CFTR)-related disorders (pwCFTR-RDs), establishing its relationship to CFTR-dysfunction and describing the individual disorders, this fourth and last paper in the series addresses some critical challenges facing health care providers and pwCFTR-RD. Topics included are: 1) benefits and obstacles to collect data from pwCFTR-RD are discussed, together with the opportunity to integrate them into established CF-registries; 2) the potential of infants designated CRMS/CFSPID to develop a CFTR-RD and how to communicate this information; 3) a description of the challenges in genetic counseling, with particular regard to phenotypic variability, unknown long-term evolution, CFTR testing and pregnancy termination 4) a proposal for the assessment of potential barriers to the implementation and dissemination of the produced documents to health care professionals involved in the care of pwCFTR-RD and a process to monitor the implementation of the CFTR-RD recommendations; 5) clinical trials investigating the efficacy of CFTR modulators in CFTR-RD and how endpoints and outcomes might be adapted to the heterogeneity of these disorders., Competing Interests: Declaration of competing interest The authors 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 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.)

This is the second in a series of four papers updating the European Cystic Fibrosis Society (ECFS) standards for the care of people with CF. This paper focuses on establishing and maintaining health. The guidance is produced using an evidence-based framework and with wide stakeholder engagement, including people from the CF community. Authors provided a narrative description of their topic and statements, which were more directive. These statements were reviewed by a Delphi exercise, achieving good levels of agreement from a wide group for all statements. This guidance reinforces the importance of a multi-disciplinary CF team, but also describes developing models of care including virtual consultations. The framework for health is reinforced, including the need for a physically active lifestyle and the strict avoidance of all recreational inhalations, including e-cigarettes. Progress with cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapy is reviewed, including emerging adverse events and advice for dose reduction and interruption. This paper contains guidance that is pertinent to all people with CF regardless of age and eligibility for and access to modulator therapy., Competing Interests: Declaration of competing interest KWS has no competing interests. See supplementary materials for full CoI statements for all authors., (Copyright © 2023. Published by Elsevier B.V.)

Cystic fibrosis is a multiorgan disease caused by impaired function of the cystic fibrosis transmembrane conductance regulator (CFTR). Since the introduction of the CFTR modulator combination elexacaftor-tezacaftor-ivacaftor (ETI), which acts directly on mutant CFTR to enhance its activity, most people with cystic fibrosis (pwCF) have seen pronounced reductions in symptoms, and studies project marked increases in life expectancy for pwCF who are eligible for ETI. However, modulator therapy has not cured cystic fibrosis and the success of CFTR modulators has resulted in immediate questions about the new state of cystic fibrosis disease and clinical challenges in the care of pwCF. In this Series paper, we summarise key questions about cystic fibrosis disease in the era of modulator therapy, highlighting state-of-the-art research and clinical practices, knowledge gaps, new challenges faced by pwCF and the potential for future health-care challenges, and the pressing need for additional therapies to treat the underlying genetic or molecular causes of cystic fibrosis., Competing Interests: Declaration of interests KBH reports funding from the National Institutes of Health (NIH) National Heart, Lung, and Blood Institute (NHLBI) and the Cystic Fibrosis Foundation (CFF), outside of the submitted work. SEB reports funding from NIH NHLBI and CFF, outside of the submitted work. DGD reports funding from Chiesi Farmaceutici and CFF to Queen's University Belfast; consulting fees from Vertex and Insmed; honoraria from Chiesi and Gilead; support for travel from the European Cystic Fibrosis Society (ECFS) and CFF; and participation on data and safety monitoring boards (DSMBs) for Nomab trial and CSL Behring, outside of the submitted work. DGD is Director of the ECFS Clinical Trials Network. JFE reports funding from NIH NHLBI and the National Institute of Diabetes and Digestive Kidney Diseases (R01 HL165404, RC2 DK124207, and NHLBI Contract 75N92019C00010) paid to the University of Iowa, outside of the submitted work. IF reports funding from AbbVie, Bayer, Boehringer Ingelheim, Insmed, Vertex, and ECFS to AP-HP-Université Paris Cité; and honoraria from AbbVie, Boehringer Ingelheim, Vertex, and Kither Biotech, outside of the submitted work. RDG reports honoraria for lectures from Vertex, outside of the submitted work. NM-H reports funding from CFF, NIH, and the Food and Drug Administration to Seattle Children's Research Institute, University of Washington; consulting fees from Enterprise Therapeutics; and honoraria for NIH DSMB participation, outside of the submitted work. CEW reports editorial support from Articulate Science outside of the submitted work; income on a per-patient basis to the University of Queensland for participation in pharmaceutical studies; participating on steering committees and international advisory boards for Vertex; and participation as a consultant and presenter at several medical education events sponsored by Vertex, outside of the submitted work. CEW has served as an Associate Editor for Respirology and Associate Editor for Thorax. KDB reports consulting fees from Arcturus, Splisense, Translate Bio, and Vertex; and honoraria from Vertex, outside of the submitted work. JPC, MEL-S, PT, and KLT declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

This paper is the first in a series providing updated guidance on the definition, evaluation and management of people with a Cystic Fibrosis Transmembrane conductance Regulator (CFTR)-Related Disorder (CFTR-RD). The need for this update relates to more precise characterisation of CFTR gene variants and improved assessment of CFTR protein dysfunction. The exercise is co-ordinated by the European CF Society Standards of Care Committee and Diagnostic Network Working Group and involves stakeholder engagement. This first paper was produced by a core group using an extensive literature review and papers graded for their quality. Subsequent wider stakeholder agreement was achieved. The definition of a CFTR-RD remains "a clinical condition with evidence of CFTR protein dysfunction that does not fulfil the diagnostic criteria for CF". Clearer guidance on CFTR dysfunction and relevant CFTR variants will be provided. Thresholds for clinical presentations are presented and the paradigm that pathobiological processes may be evident in more than one organ is agreed. In this paper we reflect on the early patient journey, highlighting that CF specialists as well as other relevant specialists should be involved in the care of people with a CFTR-RD., Competing Interests: Declaration of Competing Interest Carlo Castellani reports payments of honoraria for presentations from Vertex Pharmaceuticals and Chiesi and participation to Advisory Boards of Vertex Pharmaceuticals. Mylan, Actelion and Chiesi. Kris De Boeck reports consulting fees from Vertex Pharmaceuticals, Arcturus, Splisense, Translate Bio and Chiesi and honoraria for lectures from Vertex Pharmaceuticals. Elke De Wachter reports that her Institution received fundings from Vertex for her participation in an Advisory Board and for a presentation. Isabelle Sermet-Gaudelus reports funding for academic research from Vertex Therapeutics and participation to Scientific Boards of Vertex Therapeutics and Eliox; support for attending conferences by Vertex Therapeutics. Nicholas Simmonds reports payment of honoraria for lectures from Vertex, Chiesi, Gilead and Teva; participation to Advisory Boards of Vertex, Chiesi, Gilead and Menarini. Kevin Southern reports no competing interests, (Copyright © 2022. Published by Elsevier B.V.)

Background: In cystic fibrosis (CF), genotype-phenotype correlation is complicated by the large number of CFTR variants, the influence of modifier genes, environmental effects, and the existence of complex alleles. We document the importance of complex alleles, in particular the F508C variant present in cis with the S1251N disease-causing variant, by detailed analysis of a patient with CF, with the [S1251N;F508]/G542X genotype and a very mild phenotype, contrasting it to that of four subjects with the [S1251N;F508C]/F508del genotype and classical CF presentation., Methods: Genetic differences were identified by Sanger sequencing and CFTR function was quantified using rectal organoids in rectal organoid morphology analysis (ROMA) and forskolin-induced swelling (FIS) assays. CFTR variants were further characterised in CF bronchial epithelial (CFBE) cell lines. The impact of involved amino acid changes in the CFTR 3D protein structure was evaluated., Results: Organoids of the patient [S1251N;F508] with mild CF phenotype confirmed the CF diagnosis but showed higher residual CFTR function compared to the four others [S1251N;F508C]. CFBE cell lines showed a decrease in [S1251N;F508C]-CFTR function but not in processing when compared to [S1251N;F508]-CFTR. Analysis of the 3D CFTR structure suggested an additive deleterious effect of the combined presence of S1251N and F508C with respect to NBD1-2 dimerisation., Conclusions: In vitro and in silico data show that the presence of F508C in cis with S1251N decreases CFTR function without affecting processing. Complex CFTR alleles play a role in clinical phenotype and their identification is relevant in the context of personalised medicine for each patient with CF., Competing Interests: Declaration of Competing Interest The authors 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 © 2022. Published by Elsevier B.V.)

Background: Patients with cystic fibrosis (CF) and pancreatic insufficiency need pancreatic enzyme replacement therapy (PERT) for dietary lipids digestion. There is limited evidence for recommending the adequate PERT dose for every meal, and controlling steatorrhea remains a challenge. This study aimed to evaluate a new PERT dosing method supported by a self-management mobile-app., Methods: Children with CF recruited from 6 European centres were instructed to use the app, including an algorithm for optimal PERT dosing based on in vitro digestion studies for every type of food. At baseline, a 24h self-selected diet was registered in the app, and usual PERT doses were taken by the patient. After 1 month, the same diet was followed, but PERT doses were indicated by the app. Change in faecal fat and coefficient of fat absorption (CFA) were determined., Results: 58 patients (median age 8.1 years) participated. Baseline fat absorption was high: median CFA 96.9%, median 2.4g faecal fat). After intervention CFA did not significantly change, but range of PERT doses was reduced: interquartile ranges narrowing from 1447-3070 at baseline to 1783-2495 LU/g fat when using the app. Patients with a low baseline fat absorption (CFA<90%, n=12) experienced significant improvement in CFA after adhering to the recommended PERT dose (from 86.3 to 94.0%, p=0.031)., Conclusion: the use of a novel evidence-based PERT dosing method, based on in vitro fat digestion studies incorporating food characteristics, was effective in increasing CFA in patients with poor baseline fat absorption and could safely be implemented in clinical practice., (Copyright © 2020. Published by Elsevier B.V.)

Background: Tezacaftor-ivacaftor is an approved cystic fibrosis transmembrane conductance regulator (CFTR) modulator shown to be efficacious and generally safe and well tolerated over 8-24 weeks in phase 3 clinical studies in participants aged 12 years or older with cystic fibrosis homozygous for the Phe508del CFTR mutation (F/F; study 661-106 [EVOLVE]) or heterozygous for the Phe508del CFTR mutation and a residual function mutation (F/RF; study 661-108 [EXPAND]). Longer-term (>24 weeks) safety and efficacy of tezacaftor-ivacaftor has not been assessed in clinical studies. Here, we present results of study 661-110 (EXTEND), a 96-week open-label extension study that assessed long-term safety, tolerability, and efficacy of tezacaftor-ivacaftor in participants aged 12 years or older with cystic fibrosis who were homozygous or heterozygous for the Phe508del CFTR mutation., Methods: Study 661-110 was a 96-week, phase 3, multicentre, open-label study at 170 clinical research sites in Australia, Europe, Israel, and North America. Participants were aged 12 years or older, had cystic fibrosis, were homozygous or heterozygous for Phe508del CFTR, and completed one of six parent studies of tezacaftor-ivacaftor: studies 661-103, 661-106, 661-107, 661-108, 661-109, and 661-111. Participants received oral tezacaftor 100 mg once daily and oral ivacaftor 150 mg once every 12 h for up to 96 weeks. The primary endpoint was safety and tolerability. Secondary endpoints were changes in lung function, nutritional parameters, and respiratory symptom scores; pulmonary exacerbations; and pharmacokinetic parameters. A post-hoc analysis assessed the rate of lung function decline in F/F participants who received up to 120 weeks of tezacaftor-ivacaftor in studies 661-106 (F/F) and/or 661-110 compared with a matched cohort of CFTR modulator-untreated historical F/F controls from the Cystic Fibrosis Foundation Patient Registry. Primary safety analyses were done in all participants from all six parent studies who received at least one dose of study drug during this study. This study was registered at ClinicalTrials.gov (NCT02565914)., Findings: Between Aug 31, 2015, to May 31, 2019, 1044 participants were enrolled in study 661-110 from the six parent studies of whom 1042 participants received at least one dose of study drug and were included in the safety set. 995 (95%) participants had at least one TEAE; 22 (2%) had TEAEs leading to discontinuation; and 351 (34%) had serious TEAEs. No deaths occurred during the treatment-emergent period; after the treatment-emergent period, two deaths occurred, which were both deemed unrelated to study drug. F/F (106/110; n=459) and F/RF (108/110; n=226) participants beginning tezacaftor-ivacaftor in study 661-110 had improvements in efficacy endpoints consistent with parent studies; improvements in lung function and nutritional parameters and reductions in pulmonary exacerbations observed in the tezacaftor-ivacaftor groups in the parent studies were generally maintained in study 661-110 for an additional 96 weeks. Pharmacokinetic parameters were also similar to those in the parent studies. The annualised rate of lung function decline was 61·5% (95% CI 35·8 to 86·1) lower in tezacaftor-ivacaftor-treated F/F participants versus untreated matched historical controls., Interpretation: Tezacaftor-ivacaftor was generally safe, well tolerated, and efficacious for up to 120 weeks, and the safety profile of tezacaftor-ivacaftor in study 661-110 was consistent with cystic fibrosis manifestations and with the safety profiles of the parent studies. The rate of lung function decline was significantly reduced in F/F participants, consistent with cystic fibrosis disease modification. Our results support the clinical benefit of long-term tezacaftor-ivacaftor treatment for people aged 12 years or older with cystic fibrosis with F/F or F/RF genotypes., Funding: Vertex Pharmaceuticals Incorporated., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

CFTR modulators associated with substantial clinical benefit are expected to rapidly improve the baseline condition of people with cystic fibrosis (PWCF) as well as decrease the rate of lung function decline, the occurrence of pulmonary exacerbations and likely even other disease complications. These changes in clinical status of PWCF introduced by clinically effective modulator therapy will have major repercussions on modalities of future CF drug development. As part of its 'Strategic Plan to speed up Access to new Drugs', the European Cystic Fibrosis Society (ECFS) convened a meeting in Brussels on November 27 th 2019 with relevant stakeholders (CF researchers and clinicians, patient organization and pharmaceutical company representatives, regulators, health technology assessors; see Acknowledgments for list of attendees) to discuss the future of clinical trials in cystic fibrosis (CF) in the context of HEMT entering the clinical arena. The following is the conclusion of the presentations and discussions. It is hoped that these concepts will be considered in future regulatory guidelines and may provide rationale and support for alternative trial designs., (Copyright © 2020. Published by Elsevier B.V.)

As CFTR modulator therapy transforms the landscape of cystic fibrosis (CF) care, its lack of uniform access across the globe combined with the shift towards a new standard of care creates unique challenges for the development of future CF therapies. The advancement of a full and promising CF therapeutics pipeline remains a necessary priority to ensure maximal clinical benefits for all people with CF. It is through collaboration across the global CF community that we can optimize the evaluation and approval process of new therapies. To this end, we must identify areas for which harmonization is lacking and for which efficiencies can be gained to promote ethical, feasible, and credible study designs amidst the changing CF care landscape. This article summarizes the counsel from core advisors across multiple international regions and clinical trial networks, developed during a one-day workshop in October 2019. The goal of the workshop was to identify, in consideration of the highly transitional era of CFTR modulator availability, the drug development areas for which global alignment is currently uncertain, and paths forward that will enable advancement of CF therapeutic development., Competing Interests: Declaration of Competing Interest NMH serves as a consultant through her institution in her role as Executive Director of the CF Therapeutics Development Network Coordinating Center (CF TDNCC) and has received personal consulting fees from Kala Pharmaceuticals and Calithera. She has received grant funding from the Cystic Fibrosis Foundation (CFF) and National Institutes of Health (NIH). SvKR has received personal consulting fees from Antabio, Proteostasis Therapeutics (PTI), and Vertex Pharmaceuticals (VRTX). She has received grant support to her institution for her participation in the European Union HORIZON 2020 work. DPN serves as a consultant through his institution in his role as Medical Director of CF TDNCC. He has received grant support to his Institution from the CFF and Gilead Sciences. DRV has received personal consulting fees from AbbVie, Albumedix, AN2, Aradigm, Armata, Arrevus, Calithera, Chiesi USA, Cipla, Corbus, CFF, Eloxx, Enbiotix, Eveo, Galephar, Horizon, IBF, ICON clinical sciences, Ionis, Kala, Merck, Microbion, NDA, Protalix, PTC, Pulmocide, Recida, Savara, Vast, and VRTX. JCD has received other support from Aligipharma AS, Bayer AG, BI, Galapagos NV, ImevaX GmbH, Nivalis Therapeutics, ProQR Therapeutics, PTI, Raptor Pharamceuticals, VRTX, Enterprise, Novartis, Pulmocide, Flately and Teva for advisory board and educational activities. She has received grant support from the CF Trust. TL has received personal fees from Alan Boyd Consultants, Ltd for his participation in DSMB activities. FAR has received personal consulting fees from Novartis, Bayer, Roche, and Genentech for participation in CF related consulting activities. He has received grant support to his institution from VRTX for his participation as site PI in multicenter trials which they have funded as well as personal consulting fees. MWK has received personal consulting fees for advisory board participation, grant support to his institution for clinical trial participation, and non-financial support from VRTX, Savara, Laurent, Corbus Pharmaceuticals, PTC, and AzurRx. He has received personal consulting fees and non-financial support from Chiesi, Celtaxsys, Merck, and Kala. Personal consulting fees were received from Albumedix, Paranta, Protalix, Santhera, pH Pharma, Novartis, Ionis, the Italian Cystic Fibrosis Foundation, and the Food and Drug Administration. Grant support was provided to his Institution by NIH. Grant support was provided to his Institution by Anthera as well as personal consulting fees. SCB has received support from VRTX, Galapagos, and AbbVie for his participation in advisory boards and as site PI in multicenter trials which they have funded. JLTC has received personal consulting fees from Gilead Sciences, Protalix, and Santhera for participation in advisory board activities. She has received grant support to her institution from PTI, Celtaxsys, and VRTX as well as personal consulting fees for advisory activities. Grant support to her institution for her participation as site PI in a multicenter trial which they have funded from Eloxx. KDB has received consulting fees from Boehringer-Ingelheim (BI), Protalix Biotherapeutics, Raptor Pharmaceuticals, Novabiotics, Eloxx Pharmaceutics, Galapagos, and Chiesi. She has received speaker fees from Teva Pharmaceutical Industries and serves on the Steering Committee and Advisory Board for VRTX. DGD has received consulting fees from VRTX and consulting fees as well as grant support from PTI and Chiesi. PAF has received personal consulting fees from the Food and Drug Administration, Polyphor, and Santhera. He has received personal consulting fees and grant support from CFF, PTI, Savara, and VRTX. He has received grant support from NIH, Novartis, Novoteris, and Sound Pharmaceuticals. PD has received personal consulting fees from VRTX, PTI, and Actelion Pharmaceuticals. He has also received support for his participation as site PI in multicenter trials funded by Corbus Pharmaceuticals and VRTX. CHG has received grant funding from CFF, NIH, the European Commission and the Food and Drug Administration. He has also received honoraria from Gilead Sciences for grant reviews, honoraria from VRTX and Mylan for invited talks, and BI for participation as a PI in a multicenter trial in CF that they have funded. IF has received consulting fees and support from PTI, VRTX and BI for her participation in advisory boards as well as site PI in multicenter trials which they have funded. She has received support from Corbus Pharmaceuticals for participation as site PI in multicenter trials which they have funded ASM has received grant support to her Institution from CFF. BSQ has received grant support to his institution from the Cystic Fibrosis Canada, CFF, Michael Smith Foundation for Health Research, BC Lung Association, and Gilead Sciences. GZRB's institution has received support from the CFF, NIH and VRTX. for his participation as site PI in multicenter trials which they have funded. AGD, KP, JPC, SHD, SMS, and JMVD have nothing to disclose., (Copyright © 2020. Published by Elsevier B.V.)

Background: Most patients with cystic fibrosis (CF) suffer from pancreatic insufficiency (PI), leading to fat malabsorption, malnutrition, abdominal discomfort and impaired growth. Pancreatic enzyme replacement therapy (PERT) is effective, but evidence based guidelines for dose adjustment are lacking. A mobile app for self-management of PERT was developed in the context of the HORIZON 2020 project MyCyFAPP. It contains an algorithm to calculate individual PERT-doses for optimal fat digestion, based on in vitro and in vivo studies carried out in the same project. In addition, the app includes a symptoms diary, educational material, and it is linked to a web tool allowing health care professionals to evaluate patient's data and provide feedback., Methods: A 6-month open label prospective multicenter interventional clinical trial was performed to assess effects of using the app on gastro-intestinal related quality of life (GI QOL), measured by the CF-PedsQL-GI (shortened, CF specific version of the Pediatric Quality of Life Inventory, Gastrointestinal Symptoms Module)., Results: One hundred and seventy-one patients with CF and PI between 2 and 18 years were recruited at 6 European CF centers. Self-reported CF-PedsQL-GI improved significantly from month 0 (M0) (84.3, 76.4-90.3) to month 6 (M6) (89.4, 80.35-93.5) (p< 0.0001). Similar improvements were reported by parents. Lower baseline CF-PedsQL-GI was associated with a greater improvement at M6 (p < 0.001)., Conclusions: The results suggest that the MyCyFAPP may improve GI QOL for children with CF. This tool may help patients to improve self-management of PERT, especially those with considerable GI symptoms., Competing Interests: Declaration of competing interest All authors report grants from the European Commission Horizon 2020 during the conduct of the study. Dr. Mainz reports grants and personal fees from Vertex Corp.,  during the conduct of the study; Dr. Janssens reports grants from Vectura, personal fees from Vertex, outside the submitted work; Dr. Boon reports grants from University Hospital Leuven, outside the submitted work; Dr. De Boeck reports other financial support from Boehringer, Protalix, Raptor, Teva, Novabiotics, Eloxx, Vertex, Galapagos, Chiesi, outside the submitted work. Several authors of this publication are member of the European Reference Network for Rare Respiratory Diseases (ERN-LUNG) - Project ID No 739546., (Copyright © 2020 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.)

Background: 5T polymorphism is a CFTR mutation with unclear clinical consequences: the phenotype varies from healthy individuals to Cystic Fibrosis (CF). The aim of this study was to evaluate if nasal potential difference (NPD) and sweat testing correlate with symptoms and CF diagnosis in 5T patients., Methods: 86 patients with 5T who had undergone NPD measurement, were included (6 homozygous (5T/5T), 41 with a PI-CF causing mutation in trans (5T/PI-CF), 11 with a PS-CF causing mutation in trans (5T/PS-CF) and 28 without a known mutation in trans (5T/?). Data including age, phenotype, sweat chloride and follow up were collected., Results: 33% of the 5T/5T patients had abnormal NPD results, compared to 70% in 5T/PI-CF; 33% in 5T/PS-CF and 29% in 5T/?. The percentage of high or borderline sweat chloride was highest in 5T/PI-CF, and 5T/?, compared to 5T/5T and 5T/PS-CF (91, 96, 80, and 63%, respectively). TGm (number of TG repeats in intron 8) analysis was performed in 21 5T/PI-CF patients. TG11 was associated with lower sweat chloride, lower percentage of abnormal NPD and less progression of symptoms compared to TG12 and TG13., Conclusion: There is much variation in clinical status among 5T patients. All patients in this study with 5T/PS CF, all patients with both normal NPD and sweat test, and most patients with TG11 were stable or improving over time. Therefore, NPD measurement and TGm status aid to assess if a patient is at high risk for developing CF or CFTR-related disease and if specific follow up in a CF center is required., (Copyright © 2019 European Cystic Fibrosis Society. All rights reserved.)

Background: Ataluren was developed for potential treatment of nonsense-mutation cystic fibrosis (CF). A previous phase 3 ataluren study failed to meet its primary efficacy endpoint, but post-hoc analyses suggested that aminoglycosides may have interfered with ataluren's action. Thus, this subsequent trial (NCT02139306) was designed to assess the efficacy and safety of ataluren in patients with nonsense-mutation CF not receiving aminoglycosides., Methods: Eligible subjects with nonsense-mutation CF (aged ≥6 years; percent predicted (pp) FEV 1 ≥40 and ≤90) from 75 sites in 16 countries were randomly assigned in double-blinded fashion to receive oral ataluren or matching placebo thrice daily for 48 weeks. The primary endpoint was absolute change in average ppFEV 1 from baseline to the average of Weeks 40 and 48., Findings: 279 subjects were enrolled; 138 subjects in the ataluren arm and 136 in the placebo arm were evaluable for efficacy. Absolute ppFEV 1 change from baseline did not differ significantly between the ataluren and placebo groups at Week 40 (-0.8 vs -1.8) or Week 48 (-1.7 vs -2.4). Average ppFEV 1 treatment difference from baseline to Weeks 40 and 48 was 0.6 (95% CI -1.3, 2.5; p = 0.54). Pulmonary exacerbation rate per 48 weeks was not significantly different (ataluren 0.95 vs placebo 1.13; rate ratio p = 0.40). Safety was similar between groups. No life-threatening adverse events or deaths were reported., Interpretation: Neither ppFEV 1 change nor pulmonary exacerbation rate over 48 weeks were statistically different between ataluren and placebo groups. Development of a nonsense-mutation CF therapy remains elusive., Competing Interests: Declaration of Competing Interest JM is an employee of PTC Therapeutics, the funder of this clinical trial, and holds financial interests in the company. MWK, SMR, and DRV received compensation for consultant services from PTC Therapeutics prior to and/or during this study. EK, MW, IS-G, and KDB received compensation for travel expenses for meetings related to the study. All other authors declare no competing interests., (Copyright © 2020. Published by Elsevier B.V.)

Background: Increased abundance of Enterobacteriaceae(EB) in the respiratory microbiome of young CF patients was reported to precede Pseudomonas aeruginosa(PA) colonisation. We explored whether impending PA colonisation can be predicted by growth of EB in routine airway cultures and whether EB contribute to CF lung disease severity., Methods: We retrospectively studied the records of 62 children with CF for growth of EB and PA during the first 5 years of life and subsequent best lung function at ages 5-7 and 9-11 years., Results: At least one EB positive month occurred in 36/62 (58%) patients. Median (IQR) age at first EB isolation was 0.4 (0.2-0.8) years. PA isolation before age 5 was more frequent in the EB positive (23/36, 54%) than in EB negative children (10/26, 38%; p = 0.048). EB isolation preceded PA isolation in 19/23 (83%) cases (p = 0.003). Median (IQRf) FEV 1 at age 5 to 7 years was 105% (94-117) in the EB positive group and 108% (102-115) in the EB negative group (p = 0.154). At age 9-11, FEV 1 was lower in EB positive children (99%(88-105) vs 105%(96-110); p = 0.035). Only PA isolation (p = 0.002) before age 5 years was a significant predictor of FEV 1 at age 5-7 years. Both EB isolation (p = 0.033) and PA isolation (p = 0.023) were predictors of the FEV 1 at age 9-11 years., Conclusion: In preschool children with CF, EB were isolated in just over half of the children. In that subgroup PA isolation was more common. Both EB and PA isolation are associated with worse lung function at later age., Competing Interests: Declaration of Competing Interest Prof. F. Vermeulen, Prof. M. Proesmans, Dr. M. Vermaelen have nothing to disclose. Prof. K. De Boeck reports other from Boehringer, Protalix, Raptor, Teva, Novabiotics, Elox, Vertex, Galapagos, outside the submitted work. Prof. M. Boon reports grants from MyCyFAPP, outside the submitted work., (Copyright © 2019. Published by Elsevier B.V.)

Background: Monitoring changes in the epidemiology of cystic fibrosis (CF) pathogens is essential for clinical research, quality improvement, and clinical management., Methods: We analyzed data reported to the European Cystic Fibrosis Society Patient Registry (ECFSPR) from 2011 to 2016 to determine the overall and the age-specific annual prevalence and incidence of selected CF pathogens and their trends during these years. The ECFSPR collects data on three chronic infections: Pseudomonas aeruginosa (PsA), Burkholderia cepacia complex Species (BCC) and Staphylococcus aureus (SA), as well as on the occurrence of non-tuberculous mycobacteria (NTM) and Stenotrophomonas maltophilia (SM). The same analyses were performed for different country groups, according to their gross national income (GNI)., Results: The pathogens with the highest prevalence were SA and PsA, with prevalence, in 2016, equal to 38.3% and 29.8% respectively, followed by SM (8.1%). The pathogens with the lowest prevalence were NTM (3.3%) and BCC (3.1%). The overall prevalence and incidence significantly decreased for PsA; they also decreased for BCC, while they increased significantly for SA. The overall prevalence of NTM and SM increased significantly. The most considerable prevalence changes were observed for PsA, which decreased across all income country groups and all age strata (with the exception of 0-1 years) The prevalence and incidence of pathogens differed significantly according to GNI., Conclusions: The epidemiology of CF pathogens in Europe has changed; epidemiologic data differ significantly among countries with different socio-economic status. The causes of these observations are multifactorial and include improvements in clinical care and infection control., Competing Interests: Declaration of Competing Interest None., (Copyright © 2019 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.)

Background: Eluforsen is an antisense oligonucleotide designed to bind to the mRNA region around the F508-encoding deletion and restore the cystic fibrosis transmembrane conductance regulator (CFTR) protein function in the airway epithelium. We assessed the safety and tolerability, pharmacokinetics and exploratory measures of efficacy of inhaled eluforsen in cystic fibrosis (CF) patients homozygous for the F508del-CFTR mutation., Methods: This randomised, double-blind, placebo-controlled, dose escalation 1b study recruited adult CF subjects with a FEV 1  > 70% predicted in four single ascending dose cohorts and four multiple ascending dose cohorts. Primary objectives were safety and tolerability. Secondary endpoints included pharmacokinetics, percent predicted forced expiratory volume in 1 s (ppFEV 1 ), and Cystic Fibrosis Questionnaire-Revised (CFQ-R) Respiratory Symptom Score (RSS)., Results: Single and multiple doses of inhaled eluforsen up to 50 mg were safe and well tolerated. A maximum tolerated dose was not established. Systemic exposure was low in all cohorts and lung function remained stable throughout the study. Three of four eluforsen-treated groups in the MAD study demonstrated an improvement in CFQ-R RSS at end of treatment with adjusted mean change from baseline values ranging from 6.4 to 12.7 points. In comparison, there was a mean decrease of 6.5 points in the placebo group from baseline to end of treatment., Conclusions: Inhaled eluforsen up to 50 mg dosed 3 times per week for 4 weeks was safe and well tolerated, showed low systemic exposure, and demonstrated improvement in CFQ-R RSS, a relevant measure of clinical benefit in CF patients., Competing Interests: Conflict of interest statement WdH, JP and NT are full-time employees of ProQR Therapeutics. NP-L and NH were full-time employees of ProQR Therapeutics during design development, execution and reporting of this study, and SM was full-time employee of ProQR Therapeutics during execution and reporting of this study. FB and MB are or were statistical consultants paid by ProQR Therapeutics. KDB report grants related to the submitted work. KDB and JSE report grants outside the submitted work. KDB and JSE report activity on advisory boards during the conduct of the study and outside the submitted work. PD, KDB and JSE received fees for consultancy. CS, MC and TP have no disclosures., (Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.)

The last decade has witnessed developments in the CF drug pipeline which are both exciting and unprecedented, bringing with them previously unconsidered challenges. The Task Force group came together to consider these challenges and possible strategies to address them. Over the last 18 months, we have discussed internally and gathered views from a broad range of individuals representing patient organizations, clinical and research teams, the pharmaceutical industry and regulatory agencies. In this and the accompanying article, we discuss two main areas of focus: i) optimising trial design and delivery for speed/efficiency; ii) drug development for patients with rare CFTR mutations. We propose some strategies to tackle the challenges ahead and highlight areas where further thought is needed. We see this as the start of a process rather than the end and hope herewith to engage the wider community in seeking solutions to improved treatments for all patients with CF., (Copyright © 2019. Published by Elsevier B.V.)

The last decade has witnessed developments in the CF drug pipeline which are both exciting and unprecedented, bringing with them previously unconsidered challenges. The Task Force group was brought together to consider these challenges and possible strategies to address them. Over the last 18 months, we have discussed internally and gathered views from a broad range of individuals representing patient organisations, clinical and research teams, the pharmaceutical industry and regulatory agencies. In this and the accompanying article, we discuss two main areas of focus: i) optimising trial design and delivery for speed and efficiency; ii) drug development for patients with rare CFTR mutations. We propose some strategies to tackle the challenges ahead and highlight areas where further thought is needed. We see this as the start of a process rather than the end and hope herewith to engage the wider community in seeking solutions to improved treatments for all patients with CF., (Copyright © 2019. Published by Elsevier B.V.)

Background: Several treatment approaches in cystic fibrosis (CF) aim to correct CF transmembrane conductance regulator (CFTR) function; the efficacy of each approach is dependent on the mutation(s) present. A need remains for more effective treatments to correct functional deficits caused by the F508del mutation., Methods: Two placebo-controlled, phase 2a studies evaluated GLPG2222, given orally once daily for 29 days, in subjects homozygous for F508del (FLAMINGO) or heterozygous for F508del and a gating mutation, receiving ivacaftor (ALBATROSS). The primary objective of both studies was to assess safety and tolerability. Secondary objectives included assessment of pharmacokinetics, and of the effect of GLPG2222 on sweat chloride concentrations, pulmonary function and respiratory symptoms., Results: Fifty-nine and 37 subjects were enrolled into FLAMINGO and ALBATROSS, respectively. Treatment-related treatment-emergent adverse events (TEAEs) were reported by 29.2% (14/48) of subjects in FLAMINGO and 40.0% (12/30) in ALBATROSS; most were mild to moderate in severity and comprised primarily respiratory, gastrointestinal, and infection events. There were no deaths or discontinuations due to TEAEs. Dose-dependent decreases in sweat chloride concentrations were seen in GLPG2222-treated subjects (maximum decrease in FLAMINGO: -17.6 mmol/L [GLPG2222 200 mg], p < 0.0001; ALBATROSS: -7.4 mmol/L [GLPG2222 300 mg], p < 0.05). No significant effects on pulmonary function or respiratory symptoms were reported. Plasma GLPG2222 concentrations in CF subjects were consistent with previous studies in healthy volunteers and CF subjects., Conclusions: GLPG2222 was well tolerated. Sweat chloride reductions support on-target enhancement of CFTR activity in subjects with F508del mutation(s). Significant improvements in clinical endpoints were not demonstrated. Observed safety results support further evaluation of GLPG2222, including in combination with other CFTR modulators., Funding: Galapagos NV. Clinical trial registration numbers FLAMINGO, NCT03119649; ALBATROSS, NCT03045523., (Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Optimal nutrition for children with cystic fibrosis (CF) improves prognosis and survival, but an increased caloric intake recommendation for this population raises concerns about the nutrient profile of their diets., Objective: Our aim was to assess the relative contribution of food groups to the total macronutrient intake of European pediatric patients with CF., Design: We conducted a cross-sectional study in which the participants recorded dietary intake from 2016 to 2017. Specifically developed nutritional composition databases were used to obtain nutritional data, including macronutrients and food groups, according to previously standardized criteria., Participants/setting: Two hundred and seven pediatric patients with CF from six European centers were involved in the My App for Cystic Fibrosis self-management project., Main Outcome Measures: Participants reported dietary intake with a detailed 4-day food record., Statistical Analysis Performed: Descriptive analyses of nutrient intake, food group consumption, and dietary origin of macronutrients were conducted with R software., Results: Similar patterns were found in nutrient and food group intake; both sugar and saturated fatty acids contributed >10% each to the total daily energy intake in all the centers. Large mean and median percent differences were observed in the intake of other nutrient and food groups, because sweets and snacks were consumed once or twice a day, and fruit and vegetables were consumed two or three times a day. Milk, meat, sweets and snacks, and oils were the main sources of fat in all centers., Conclusions: Study findings indicated less than optimal nutrient profiles, especially for sugars and saturated fatty acids, resulting from the high consumption of meat, dairy, and processed products and low consumption of fish, nuts, and legumes. These results can serve as a basis for future tailored interventions that target improved adherence to nutritional recommendations for patients with CF., (Copyright © 2019 Academy of Nutrition and Dietetics. Published by Elsevier Inc. All rights reserved.)

Background: Cystic fibrosis (CF) is caused by mutations in the CF transmembrane conductance regulator (CFTR) gene. In this study we assessed the effect of antisense oligonucleotide eluforsen on CFTR biological activity measured by Nasal Potential Difference (NPD) in patients with the most common mutation, F508del-CFTR., Methods: This multi-centre, exploratory, open-label study recruited adults with CF homozygous or compound heterozygous for the F508del-CFTR mutation. Subjects received intranasal eluforsen three times weekly for 4 weeks. The primary endpoint was the within-subject change from baseline in total chloride transport (Cl-free+iso), as assessed by NPD. Secondary endpoints included within-subject change from baseline in sodium transport., Results: In the homozygous cohort (n = 7; per-protocol population), mean change (90% confidence interval) in Cl-free+iso was -3.0 mV (-6.6; 0.6) at day 15, -4.1 mV (-7.8; -0.4, p = .04) at day 26 (end of treatment) and - 3.7 mV (-8.0; 0.6) at day 47. This was supported by improved sodium transport as assessed by an increase in average basal potential difference at day 26 of +9.4 mV (1.1; 17.7, p = .04). The compound heterozygous cohort (n = 7) did not show improved chloride or sodium transport NPD values. Eluforsen was well tolerated with a favourable safety profile., Conclusions: In F508del-CFTR homozygous subjects, repeated intranasal administration of eluforsen improved CFTR activity as measured by NPD, an encouraging indicator of biological activity., (Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Airway infections in Primary Ciliary Dyskinesia (PCD) are caused by different microorganisms, including pseudomonas aeruginosa (PA). The aim of this study was to investigate the association of PA colonization and the progression of lung disease in PCD., Methods: Data from 11PCD centers were retrospectively collected from 2008 to 2013. Patients were considered colonized if PA grew on at least two separate sputum cultures; otherwise, they were classified as non-colonized. These two groups were compared on the lung function computed tomography (CT) Brody score and other clinical parameters., Results: Data were available from 217 patients; 60 (27.6%) of whom were assigned to the colonized group. Patients colonized with PA were older and were diagnosed at a later age. Baseline forced expiratory volume at 1 s (FEV 1 ) was lower in the colonized group (72.4 ± 22.0 vs. 80.1 ± 18.9, % predicted, p = 0.015), but FEV 1 declined throughout the study period was similar in both groups. The colonized group had significantly worse CT-Brody scores (36.07 ± 24.38 vs. 25.56 ± 24.2, p = 0.034). A subgroup analysis with more stringent definitions of colonization revealed similar results., Conclusions: Lung PA colonization in PCD is associated with more severe disease as shown by the FEV 1 and CT score. However, the magnitude of decline in pulmonary function was similar in colonized and non-colonized PCD patients., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Evidence based guidelines exist for sweat testing, which remains a key component of a diagnosis of cystic fibrosis (CF), especially following newborn bloodspot screening (NBS). There are emerging challenges with respect to maintaining a valid sweat test service, notably a smaller number of sweat tests ordered in regions with established NBS programmes where Pediatricians refer less children for sweat testing, younger patients and equipment becoming obsolete. The ECFS Diagnostic Network Working Group has undertaken a comprehensive survey to better define sweat test practice across Europe. The survey was completed by 136 European respondents representing a CF center or laboratory providing a sweat test service (65% from regions with NBS for CF). There was considerable variance in practice, often not consistent with guidelines. In particular collection of sweat from two sites was rarely reported in European centres in contrast to US guidelines. There was a range of different references quoted for cut-off for both a positive and intermediate test. Most responses suggest cost is becoming an increasing issue and is not sufficiently reimbursed. This work will inform best practice guidelines and resources to sustain and improve sweat testing in Europe., (Copyright © 2017 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.)

Background: The New European guidelines have established the most updated recommendations on nutrition and pancreatic enzyme replacement therapy (PERT) in CF. In the context of MyCyFAPP project - a European study in children with CF aimed at developing specific tools for improvement of self-management - the objective of the current study was to assess nutritional status, daily energy and macronutrient intake, and PERT dosing with reference to these new guidelines., Methods: Cross sectional study in paediatric patients with CF from 6 European centres. SD-scores for weight-for-age (WFA), height-for-age (HFA) and body mass index-for-age (BMI) were obtained. Through a specific 4-day food and enzyme-dose record, energy and macronutrients intake and PERT-use (LU/g lipids) were automatically calculated by the MyCyFAPP system. Comparisons were made using linear regression models., Results: The lowest quartiles for BMI and HFA were between 0 and -1SD in all the centres with no significant differences, and 33.5% of the patients had a SD-score <0 for all three parameters. The minimum energy intake recommendation was not reached by 40% of the children and mean nutrients intake values were 14%, 51% and 34% of the total energy for protein, carbohydrates and lipids respectively. When assessed per centre, reported PERT doses were in the recommended range in only 13.8% to 46.6% of the patients; from 5.6% up to 82.7% of children were above the recommended doses and 3.3% to 75% were below., Conclusion: Among the 6 centres, a large variability and inconsistency with new guidelines on nutrition and PERT-use was found. Our findings document the lack of a general criterion to adjust PERT and suggest the potential benefit of educational and self-managerial tools to ensure adherence to therapies, both for clinical staff and families. They will be taken into account when developing these new tools during the next stages of MyCyFAPP Project., (Copyright © 2017 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.)

Background: The diagnosis of Cystic Fibrosis (CF) is by consensus based on the same parameters in all patients, yet the influence of ethnicity has only scarcely been studied. We aimed at elucidating the impact of Asian descent on the diagnosis of CF., Methods: We performed a retrospective analysis of the CFTR2 and UK CF databases for clinical phenotype, sweat chloride values and CFTR mutations and compared the diagnostic characteristics of Asian to non-Asian patients with CF., Results: Asian patients with CF do not have a worse clinical phenotype. The repeatedly reported lower FEV 1 of Asian patients with CF is attributable to the influence of ethnicity on lung function in general. However, pancreatic sufficiency is more common in Asian patients with CF. The diagnosis of CF in people with Asian ancestry is heterogeneous as mean sweat chloride values are lower (92±26 versus 99±22mmol/L in controls) and 14% have sweat chloride values below 60mmol/L (versus 6% in non-Asians). Also, CFTR mutations differ from those in Caucasians: 55% of British Asian patients with CF do not have one mutation included in the routine newborn screening panel., Conclusions: Bringing together the largest cohort of patients with CF and Asian ethnicity, we demonstrate that Asian roots impact on all three CF diagnostic pillars. These findings have implications for clinical practice in the increasingly ethnically diverse Western population., (Copyright © 2017 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.)

Introduction: Inhaled mannitol has beneficial effects on lung function, mucociliary clearance, quality of life and sputum properties. This trial examined the efficacy of inhaled mannitol in children with cystic fibrosis (CF)., Methods: The efficacy of inhaled mannitol in children with CF aged 6-17years was assessed in a phase 2, randomised, placebo-controlled crossover study. Subjects were randomly assigned to mannitol 400mg every 12h or matching placebo for 8weeks, followed by an 8week washout and an 8week period with the alternate treatment. The primary endpoint was the absolute change from baseline in ppFEV1 (percent predicted FEV1)., Results: A total of 92 subjects were studied, with a mean age of 12years and mean baseline ppFEV1 of 72.2%. During mannitol treatment ppFEV1 was 3.42% (p=0.004) higher compared to placebo or a 4.97% (p=0.005) relative difference; relative change from baseline FEF25-75 was 10.52% (p=0.013). During mannitol treatment, acute post-treatment sputum weight was higher (p=0.012). In pre-specified subgroups (rhDNase use, age, and disease severity), the treatment differences consistently favoured mannitol. The most common AEs were cough and pulmonary exacerbations. Pulmonary exacerbation AEs were approximately 30% lower in the mannitol group., Conclusions: In children with CF, inhaled mannitol was associated with significant improvements in lung function and sputum weight, irrespective of rhDNase use, age or disease severity. Inhaled mannitol was well tolerated and was associated with a reduced incidence of pulmonary exacerbation AEs. (Clinical Trials.Gov: NCT 01883531)., (Copyright © 2017 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.)

In patients with cystic fibrosis, most treatments addressing the underlying basic defect are mutation or mutation class specific. These treatments are disease modifying if they lower the year to year change in lung function. We therefore calculated the current loss of lung function, measured by year to year change in forced expired volume in 1s in 11,417 patients included in the European Cystic Fibrosis Society Patient Registry. Whereas patients with at least one mutation of class IV or V have on average a lower year to year change, we did not find a difference between patients with a stop codon mutation, homozygous for F508del or at least one class III mutation. These data are useful background information to discuss the impact of different disease modifying treatments., (Copyright © 2016 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.)

Introduction: Sweat chloride concentration, a biomarker of CFTR function, is an appropriate outcome parameter in clinical trials aimed at correcting the basic CF defect. Although there is consensus on a cut-off value to diagnose CF, we have only limited information on the within subject variability of sweat chloride over time. Such information would be useful for sample size calculations in clinical trials. Therefore, we retrospectively analyzed repeated sweat chloride values obtained in patients with G551D mutation(s) assigned to placebo in an ivacaftor interventional trial., Methods: In subjects with G551D at least 12years of age, a pilocarpine sweat test using Macroduct collector was taken on both arms at 8 time points over 48weeks. We explored 1062 pilocarpine sweat test values obtained in 78 placebo patients of the VX08-770-102 trial., Results: Mean overall sweat chloride value (all patients, all tests, n=1062) was 100.8mmol/L (SD 12.7mmol/L). Using a multilevel mixed model, the between-subject standard deviation (SD) for sweat chloride was 8.9mmol/L (95% CI 7.4-10.6) and within-subject SD was 8.1mmol/L (95% CI 7.5-8.7). Limits of repeatability for repeat measurements were -19.7 to +21.6mmol/L using values from one arm, and -13.3 to 11.8mmol/L using mean of values obtained at 4 test occasions. Sample size calculations showed that the minimal treatment effect on sweat chloride concentration that can be demonstrated for a group of 5 patients is around 15mmol/L, using a cross-over design and combinations of 4 tests for each phase of the trial., Conclusion: Although the sweat test is considered a robust measure, sweat chloride measurements in patients with CF and a G551D mutation had an inherent biological variability that is higher than commonly considered. Further analyses of placebo group data are crucial to learn more about the natural variability of this outcome parameter., (Copyright © 2016 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.)

Background: The sweat test is the current gold standard for the diagnosis of cystic fibrosis (CF). CF is unlikely when sweat chloride (Cl sw ) is lower than 30mmol/L, Cl sw >60 is suggestive of CF, with intermediate values between 30 and 60mmol/L. To correctly interpret a sweat chloride value, the biological variability of the sweat chloride has to be known., Methods: Sweat tests performed in two centers using the classic Gibson and Cooke method were retrospectively reviewed (n=5904). Within test variability of Cl sw was measured by comparing results from right and left arm collected on the same day. Between test variability was calculated from subjects with sweat tests performed on more than one occasion., Results: Within test variability of Cl sw calculated in 1022 subjects was low with differences between -3.2 (p5) and +3.6mmol/L (p95). Results from left and right arm were classified differently in only 3 subjects. Between test variability of Cl sw in 197 subjects was larger, with differences between -18.2mmol/L (p5) and +14.1mmol/L (p95) between repeat tests. Changes in diagnostic conclusion were seen in 55/197 subjects, the most frequent being changing from indeterminate to 'CF unlikely' range (48/102)., Conclusion: Variability of sweat chloride is substantial, with frequent changes in diagnostic conclusion, especially in the intermediate range., (Copyright © 2016 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.)

The use of 3 novel tools available for the diagnosis and treatment in cystic fibrosis are described here. 1) The lung clearance index is a sensitive method which can detect functional impairment in the first months after birth. 2) Detailed morphological analyses of the lung can be performed with the new MRI sequences, without any contrast medium or risk of radiation. The analysis of functional MRI data (perfusion, diffusion, ventilation, inflammation) will be possible, and these data will be correlated to morphological data. The exploration of other organs such as the sinuses, liver and abdomen during the same examination represents another definite advantage. 3) Organoïds are a good example of personalized medicine. This tool explores CFTR function and treatment response in each of the 2000 or so known CFTR mutations. These tests are limited to specialized centers, mostly within a research context. However, their generalization after standardization is expected in the near future., (Copyright © 2016 Elsevier Masson SAS. All rights reserved.)

Introduction: The efficacy of inhaled antibiotics to treat chronic Pseudomonas aeruginosa pulmonary infection in patients with cystic fibrosis (CF) has been well established. Few data are available on the value of continuous alternating inhaled antibiotic therapy (CAIT), a strategy increasingly used in the management of CF., Objective: To investigate the effect of CAIT on clinical outcome in adult CF patients treated at the University Hospital Leuven., Methods: Patients with a documented CF diagnosis who received inhaled antibiotics between March 2010 and January 2015 were retrospectively evaluated. In patients receiving CAIT patient characteristics, recorded spirometry data and number of IV antibiotic days were collected retrospectively at fixed time intervals, from 6months before to one year after the start of the 2nd inhaled antibiotic. For patients on inhaled antibiotic monotherapy (IAMT), the same data were obtained at similar intervals during the study period., Results: A total of 49 of 89 patients using chronic inhaled antibiotic therapy received CAIT. Patients receiving CAIT had a lower baseline FEV 1 and were more likely to be homozygous for F508del compared to patients receiving IAMT. FEV 1 deteriorated on average by a factor of 0.904 per year (95% CI: 0.851-0.960) prior to the start of CAIT. The initiation of CAIT was associated with an average improvement in FEV 1 by a factor of 1.148 per year (95% CI: 1.068-1.236, p=0.0002). The analysis of specific types of antibiotics revealed evidence of positive effects of adding COLI to TOBI and COLI to AZLI. We found no effect of the initiation of CAIT on the number of IV antibiotic days (p=0.80)., Conclusion: CF patients with more advanced lung disease are more likely to receive CAIT. In this patient group, CAIT was associated with a significant improvement in FEV 1 . Further data are warranted to identify the value of CAIT., (Copyright © 2016 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.)

Standard follow-up and symptomatic treatment have allowed most patients with cystic fibrosis to live to young adulthood. However, many patients still die prematurely from respiratory insufficiency. Hence, further investigations to improve these therapies are important and might have relevance for other diseases-eg, exploring how to increase airway hydration, how to safely downscale the increased inflammatory response in the lung, and how to better combat lung infections associated with cystic fibrosis. In parallel, development of modulators that target the underlying dysfunction in the cystic fibrosis transmembrane conductance regulator (CFTR) is fast moving forward. Existing treatments are specific to certain mutations, or mutation class, in CFTR. An effective, although not yet entirely corrective, treatment is available for patients with class III mutations, and a treatment with modest effectiveness is available for patients who are homozygous for Phe508del, albeit at a very high cost. Corrective treatments that are non-specific to mutation class and thus applicable to all patients-eg, gene therapy, cell-based therapies, and activation of alternative ion channels that bypass CFTR-are being explored, but they are still in early stages of development. In view of the large number of patients with very rare mutations, a plan to advance personalised biomarkers to predict treatment effect is also being investigated and validated., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Background: Several microbial studies reported gut microbiota dysbiosis in patients with cystic fibrosis (CF). The functional consequences of this phenomenon are poorly understood. Faecal metaproteomics allows the quantitative analysis of host and microbial proteins to address functional changes resulting from this dysbiosis., Methods: We analysed faecal protein extracts from fifteen patients with CF that have pancreatic insufficiency and from their unaffected siblings by shotgun proteomics. Novel computational and statistical tools were introduced to evaluate changes in taxonomic composition and protein abundance., Results: Faecal protein extracts from patients with CF were dominated by host proteins involved in inflammation and mucus formation. Taxonomic analysis of the microbial proteins confirmed the strong reduction of butyrate reducers such as Faecalibacterium prausnitzii and increase of Enterobacteriaceae, Ruminococcus gnavus and Clostridia species., Conclusion: Faecal metaproteomics provides insights in intestinal dysbiosis, inflammation in patients with CF and can be used to monitor different disease markers in parallel., (Copyright © 2015 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.)

Unlabelled: The European Cystic Fibrosis Society Clinical Trial Network (ECFS-CTN) has established a Standardization Committee to undertake a rigorous evaluation of promising outcome measures with regard to use in multicentre clinical trials in cystic fibrosis (CF). The aim of this article is to present a review of literature on clinimetric properties of the infant raised-volume rapid thoracic compression (RVRTC) technique in the context of CF, to summarise the consensus amongst the group on feasibility and answer key questions regarding the promotion of this technique to surrogate endpoint status., Methods: A literature search (from 1985 onwards) identified 20 papers that met inclusion criteria of RVRTC use in infants with CF. Data were extracted and tabulated regarding repeatability, validity, correlation with other outcome measures, responsiveness and reference values. A working group discussed the tables and answered 4 key questions., Results: Overall, RVRTC in particular forced expiratory volume in 0.5s, showed good clinimetric properties despite presence of individual variability. Few studies showed a relationship between RVRTC and inflammation and infection, and to date, data remains limited regarding the responsiveness of RVRTC after an intervention. Concerns were raised regarding feasibility in multi-centre studies and availability of reference values., Conclusion: The ECFS-CTN Working Group considers that RVRTC cannot be used as a primary outcome in clinical trials in infants with CF before universal standardization of this measurement is achieved and implementation of inter-institutional networking is in place. We advise its use currently in phase I/II trials and as a secondary endpoint in phase III studies. We emphasise the need for (1) more short-term variability and longitudinal 'natural history' studies, and (2) robust reference values for commercially available devices., (Copyright © 2015 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.)

Background: The acquisition of Pseudomonas aeruginosa in cystic fibrosis (CF) is associated with lower survival, decreased lung function, worse radiological scores, increased exacerbations and reduced nutritional status. Open water is a known reservoir and a potential source of exposure to P. aeruginosa., Methods: Twenty eight adult CF patients who had no history of P. aeruginosa and had negative P. aeruginosa IgG antibody levels, were matched by age and sex with 28 CF patients with chronic P. aeruginosa colonization. Straight line and closest walking distance from patient's residence to the nearest "blue space", i.e. surface water as determined by Google Earth, were compared between the two groups, and odds ratios (OR) were estimated using conditional logistic regression., Results: Patients who were never infected with P. aeruginosa lived significantly further away from a natural water source than P. aeruginosa colonized patients, both when considering shortest walking distance (mean 487 m vs 308 m, p=0.014) and beeline (mean 324 m vs 202 m, p=0.021). Conditional logistic regression (correcting for FEV1%) revealed ORs for chronic P. aeruginosa colonization of 0.35 (95% CI 0.13-0.98; p=0.045) and 0.12 (95% CI 0.02-0.81; p=0.028) for each doubling in the beeline or walking distance, respectively, between residence and open water., Conclusion: We discovered that adult CF patients without P. aeruginosa infection live significantly further from blue space than CF patients with chronic P. aeruginosa colonization. Within the limitations of a case-control study, this may indicate that natural open water represents a source of infection by P. aeruginosa in CF., Registration: The study was approved by the local ethical committee of the UZ Leuven, Belgium (ML-5028)., (Copyright © 2015 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.)

Background: The day parents are told their child has cystic fibrosis (CF) is imprinted in their memory. Parents often show strong emotions (e.g. shock, anxiety); they need to cope with bad news and restructure their lives taking into account CF., Aims: The aims of this study are (1) to explore how parents recall circumstances of the CF diagnosis and the information they received and (2) to investigate their current coping styles., Methods: Parents (n=38) of 20 children (diagnosed during the past 5 years) were interviewed using a semi-structured interview. Coping was assessed using the Utrecht Coping List. The association between coping and time since diagnosis/severity of illness was investigated., Results: Fifteen parents first heard the term 'CF' from their local pediatrician or GP. All were informed in detail by the CF specialist. All parents recalled specifics about the information, the attitude of the doctor, their thoughts and emotions. Most parents were satisfied with the content and manner in which they had received information. Nineteen appreciated the doctor showing some emotions during the talks. One couple criticized the doctor for not showing emotions. Parents reported higher use (than normative scores) of the active coping style 'social support seeking' and the accommodative coping styles 'palliative reaction pattern' and 'comforting cognitions'. Perception of severity of illness was associated with higher scores on palliative coping., Conclusions: This study shows the importance of physicians and CF teams to tailor the way of providing bad news to parents' needs and preferences. It is important to help and encourage parents to use active or accommodative coping strategies. The diagnosis is the starting point of a long-term relationship. 'Doing things well from the start' helps families to learn to live with CF and treatment., (Copyright © 2014 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.)

Objective: To increase the power of nasal potential difference (NPD) as a biomarker of CFTR function, improvement of its repeatability is needed. We evaluated the improvement in repeatability resulting from measuring NPD (1) over a larger surface area and (2) at a fixed location., Methods: To assess repeatability, NPD was measured on two occasions with a new method using a larger surface catheter at fixed locations on the nasal floor (LSC-floor(5cm) and LSC-floor(3cm)) or at the most negative basal potential (LSC-floor(max)); with a sidehole catheter on the nasal floor at 5 cm) from the nasal margin (SHC-floor(5cm)) or at the most negative potential (SHC-floor(max)); and with an endhole catheter below the inferior surface of the lower turbinate at the most negative potential (EHC-turb(max))., Results: The within-subject standard deviation (S(w)) for repeated measurements of the total chloride response in the controls was smallest with the LSC-floor at a fixed location (LSC-floor(5cm) 3.1 mV; 95% CI 2.3-4.6 mV) and highest with the SHC-floor (SHC-floor(max) 14.6 mV; 95% CI 10.9-22.2 mV) or the EHC-turbinate (EHC-turb(max) 12.5 mV; 95% CI 10.7-23.0 mV) at the most negative basal potential. Measuring with the LSC-floor at the maximal potential increased the Sw (LSC-floor(max) 8.8 mV, 95% CI 6.0-16.1 mV, p=0.009 vs LSC-floor(5cm)), while measuring with the SHC-floor at a fixed location slightly decreased the Sw (SHC-floor(5cm) 9.8 mV, 95% CI 8.9-20.6 mV, p=0.06 vs SHC-floor(max)). In patients with cystic fibrosis, the S(w) was comparable, between 2.2 mV and 4.3 mV. Sample size calculations for trials using NPD to assess changes in ion transport showed that the number of subjects to be included could be approximately halved measuring with the larger surface catheter at a fixed location vs SHC or EHC at fixed locations., Conclusion: Measuring the NPD at a fixed location and over a larger surface resulted in increased repeatability and thereby also power as a biomarker of CFTR modulation., (Copyright © 2014 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.)

Background: Consensus guidelines recommend early treatment to eradicate newly acquired Pseudomonas aeruginosa (Pa) infection in cystic fibrosis (CF) patients although there is no single preferred regimen. Aztreonam for inhalation solution (AZLI) significantly reduces sputum Pa density in CF patients with chronic Pa infection and has been well tolerated in the pediatric population. This single-arm, open-label Aztreonam Lysine for Pseudomonas Infection Eradication (ALPINE) study was conducted to evaluate the safety and efficacy of a 28-day treatment course of AZLI to eradicate newly acquired Pa infection in pediatric CF patients., Methods: CF patients (3 months to <18 years) with new onset Pa infection were treated with AZLI 75 mg 3 times daily for 28 days. New onset Pa infection was defined as first lifetime Pa-positive respiratory tract culture (throat swab, sputum) or Pa-positive culture after a ≥2-year history of Pa-negative cultures (≥ 2 cultures/year). Sputum or throat swab cultures were collected at study entry (baseline) and at weeks 4 (end of treatment), 8, 16, and 28. Primary endpoint was the percentage of patients with cultures negative for Pa at all post-treatment time points., Results: A total of 105 pediatric CF patients enrolled (3 months to <2 years, n=24; 2 to <6 years, n=25; 6 to <18 years, n=56). Of the 101 patients who completed treatment, 89.1% (n=90) were free of Pa at the end of treatment and 75.2% (n=76) were free of Pa 4 weeks after the end of treatment. Of the 79 patients evaluable for the primary endpoint, 58.2% were free of Pa at all post-treatment time points., Conclusions: AZLI was effective and well tolerated in eradicating Pa from newly infected pediatric patients with CF. These eradication rates are consistent with success rates reported in the literature for various antibiotic regimens, including other inhaled antibiotics studied for eradication. ClinicalTrials.gov: NCT01375049., (Copyright © 2014. Published by Elsevier B.V.)

Background: Ivacaftor is used to treat patients with CF and a G551D gating mutation; the KONNECTION study assessed the efficacy and safety of ivacaftor in patients with CF and a non-G551D gating mutation., Methods: Patients with CF ≥6-years- old with non-G551D gating mutations received ivacaftor 150mg q12h or placebo for 8weeks in this 2-part, double-blind crossover study (Part 1) with a 16-week open-label extension (Part 2). The primary efficacy outcome was absolute change in FEV1 through 8 and 24weeks of ivacaftor treatment; secondary outcomes were changes in BMI, sweat chloride, and CFQ-R and safety through 8 and 24weeks of treatment., Results: Eight weeks of ivacaftor resulted in significant improvements in percent predicted FEV1, BMI, sweat chloride, and CFQ-R scores that were maintained through 24weeks. Ivacaftor was generally well tolerated., Conclusions: Ivacaftor was efficacious in a group of patients with CF who had selected non-G551D gating mutations., (Copyright © 2014 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.)

The terms consensus, guideline and position paper are sometimes employed as if they were interchangeable, but the purpose of such documents and the robustness of advice vary as the evidence base does not have the same depth in each. The Board of the European Cystic Fibrosis Society deemed it to be helpful to provide a short commentary on the definition of these terms, on their interconnections and on how ECFS considers them in documents endorsed by the society., (Copyright © 2014 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.)