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Background: Monitoring multiple-breath washout (MBW) of a xenon tracer using magnetic resonance imaging (MBW Xe-MRI) provides quantitative regional measures of gas washout (fractional ventilation, FV) and spatial ventilation heterogeneity (coefficient of variation, CoV FV ) in pediatric CF lung disease, but has yet to be evaluated in an interventional setting., Methods: 12 pediatric CF participants (median age 15.3 ± 2 years) completed MBW Xe-MRI, pulmonary function tests (PFTs) (spirometry, N 2 MBW for lung clearance index (LCI)) and single-breath Xe-MRI ventilation defect percent (VDP) measurements at baseline and 1-month post-initiation of elexacaftor/tezacaftor/ivacaftor (ETI) therapy. FV maps were calculated from MBW Xe-MRI washout images, and CoV FV maps were derived from FV maps. Significant changes between visits were determined using a paired Wilcoxon signed-rank test. For correlations between absolute changes, Pearson's correlation was used., Results: All measures changed significantly 1-month post-ETI therapy compared to baseline. For MRI metrics, median [IQR] VDP was significantly (P < 0.001) lower at 1 month (8.0 [3.7 12.4]) compared to baseline (17.8 [8.3 22.5]), FV was significantly (P < 0.05) higher at 1 month (0.42 [0.41 0.46]) compared to baseline (0.38 [0.33 0.44]), and CoV FV was significantly (P < 0.001) lower at 1 month (0.06 [0.05 0.07]) compared to baseline (0.09 [0.08 0.12]). Both absolute and relative differences in CoV FV and LCI were found to correlate highly (R = 0.92, P < 0.0001 and R = 0.91, P < 0.0001, respectively)., Conclusions: Functional information derived from MBW Xe-MRI, particularly CoV FV , can be used to assess regional lung function in pediatric CF patients in an interventional setting and may be complementary to VDP and pulmonary function tests., Competing Interests: Declaration of competing interest The authors declare that they have no conflict of interest., (Copyright © 2024 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.)

Background: Short palate, lung, and nasal epithelium clone 1 (SPLUNC1) is an innate defence protein that acts as an anti-microbial agent and regulates airway surface liquid volume through inhibition of the epithelial sodium channel (ENaC). SPLUNC1 levels were found to be reduced in airway secretions of adults with cystic fibrosis (CF). The potential of SPLUNC1 as a biomarker in children with CF is unknown., Methods: We quantified SPLUNC1, interleukin-8 (IL-8) and neutrophil elastase (NE) in sputum of CF children treated with either intravenous antibiotics or oral antibiotics for a pulmonary exacerbation (PEx)s, and in participants of a prospective cohort of CF children with preserved lung function on spirometry, followed over a period of two years., Results: Sputum SPLUNC1 levels were significantly lower before compared to after intravenous and oral antibiotic therapy for PEx. In the longitudinal cohort, SPLUNC1 levels were found to be decreased at PEx visits compared to both previous and subsequent stable visits. Higher SPLUNC1 levels at stable visits were associated with longer PEx-free time (hazard ratio 0.85, p = 0.04). SPLUNC1 at PEx visits did not correlate with IL-8 or NE levels in sputum or forced expiratory volume in one second (FEV 1 ) but did correlate with the lung clearance index (LCI) (r=-0.53, p < 0.001)., Conclusion: SPLUNC1 demonstrates promising clinometric properties as a biomarker of PEx in children 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 © 2024 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.)

This is the third 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 recognising and addressing CF health issues. The guidance was produced with wide stakeholder engagement, including people from the CF community, using an evidence-based framework. Authors contributed sections, and summary statements which were reviewed by a Delphi consultation. Monitoring and treating airway infection, inflammation and pulmonary exacerbations remains important, despite the widespread availability of CFTR modulators and their accompanying health improvements. Extrapulmonary CF-specific health issues persist, such as diabetes, liver disease, bone disease, stones and other renal issues, and intestinal obstruction. These health issues require multidisciplinary care with input from the relevant specialists. Cancer is more common in people with CF compared to the general population, and requires regular screening. The CF life journey requires mental and emotional adaptation to psychosocial and physical challenges, with support from the CF team and the CF psychologist. This is particularly important when life gets challenging, with disease progression requiring increased treatments, breathing support and potentially transplantation. Planning for end of life remains a necessary aspect of care and should be discussed openly, honestly, with sensitivity and compassion for the person with CF and their family. CF teams should proactively recognise and address CF-specific health issues, and support mental and emotional wellbeing while accompanying people with CF and their families on their life journey., Competing Interests: Declaration of competing interest The authors had no declarations of interest in relation to the current work. Declarations of interest for each author outside the current work are summarised in Supplementary Table 4., (Copyright © 2024. Published by Elsevier B.V.)

Competing Interests: Declaration of Competing Interest The above authors declare no conflict of interest in this observational study.

Background: Elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) significantly improves health outcomes in people with cystic fibrosis (pwCF) carrying one or two F508del mutations. According to in vitro assays performed in FRT cells, 178 additional mutations respond to ELX/TEZ/IVA. The N1303K mutation is not included in this list of mutations. Recent in vitro data suggested that ELX/TEZ/IVA increases N1303K-CFTR activity. Based on the in vitro response, eight patients commenced treatment with ELX/TEZ/IVA., Methods: Two homozygotes; and six compound heterozygotes N1303K/nonsense or frameshift mutation pwCF were treated off label with ELX/TEZ/IVA. Clinical data before and 8 weeks after starting treatment were prospectively collected. The response to ELX/TEZ/IVA was assessed in intestinal organoids derived from 5 study patients and an additional patient carrying N1303K that is not receiving treatment., Results: Compared to the values before commencing treatment, mean forced expiratory volume in 1 second increased by 18.4 percentage points and 26.5% relative to baseline, mean BMI increased by 0.79 Kg/m 2 , and mean lung clearance index decreased by 3.6 points and 22.2%. There was no significant change in sweat chloride. Nasal potential difference normalized in four patients and remained abnormal in three. Results in 3D intestinal organoids and 2D nasal epithelial cultures showed a response in CFTR channel activity., Conclusions: This report supports the previously reported in vitro data, performed in human nasal and bronchial epithelial cells and intestinal organoids, that pwCF who carry the N1303K mutation have a significant clinical benefit by ELX/TEZ/IVA treatment., 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 © 2023 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.)

Pulmonary exacerbations treated with oral antibiotics (oPEx) have a significant effect on lung function decline in people with cystic fibrosis (CF). However, factors associated with lung function response with oPExs are not well defined. We performed a retrospective cohort study of pediatric and adult patients with CF followed in the Toronto CF Database. Lung function response was measured both as the change in forced expiratory volume in 1 second (FEV 1 ) from Day 0 of antibiotic therapy to end of treatment as well as from baseline to end of treatment. Drop from baseline to Day 0 FEV 1 was strongly associated with lung function response (p<0.001). Greater FEV 1 improvements were associated with longer antibiotic treatment durations. Older, female patients had less improvements in FEV 1 at end of treatment compared to younger, male patients., 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 © 2023. Published by Elsevier B.V.)

Background: Cystic fibrosis (CF) transmembrane conductance regulator (CFTR) modulator therapies show variable efficacy for patients with CF. Patient-derived predictive tools may identify individuals likely to respond to CFTRs, but are not in routine use. We aimed to determine the cost-utility of predictive tool-guided treatment with CFTRs as add-on to standard of care (SoC) for individuals with CF., Methods: This economic evaluation compared two strategies using an individual level simulation: (i) Treat All, where all patients received CFTRs plus SoC and (ii) Test→Treat, where patients who tested positive on predictive tools received CFTRs plus SoC and those who tested negative received SoC only. We simulated 50,000 individuals over their lifetime, and estimated costs (2020 CAD) per quality-adjusted life year (QALY) from the healthcare payer's perspective, discounted at 1.5% annually. The model was populated using Canadian CF registry data and published literature. Probabilistic and deterministic sensitivity were conducted., Results: The Treat All and Test→Treat and strategies yielded 22.41 and 21.36 QALYs, and cost $4.21 M and $3.15 M respectively. Results of probabilistic sensitivity analysis showed that Test→Treat was highly cost-effective compared to Treat All in 100% of simulations at cost-effectiveness thresholds as high as $500,000 per QALY. Test→Treat may save between $931 K to $1.1 M per QALY lost, depending on sensitivity and specificity of predictive tools., Conclusion: The use of predictive tools could optimize the health benefits of CFTR modulators while reducing costs. Our findings support the use of pre-treatment predictive testing and may help inform coverage and reimbursement policies for individuals with CF., Competing Interests: Declaration of Competing Interests Felix Ratjen acts as an advisor to Vertex Pharmaceuticals; Drs. Sahakyan Y, Abrahamyan L, Bear C, Strug L, Eckford P, Peel J, Krahn M, Sander B: no conflicts, (Copyright © 2023 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.)

Background: An electronic nose (eNose) can be used to detect volatile organic compounds (VOCs). Exhaled breath contains numerous VOCs and individuals' VOCs mixtures create distinct breath profiles. Previous reports have shown that eNose can detect lung infections. Whether eNose can detect Staphylococcus aureus airway infections in breath of children with cystic fibrosis (CF) is currently unclear., Methods: In this cross-sectional observational study, a cloud-connected eNose was used for breath profile analysis of clinically stable paediatric CF patients with airway microbiology cultures positive or negative for CF pathogens. Data-analysis involved advanced signal processing, ambient correction and statistics based on linear discriminant and receiver operating characteristics (ROC) analyses., Results: Breath profiles from 100 children with CF (median predicted FEV 1 91%) were obtained and analysed. CF patients with positive airway cultures for any CF pathogen were distinguishable from no CF pathogens (no growth or usual respiratory flora) with accuracy of 79.0% (AUC-ROC 0.791; 95% CI: 0.669-0.913) and between patients positive for Staphylococcus aureus (SA) only and no CF pathogen with accuracy of 74.0% (AUC-ROC 0.797; 95% CI: 0.698-0.896). Similar differences were seen for Pseudomonas aeruginosa (PA) infection vs no CF pathogens (78.0% accuracy, AUC-ROC 0.876, 95% CI: 0.794-0.958). SA- and PA-specific signatures were driven by different sensors in the SpiroNose suggesting pathogen-specific breath signatures., Conclusions: Breath profiles of CF patients with SA in airway cultures are distinct from those with no infection or PA infection, suggesting the utility of eNose technology in the detection of this early CF pathogen in children with CF., Competing Interests: Declaration of Competing Interest Rianne de Vries receives personal fees and has a substantial interest in the start-up company Breathomix BV. Gitte Slingers receives personal fees from the start-up company Breathomix BV. The remaining authors have nothing to disclose. 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 © 2023 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.)

Background: SHIP-CT showed that 48-week treatment with inhaled 7% hypertonic saline (HS) reduced airway abnormalities on chest CT using the manual PRAGMA-CF method relative to isotonic saline (IS) in children aged 3-6 years with cystic fibrosis (CF). An algorithm was developed and validated to automatically measure bronchus and artery (BA) dimensions of BA-pairs on chest CT. Aim of the study was to assess the effect of HS on bronchial wall thickening and bronchial widening using the BA-analysis., Methods: The BA-analysis (LungQ, version 2.1.0.1, Thirona, Netherlands) automatically segments the bronchial tree and identifies the segmental bronchi (G 0 ) and distal generations (G 1 -G 10 ). Dimensions of each BA-pair are measured: diameters of bronchial outer wall (B out ), bronchial inner wall (B in ), bronchial wall thickness (B wt ), and artery (A). BA-ratios are computed: B out /A and B in /A to detect bronchial widening and B wt /A and B wa /B oa (=bronchial wall area/bronchial outer area) to detect bronchial wall thickening., Results: 113 baseline and 102 48-week scans of 115 SHIP-CT participants were analysed. LungQ measured at baseline and 48-weeks respectively 6,073 and 7,407 BA-pairs in the IS-group and 6,363 and 6,840 BA-pairs in the HS-group. At 48 weeks, B wt /A (mean difference 0.011; 95%CI, 0.0017 to 0.020) and B wa /B oa (mean difference 0.030; 95% 0.009 to 0.052) was significantly higher (worse) in the IS-group compared to the HS-group representing more severe bronchial wall thickening in the IS-group (p=0.025 and p=0.019 respectively). B wt /A and B wa /B oa decreased and B in /A remained stable from baseline to 48 weeks in the HS while it declined in the IS-group (all p<0.001). There was no difference in progression of B out /A between two treatment groups., Conclusion: The automatic BA-analysis showed a positive impact of inhaled HS on bronchial lumen and wall thickness, but no treatment effect on progression of bronchial widening over 48 weeks., Competing Interests: Declaration of Competing Interest HAWMT reports grants from the Cystic Fibrosis Foundation and Health Holland, has received in the last 5 years multiple grants from the following public and institutional grant institutions for lung structure and function research: NHMRC, NIH, CFF, ECFS, IMI, Sophia Foundation and unconditional grants for investigator-initiated research from Chiesi, Vectura, Novartis, and Insmed, has acted as consultant for Insmed, TBIO, Thirona, Neupharma and Boehringer, has a part time position as chief medical officer for Thirona, functions as vice chair and faculty for the Advance course sponsored by Vertex, and owns no shares. Erasmus MC and Telethon Kids Institute have licensed the use of PRAGMA-CF to Thirona and Resonance Health. LGE is a scientist working at Thirona. JPC is Co-founder and shareholder at Thirona. DC is director of the Erasmus MC- LungAnalysis laboratory. SDD reports grants from Cystic Fibrosis Foundation. MR reports grants from Cystic Fibrosis Foundation. FR serves as consultant for Vertex, Bayer, Roche, Genentech, and Proteostasis. RAK reports grants from Cystic Fibrosis Foundation. KDHS reports grants from Cystic Fibrosis Foundation. SMS reports grants from the Cystic Fibrosis Foundation and National Health and Medical Research Foundation and Erasmus MC and Telethon Kids Institute have licensed the use of PRAGMA-CF to Thirona and Resonance Health. All other authors declare no competing interests., (Copyright © 2023. Published by Elsevier B.V.)

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

Background: Patient-reported outcomes (PROs) are important outcome measures in research and clinical practice. This study describes the longitudinal variability the Cystic Fibrosis Questionnaire-Revised (CFQ-R) Respiratory score and the Chronic Respiratory Infection Symptom Score (CRISS), as well as their ability to identify acute respiratory events in children with CF., Methods: In this prospective observational study, the parent-proxy (6 -13 years) and self-reported (6-18 years) CFQ-R Respiratory score and CRISS (6-18 years) were measured every 3 months over 2 years. The lung clearance index (LCI) and FEV 1 were also measured. We compared the diagnostic accuracy of the PROs in distinguishing acute respiratory events and clinically stable visits, using the minimal important difference of each PRO as the threshold., Results: A total of 98 children with CF were included. On average, the symptom scores did not change between clinically stable visits. The positive predictive value (PPV) and negative predictive value (NPV) of a ≥8.5-point worsening in the parent-proxy CFQ-R score to identify acute respiratory events (n=119) (PPV 70.2% and NPV 87.0%) were higher than for the self-reported CFQ-R score (PPV 58.9% and NPV 72.2%). The PPV and NPV of an ≥11-point change in the CRISS for acute respiratory events (n=137) was 56.5% and 79.6%, respectively. The PPV and NPV of all PROs were increased when combined with the LCI and/or FEV 1 pp., Conclusion: Symptoms scores differ in their ability to identify acute respiratory events in children with CF; PPV and NPV of all PROs were improved when combined with lung function outcomes., (Copyright © 2022. Published by Elsevier B.V.)

Background: Elexacaftor/tezacaftor/ivacaftor (ETI) improves pulmonary disease in people with cystic fibrosis (PwCF), but its effect on gastrointestinal symptoms, which also affect quality of life, is not clear., Methods: PROMISE is a 56-center prospective, observational study of ETI in PwCF >12 years and at least one F508del allele. Gastrointestinal symptoms, evaluated by validated questionnaires: Patient Assessment of Upper Gastrointestinal Disorders-Symptom (PAGI-SYM), Patient Assessment of Constipation-Symptom (PAC-SYM), Patient Assessment of Constipation-Quality of Life (PAC-QOL)), fecal calprotectin, steatocrit and elastase-1 were measured before and 6 months after ETI initiation. Mean difference and 95% confidence intervals were obtained from linear regression with adjustment for age and sex., Results: 438 participants fully completed at least 1 questionnaire. Mean (SD) for baseline PAGI-SYM, PAC-SYM, and PAC-QOL total scores were 0.56 (0.59), 0.47 (0.45), and 0.69 (0.53) out of maximum 5, 4, and 5, respectively (higher score indicates greater severity). Corresponding age- and sex-adjusted 6 months mean changes (95% CI) in total scores were -0.15 (-0.21, -0.09) for PAGI-SYM, -0.14 (-0.19, -0.09) for PAC-SYM, and -0.15 (-0.21, -0.10) for PAC-QOL. While statistically significant, changes were small and unlikely to be of clinical importance. Fecal calprotectin showed a change (95% CI) from baseline of -66.2 µg/g (-86.1, -46.2) at 6 months, while fecal elastase and steatocrit did not meaningfully change., Conclusions: After 6 months of ETI, fecal markers of inflammation decreased. Gastrointestinal symptoms improved, but the effect size was small. Pancreatic insufficiency did not improve., Competing Interests: Declaration of Competing Interest SJS-Consultant for UpToDate, Abbvie, Mirium, Nestle; Grant funding from Gilead, Cystic Fibrosis Foundation, NIH. SDF – Consultant for UpToDate, Abbvie, Nestle, Synspira; Grant funding from NIH, Cystic Fibrosis Foundation, Amagma Therapeutics. MRN – Consultant for UpToDate, Vertex: Grant funding from Gilead, AbbVie, Cystic Fibrosis Foundation, NIH SMR: Consultant for Vertex; Grant funding from Vertex, Cystic Fibrosis Foundation, NIH DPN: Consultant for Vertex, Genentech; Grant funding from Vertex, Cystic Fibrosis Foundation, NIH GMS: Consultant for Genentech, Electromed; Grant Funding from Vertex, Cystic Fibrosis Foundation, NIH DG: Consultant for Vertex, Abbvie, Chiesi USA, Eli Lilly AK: Grant funding from NIH, Cystic Fibrosis Foundation, SDS – Grant funding from Cystic Fibrosis Foundation and NIH MSS—Grant funding from Cystic Fibrosis Foundation, (Copyright © 2022. Published by Elsevier B.V.)

Background: With the increasing availability of highly effective modulators for people living with cystic fibrosis (CF), there is a need to re-design research studies to reflect the changing epidemiology of the CF population. The lung clearance index (LCI), a sensitive physiological measure of lung function, may be ideally suited as an endpoint in the era of CF modulator therapies. In this study we describe study design considerations for implementing LCI into interventional and observational research., Methods: Simulations were used to estimate the required sample size to detect a range of treatment effects for interventional studies (including cross-over trials) and to track lung disease progression in observational studies., Results: Using published treatment effects to inform the design of prospective studies can lead to inefficient study designs. Large improvements in LCI for a few individuals can skew results and can influence interpretations of treatment effects. Adjusting for baseline LCI can help to improve the efficiency of a study. Compared to the forced expiratory volume in 1 second (FEV 1 ), analysis using LCI as an endpoint requires as little as one third of the total sample size., Conclusions: Planning of prospective studies that include LCI as an endpoint need to consider baseline LCI and disease severity of the study population; whereas interpretation of results needs to consider whether a few individuals skew the overall treatment effect., (Copyright © 2022 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.)

Introduction: While antibiotic eradication therapy (AET) of early Pseudomonas aeruginosa infection is considered standard of care, its long-term effect on the subsequent course of cystic fibrosis (CF) lung disease remains unclear., Methods: CF patients who were P. aeruginosa-free for at least a year and had a minimum of 10 years of pulmonary function measurements were included. Subjects were categorized as Never if they never had P. aeruginosa isolated from a respiratory tract sample. Subjects changed to the Eradicated group if they had a P. aeruginosa infection, were treated with AET, and subsequently cleared their infection. Subjects changed to the Chronic group if AET did not clear their P. aeruginosa infection. The primary outcome was absolute FEV 1 decline over time, with age as the time variable. Mixed-effects linear regression models were used to account for the repeated lung function measurements over time within each patient., Results: 205 CF subjects (48% female) were included; the median (IQR) age at first infection was 9.6 (5.6, 14.6) years. The median (IQR) follow-up was 10.2 (5.7, 14.7) years for the Eradicated group, 8.8 (4.5, 14.9) years for the Chronic group and 2.8 (1.0, 5.7) years for the Never group was among those patients that had at least one P. aeruginosa infection over the study period, annual lung function decline of FEV 1 was significantly less (-1.11% predicted/year; 95% CI: -1.18, -1.04) in the Eradication group compared to the Chronic group (-1.57%; -1.64, -1.50) (p<0.001)., Conclusions: AET against P. aeruginosa improves lung function trajectory in CF patients., Competing Interests: Declaration of Competing Interest All authors have nothing to disclose. 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 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.)

Background: Antibiotics are often changed during treatment of pulmonary exacerbations (PEx) in people with cystic fibrosis (CF) who have a poor clinical response. We aimed to characterize the reasons CF providers change antibiotics and examined the effects of antibiotic changes on lung function recovery., Methods: This was a retrospective cohort study using the Toronto CF Database from 2009 to 2015 of adults and children with CF PEx treated with intravenous antibiotics. The co-primary outcome measure was absolute and relative change in forced expiratory lung volume in 1 s (FEV 1 ) at end of treatment and follow-up. Secondary outcome assessed the proportion of patients returning to > 90% or > 100% previous baseline FEV 1 ., Results: A total of 399 PEx were included of which 105 had antibiotic changes. Reasons for antibiotic changes included change in antibiotic route prior to discharge (26%), drug reactions (20%), poor FEV 1 response (25%), targeting additional microbes (16%) and lack of symptom improvement (13%). In our multivariable analysis, among non-responders (< 90% FEV 1 recovery to baseline or lack of symptom improvement at the interim time point), a change in antibiotics was not associated with any significant difference in absolute or relative FEV 1 at end of treatment or at follow-up. Antibiotic change in non-responders was not associated with improved return to 90% or 100% baseline FEV 1 at end of treatment or follow-up., Conclusions: Changing antibiotics during CF PEx treatment in those with poor clinical response was not associated with any improved FEV 1 response or return to baseline lung function., Competing Interests: Declaration of Competing Interest The authors have no conflicts of interest to disclose including no financial or personal relationships with people or organizations that could influence this study., (Copyright © 2022. Published by Elsevier B.V.)

Airway nitric oxide (NO) deficiency is a hallmark of cystic fibrosis (CF), but the reasons for the reduced NO production in CF airways are unclear. Interleukin (IL)-1 pathway activation plays a role in early CF lung disease and is also involved in the regulation of NO synthase activity. Treatment of CF patients with the CFTR-targeting drug ivacaftor, among other beneficial effects, results in an increase in airway NO levels. In this longitudinal observational trial, we show that ivacaftor therapy leads to a significant reduction in sputum IL-1β concentration but not in other IL-1- or Th17-associated cytokines. IL-1β concentrations were closely linked to improvement in pulmonary function, measures of NO metabolism in sputum and exhaled NO. These data therefore suggest a potential interaction between transepithelial chloride conductance, IL-1β and airway NO production., Competing Interests: Declaration of interests 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.)

Competing Interests: Declaration of Competing Interest Ms Jensen, Mr Seeto, Dr Stanojevic and Dr Ratjen report other from Vertex Pharmaceuticals and grants (#SHIP14K0) from the CF Foundation during the conduct of the study. Ms Saunders and Mr Short report other from Vertex Pharmaceuticals and ECFS CTN during the conduct of the study. Dr. Robinson reports other from Vertex Pharmaceuticals Ltd during the conduct of the study. Dr. Davies reports other from Algipharma AS, other from Bayer AG, other from Boehringer Ingelheim Pharma GmbH & Co. KG, other from Galapagos NV, other from ImevaX GmbH, other from Nivalis Therapeutics, Inc., other from ProQR Therapeutics III B.V., other from Proteostasis Therapeutics, INC., other from Raptor Pharmaceuticals, Inc, other from Vertex Pharmaceuticals (Europe) Limited, other from Enterprise, other from Novartis, other from Pulmocide, other from Flatley, other from Nivalis Therapeutics Inc., grants from CF Trust, other from Teva, outside the submitted work.

Aquagenic wrinkling of palms (AWP) in cystic fibrosis (CF) patients and common CFTR mutations is recognized as a frequent symptom of the disease. The long-term effect of CFTR targeting therapy on AWP has not been studied. AWP was monitored in 16 CF patients (8 children and 8 adults) before and for 6 months after initiation of ivacaftor therapy. Thirteen (81.3%) patients had at least mild and 8/16 (50%) moderate-to-severe AWP at baseline. AWP improved with ivacaftor therapy. This observation suggests that AWP is also common in individuals with CF and relatively rare mutations and is directly related to CFTR function., Competing Interests: Declaration of competing interest Felix Ratjen received research grants from Vertex Pharmaceuticals on the original ivacaftor study from which patients were recruited. There was no direct funding for this research. Melinda Solomon received consultation fees from Vertex Pharmaceuticals. Parts of this study were supported by investigator-initiated study grants from Vertex Pharmaceuticals to Tanja Gonska and Hartmut Grasemann. The remaining authors have nothing to disclose., (Copyright © 2022 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.)

Exercise intolerance is common in people with CF (pwCF), but not universal among all individuals. While associated with disease prognosis, exercise intolerance is not simply a reflection of the degree of lung disease. In people with severe CF, respiratory limitations may contribute more significantly to impaired exercise capacity than in those with mild-moderate CF. At all levels of disease severity, there are peripheral factors e.g., abnormal macro- and micro-vascular function that impair blood flow and reduce oxygen extraction, and mitochondrial defects that diminish metabolic efficiency. We discuss advances in understanding the central and peripheral mechanisms underlying exercise intolerance in pwCF. Exploring both the central and peripheral factors that contribute to exercise intolerance in CF can help inform the development of new therapeutic targets, as well as help define prognostic criteria., (Copyright © 2021. Published by Elsevier B.V.)

CFTR function is required for normal mucociliary clearance (MCC) and cough-assisted clearance (CC). Lumacaftor-ivacaftor is approved for use in people with cystic fibrosis (CF) carrying two copies of F508del-CFTR. In this observational study performed at four study sites, we characterized the effect of lumacaftor-ivacaftor on mucociliary and cough clearance and related this to other clinical and research endpoints after one month of treatment. Twenty-five adolescents and adults were enrolled. No effect on whole lung MCC was observed, but CC was significantly increased. Sweat chloride improved by 18 mEq/L in this group, indicating a modest restoration of CFTR activity, but no demonstrable change in FEV 1 or lung clearance index was observed. We speculate that the modest effect of lumacaftor-ivacaftor on CFTR function was insufficient to yield an improvement in MCC., (Copyright © 2021 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.)

Background: Riociguat is a first-in-class soluble guanylate cyclase stimulator for which preclinical data suggested improvements in cystic fibrosis transmembrane conductance regulator (CFTR) function., Methods: This international, multicenter, two-part, Phase II study of riociguat enrolled adults with cystic fibrosis (CF) homozygous for Phe508del CFTR. Part 1 was a 28-day, randomized, double-blind, placebo-controlled study in participants not receiving CFTR modulator therapy. Twenty-one participants were randomized 1:2 to placebo or oral riociguat (0.5 mg three times daily [tid] for 14 days, increased to 1.0 mg tid for the subsequent 14 days). The primary and secondary efficacy endpoints were change in sweat chloride concentration and percent predicted forced expiratory volume in 1 second (ppFEV 1 ), respectively, from baseline to Day 14 and Day 28 with riociguat compared with placebo., Results: Riociguat did not alter CFTR activity (change in sweat chloride) or lung function (change in ppFEV 1 ) at doses up to 1.0 mg tid after 28 days. The most common drug-related adverse event (AE) was headache occurring in three participants (21%); serious AEs occurred in one participant receiving riociguat (7%) and one participant receiving placebo (14%). This safety profile was consistent with the underlying disease and the known safety of riociguat for its approved indications., Conclusions: The Rio-CF study was terminated due to lack of efficacy and the changing landscape of CF therapeutic development. The current study⁠, within its limits of a small sample size, did not provide evidence that riociguat could be a valid treatment option for CF., Clinical Trial Registration Number: NCT02170025., Competing Interests: Declaration of Competing Interest N. Derichs received a speaker honorarium from Vertex Pharmaceuticals, Inc. for participation in a symposium, and served as a consultant for Vertex Pharmaceuticals, Inc. at educational activities and advisory boards. J.L. Taylor-Cousar reports grants paid to her institution from the Cystic Fibrosis Foundation; grants paid to her institution and consulting and speaking fees from Vertex Pharmaceuticals, Inc.; grants paid to her institution from Bayer; grants, consulting, and speaking fees from Celtaxys; grants paid to her institution and consulting fees from Proteostasis Therapeutics, Inc.; consulting fees from Santhera, 4DMT, AbbVie, and Polarean; and grants paid to her institution from Eloxx Pharmaceuticals. J.C. Davies reports grants from the CF Trust and other funding from Algipharma AS, Bayer AG, Boehringer Ingelheim Pharma GmbH & Co. KG, Galapagos NV, ImevaX GmbH, Nivalis Therapeutics, Inc., ProQR Therapeutics III B.V., Proteostasis Therapeutics, Inc., Raptor Pharmaceuticals, Inc., Vertex Pharmaceuticals, Inc., Enterprise, Novartis, Pulmocide, Flatley, Nivalis Therapeutics, Inc., and Teva. I. Fajac received speaker honoraria from Vertex Pharmaceuticals, Inc. for participation in symposia and served as a consultant for Novartis, Proteostasis Therapeutics, Inc., and Vertex Pharmaceuticals, Inc. E. Tullis reports grants paid to her institution from Vertex Pharmaceuticals, Inc., Proteostasis Therapeutics, Bayer AG, Boehringer Ingelheim, AbbVie, Celtaxis, Corbus, and Spyryx, and consultancy fees and honoraria from Vertex Pharmaceuticals, Proteostasis Therapeutics, Astra Zeneca and Horizon. D. Nazareth has nothing to disclose. D.G. Downey reports grants from Vertex Pharmaceuticals, Inc., Proteostasis Therapeutics, Inc., Gilead, and Chiesi; and honoraria or speaker fees from Vertex Pharmaceuticals, Inc., Proteostasis Therapeutics, Inc., and Chiesi. D. Rosenbluth has nothing to disclose. A. Malfroot has nothing to disclose. C. Saunders has nothing to disclose. R. Jensen has nothing to disclose. G.M. Solomon reports work on advisory boards for Bayer and Electromed. F. Vermeulen has nothing to disclose. A. Kaiser is an employee of Bayer AG. S. Willmann is an employee of Bayer AG. S. Saleh is an employee of Bayer AG. K. Droebner is an employee of Bayer AG. P. Sandner is an employee of Bayer AG. C.E. Bear has nothing to disclose. A. Hoffmann is an employee of Bayer AG. F. Ratjen reports other consultancy fees from Vertex Pharmaceuticals, Inc., Bayer, Talecris, CSL Behring, Roche, and Gilead; grants and consultancy from Novartis; and developed speaker bureau for Genentech outside the submitted work. S.M. Rowe reports grants and consulting fees from Arrowhead, Bayer, Celtaxsys, Galapagos/AbbVie, Novartis, Renovion, Synedgen/Synspira, andVertex Pharmaceuticals Inc.; consulting fees from Arcturus, and Cysteic Medicines; and grants from AstraZeneca, Eloxx, N30 Pharmaceuticals, PTC Therapeutics, Translate Bio, and Proteostasis Therapeutics, Inc., (Copyright © 2021. Published by Elsevier B.V.)

Background: Infant pulmonary function testing using the raised volume rapid thoracoabdominal compression (RVRTC) technique requires sedation and is time consuming. Many cystic fibrosis (CF) centers do not have access to equipment and the utility of routine testing remains to be determined. We aimed to assess whether RVRTC tests performed during infancy predict spirometry at early school age., Methods: The RVRTC-based forced expiratory flow measures in infants were compared to the first adequately performed spirometry at school age. All tests were carried out during routine clinic visits and expressed as age related z-scores; only test occasions where patients were considered stable were included in the analysis., Results: 47 patients had useable infant RVRTC as well as matching school age spirometry data. There was weak correlation between infant FEV 0.5 and early school age FEV 1 (R = 0.29, p = 0.05). Four infants had significantly low zFEV 0.5 (zFEV 0.5 < -1.96), of which one of those remained under that limit at childhood. Changes in spirometry between infancy and early childhood were negatively correlated to baseline FEV 0.5 (R = 0.61 p<0.001) reflecting that the change was driven by where individuals started off with. There was no difference in clinical characteristics between those improving, those with stable or deteriorating in lung function., Conclusion: Infant RVRTC measures were not predictive of pulmonary function in early school age, likely due to the high proportion of measures of forced expiratory flows within the normal range at both time points., Competing Interests: Declaration of Competing Interest Dr. Ratjen reports grants and personal fees from Vertex, Calithera, Proteostasis, TranslateBio, Genentech, Bayer and Boehringer Ingelheim, outside the submitted work., (Copyright © 2020 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.)

Background: Increased (abnormal) ventilation inhomogeneity in individuals with mild Cystic Fibrosis (CF) lung disease may become a treatable trait for small-molecule therapeutics improving Cystic Fibrosis Transmembrane Regulator (CFTR) function. The relationship between CFTR function and ventilation inhomogeneity is unknown. We aimed to identify and quantify increased ventilation inhomogeneity in relation to CFTR function., Methods: This was an international, multi-center, cross-sectional study. We collated data from individuals aged 3-25 years with minimal (CFTR-MF) or residual (CFTR-RF) function of a variety of CFTR genotypes and FEV 1 ≥ 70% predicted. We measured lung function using nitrogen multiple-breath washout and spirometry. We compared lung clearance index (LCI) and FEV 1 between individuals with CFTR-MF vs CFTR-RF using a mixed effects multi-variable linear regression model to account for study differences and a logistic model based on propensity-score matching to adjust for possible confounding., Results: We included 141 with CFTR-MF and 35 with CFTR-RF. LCI (> 1.96 z-score) was elevated in 71.6% individuals with CFTR-MF and in 40.0% with CFTR-RF. FEV 1 (< -1.96 z-score) was reduced in 11.3% individuals with CFTR-MF and in 5.7% with CFTR-RF. The mean difference (95% CI) of LCI and FEV 1 between CFTR-MF and CFTR-RF was 3.71 (1.63 to 5.79) and -0.40 (-0.83 to 0.02) z-score. The LCI differences were similar after adjustment for confounders and in individuals with normal FEV 1 ., Conclusion: Increased ventilation inhomogeneity is associated with less CFTR function. In individuals with mild CF lung disease, LCI can identify and quantify increased ventilation inhomogeneity, a candidate treatable trait., Competing Interests: Declaration of Competing Interest Dr. Bernasconi has no conflicts of interest to disclose. Dr. Kieninger reports grants from the Swiss Society of Cystic Fibrosis (CFCH), outside the submitted work. Mrs. Shaw has no conflicts of interest to disclose. Mrs. Kurz has nothing to disclose. Dr. Moeller has no conflicts of interest to disclose. Dr. Ratjen reports grants and personal fees from Vertex, personal fees from Boehringer/Ingelheim, Calithera, Proteostasis, and Translate Bio, outside the submitted work. Dr Rochat has nothing to disclose. Dr. Stanojevic has nothing to disclose. Dr. Singer reports personal fees from Vertex, personal fees from Novartis, grants from the Swiss Society of Cystic Fibrosis (CFCH), Lungenliga Bern, outside the submitted work., (Copyright © 2020. Published by Elsevier B.V.)

Highly effective CFTR modulator drug therapy is increasingly available to those with cystic fibrosis. Multiple observational research studies are now being conducted to better understand the impacts of this important therapeutic milestone on long-term outcomes, patient care needs, and future research priorities. PROMISE is a large, multi-disciplinary academic study focused on the broad impacts of starting elexacaftor/tezacaftor/ivacaftor in the US population age 6 years and older. The many areas of investigation and rationale for each are discussed by organ systems, along with recognition of remaining important questions that will not be addressed by this study alone. Knowledge gained through this and multiple complementary studies around the world will help to understand important health outcomes, clinical care priorities, and research needs for a large majority of people treated with these or similarly effective medications targeting the primary cellular impairment in cystic fibrosis., Competing Interests: Declaration of Competing Interest The primary author declares no conflict of interest with the content of this manuscript. Any potential conflicts of interest among all authors related to funding or other financial agreements will be collected and updated during the review process., (Copyright © 2021. Published by Elsevier B.V.)

Background: Therapies that target the underlying defect in Cystic Fibrosis (CF) will likely impact the future characteristics of the CF population and healthcare utilization. The objectives of this study were to estimate the potential impact of elexacaftor/tezacaftor/ivacaftor on morbidity and mortality, and the impact of delayed access., Method: A microsimulation transition model was applied to Canadian CF Registry data to forecast lung disease severity, pulmonary exacerbations, deaths and transplants to 2030 under three scenarios: 1) no availability of elexacaftor/tezacaftor/ivacaftor, 2) availability in 2021 ('early') or 3) availability in 2025 ('delayed'). Published Phase III data on treatment effects were used to estimate transition rates between disease severity states., Results: Under specific assumptions regarding disease state and treatment effect applied to the Canadian CF population it is projected that by 2030, early introduction of elexacaftor/tezacaftor/ivacaftor is expected to reduce the number of individuals with severe lung disease by 60% (95% CI 55.3; 63.9), increase the number of individuals with mild lung disease by 18% (95%CI 18.2; 19.0) and reduce the number of pulmonary exacerbations by 19% (95%CI 18.9; 19.5). Earlier introduction of elexacaftor/tezacaftor/ivacaftor could reduce deaths by 15% (95% 13.2; 18.4) and improve the median age of survival by 9.2 years (7.5; 10.8) over a 10-year period. The expected benefits of therapy are cumulative, therefore delayed access to elexacaftor/tezacaftor/ivacaftor will result in preventable health care utilization and deaths., Conclusions: Delayed access to elexacaftor/tezacaftor/ivacaftor will have a negative impact on lung health and survival in the CF population., Competing Interests: Declaration of Competing Interest ET reports grants, personal fees and nonfinancial support from Vertex Pharmaceuticals Inc., during the conduct of the study unrelated to this work. FR reports grants, personal fees and nonfinancial support from Vertex Pharmaceuticals Inc., during the conduct of the study unrelated to this work. AS reports personal fees from Cystic Fibrosis Canada in her role as Medical Director of the Canadian Cystic Fibrosis Registry; personal fees from Vertex Pharmaceuticals Inc. from educational programs supported by Vertex, specifically CF Annual, unrelated to this work. SS reports grant funding from Vertex Pharmaceuticals Inc. unrelated to this work., (Copyright © 2020 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.)

Background: Lancovutide activates a chloride channel (TMEM-16A) other than the cystic fibrosis (CF) transmembrane conductance regulator protein and could benefit CF patients., Methods: In this randomized, multi-center, double-blind, placebo-controlled, parallel-group trial 161 patients ≥12 years with a confirmed diagnosis of CF were randomized to either placebo (saline) or active drug in 3 different dosing schemes of 2.5mg inhaled lancovutide (once daily, every other day or twice a week) for eight weeks. The primary endpoint was the change in the forced expiratory volume in 1 second (FEV1) percent predicted. Secondary endpoints included further lung function parameters (FEV1 (absolute), functional vital capacity percent predicted, forced expiratory flow percent predicted, pulse oximetry), quality of life assessment, pulmonary exacerbations, hospitalization due to pulmonary exacerbations, time to first pulmonary exacerbation, duration of anti-inflammatory, mucolytic or antibiotic treatment, and safety., Results: There was no significant difference in the change in FEV1 percent predicted, quality of life, other lung function parameters, pulmonary exacerbations or requirement of additional treatment between groups. Overall, the inhalation of lancovutide was safe although a higher rate of adverse events, especially related to the respiratory system, occurred as compared to placebo., Conclusions: Lancovutide did not improve FEV1 percent predicted when compared to placebo (NCT00671736)., Competing Interests: Declaration of Competing Interest RW is founder and employee of AOP Orphan Pharmaceuticals AG. EE reports receiving consultancy fees from Vertex Pharmaceuticals, Chiesi Pharmaceuticals, Gilead Sciences, Vifor, and Insmed, and speaker's honoraria from Vertex Pharmaceuticals, Chiesi Pharmaceuticals, and Gilead Sciences. Dr. Ratjen reports grants and personal fees from Vertex, personal fees from Proteostasis, personal fees from Bayer, personal fees from TranslateBio, personal fees from Genentech, personal fees from Boehringer Ingelheim, personal fees from Calithera, outside the submitted work. All other authors report no relevant conflicts of interest regarding this work., (Copyright © 2020 The Author(s). Published by Elsevier B.V. All rights reserved.)

The PROSPECT study, a post-approval observational study in the U.S., showed no significant changes in lung function as measured by spirometry with clinical initiation of lumacaftor/ivacaftor. A sub-study within the PROSPECT study assessed the lung clearance index (LCI), as measured by multiple breath washout (MBW), a measure of lung function demonstrated to be sensitive among people with normal spirometry. Participants performed MBW prior to clinically initiating lumacaftor/ivacaftor therapy and for one year of follow-up. Similar to the whole PROSPECT study, this sub-study cohort (N = 49) had no significant absolute or relative changes in FEV 1 % predicted at any time point. LCI, however, decreased (improved) by 0.81 units or 5.3% (95% CI -9.7, -0.9%) at 1 month, 0.77 units or 5.9% at 3 months, 0.67 units or 5.9% at 6 months, and 0.55 units or 4.3% at 12 months. These results demonstrate the utility of the LCI in assessing treatment effects of relatively modest size in a heterogenous study population., Competing Interests: Declaration of Competing Interest MS has nothing to disclose. UK reports grants from Cystic Fibrosis Foundation, during the conduct of the study and outside the submitted work. JPC reports grants from Cystic Fibrosis Foundation, during the conduct of the study. SHD reports grants from Cystic Fibrosis Foundation, during the conduct of the study. SDS reports a grant from the Cystic Fibrosis Foundation that funds the work under consideration, and grants from the Cystic Fibrosis Foundation and National Institutes of Health funding activities outside the submitted work. SMR reports grants, contracts, and consulting services from Vertex Pharmaceuticals related to the conduct of clinical trials. FR reports grants and personal fees from Vertex, personal fees from Novartis, personal fees from Bayer, personal fees from Roche, personal fees from Genetech, outside the submitted work., (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: The lung clearance index (LCI), derived from the Multiple Breath Washout (MBW) test, is sensitive to treatment effects and compared with spirometry has higher feasibility in younger children and requires smaller sample sizes. As a result, the LCI has been endorsed by the European CF Society Clinical Trials Network for use as a primary outcome measure in CF clinical trials., Methods: Here we describe the implementation of standardised protocols for MBW test performance, data collection and quality control to successfully incorporate LCI as a novel outcome measure in a large multicentre phase III clinical trial., Results: Three regional (North America (NA), Europe (EU), Australia (AUS)) central over-reading centres (CORC) were established to provide a collaborative platform for MBW training, certification and quality control of data. One hundred and thirty-two naïve operators from 53 sites across NA, EU and AUS were successfully trained and certified to perform MBW testing.  Incorporation of a re-screening opportunity in the study protocol resulted a final screening feasibility rate of 93%, success remained high throughout the study resulting in an overall feasibility of MBW study data of 88.1% (1107/1257). MBW test acceptability was similar between geographical regions: NA (88%), EU (89%) and AUS (89%)., Conclusion: With this approach we achieved high MBW test feasibility and sustained collection of good quality data, demonstrating the utility of LCI as an effective primary endpoint in the first international phase III clinical trial to report LCI as the primary outcome., (Copyright © 2019. Published by Elsevier B.V.)

Background: Antimicrobial susceptibility testing (AST) is a cornerstone of infection management in cystic fibrosis. However, there is little evidence that AST predicts the clinical outcome of CF antimicrobial treatment. It has been suggested there is a need for careful consideration of current AST use by the CF community., Methods: We engaged a group of experts consisting of pulmonary (adult and pediatric) and infectious disease clinicians, microbiologists, and pharmacists representing a broad international experience. We conducted an iterative systematic survey (Delphi) to determine and quantify consensus regarding key questions facing CF clinicians in the use of respiratory culture results including what tests to order, when to obtain them, and how to act upon the results of the testing., Results: Consensus was reached for many questions but there was not universal agreement to the questions that were addressed. There were some differences with respect to cultures obtained for surveillance compared to when there is clinical worsening. Areas of general consensus include when and how respiratory cultures should be performed, what information should be reported, and when AST should be performed. A key finding is that clinical response to treatment is used to guide treatment decisions rather than AST results., Conclusions: Recommendations are presented regarding questions related to microbiology testing for patients with CF. We have also offered recommendations for priority research questions., Competing Interests: Declaration of Competing Interest None., (Copyright © 2019 European Cystic Fibrosis Society. All rights reserved.)

Introduction: The Cystic Fibrosis Questionnaire-Revised (CFQ-R) Respiratory score is a validated and widely used patient-reported outcome. This study aimed to establish changes in the score with acute respiratory events in preschool children with CF and to investigate its' relationship with physiological outcomes., Methods: The Parent CFQ-R, multiple breath washout test and spirometry were performed at six study visits over one year. The clinical status of participants, stable or symptomatic, was defined by the patient's physician. Linear regression and distribution-based statistical methods were used to examine the changes in the CFQ-R from the last stable visit and to investigate its relationship with physiological outcomes., Results: There were 272 stable and 115 symptomatic visits from 78 participants. The mean CFQ-R Respiratory score did not change between consecutive stable visits (-0.73, SD 20.4). The mean (SD) score deteriorated by 15.5 (20.7) points between stable and symptomatic visits and improved by 14.8 (20.1) points between symptomatic and stable follow-up visits. When a clinically important change is defined as 0.5SD change (10-points), the positive predictive value (PPV) was 45% and the negative predictive value (NPV) was 84%. For visits with a 10-point worsening in the CFQ-R Respiratory score and a 15% increase in LCI, the PPV was better (81%) than using either measure alone., Conclusion: The CFQ-R Respiratory score is responsive to acute respiratory events in preschool children with CF and its utility to monitor individual patients is improved when combined with LCI., Competing Interests: Conflict of Competing Interest None, (Copyright © 2020. Published by Elsevier B.V.)

In CF, pulmonary exacerbations (PEx) can lead to permanent loss in lung function and thus should be prevented. Previously, we identified a blood protein biosignature consisting of 6 proteins capable of predicting short-term PEx events in CF adults. In this study, we utilized blood samples from the placebo arm of a randomized controlled trial to assess whether this candidate protein biosignature was also capable of predicting short-term PEx events in CF children and adolescents. This pilot study provides preliminary evidence that blood inflammation can be monitored to predict short-term PEx risk in CF children and adolescents., (Copyright © 2019. Published by Elsevier B.V.)

Introduction: Cystic fibrosis-related diabetes (CFRD) is a common complication of cystic fibrosis (CF) directly linked to increased morbidity and mortality. Both the incidence of type I and type II diabetes has been shown to increase in the general population. In this study, we investigated the incidence and risk factors of CFRD in a paediatric CF population., Methods: Prospectively collected data from the Canadian CF Registry (CCFR) from 2000 to 2016 for patients ages 10 to 18 years was used to determine the incidence of CFRD. Risk factors for CFRD in the Canadian population were investigated using a nested case-control design. Conditional logistic regression analysis with a 4:1 control: case matching was used., Results: From 2000 to 2016, 2326 patients with CF aged between 10 through 18 years were included in the CCFR, during this time the overall incidence rate of CFRD was 2.1 cases per 100 patient-years (95% confidence interval 1.8 to 2.3). Incidence rates were stable in the Canadian cohort over three consecutive time periods 2000-2005, 2006-2010; 2011-2016. Worse lung function, female gender, history of allergic bronchopulmonary aspergillosis, Gastrostomy tube insertion and liver disease were statistically significant risk factors for CFRD., Conclusion: The incidence of CFRD in the Canadian paediatric population has been stable over time, in contrast to the rising rates of Type 1 and Type 2 diabetes in the general paediatric population. The risk factor for CFRD in this contemporary population were consistent with previous studies., (Copyright © 2019. Published by Elsevier B.V.)

Background: Balanced composition of a well-functioning pulmonary surfactant is crucial and essential for normal breathing. Here, we explored whether the composition of lipids recovered by broncho-alveolar lavage (BAL) in children with cystic fibrosis (CF) differ from children with protracted bacterial bronchitis (PBB) and controls. We wanted to differentiate, if alterations are primarily caused by the disease process or secondary due to an increased amount of cell-membrane lipids derived from inflammatory cells., Methods: Comprehensive lipidomics profiles of BAL fluid from children diagnosed with CF, PBB and controls were generated by electrospray ionization tandem mass spectrometry analysis. BAL cell differential and numbers were examined., Results: 55 children (37 patients with CF, 8 children with PBB and 10 controls) were included in this study. Results showed comparable total quantities of lipids in all groups. Phospholipids were the major lipid fraction and similar in all groups, whereas the fractions of cholesteryl esters were less and of free cholesterol were increased in children with CF. Among the phospholipids, patients with CF had higher proportion of the non-surfactant membrane-lipids in the classes phosphatidylethanolamine based plasmalogens (PE P), phosphatidylethanolmine (PE) and phosphatidylserine (PS), but a lower proportion of phosphatidylcholine (PC) compared to healthy controls. No such changes were identified in the BAL fluid of children diagnosed with PBB. No differences were observed for the surfactant lipids dipalmitoyl-phosphatidylcholin (PC 32:0) and phosphatidylglycerol (PG)., Conclusions: In CF patients with neutrophilic airway inflammation the lipid composition for surfactant phospholipid components were unchanged, whereas alteration in lipid profile were characteristic for those found in membranes of inflammatory cells. We suspect that the changes in CF were caused by the prolonged inflammation in contrast to a relatively short standing process in PBB., (Copyright © 2019 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.)

Background: The ventilation defect percent (VDP), measured from hyperpolarized (HP) 129 Xe magnetic resonance imaging (MRI), is sensitive to functional changes in cystic fibrosis (CF) lung disease. The purpose of this study was to measure and compare VDP from HP 129 Xe MRI acquired at two institutions in stable pediatric CF subjects with preserved lung function., Methods: This retrospective analysis included 26 participants from two institutions (18 CF, 8 healthy, age range 10-17). Pulmonary function tests, N 2 multiple breath washout (to measure lung clearance index, LCI), and HP 129 Xe MRI were performed. VDP measurements were compared between two trained analysts using mean-anchored linear binning. Correlations were investigated for VDP compared to the forced expiratory volume in one second (FEV 1 ) and LCI., Results: VDP measurements agreed for the two analysts with an intraclass correlation coefficient of 0.99. In the combined dataset, VDP measured by Analyst 1 was 5.96 ± 1.82% and 15.96 ± 6.76% for the healthy and CF groups, respectively (p = .0004). Analyst 2 showed similar differences between healthy and CF (p = .0003). VDP measured by either analyst was shown to correlate with FEV 1 (R 2  = 0.33, p = .003; and R 2  = 0.26, p = .009 for Analysts 1 and 2, respectively) and LCI (R 2  = 0.76, p < .0001; and R 2  = 0.77, p < .0001 for Analysts 1 and 2, respectively)., Conclusion: HP 129 Xe MRI provides a robust measurement of ventilation heterogeneity in stable pediatric CF subjects at two sites. Since measurements performed at two sites yielded similar VDP values with near-identical values between different analysts, implementation of the technique in multi-center trials in CF appears feasible., (Copyright © 2019. Published by Elsevier B.V.)

Objective: Antibiotic eradication treatment is the standard-of-care for cystic fibrosis (CF) patients with early Pseudomonas aeruginosa (Pa)-infection; however, evidence from placebo-controlled trials is limited., Methods: This double-blind, placebo-controlled trial randomised CF patients <7 years (N = 51) with early Pa-infection to tobramycin inhalation solution (TOBI 300 mg) or placebo (twice daily) for 28 days with an optional cross-over on Day 35. Primary endpoint was proportion of patients having throat swabs/sputum free of Pa on Day 29., Results: On Day 29, 84.6% patients in the TOBI versus 24.0% in the placebo group were Pa-free (p < 0.001). At the end of the cross-over period, 76.0% patients receiving TOBI in the initial 28 days were Pa-free compared to 47.8% receiving placebo initially. Adverse events were consistent with the TOBI safety profile with no differences between TOBI and placebo., Conclusion: TOBI was effective in eradicating early Pa-infection with a favourable safety profile in young CF patients., Trial Registration Number: NCT01082367., (Copyright © 2018 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.)

Background: Therapies targeting certain CFTR mutants have been approved, yet variations in clinical response highlight the need for in-vitro and genetic tools that predict patient-specific clinical outcomes. Toward this goal, the CF Canada-Sick Kids Program in Individual CF Therapy (CFIT) is generating a "first of its kind", comprehensive resource containing patient-specific cell cultures and data from 100 CF individuals that will enable modeling of therapeutic responses., Methods: The CFIT program is generating: 1) nasal cells from drug naïve patients suitable for culture and the study of drug responses in vitro, 2) matched gene expression data obtained by sequencing the RNA from the primary nasal tissue, 3) whole genome sequencing of blood derived DNA from each of the 100 participants, 4) induced pluripotent stem cells (iPSCs) generated from each participant's blood sample, 5) CRISPR-edited isogenic control iPSC lines and 6) prospective clinical data from patients treated with CF modulators., Results: To date, we have recruited 57 of 100 individuals to CFIT, most of whom are homozygous for F508del (to assess in-vitro: in-vivo correlations with respect to ORKAMBI response) or heterozygous for F508del and a minimal function mutation. In addition, several donors are homozygous for rare nonsense and missense mutations. Nasal epithelial cell cultures and matched iPSC lines are available for many of these donors., Conclusions: This accessible resource will enable development of tools that predict individual outcomes to current and emerging modulators targeting F508del-CFTR and facilitate therapy discovery for rare CF causing mutations., (Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Infection with Pseudomonas aeruginosa (Pa) with a chronic phenotype is associated with antibiotic eradication therapy (AET) failure. Our objective was to determine whether higher levels of Pa (detected using qPCR) prior to culture positivity were associated with AET failure in pediatric CF patients., Methods: Pa-specific qPCR was performed on stored sputa prior to culture positivity in pediatric CF patients with new-onset culture-positive Pa infections undergoing AET with a 28-day course of tobramycin-inhaled solution (TIS). DNA concentrations were compared in patients in whom AET was successful (Eradicated) to those with persistently positive sputum cultures (Persistent)., Results: Forty-seven patients were included. AET was successful in 32 cases (68%), but failed in 15 cases (32%). Median sputum Pa-specific DNA concentration preceding the positive sputum culture was 2.2 × 10 -6  μg/mL in Eradicated cases compared to 3 × 10 -5  μg/mL in Persistent cases (p = 0.14). There was no significant difference in DNA concentration in the last sputum sample prior to culture positivity, nor in maximal DNA values. There was also no difference in sputum Pa DNA concentrations in patients who had a mucoid (compared to non-mucoid) Pa infection., Conclusions: Pediatric CF patients with new-onset Pa infections have detectable Pa-specific DNA in the year preceding a positive culture, however, there is no significant difference in Pa DNA concentrations between patients in whom AET is successful compared to those in whom it fails. Therefore, early molecular detection of Pa may not lead to improved eradication success rates., (Crown Copyright © 2018. Published by Elsevier B.V. All rights reserved.)

Background: Different interfaces (mouthpiece/nose clip vs. facemask) are used during multiple breath washout (MBW) tests in young children., Methods: We investigated the effect of interface choice and breathing modalities on MBW outcomes in healthy adults and preschool children., Results: In adults (n = 26) facemask breathing significantly increased LCI, compared to mouthpiece use (mean difference (95% CI) 0.4 (0.2; 0.6)), with results generalizable across sites and different equipment. Exclusively nasal breathing within the facemask increased LCI, as compared to oral breathing. In preschoolers (2-6 years, n = 46), no significant inter-test difference was observed across interfaces for LCI or FRC. Feasibility and breathing stability were significantly greater with facemask (incorporating dead space volume minimization), vs. mouthpiece. This was more pronounced in subjects <4 years of age., Conclusion: Both nasal vs. oral breathing and mouthpiece vs. facemask affect LCI measurements in adults. This effect was minimal in preschool children, where switching between interfaces is most likely to occur., (Copyright © 2018 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.)

Developments in managing CF continue to drive dramatic improvements in survival. As newborn screening rolls-out across Europe, CF centres are increasingly caring for cohorts of patients who have minimal lung disease on diagnosis. With the introduction of mutation-specific therapies and the prospect of truly personalised medicine, patients have the potential to enjoy good quality of life in adulthood with ever-increasing life expectancy. The landmark Standards of Care published in 2005 set out what high quality CF care is and how it can be delivered throughout Europe. This underwent a fundamental re-write in 2014, resulting in three documents; center framework, quality management and best practice guidelines. This document is a revision of the latter, updating standards for best practice in key aspects of CF care, in the context of a fast-moving and dynamic field. In continuing to give a broad overview of the standards expected for newborn screening, diagnosis, preventative treatment of lung disease, nutrition, complications, transplant/end of life care and psychological support, this consensus on best practice is expected to prove useful to clinical teams both in countries where CF care is developing and those with established CF centres. The document is an ECFS product and endorsed by the CF Network in ERN LUNG and CF Europe., (Copyright © 2018 The Author(s). Published by Elsevier B.V. All rights reserved.)

There is no effective chronic suppressive therapy Burkholderia cepacia complex infection in cystic fibrosis (CF) patients. This was a pilot, open-label clinical trial of tobramycin inhalation powder (TIP) delivered via Podhaler twice daily for 28days in adults and children with CF and chronic B. cepacia complex infection in Toronto, Canada. A total of 10 subjects (4 pediatric, 6 adult patients) were treated. There was a mean drop of 1.4 log (CFU/ml) in sputum bacterial density (p=0.01) and sputum IL-8 levels decreased significantly after 28days of TIP (p=0.04). The mean relative change in FEV 1 (L) from Day 0 to Day 28 of TIP administration was a 4.6% increase but this was not statistically significant. The majority of patients (70%) had no or mild adverse events., (Copyright © 2017 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.)

Introduction: Antibiotic eradication therapy (AET) for initial Pseudomonas aeruginosa (Pa) infection is standard of care in children with cystic fibrosis (CF), but information is limited on treatment for patients who fail initial AET. The aim of this study was to evaluate the effectiveness of a multi-step protocol for AET for new-onset Pa infections in children with CF., Methods: A three-step AET protocol which includes: (step 1) 28days of tobramycin inhalation solution (TIS) for new-onset Pa infection; (step 2) a second course of TIS for patients with positive respiratory tract culture after step 1; (step 3) 14days of intravenous antibiotics followed by 28days of TIS for patients with a subsequent positive culture. We conducted a retrospective review of all pediatric CF patients who underwent the eradication protocol between January 2010 and December 2015. The success rate of each step and of the overall protocol was recorded., Results: During the study period, 128 patients had a total of 213 new-onset Pa infections. Of 195 asymptomatic episodes, 150 (76.9%, 95% CI 70.4; 82.6) cleared after step 1 and 12 cleared after step 2 (33.3% (95% CI 18.6; 50.9) stepwise success rate and 87.1% (95% CI 77.1; 88.1) cumulative success rate). Intravenous antibiotics followed by 28days of TIS were administered in 24 episodes; this was successful in 10 episodes (41.7%; 95% CI 22.1; 63.4). The regimen in asymptomatic patients failed in fourteen episodes (7.5%; 95% CI 4.2; 12.3) then considered chronically infected with Pa. Overall, the cumulative success rate of the asymptomatic arm was 88.2% (95% CI 82.8; 92.4)., Conclusion: The first step of the AET protocol led to the greatest eradication success. Subsequent eradication attempts have a success rate below 50%. Prospective studies of eradication protocols for this population are needed to determine the most effective treatment strategy., (Copyright © 2017 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.)

Background: Previous studies have shown an association between higher Stenotrophomonas maltophilia antibody levels and decreased lung function in patients with cystic fibrosis (CF). The purpose of this study was to assess the serologic response to S. maltophilia over time and to determine whether changes in antibody levels could predict clinical outcomes., Methods: Changes in S. maltophilia antibody levels in adult and pediatric patients with CF from 2008 to 2014 were assessed between groups of infection patterns. Regression models accounting for repeated measures were used to assess whether antibody levels could predict subsequent S. maltophilia microbiological status, and whether they are associated with lung function and subsequent pulmonary exacerbation., Results: A total of 409 S. maltophilia antibody samples from 135 CF patients showed that antibody levels did not change significantly between study visits, regardless of infection group. Higher antibody levels were independently associated with future culture positivity (OR 1.62; 95% CI 1.09, 2.41; p=0.02). While higher antibody levels were not independently associated with decreases in FEV 1 % predicted, they were associated with an increased hazard ratio for subsequent pulmonary exacerbation (HR 1.3; 95% CI 1.1, 1.6; p<0.001)., Conclusions: S. maltophilia antibody levels may be helpful to identify individuals at risk of exacerbation who may benefit from earlier antimicrobial treatment., (Copyright © 2016 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.)

The cystic fibrosis (CF) drug development pipeline promises many exciting new treatments for patients with CF, all which will require clinical studies to prove their benefits on CF lung disease. Historically many pivotal CF studies have used the Forced Expiratory Volume in 1s (FEV1) as the primary outcome measure, and after demonstrating significant improvements in the treatment group relative to placebo have led to regulatory approval of therapies for routine clinical care. Widespread implementation of these therapies has subsequently led to significant improvements in outcomes for patients with CF. While preserving lung function has obvious benefits to CF patients, as more patients maintain FEV1 in the normal range, it has become increasingly difficult to conduct clinical trials using FEV1 as the primary outcome measure. With multiple concurrent trials competing to enroll from the same pool of patients, there is a need for novel approaches to study end points as well as new physiological outcomes for CF therapeutic trials. In this review we will discuss some of the limitations of FEV1 in the current era of CF care, describe alternative physiological endpoints and outline areas for further research., (Copyright © 2016 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.)

Background: The Infant Study of Inhaled Saline (ISIS) in CF was the first multicenter clinical trial to utilize infant pulmonary function tests (iPFTs) as an endpoint., Methods: Secondary analysis of ISIS data was conducted in order to assess feasibility of iPFT measures and their associations with respiratory symptoms. Standard deviations were calculated to aid in power calculations for future clinical trials., Results: Seventy-three participants enrolled, 70 returned for the final visit; 62 (89%) and 45 (64%) had acceptable paired functional residual capacity (FRC) and raised volume measurements, respectively. Mean baseline FEV0.5, FEF75 and FRC z-scores were 0.3 (SD: 1.2), -0.2 (SD: 2.0), and 1.8 (SD: 2.0)., Conclusions: iPFTs are not appropriate primary endpoints for multicenter clinical trials due to challenges of obtaining acceptable data and near-normal average raised volume measurements. Raised volume measures have potential to serve as secondary endpoints in future clinical CF trials., (Copyright © 2015 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.)

Background: Pulmonary exacerbations frequently lead to an irrevocable loss of lung function in cystic fibrosis (CF) patients. Although extended antibiotic duration has not been shown to be associated with improved outcomes in CF overall, it is not known whether there is a subset of patients who may benefit from longer treatment courses., Methods: This was a retrospective cohort study, using the Toronto CF Database from 1997 to 2012, of CF individuals with pulmonary exacerbations requiring intravenous antibiotic treatment. We investigated factors associated with improvement in forced expiratory volume in 1 second (FEV1) in patients treated with ≤14 days and >14 days of antibiotic treatment., Results: A total of 538 pulmonary exacerbations in 253 patients were used for these analysis; 39% of these exacerbations fully recovered lung function at follow-up. Exacerbations were more frequently treated with >14 days of antibiotics in older patients with lower FEV1 at exacerbation and higher rates of B. cepacia complex infections. Subjects with exacerbations treated for >14 days had a significantly greater increase in FEV1 from day 14 to follow up compared to those with ≤14 days (p<0.001). On multivariable analysis, smaller changes from days 0 to 14 of antibiotics and treatment duration>14 days were associated with greater increases in FEV1 from day 14 to follow-up. In those who received >14 days of antibiotic therapy, smaller improvements in FEV1 change from day 0 to 14 and younger age at exacerbation were significantly associated with a greater FEV1 response from day 14 to end of treatment. Antibiotic treatment >14 days was not associated with longer time to subsequent exacerbation., Conclusions: This study highlights that in the treatment of pulmonary exacerbations, maximum lung function is not achieved within 14 days in all patients, and that there is continued improvement beyond this period., (Copyright © 2015 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.)