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Background: Highly effective CFTR modulator therapy (HEMT) has improved the health of many people with cystic fibrosis (pwCF), offering opportunities to discontinue burdensome therapies. SIMPLIFY included randomized, controlled trials that confirmed non-inferiority of discontinuing versus continuing dornase alfa (DA) or hypertonic saline (HS) for 6 weeks in pwCF on HEMT. In this study of post-trial treatment use by SIMPLIFY participants, we hypothesized that randomization to discontinue DA or HS during the trial would be associated with a higher likelihood of non-use of each medication during follow-up., Methods: We electronically surveyed SIMPLIFY participants every 4 weeks for 24 weeks after trial completion but before the main trial results were publicly disclosed. We asked them how often they used medications during the previous week. We estimated covariate-adjusted odds ratios (ORs) of DA or HS non-use by logistic regression with generalized estimating equations., Results: After exclusions mostly due to lack of any surveys, 472 participants were included in the analysis population, 181 from the HS trial and 291 from the DA trial. Approximately half of the analysis population completed all six surveys. At every month of follow-up in both trials, the percentage of individuals reporting non-use of DA or HS during the previous week was greater among those randomized to discontinue therapy. Among participants with responses at 24 weeks, 30/122 (24.6 %) in the HS trial and 79/222 (35.6 %) in the DA trial reported non-use of the respective study medication. After adjusting for covariates, participants randomized to discontinue DA were 8.7-times (95 % CI: 4.3-17.7) more likely to not use DA during follow-up than those randomized to continue DA, and participants randomized to discontinue HS were 5.2-times (95 % CI: 2.1-12.8) more likely to not use HS during follow-up compared to those randomized to continue., Conclusions: In healthy pwCF on ETI, randomization to discontinue DA or HS during SIMPLIFY was associated with greater odds of not using each medication after the trial compared to randomization to continue. These findings suggest that participation in a treatment discontinuation trial can influence participants' post-trial treatment decisions. This possibility may be relevant during discussions about research participation and clinical care., Competing Interests: Declaration of competing interest AHG was supported by a grant from the Cystic Fibrosis Foundation (SIMPLIFY-GIFFOR20K0-CI). KR was supported by a grant from the Cystic Fibrosis Foundation (RIEKER15PE0). NM-H was supported by a grant from the Cystic Fibrosis Foundation (HAMBLE20K0). DPN was supported by a grant from the Cystic Fibrosis Foundation (NICHOL20K0). KO-D, MK, BPO, GJO, SLM, JPC, and GSS have no financial conflict of interest to disclose related to this study., (Copyright © 2024 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.)

Background: Minimal clinically important difference (MCID) is important to establish as a meaningful outcome in research when using patient reported outcome measures (PROMs). We determined the MCID using the distribution-based approach for three measurements used as part of the GALAXY study, which is an observational prospective study on gastrointestinal (GI) symptoms in cystic fibrosis (CF)., Methods: Four hundred and two persons with cystic fibrosis (PwCF) participated in the GALAXY study, all with baseline values available for all questionnaires. Mean age was 20.9 years (2.1- 61.1) with 75 females and 94 males under the age of 18 (42.04 %) and 118 females and 115 males aged 18 or older (57.99 %). MCID was measured for Patient Assessment of Constipation Symptoms (PAC-SYM), Patient Assessment of Upper Gastrointestinal Symptoms (PAGI-SYM), Patient Assessment of Constipation-Quality of Life (PAC-QOL) and their subscales. Two distribution-based approaches, defined as multiplications of the standard deviation (SD) or standard error of the mean (SEM), were used to approximate the MCID., Results: The two distribution-based approaches for determining the MCID estimates produced comparable results in trends in MCIDs across the subscales and total scores. In general, MCID estimates of subscales for all three measurements were higher than their total score MCIDs. The one-half SD- and SEM-based MCID estimates for total scores of each questionnaire are as follows: PAC-SYM: 0.26 and 0.14; PAGI-SYM: 0.32 and 0.15; PAC-QOL: 0.27 and 0.18, respectively., Conclusion: This paper establishes initial MCIDs estimated by the distribution-based approach for the PAC-SYM, PAGI-SYM and PAC-QOL that can now be used to evaluate interventional studies that may impact gastrointestinal symptoms in PwCF., Competing Interests: Declaration of competing interest Dr. Meghana Sathe has received research support from Anagram Therapeutics, Inc and the Cystic Fibrosis Foundation. Dr. Sarah Jane Schwarzenberg consults with Abbvie, Renexxion, and UpToDate. Dr. Baha Moshiree has the following COI to report: She is a consultant for Salix Pharmaceuticals, Ardelyx, and Ironwood. She is on advisory boards for AbbVie, Takeda and Salix and has grant support from Restalsis, ATMO, CF Foundation and Medtronic. She has served as speaker for Ardelyx, Ironwood, Nestle Foundation and QOL Medical. She also has two patents through University of Miami and Wake Forest Medical University pertaining to small bowel capsule (Gut capsule) and blue muffin stool transit test. Dr. A Jay Freeman serves as a consultant for AbbVie and Takeda. He has received research support from the CFF, NIH, Allergan and Travere Therapeutics., (Copyright © 2024. Published by Elsevier B.V.)

Clinical trials often demonstrate treatment efficacy through change in forced expiratory volume in one second (FEV 1 ), comparing single FEV 1 measurements from post- versus pre-treatment timepoints. Day-to-day variation in measured FEV 1 is common for reasons such as diurnal variation and intermittent health changes, relative to a stable, monthly average. This variation can alter estimation of associations between change in FEV 1 and baseline in predictable ways, through a phenomenon called regression to the mean. We quantify and explain day-to-day variation in percent-predicted FEV 1 (ppFEV 1 ) from 4 previous trials, and we present a statistical, data-driven explanation for potential bias in ceiling and floor effects due to commonly observed amounts of variation. We recommend accounting for variation when assessing associations between baseline value and change in CF outcomes in single-arm trials, and we consider possible impact of variation on conventional standards for study eligibility., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Related to other projects, CHG has received consultancy, honoraria and/or travel fees from Enterprise Therapeutics, Gilead Sciences, and Vertex Pharmaceuticals. LJC, EAC, EG, ASM, AP, MR, CST report only CFF and/or NIH grants related to the work., (Copyright © 2024. Published by Elsevier B.V.)

The COVID-19 pandemic necessitated a rapid shift in clinical research to perform virtual visits and remote endpoint assessments, providing a key opportunity to optimize the use of remote endpoints for clinical trials in cystic fibrosis. The use of remote endpoints could allow more diverse participation in clinical trials while minimizing participant burden but must be robustly evaluated to ensure adequate performance and feasibility. In response, the Cystic Fibrosis Foundation convened the Remote Endpoint Task Force (Supplemental Table 1), a multidisciplinary group of CF researchers with remote endpoint expertise and community members tasked to better understand the current and future use of remote endpoints for clinical research. Here, we describe the current use of remote endpoints in CF clinical research, address key unanswered questions regarding their use and feasibility, and discuss the next steps to determine clinical trial readiness., Competing Interests: Declaration of competing interest Related to this work, MEJ reports employment by the Cystic Fibrosis Foundation (CFF). Unrelated to this work the authors report the following: DB reports consulting fees and stocks from Anagram Therapeutics Scientific Advisory Group and is a member of the Board of Directors for Anagram Therapeutics Scientific Advisory Group. CE reports honoraria for teaching presentations from Vertex and Chiesi. CHG reports grant funding from NIH NIDDK and NCRR, CFF, FDA Orphan Prod. Div. He received consulting fees from Enterprise Therapeutics and honoraria from Gilead and Vertex. He has received travel support from Vertex Pharmaceuticals and Enterprise Therapeutics. He participates on the DSMB for Novartis. He is a deputy editor for Annals of the ATS. He has stock in Air Therapeutics. GH reports grant funding from NIH NHLBI and CFF and support from CFCanada for travel. JEH reports grant funding from CFF and NIH, travel support from CF Canada, consulting fees from Vertex Pharmaceuticals and participation on an advisory board for Vertex Pharmaceuticals. DP reports grant funding from the CFF and consulting fees from Renexion Pharma. MSP reports grant funding from Dexcom Inc, CFF and Vertex Pharmaceuticals. She also reports consulting fees from Anagram Therapeutics and honoraria from Vertex Pharmaceuticals and TD Cowan. She is a member of the CFF DSMB and an associate editor for Endocrine Practice: Journal of the American Association of Clinical Endocrinologists. KAR reports grant funding from the CFF. MS reports grant funding from the CFF and Anagram Therapeutics. She has received consulting fees from Nestle International and Alcresta Therapeutics. She has received travel support from the CFF and serves on the CFF DSMB and reports a leadership role in the CFF. JS reports being a member of the CFF DSMB and advisory boards. ST reports honoraria from Vertex Pharmaceuticals. ETZ reports grant funding from CFF, NIH NHLBI, Vertex Pharmaceuticals. She has received consulting fees from CFF and Vertex Phamaceuticals and honoraria from the CFF and Asosciation for Diagnostic and Laboratory Medicine. She has received travel support from Vertex Pharmaceuticals, CFF and European Cystic Fibrosis Society. She has participated on advisory boards for CFF, CFF Therapeutics Development Network and Vertex Pharmaceuticals. MB, NL, KP and MR have no conflicts to report., (Copyright © 2024. Published by Elsevier B.V.)

Background: We undertook a human-centered design approach to design the OUTREACH study of home spirometry as a CF clinical trial endpoint. We conducted a qualitative needs assessment to elicit the perspectives of people with CF (PwCF) and research coordinators (RCs) about home spirometry in the research setting and co-produced written and video home spirometry instructions in partnership with representatives from these stakeholder groups., Methods: We conducted 7 focus groups of PwCF (N = 27), caregivers of children with CF (N = 6), or RCs (N = 24) to elicit current experiences, barriers and facilitators of home spirometry across 6 target areas, followed by discussion and prioritization. The co-production team, composed of 3 PwCF, 3 RCs and study team members created written and video training materials., Results: While most PwCF and caregivers found home spirometry convenient, many experienced technical barriers, reported a "learning curve", and expressed uncertainty about the quality and reliability of measurements. Major barriers identified by RCs included tailoring participant training to individual needs, scheduling remote coaching, and performing effective coaching remotely. Participants offered age-specific recommendations in key domains: training materials and procedures, remote coaching, monitoring progress and maintaining engagement. Co-produced training materials included handouts and videos on how to perform spirometry, and troubleshooting, cleaning, and maintaining home spirometers., Conclusions: The OUTREACH design was improved by incorporating results of the needs assessment. The home spirometry training materials are freely available for public use. We hope our results and materials can help to inform the design and success of remote clinical trials of the future., Competing Interests: Declaration of competing interest All authors declare that they have no conflict of interest, (Copyright © 2024 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.)

Background: Relieving gastrointestinal symptoms is a research priority in cystic fibrosis. Emerging evidence highlights effects of cystic fibrosis transmembrane conductance regulator (CFTR) modulators on gastrointestinal function, including pancreatic sufficiency. This study explores ivacaftor licensing and treatment on recorded pancreatic enzyme replacement therapy (PERT) prescription in the US and UK CF registries., Methods: Retrospective longitudinal registry study of recorded pancreatic PERT use between 2008 and 2017. Interrupted time series analysis in propensity-matched cohorts estimated annual change and step change according to ivacaftor eligibility before and after licensing year, 2012. Generalised estimating equations assessed adjusted risk of PERT use in individuals treated with ivacaftor after 2012 compared to untreated individuals., Results: In the US CF registry, the difference in annual change in prevalence of PERT use post-2012 between eligible cases and ineligible controls was -5.0 per 1000 people/year (95 %CI -7.6; -2.3, p = 0.001). The step change and annual change in prevalence of PERT use in eligible cases was not significantly different to controls in the UK CF registry. Relative to the relationship in 2013, ivacaftor treatment in the US CF registry was associated with a lower adjusted risk ratio of PERT use compared to untreated individuals by 2016 (0.97, 95 %CI 0.96; 0.99), which was not observed in the UK CF registry., Conclusions: Licensing of ivacaftor was followed by a lower prevalence of PERT use in the eligible US population compared to pre-licensing period, as well as lower risk of PERT use in those who received treatment. Inconsistencies in US and UK CF registries were observed., Competing Interests: Declaration of competing interest A.R. Smyth has research grants (paid to the University of Nottingham) from Vertex Pharmaceuticals and payment for an advisory board (paid to the University of Nottingham) from Viatris Pharmaceuticals, all outside the current work. A.R. Smyth has patents issued (Camara M, Williams P, Barrett D, Halliday N, Knox A, Smyth A, Fogarty A, Barr H, Forrester D. Alkyl quinolones as biomarkers of Pseudomonas aeruginosa infection and uses thereof. US2016131648-A1; https://pubchem.ncbi.nlm.nih.gov/patent/US-2016131648-A1 Outside the current work, A.R. Smyth reports participation on a Data Safety Monitoring Board for the North American Cystic Fibrosis Foundation Therapeutic Development Network., (Copyright © 2024. Published by Elsevier B.V.)

Introduction: People with cystic fibrosis (PwCF) experience frequent symptoms associated with chronic lung disease. A complication of CF is a pulmonary exacerbation (PEx), which is often preceded by an increase in symptoms and a decline in lung function. A symptom cluster is when two or more symptoms co-occur and are related; symptom clusters have contributed meaningful knowledge in other diseases. The purpose of this study is to discover symptom clustering patterns in PwCF during a PEx to illuminate symptom phenotypes and assess differences in recovery from PExs., Methods: This study was a secondary, longitudinal analysis (N = 72). Participants at least 10 years of age and being treated with intravenous antibiotics for a CF PEx were enrolled in the United States. Symptoms were collected on treatment days 1-21 using the CF Respiratory Symptom Diary (CFRSD)-Chronic Respiratory Symptom Score (CRISS). K-means clustering was computed on day 1 symptom data to detect clustering patterns. Linear regression and multi-level growth models were performed., Results: Symptoms significantly clustered based on severity: low symptom (LS)-phenotype (n = 42), high symptom (HS)-phenotype (n = 30). HS-phenotype had worse symptoms and CRISS scores (p< 0.01) than LS-phenotype. HS-phenotype was associated with spending 5 more nights in the hospital annually (p< 0.01) than LS-phenotype. HS-phenotype had worse symptoms over 21 days than LS-phenotype (p< 0.0001)., Conclusion: Symptoms significantly cluster on day 1 of a CF-PEx. PwCF with HS-phenotype spend more nights in the hospital and are less likely to experience the same resolution in symptoms by the end of PEx treatment than LS-phenotype., Competing Interests: Declaration of competing interest Authors Eliana R. Gill, Christopher Dill, Christopher H. Goss, Scott D. Sagel, Michelle L. Wright, Sharon D. Horner, and Julie A. Zuñiga have no conflicts of interest to report., (Copyright © 2024. Published by Elsevier B.V.)

Background: Ivacaftor (IVA) has been shown to be safe and efficacious in children aged ≥4 months with cystic fibrosis (CF) and CFTR gating variants. We evaluated safety, pharmacokinetics (PK), and efficacy of IVA in a small cohort of infants aged 1 to <4 months with CF., Methods: In this phase 3, open-label study, infants 1 to <4 months with CF and an IVA-responsive CFTR variant received an initial low dose of IVA based on age and weight. Because IVA is a sensitive CYP3A substrate and CYP3A maturation is uncertain in infants, doses were adjusted at day 15 to better match median adult exposures based on individual PK measurements taken on day 4. Primary endpoints were safety and PK measurements., Results: Seven infants (residual function CFTR variants [n=5]; minimal function CFTR variants [n=2]) received ≥1 dose of IVA. Six infants had doses adjusted at day 15 and one infant did not require dose adjustment; subsequent PK analyses showed mean trough concentrations for IVA and metabolites were within range of prior clinical experience. Four infants (57.1%) had adverse events (AEs); no serious AEs were noted. One infant discontinued study drug due to a non-serious AE of elevated alanine aminotransferase >8x the upper limit of normal. Mean sweat chloride concentration decreased (-40.3 mmol/L [SD: 29.2]) through week 24. Improvements in biomarkers of pancreatic function and intestinal inflammation, as well as growth parameters, were observed., Conclusions: In this small, open-label study, IVA dosing in infants achieved exposures previously shown to be safe and efficacious. Because PK was predictable, a dosing regimen based on age and weight is proposed. IVA was generally safe and well tolerated, and led to improvements in CFTR function, markers of pancreatic function and intestinal inflammation, and growth parameters, supporting use in infants as young as 1 month of age., Competing Interests: Declaration of competing interest MR has received research grant funding and an advisory board role for Vertex Pharmaceuticals Incorporated for which her institution received payment. AS has received grants/contracts as a principal investigator from Vertex Pharmaceuticals Incorporated. SAM has received compensation to institution as principal investigator and advisory board consulting fees from Vertex Pharmaceuticals Incorporated. PM has received compensation to his institution as co-investigator, advisory board participation, and honoraria for speaker events from Vertex Pharmaceuticals Incorporated. JD has received payment for clinical trial leadership, advisory board participation, and speaker events from Vertex Pharmaceuticals Incorporated. MH, ML, JL, and VR-R are employees of Vertex Pharmaceuticals Incorporated and may own stock or stock options., (Copyright © 2024. Published by Elsevier B.V.)

Many people with CF (pwCF) desire a reduction in inhaled treatment burden after initiation of elexacaftor/tezacaftor/ivacaftor. The randomized, open-label SIMPLIFY study showed that discontinuing hypertonic saline (HS) or dornase alfa (DA) was non-inferior to continuation of each treatment with respect to change in lung function over a 6-week period. In this SIMPLIFY substudy, we used gamma scintigraphy to determine whether discontinuation of either HS or DA was associated with deterioration in the rate of in vivo mucociliary clearance (MCC) in participants ≥12 years of age. While no significant differences in MCC endpoints were associated with HS discontinuation, significant improvement in whole and peripheral lung MCC was observed after discontinuing DA. These results suggest that pwCF on ETI with mild lung disease do not experience a subclinical deterioration in MCC that could later impact health outcomes after discontinuing HS, and in fact may benefit from improved MCC after stopping DA treatment., Competing Interests: Declaration of competing interest Unrelated to the submitted work, SHD reports research funding from Chiesi USA, Vertex Pharmaceuticals, Calithera Biosciences, and 4D Molecular Therapeutics, and consulting income from Boehringer Ingelheim and Abbvie. PJM reports grant funding from Vertex Pharmaceuticals and Eloxx. SMR reports grant funding from Vertex Pharmaceuticals, Galapagos/Abbvie, Eloxx, Synspira, Translate Bio, Arcturus, Astra-Zenica, and Ionis, and consulting income from Vertex Pharmaceuticals, Synspira, Renovion, Cystetic Medicines, and Arcturus; all personal conflicts to SMR were resolved or ended in 2022 or before. AHG has clinical trial agreements with AbbVie, 4D Molecular Therapeutics, and Insmed. TEC reports research funding from NIH, Astra Zeneca, Regeneron, Pieris, and the CF Foundation through a Research Development Program award. NMH reports grants from CFF, NIH, and FDA, and DSMB membership for the NIH., (Copyright © 2024. Published by Elsevier B.V.)

Cystic fibrosis transmembrane conductance regulator (CFTR) modulators, including elexacaftor/tezacaftor/ivacaftor (ETI), significantly improve outcomes and quality of life for people with cystic fibrosis (CF). However, little is known about how lung transplant recipients (LTRs) perceive the use of ETI. We conducted a survey to assess perspectives on ETI among LTRs with CF at our lung transplant program. Of 81 CF LTRs, 46 participants (58 %) responded. The majority of respondents (88 %) were aware of ETI. Over 80 % considered treating non-lung symptoms of CF to be very important. Concerns regarding ETI included potential drug interactions with transplant medications (77 %), side effects (53 %), cost of medication (49 %), and lack of clinical trial data for LTRs (43 %). Half reported they would only consider taking ETI if their CF or transplant doctor recommended it. The findings suggest that CF LTRs seek informational support and shared decision-making about ETI from their clinicians., 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.)

Background: Cystic fibrosis associated liver disease (CFLD) carries a significant disease burden with no effective preventive therapies. According to the gut-liver axis hypothesis for CFLD pathogenesis, dysbiosis and increased intestinal inflammation and permeability permit pathogenic bacterial translocation into the portal circulation, leading to hepatic inflammation and fibrosis. Evaluating the effect of CFTR (cystic fibrosis transmembrane conductance regulator) modulation with elexacaftor/tezacaftor/ivacaftor (ETI) may help determine the role of CFTR in CFLD and increase understanding of CFLD pathogenesis, which is critical for developing therapies. We aimed to characterize the fecal microbiota in participants with CF with and without advanced CFLD (aCFLD) before and after ETI., Methods: This is an ancillary analysis of stool samples from participants ages ≥12 y/o enrolled in PROMISE (NCT04038047). Included participants had aCFLD (cirrhosis with or without portal hypertension, or non-cirrhotic portal hypertension) or CF without liver disease (CFnoLD). Fecal microbiota were defined by shotgun metagenomic sequencing at baseline and 1 and 6 months post-ETI., Results: We analyzed 93 samples from 34 participants (11 aCFLD and 23 CFnoLD). Compared to CFnoLD, aCFLD had significantly higher baseline relative abundances of potential pathogens Streptococcus salivarius and Veillonella parvula. Four of 11 aCFLD participants had an initially abnormal fecal calprotectin that normalized 6 months post-ETI, correlating with a significant decrease in S. salivarius and a trend towards decreasing V. parvula., Conclusions: These results support an association between dysbiosis and intestinal inflammation in CFLD with improvements in both post-ETI, lending further support to the gut-liver axis in aCFLD., Competing Interests: Declaration of competing interest JTD – Grant funding from CFF SJS – Grant funding from Vertex, CFF, NIH SMR – Consultant for Vertex; Grant funding from Vertex, CFF, NIH GMS – Consultant for GSK, Genentech, Electromed; Grant funding from Vertex, CFF, NIH DPN – Consultant for Vertex, Genentech; Grant funding from Vertex, CFF, NIH LRH – Grant funding from CFF, NIH MRN – Consultant for UpToDate, Vertex: Grant funding from Gilead, AbbVie, CFF, NIH NG – Grant funding from SCRI-CRSP, (Copyright © 2024. Published by Elsevier B.V.)

Antibiotics are frequently utilized for cystic fibrosis (CF)-related pulmonary exacerbation treatment. The antibiotic spectrum index (ASI) is an antimicrobial stewardship tool developed to compare the relative breadth of individual antibiotics. This study aimed to create two expanded CF-specific ASI scoring indices for use in antimicrobial stewardship research and clinical care. The first scoring index expanded the original ASI to include bacterial microorganisms common to CF airway infections (CF-ASI). The second scoring system only included scores for bacterial microorganisms classically identified in CF airway infections (CF-sASI). Sixty-two antibiotics were evaluated and included in the updated ASIs. When multiple antibiotics are prescribed, we proposed using an additive ASI approach whereby the sum of the individual prescribed antibiotic scores represents the total ASI score. The application of CF-focused ASIs into CF research and stewardship programs can help to optimize antibiotic benefits, minimize harms and allow for increased sustainability of antibiotic use in CF., Competing Interests: Declaration of competing interest Dr. VanDevanter notes consulting fees from Arcturus, Arrevus, BiomX, Clarametryx, Enbiotix, Microbion, Pyros, Respirion, and Zambon. Drs. Cogen, Heltshe, Brothers, Gerber, Kronman and Somayaji have no reflect conflict of interests to disclose., (Copyright © 2024. Published by Elsevier B.V.)

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.)

Previous studies indicate that hospital rather than home treatment of pulmonary exacerbations (PEx) in people with cystic fibrosis (CF) can improve outcomes. We evaluated characteristics of adult participants from the Standardized Treatment of Pulmonary Exacerbations (STOP2) trial with two separate comparisons: (1) those who were treated initially in hospital (N = 768) to those treated initially at home (N = 214) and (2) those treated only in hospital (N = 328) to those who were treated only at home or both at home and in hospital (N = 654). Participants who had Medicaid insurance, were treated for shorter duration, and traveled longer to reach treatment centers were more likely to have been treated initially in the hospital. Having Medicaid insurance, being treated for a shorter duration, and being male were associated with being treated only in the hospital. This analysis suggests decisions about the location of treatment are based on pragmatic factors rather than on clinical characteristics., Competing Interests: Declaration of Competing Interest Grants from the Cystic Fibrosis Foundation in part supported the salaries of LSG, RNH, SLH, PAF, CHG, NEW, DBS, and LK. Grants from the NIH in part supported the salaries of SLH, PAF, and CHG. DBS received payments for committee work from the Cystic Fibrosis foundation. DBS's institution also grant support payments from Gilead Sciences and the CHEST Foundation. DBS received personal payment for participation on an advisory board for Vertex Pharmaceuticals., (Copyright © 2023. Published by Elsevier B.V.)

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.)

Background: Nontuberculous mycobacteria (NTM) are an important cause of airway infections in people with cystic fibrosis (pwCF). Isolation of NTM from respiratory specimens of pwCF do not mandate treatment in the absence of clinical and radiologic features of NTM pulmonary disease (NTM-PD), as some pwCF clear the infection without treatment and others do not appear to progress to NTM-PD despite persistent infection. An evidence-based protocol to standardize diagnosis of NTM-PD is needed to systematically identify pwCF who may benefit from treatment., Methods: In this multicenter observational study, eligible pwCF who are 6 years of age and older and who have had a recent positive NTM culture are systematically evaluated for NTM-PD. Participants are identified based on positive NTM culture results obtained during routine clinical care and following enrollment are evaluated for NTM-PD and CF-related comorbidities. Participants are followed in PREDICT until they meet NTM-PD diagnostic criteria and are ready to initiate NTM treatment, or until study termination. Active participants who have not met these criteria are re-consented every 5 years to enable long-term participation., Results: The primary endpoint will summarize the proportion of participants who meet the NTM-PD diagnosis definition. The time from enrollment to NTM-PD diagnosis will be derived from Kaplan-Meier estimates., Conclusion: A prospective protocol to identify NTM-PD in pwCF will test if this standardized approach defines a cohort with signs and symptoms associated with NTM-PD, to assist with clinical decision making and to build a framework for future therapeutic trials., Trial Registration: ClinicalTrials.gov Identifier: NCT02073409., Competing Interests: Declaration of Competing Interest The authors declare that they have no competing or conflicting interests. The authors have no financial or other relationship with other people or organizations that may inappropriately influence their work, (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

People with CF (PwCF), particularly those with advanced lung disease (ALD), experience frequent respiratory symptoms. A major CF breakthrough was the approval of elexacaftor/tezacaftor/ivacaftor (ETI) in 2019, which has been shown to improve symptoms and lung function in the CF population, and decrease pulmonary exacerbations. The purpose of this study was to analyze longitudinal changes in respiratory symptoms over 24 months in ETI-treated and untreated PwCF with ALD Symptoms were measured among CF adults with ppFEV 1 < 40% (N = 48, 24 ETI-treated, 24 untreated) using the CFRSD-CRISS and the CFQ-R [respiratory]. Two multilevel growth models assessed the rate of change in symptoms overall and within the ETI-treated and untreated groups. PwCF on ETI had significantly lower symptom severity over 24 months than those not on ETI as measured by the CRISS and CFQ-R. The ETI-treated group maintained an -11.7 and +19.3 point difference(p<0.01) in CRISS and CFQ-R scores over the study compared to the non-ETI group, achieving minimal clinically important differences on average between groups on both instruments. No change in the symptom burden trajectory between groups was observed (p = 0.58). Even with ALD, ETI-treated PwCF have a lower respiratory burden than those not on ETI. This may be confounded by survivorship bias in the non-ETI group. Of note, in this ALD cohort, neither instrument demonstrated ceiling effects. Our results suggest that, while ETI has significantly improved the lived experience, PwCF with ALD are still plagued by respiratory symptoms., Competing Interests: Declaration of Competing Interest Authors Eliana R. Gill, Lauren E. Bartlett, Tijana Milinic, Nora Burdis, Joseph M. Pilewski, Jordan M. Dunitz, Siddhartha G. Kapnadak, Christopher H. Goss, and Kathleen J. Ramos report no conflicts of interest., (Copyright © 2023 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.)

Background: While elexacaftor/tezacaftor/ivacaftor (ETI) has improved the pulmonary health of many people with cystic fibrosis (PwCF), less is known about ETI effectiveness for extra-pulmonary manifestations, including fat-soluble vitamin malabsorption. This study aims to evaluate ETI's impact on vitamin A, D, E, and international normalized ratio (INR, an indirect marker for Vitamin K) serum levels., Methods: Retrospective cohort study of PwCF ≥12 years receiving ETI. Vitamin levels up to four years preceding and up to two years following ETI initiation were collected. Pairwise comparisons of vitamin levels pre/post-ETI initiation were made using Wilcoxon signed rank and McNemar's tests. Linear mixed effect models were used to regress vitamin levels on time since starting ETI, ETI use (yes/no), the interaction between time and ETI use, and age., Results: Two hundred and sixty-four participants met study inclusion, and 169 (64%) had post-ETI initiation vitamin levels. Median vitamin A levels increased from 422.0 to 471.0 mcg/L (p < 0.001), median vitamin D levels increased from 28.5 to 30.8 ng/mL (p = 0.003), and there were no significant changes in median vitamin E or INR. Vitamin A levels rose at a rate of 40.7 mcg/L/year (CI 11.3, 70.2) after ETI start., Conclusions: ETI initiation is associated with increased median vitamin A and vitamin D levels, but no change in median vitamin E or INR levels. Ongoing monitoring of vitamin levels after ETI initiation is needed to screen for potential deficiencies and toxicities, particularly in light of case reports of hypervitaminosis A following ETI initiation., Competing Interests: Declaration of Competing Interest DPN reports consulting fees from Vertex Pharmaceuticals. GEH, AF, GB, LEB, JDC, NG, SM, and KJR have no competing interests to declare., (Copyright © 2023. Published by Elsevier B.V.)

CF registry pulmonary exacerbation (PEx) analyses have employed "before and after" spirometry recovery, where the best percent predicted forced expiratory volume in 1 s (ppFEV 1 ) prior to PEx ("baseline") is compared to the best ppFEV 1 <3 months post-PEx. This methodology lacks comparators and ascribes recovery failure to PEx. Herein, we describe 2014 CF Foundation Patient Registry PEx analyses including a comparator: recovery around nonPEx events, birthdays. 49.6% of 7357 individuals with PEx achieved baseline ppFEV 1 recovery while 36.6% of 14,141 achieved baseline recovery after birthdays; individuals with both PEx and birthdays were more likely to recover baseline after PEx than after birthdays (47% versus 34%); mean ppFEV 1 declines were 0.3 (SD=9.3) and 3.1 (9.3), respectively. Post-event measure number had more effect on baseline recovery than did real ppFEV 1 loss in simulations, suggesting that PEx recovery analyses lacking comparators are prone to artifact and poorly describe PEx contributions to disease progression., Competing Interests: Declaration of Competing Interest None., (Copyright © 2023. Published by Elsevier B.V.)

Background: Pulmonary exacerbations (PEx) remain a major cause of morbidity and mortality in people with cystic fibrosis (PWCF). Although the combination cystic fibrosis transmembrane conductance regulator (CFTR) modulators lumacaftor/ivacaftor and tezacaftor/ivacaftor have been shown to reduce PEx frequency, their influence on clinical and biochemical responses to acute PEx treatment is unknown., Methods: We performed a secondary analysis of STOP2, a large multicenter randomized controlled trial of antimicrobial treatment durations for adult PWCF presenting with PEx. Propensity score matching was used to compare outcomes in antibiotic-treated F508del/F508del PWCF receiving lumacaftor/ivacaftor or tezacaftor/ivacaftor with those observed in antibiotic-treated F508del/F508del controls not receiving CFTR modulator therapy. The primary outcome measure was the change in percent predicted FEV 1 (ppFEV 1 ) following completion of intravenous (IV) antibiotics, with post-antibiotic changes in symptoms, serum C-reactive protein (CRP) concentrations and weight included as secondary endpoints., Results: Among 982 PEx events in randomized PWCF, 480 were homozygous for F508del, of whom 289 were receiving lumacaftor/ivacaftor or tezacaftor/ivacaftor at initiation of antibiotic therapy. Modulator-treated F508del/F508del PWCF did not demonstrate greater improvements in ppFEV 1 , symptoms, serum CRP or weight following antibiotic treatment compared to modulator-naïve controls matched for age, sex, baseline ppFEV 1 , genotype, body mass index, initial CRP, initial symptoms, exacerbation history, diabetic status, randomization arm and concomitant medical therapy., Conclusion: In the acute setting, CFTR modulator therapy with lumacaftor/ivacaftor or tezacaftor/ivacaftor does not convey additional clinical or biochemical advantage above standardized PEx treatment in F508del/F508del PWCF., Competing Interests: Declaration of Competing Interest O.J.McE. has been an investigator for Chiesi and Grifols. P.A.F. has been an investigator for Novartis, Novoteris, Proteostasis, Savara, Sound, Chiesi and Vertex. C.H.G. has been an investigator for Boehringer Ingelheim and a DSMB chair for Novartis. The remaining authors have no relevant or competing interests to disclose., (Copyright © 2023. Published by Elsevier B.V.)

Background: Hyperglycemia could affect treatment response during cystic fibrosis (CF) exacerbations. We aimed to evaluate the prevalence and associations of hyperglycemia with exacerbation outcomes. We also evaluated feasibility of continuous glucose monitoring (CGM) during exacerbations., Methods: The STOP2 study assessed efficacy and safety of different durations of intravenous antibiotics for CF exacerbations. We conducted a secondary data analysis of random glucose levels measured as part of clinical care during exacerbations. A small subset of participants also underwent CGM per research protocol. The associations between hyperglycemia, defined as random glucose ≥140 mg/dL, and changes in weight and lung function with exacerbation treatment were evaluated with linear regression after adjustment for confounding variables., Results: Glucose levels were available for 182 STOP2 participants of mean (SD) age 31.6 (10.8) years, baseline percent predicted (pp) FEV1 53.6 (22.5); 37% had CF related diabetes and 27% were on insulin. Hyperglycemia was detected in 44% of participants. Adjusted mean difference (95% CI) was 1.34% (-1.39, 4.08) (p = 0.336) for change in ppFEV1 and 0.33 kg (-0.11, 0.78) (p = 0.145) for change in weight between hyperglycemic and non-hyperglycemic groups. Ten participants not on antidiabetic agents in the 4 weeks prior to enrollment underwent CGM; mean (SD) time spent >140 mg/dL was 24.6% (12.5) with 9/10 participants spending >4.5% time >140 mg/dL., Conclusions: Hyperglycemia identified with random glucose is prevalent during CF exacerbations but not associated with changes in lung function or weight with exacerbation treatment. CGM is feasible and may provide a useful tool for hyperglycemia monitoring during exacerbations., 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.)

Background: Pseudomonas aeruginosa (Pa) infection in cystic fibrosis (CF) is characterized in stages: never (prior to first positive culture) to incident (first positive culture) to chronic. The association of Pa infection stage with lung function trajectory is poorly understood and the impact of age on this association has not been examined. We hypothesized that FEV 1 decline would be slowest prior to Pa infection, intermediate after incident infection and greatest after chronic Pa infection., Methods: Participants in a large US prospective cohort study diagnosed with CF prior to age 3 contributed data through the U.S. CF Patient Registry. Cubic spline linear mixed effects models were used to evaluate the longitudinal association of Pa stage (never, incident, chronic using 4 different definitions) with FEV 1 adjusted for relevant covariates . Models contained interaction terms between age and Pa stage., Results: 1,264 subjects born 1992-2006 provided a median 9.5 (IQR 0.25 to 15.75) years of follow up through 2017. 89% developed incident Pa; 39-58% developed chronic Pa depending on the definition. Compared to never Pa, incident Pa infection was associated with greater annual FEV 1 decline and chronic Pa infection with the greatest FEV 1 decline. The most rapid FEV 1 decline and strongest association with Pa infection stage was seen in early adolescence (ages 12-15)., Conclusions: Annual FEV 1 decline worsens significantly with each Pa infection stage in children with CF. Our findings suggest that measures to prevent chronic infection, particularly during the high-risk period of early adolescence, could mitigate FEV 1 decline and improve survival., Competing Interests: Declaration of Competing Interest The authors have no conflicts of interest to declare, (Copyright © 2023. Published by Elsevier B.V.)

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: No data exist to guide antibiotic selection among people with CF (PwCF) with respiratory cultures positive for multiple CF-related bacteria (polymicrobial infections). This study aimed to describe the number of polymicrobial in-hospital treated pulmonary exacerbations (PEx), to determine the proportion of polymicrobial PEx where antibiotics were prescribed with activity against all bacteria detected (termed complete antibiotic coverage), and to determine clinical and demographic factors associated with complete antibiotic coverage., Methods: Retrospective cohort study using the CF Foundation Patient Registry-Pediatric Health Information System dataset. Children aged 1-21 years with an in-hospital treated PEx from 2006 to 2019 were eligible for inclusion. Bacterial culture positivity was based on any positive respiratory culture in the 12 months prior to a study PEx., Results: A total of 4,923 children contributed 27,669 total PEx of which 20,214 were polymicrobial; of these, 68% of PEx had complete antibiotic coverage. In regression modeling, a prior PEx with complete antibiotic coverage for MRSA was associated with a higher likelihood of having complete antibiotic coverage at a subsequent study PEx (OR (95% CI) 3.48 (2.50, 4.83))., Conclusions: The majority of children with CF hospitalized for polymicrobial PEx were prescribed complete antibiotic coverage. Prior PEx treatment with complete antibiotic coverage predicted complete antibiotic coverage at a future PEx for all bacteria studied. Studies are needed comparing outcomes of polymicrobial PEx treated with different antibiotic coverages to optimize PEx antibiotic selection., (Copyright © 2023 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.)

Introduction: Although work to date in cystic fibrosis (CF) has elucidated frequencies and characteristics of adverse events, the accuracy of attribution of relatedness to study drug by investigators has not been assessed. We aimed to determine whether there was an association of attribution by group allocation in CF clinical trials., Methods: We conducted a secondary analysis from 4 CF trials of all persons who experienced an AE. Our primary outcome was the odds of an AE related to active study drug and predictor of interest was the treatment allocation. We constructed a multivariable generalized estimating equation model allowing for repeated measures., Results: A total of 785 subjects (47.5% female, mean age 12 years) had 11,974 AEs, of which 430 were serious. AE attribution was greater with receipt of active study drug as compared to placebo but did not reach statistical significance (OR 1.38, 95% CI 0.98-1.82). Significantly associated factors included female sex (OR 0.58, 95% 0.39-0.87), age (OR 1.24, 95% CI 1.06-1.46) and baseline lung function (per 10%, OR 1.16, 95% CI 1.05-1.28)., Conclusion: In our large study, there was a non-significant but greater odds of AE attribution (a key element of clinical trial reporting) to active study drug based on assigned treatment to study drug or control which suggests that there is a trend in physicians to attribute blinded safety data to the active drug. Interestingly, females were less likely to have AE attribution to study drug and warrants further work in development and validation of monitoring guidelines and processes., 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: Changes in upper airway microbiota may impact early disease manifestations in infants with cystic fibrosis (CF). To investigate early airway microbiota, the microbiota present in the oropharynx of CF infants over the first year of life was assessed along with the relationships between microbiota and growth, antibiotic use and other clinical variables., Methods: Oropharyngeal (OP) swabs were collected longitudinally between 1 and 12 months of age from infants diagnosed with CF by newborn screen and enrolled in the Baby Observational and Nutrition Study (BONUS). DNA extraction was performed after enzymatic digestion of OP swabs. Total bacterial load was determined by qPCR and community composition assessed using 16S rRNA gene analysis (V1/V2 region). Changes in diversity with age were evaluated using mixed models with cubic B-splines. Associations between clinical variables and bacterial taxa were determined using a canonical correlation analysis., Results: 1,052 OP swabs collected from 205 infants with CF were analyzed. Most infants (77%) received at least one course of antibiotics during the study and 131 OP swabs were collected while the infant was prescribed an antibiotic. Alpha diversity increased with age and was only marginally impacted by antibiotic use. Community composition was most highly correlated with age and was only moderately correlated with antibiotic exposure, feeding method and weight z-scores. Relative abundance of Streptococcus decreased while Neisseria and other taxa increased over the first year., Conclusions: Age was more influential on the oropharyngeal microbiota of infants with CF than clinical variables including antibiotics in the first year of life., Competing Interests: Declaration of Competing Interest Dr. Harris reports grants from the Cystic Fibrosis Foundation during the conduct of the study Dr. Wagner has nothing to disclose Dr. Robertson has nothing to disclose Dr. Lingard has nothing to disclose Dr. Borowitz has nothing to disclose Dr. Leung reports other from Merck, grants and other from Gilead, grants from Abbvie, grants from CF Foundation, outside the submitted work Dr. Heltshe has nothing to disclose Dr. Ramsey has nothing to disclose Dr. Zemanick reports grants from Cystic Fibrosis Foundation, NIH/NCATS, NIH/NHLBI, Savara and Calithera Biosciences during the conduct of the study, grants and fees from Vertex Pharmaceuticals, Cystic Fibrosis Foundation outside the submitted work, (Copyright © 2023. Published by Elsevier B.V.)

Background and Aims: People with cystic fibrosis (PwCF) suffer from gastrointestinal (GI) symptoms affecting their quality of life (QOL). Despite the relevance of GI symptoms to the overall health of PwCF, a paucity of studies only have comprehensively assessed the prevalence, severity and QOL of GI symptoms in both children and adults with Cystic Fibrosis (CF)., Methods: Eligible participants ≥2 years of age across 26 US CF centers were followed for 4 weeks. Three validated GI electronic patient-reported outcome measures (ePROMs) with a recall period of 2 weeks and a stool-specific questionnaire were administered weekly over four weeks. Total and domain scores of ePROMs were evaluated overall and in subgroups using linear mixed-effect models., Results: Of 402 enrolled, 58% were ≥ 18 years of age (52% male). The mean (SD) of the total score for PAC-SYM was 0.52 (0.55), for PAGI-SYM was 0.63 (0.67), and for PAC-QOL was 0.67 (0.55). For specific ePROM questions, prevalence of moderate to very severe symptoms were as follows: straining (20.3%), fullness (18.3%), incomplete bowel movements (17.1%), bloating (16.4%), distension (16.4%), abdominal pain (upper-5.1%, lower-7.5%). Comparing participants ≥18 versus <18, a higher prevalence of bloating (63.7% versus 27.3%), lower abdominal pain (39.8% vs 26.2%), stomach fullness (75.6% versus 56.2%), and abdominal distension (60.2% versus 34.9%) was found. Both age groups reported high treatment dissatisfaction as measured with PAC-QOL, mean 1.39 (95% CI: 1.30, 1.47)., Conclusion: GI symptoms were reported in all age ranges irrespective of gender, with higher prevalence observed amongst older and female subgroups. Dissatisfaction with GI targeted treatments were reported in a large proportion of participants despite therapy, highlighting an unmet need for clinical interventions., Clinicaltrials: GOV: NCT03801993., (Copyright © 2022 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.)

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: Limited data exist to inform antibiotic selection among people with cystic fibrosis (CF) with airway infection by multiple CF-related microorganisms. This study aimed to determine among children with CF co-infected with methicillin-resistant Staphylococcus aureus (MRSA) and Pseudomonas aeruginosa (Pa) if the addition of anti-MRSA antibiotics to antipseudomonal antibiotic treatment for pulmonary exacerbations (PEx) would be associated with improved clinical outcomes compared with antipseudomonal antibiotics alone., Methods: Retrospective cohort study using data from the CF Foundation Patient Registry-Pediatric Health Information System linked dataset. The odds of returning to baseline lung function and having a subsequent PEx requiring intravenous antibiotics were compared between PEx treated with anti-MRSA and antipseudomonal antibiotics and those treated with antipseudomonal antibiotics alone, adjusting for confounding by indication using inverse probability of treatment weighting., Results: 943 children with CF co-infected with MRSA and Pa contributed 2,989 PEx for analysis. Of these, 2,331 (78%) PEx were treated with both anti-MRSA and antipseudomonal antibiotics and 658 (22%) PEx were treated with antipseudomonal antibiotics alone. Compared with PEx treated with antipseudomonal antibiotics alone, the addition of anti-MRSA antibiotics to antipseudomonal antibiotic therapy was not associated with a higher odds of returning to ≥90% or ≥100% of baseline lung function or a lower odds of future PEx requiring intravenous antibiotics., Conclusions: Children with CF co-infected with MRSA and Pa may not benefit from the addition of anti-MRSA antibiotics for PEx treatment. Prospective studies evaluating optimal antibiotic selection strategies for PEx treatment are needed to optimize clinical outcomes following PEx treatment., Competing Interests: Declaration of Competing Interest Drs. Cogen and Ms. Faino received support from the Cystic Fibrosis Foundation (COGEN19A0) Dr. Gibson received support from the Cystic Fibrosis Foundation (GIBSON1R0) Drs. Hall, Ambroggio, Blaschke, Brogan, Cotter, Grijalva, Hersh, Lipsett, Shah, Shapiro, Neuman and Gerber have nothing to disclose at it relates to this manuscript., (Copyright © 2022 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.)

In this review, we summarize the main points that were raised and highlighted during the pre-conference meeting to the 17 th European Cystic Fibrosis Society Basic Science Conference, held from 30 March to 2 April, 2022 in Albufeira, Portugal. Keynote lectures provided an update on the latest information regarding the phenomenon of antimicrobial resistance (AMR) in cystic fibrosis (CF). Traditional themes such as in vitro antibiotic susceptibility testing and its clinical value, AMR evolution in persistent Pseudomonas aeruginosa infection and the impact of biofilm on AMR were discussed. In addition, the report gives an overview on very recent AMR-related topics that include an ecological view of AMR in CF lung, referred to as resistome, and novel anti-infective approaches in preclinical or early clinical research such as antibiofilm drugs and bacteriophages., Competing Interests: Declaration of Competing Interest P.D. reports personal fees from Vertex Pharmaceuticals, Chiesi CZ and I.T.A.-Intertact outside the submitted work. P-R. B. reports grants and/or personal fees from Vertex Pharmaceuticals, GlaxoSmithKline, AstraZeneca, Chiesi, Insmed, Viatris, Zambon, Pari, Pfizer, Boehringer Ingelheim outside the submitted work. J.C.D. reports grants and/or personal fees from UK CF Trust, CF Foundation, CF Ireland, EPSRC, Vertex Pharmaceuticals, Boehringer Ingelheim, Eloxx, Algipharma, Abbvie, Arcturus, Enterprise Therapeutics, Recode, LifeArc, Genentech outside the submitted work. All other authors have no conflicts of interest., (Copyright © 2022. Published by Elsevier B.V.)

Background: Concerns related to stool consistency are common in the first year of life among children with cystic fibrosis (CF). However, normal stool patterns for infants with CF have not been described., Methods: Secondary analysis was completed from the previously described BONUS cohort which followed 231 infants with CF through the first 12 months of life. Pain, stool category, stool frequency, feeding type, PERT dose, acid suppression medication, antibiotics usage, stool softener usage and fecal calprotectin were described at 3, 6, and 12 months. Repeated measure ANOVA was used to test the difference in mean stool number. Generalized linear mixed models were used to investigate the relationship between stool characteristics and various factors., Results: The frequency of constipation was stable throughout the first year of life (10-13%) while watery stool significantly decreased from 21.3% at 3 months to 5.8% at 12 months (p=<0.001). The number of stools at months 6 (mean=2.40) and 12 (mean=2.50) are significantly lower than in month 3 (mean=2.83), p<0.025. Exclusive breast feeding was associated with an increased risk for constipation (OR=2.64  [1.60-4.37], p = 0.002) while exclusive formula feeding and acid suppression was associated with decreased risk for constipation (OR=0.40  [0.26-0.61], p=<0.0001 and OR=0.59  [0.39-0.89], p = 0.01 respectively). Pain was not significantly associated with stool consistency., Conclusion: Stool frequency and consistency evolves in infant with CF in a fashion similar to that reported in non-CF infants over the first year. Constipation was not associated with pain and was less common among infants receiving acid suppression or exclusively formula feeding., (Copyright © 2022. Published by Elsevier B.V.)

Background: Cystic fibrosis (CF) pulmonary exacerbation (PEx) treatment guidelines suggest that Pseudomonas aeruginosa (Pa) airway infection be treated with two antipseudomonal agents., Methods: We retrospectively studied treatment responses for STOP2 PEx treatment trial (NCT02781610) participants with a history of Pa infection. Mean lung function and symptom changes from intravenous (IV) antimicrobial treatment start to Visit 2 (7 to 10 days later) were compared between those receiving one, two, and three+ antipseudomonal classes before Visit 2 by ANCOVA. Odds of PEx retreatment with IV antimicrobials within 30 days and future IV-treated PEx hazard were modeled by logistic and Cox proportional hazards regression, respectively. Sensitivity analyses limited to the most common one-, two-, and three-class regimens, to only IV/oral antipseudomonal treatments, and with more stringent Pa infection definitions were conducted., Results: Among 751 participants, 50 (6.7%) were treated with one antipseudomonal class before Visit 2, while 552 (73.5%) and 149 (19.8%) were treated with two and with three+ classes, respectively. Females and participants with a negative Pa culture in the prior month were more likely to be treated with a single class. The most common single, double, and triple class regimens were beta-lactam (BL; n = 42), BL/aminoglycoside (AG; n = 459), and BL/AG/fluoroquinolone (FQ; n = 73). No lung function or symptom response, odds of retreatment, or future PEx hazard differences were observed by number of antipseudomonal classes administered in primary or sensitivity analyses., Conclusions: We were unable to identify additional benefit when multiple antipseudomonal classes are used to treat PEx in people with CF and Pa., (Copyright © 2022. Published by Elsevier B.V.)

Background: In the STOP2 (Standardized Treatment of Pulmonary Exacerbations-2) study, intravenous (IV) antimicrobial treatment duration for adults with cystic fibrosis (CF) experiencing pulmonary exacerbations (PEx) was determined based on initial treatment response. The impact of home vs hospital care remains an important clinical question in CF. Our hypothesis was that STOP2 participants treated at home would have less improvement in lung function compared to those treated in the hospital., Methods: Treating clinicians determined PEx treatment location, which was a stratification factor for STOP2 randomization. Lung function, weight, and symptom recovery were evaluated by treatment location. Propensity scores and inverse probability treatment weighting were used to test for differences in clinical response by treatment location., Results: In all, 33% of STOP2 participants received IV antimicrobials in the hospital only, 46% both in the hospital and at home, and 21% at home only. Mean (95% CI) ppFEV 1 improvement was significantly (p < 0.05) lower for those treated at home only, 5.0 (3.5, 6.5), compared with at home and in the hospital, 7.0 (5.9, 8.1), and in the hospital only, 8.0 (6.7, 9.4). Mean weight (p < 0.001) and symptom (p < 0.05) changes were significantly smaller for those treated at home only compared to those treated in the hospital only., Conclusions: Compared to PEx treatment at home only, treatment in the hospital was associated with greater mean lung function, respiratory symptom, and weight improvements. The limitations of home IV therapy should be addressed in order to optimize outcomes for adults with CF treated at home., (Copyright © 2021. Published by Elsevier B.V.)

Background: The purpose of these analyses was to determine whether overall costs were reduced in cystic fibrosis (CF) patients experiencing pulmonary exacerbation (PEx) who received shorter versus longer durations of treatment., Methods: Among people with CF experiencing PEx, we calculated 30-day inpatient, outpatient, emergency room, and medication costs and summed these to derive total costs in 2020 USD. Using the Kaplan-Meier sample average (KMSA) method, we calculated adjusted costs and differences in costs within two pairs of randomized groups: early robust responders (ERR) randomized to receive treatment for 10 days (ERR-10 days) or 14 days (ERR-14 days), and non-early robust responders (NERR) randomized to receive treatment for 14 days (NERR-14 days) or 21 days (NERR-21 days)., Results: Patients in the shorter treatment duration groups had shorter lengths of stay per hospitalization (mean ± standard deviation (SD) for ERR-10 days: 7.9 ± 3.0 days per hospitalization compared to 10.1 ± 4.2 days in ERR-14 days; for NERR-14 days: 8.7 ± 4.9 days per hospitalization compared to 9.6 ± 6.5 days in NERR-21 days). We found statistically significantly lower adjusted mean costs (95% confidence interval) among those who were randomized to receive shorter treatment durations (ERR-10 days: $60,800 ($59,150 - $62,430) vs $74,420 ($72,610 - $76,450) in ERR-14 days; NERR-14 days: $66,690 ($65,960-$67,400) versus $74,830 ($73,980-$75,650) in NERR-21 days)., Conclusions: Tied with earlier evidence that shorter treatment duration was not associated with worse clinical outcomes, our analyses indicate that treating with shorter antimicrobial durations can reduce costs without diminishing clinical outcomes., Competing Interests: Declaration of Competing Interest Grants from the Cystic Fibrosis Foundation in part supported the salaries of LSG, RNH, DLP, AT, SLH, PAF, CHG, NEW, DBS, DRV, and LK. Grants from the NIH in part supported the salaries of SLH, PAF, and CHG. DBS received payments for committee work from the Cystic Fibrosis foundation. DBS's institution also grant support payments from Gilead Sciences and the CHEST Foundation. DBS received personal payment for participation on an advisory board for Vertex Pharmaceuticals., (Copyright © 2022. Published by Elsevier B.V.)

In 2017, Nkam et al. published a prognostic score to predict death or lung transplant within 3 years among adult cystic fibrosis (CF) patients. Their model was developed using French CF registry data and was subsequently validated in the Canadian CF registry. We evaluated this prognostic score using data from adult patients with CF in the United States (US) CF Foundation Patient registry, combined with lung transplant records from the United Network for Organ Sharing (UNOS) Registry (2013 to 2016) (n=11,542). We found that the prognostic score had a very good discriminative index predicting death or lung transplant in the US CF population (AUC 0.88, 95% CI 0.88-0.89) with an odds ratio (OR) of 2.83 (95% CI 2.69 - 2.97) for each unit increase in the score. However, it did not provide significant additional utility over an FEV 1 ≤30% of predicted as a predictor of death or lung transplant., Competing Interests: Declarations of Competing Interest The authors report no conflicts of interest., (Copyright © 2021. Published by Elsevier B.V.)

Chronic Pseudomonas aeruginosa (Pa) infection is associated with increased morbidity and mortality in people with cystic fibrosis (CF). There is no gold standard definition of chronic Pa infection in CF. We compared chronic Pa definitions using encounter-based versus annualized data in the Early Pseudomonas Infection Control (EPIC) Observational study cohort, and subsequently compared annualized chronic Pa definitions across a range of U.S. cohorts spanning decades of CF care. We found that an annualized chronic Pa definition requiring at least 1 Pa+ culture in 3 of 4 consecutive years ("Green 3/4") resulted in chronic Pa metrics similar to established encounter-based modified Leeds criteria definitions, including a similar age at and proportion who fulfilled chronic Pa criteria, and a similar proportion with sustained Pa infection after meeting the chronic Pa definition. The Green 3/4 chronic Pa definition will be valuable for longitudinal analyses in cohorts with limited culture frequency., Competing Interests: Conflict of interest statement All authors confirm that they have no conflicts of interest relevant to this work, (Copyright © 2021. Published by Elsevier B.V.)

Background: The COVID-19 pandemic has accelerated the transition to telehealth, including the use of home spirometry in cystic fibrosis. Evaluating the accuracy and precision of longitudinal home spirometry is a requisite for telehealth-based research. This secondary analysis of a CF study (eICE) evaluates whether there are cross-sectional or longitudinal differences between home and clinic spirometry., Methods: Participants age ≥14 years with ppFEV 1 >25 were recruited from 2011-2015, issued a home spirometer, and asked to complete spirometry efforts twice per week for one year. Clinic spirometry was collected at baseline and every three months. Cross-sectional differences between clinic spirometry and the closest home spirometry measurement were analyzed. Longitudinally, we apply 5 methods to analyze the precision of home spirometry, and differences between clinic vs. home data., Results: Home spirometry is estimated to be 2.0 (95% CI: 0.3, 3.5) percentage points lower than clinic spirometry cross-sectionally. Longitudinally, the estimates of 12-month change in home spirometry varied by analysis method from -2.6 to -1.0 ppFEV 1 / year, with precision markedly different. However, home spirometry change estimates were qualitatively similar to the clinic results: -3.0 ppFEV 1 /year (95% CI: -4.1, -1.9)., Conclusions: To leverage the potential cost, feasibility and convenience of home spirometry, the differences with clinic spirometry must be acknowledged. Significantly lower ppFEV 1 in home devices shows that direct comparison to clinic spirometers may induce a spurious change from baseline, and additional variability in home devices impacts statistical power. The effect of coaching, setting, and equipment must be understood to use and improve home spirometry in 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 © 2021. Published by Elsevier B.V.)

Background: The Characterizing CFTR Modulated Changes in Sweat Chloride and their Association with Clinical Outcomes (CHEC-SC) study is a large epidemiologic study designed to determine the relationship between sweat chloride response and clinical outcomes in people with cystic fibrosis (CF) on commercially approved CFTR modulators. A challenge to study feasibility was capturing sweat chloride measurements before modulator initiation. We tested the hypothesis that historic sweat chloride approximated contemporary pre-modulator values to estimate CFTR modulator-induced changes, allowing a single-visit study design., Methods: GOAL and PROSPECT were multi-center prospective studies of individuals initiating ivacaftor or lumacaftor-ivacaftor. At enrollment, pre-modulator sweat chloride was measured and historic results recorded. Post-modulator sweat chloride was measured at 1, 3 and 6 months. For this analysis, differences between historic and pre-modulator sweat chloride were estimated. CFTR modulator-induced sweat chloride mean changes were compared using historic and pre-modulator sweat chloride., Results: Paired historic and pre-modulator sweat chloride (n=406 participants) revealed a non-significant mean change of -1.0 mmol/L (95% CI: -2.71, 0.66) over an average of 17.2 years. Calculating sweat response to ivacaftor or lumacaftor-ivacaftor using historic or pre-modulator values resulted in similar estimates of modulator response. Based on these results, the CHEC-SC study was designed with a single, post-modulator sweat chloride measurement., Conclusions: Historic sweat chloride values provide a reliable estimate of pre-modulator sweat chloride for people starting on modulator therapy. The CHEC-SC study anticipates capturing approximately 5,000 sweat chloride values, providing an unprecedented understanding of sweat chloride across the CF population in the era of CFTR modulators., Competing Interests: Declaration of Competing Interest ETZ, NMH, DRV, SMR, MWK: grants or consulting CFF; DRV consults for aMoon, Arrevus, Eloxx, Enbiotix, Felix, Ionis, Matinas, Merck, Polyphor, Respirion, Savara; SMR consults for Vertex; MWK consults for Anthera, AzurRx, Celtaxsys, Chiesi, Ionis, Kala, Laurent, Merck, Paranta, pH Pharma, Santhera, Vertex; JPC, KOD and MS: none., (Copyright © 2021. Published by Elsevier B.V.)

Background: Retrospective studies indicate that more cystic fibrosis (CF) pulmonary exacerbations (PEx) are treated with oral (PO) than with intravenous (IV) antimicrobials despite little knowledge of the relative effects of PO treatment on lung function recovery or long-term impacts on lung disease progression. Previous studies have suggested that PO treatment may be associated with slower lung function recovery compared with IV treatment. We used longitudinal home spirometry data from the eICE study (NCT01104402) to compare PO versus IV antimicrobial treatment responses for PEx diagnosed by home spirometry and symptom assessment., Methods: Adolescent and adult eICE participants performed home spirometry twice weekly for one year. PEx were diagnosed by a protocol-defined algorithm of change in percent predicted forced expiratory volume in 1 second (ppFEV 1 ) and/or respiratory signs and symptoms. PO- and IV-treated PEx were grouped by initial ppFEV 1 drop magnitude. Group ppFEV 1 treatment responses were modeled with multivariate, repeat-measure linear regression., Results: Of 87 qualifying PEx from 56 participants, 62 were PO-treated and 25 were IV-treated. The average drop from best ppFEV 1 to PEx start was 11.0 [95%CI: 8.5, 13.5] with similar treatment group means (p=0.72). Participants with IV-treated PEx averaged 0.72 [0.24, 1.20] ppFEV 1 /day greater response than those treated with PO, who experienced minimal ppFEV1 recovery. Many PO-treated participants who had <10 ppFEV 1 drop from baseline tended to worsen or show no ppFEV 1 improvement., Discussion: These results suggest that, in this cohort, PO antimicrobial treatment of CF PEx were less effective than IVs at improving ppFEV 1 during treatment., (Copyright © 2021. Published by Elsevier B.V.)

Background: Cystic fibrosis (CF) is an autosomal recessive disease characterized by chronic sinopulmonary symptoms and chronic gastrointestinal symptoms that begins in infancy. Children with CF are increasingly being included in clinical trials. In order to fully evaluate the impact of new therapies in future clinical trials, an understanding of baseline adverse event (AE) rates in children with CF is needed. To address this, we determined the rates of common AEs in pediatric patients with CF who participated in two clinical trials., Methods: We reviewed AEs for placebo recipients in the AZ0004 study and inhaled tobramycin recipients in the Early Pseudomonas Infection Control (EPIC) clinical trial. AEs were categorized based on Medical Dictionary for Regulatory Activities (MedDRA) coding classifications and pooled into common, batched AE descriptors. AE rates were estimated from negative binomial models according to age groups, severity of lung disease, and season., Results: A total of 433 children had 8,266 total AEs reported, or 18.1 (95% CI 17.0, 19.2) AEs per person per year. Respiratory AEs were the most commonly reported AEs, with a rate of 7.6 events per person-year. The total SAE rate was 0.33 per person per-year. Cough was the most commonly reported respiratory AE, with 61% of subjects reporting at least one episode of cough within 4 months. The rate ratio of any AE was higher in Spring, Fall, and Winter, compared with Summer., Conclusions: AEs occur commonly in pediatric CF clinical trial participants. Season of enrollment could affect AE rates., Competing Interests: Declaration of Competing Interest None, (Copyright © 2021. Published by Elsevier B.V.)

Background: The Food and Drug Administration considers patient-reported outcome measures (PROMs) an essential part of clinical research studies for approval of new drugs and new indications for existing drugs. GALAXY evaluated the feasibility of electronic PROMs (ePROMS) to conduct a comprehensive evaluation of gastrointestinal (GI) symptoms in persons with cystic fibrosis (pwCF)., Methods: Three validated GI ePROMs (PAC-SYM, PAGI-SYM and PAC-QOL) were combined with a Stool-Specific questionnaire to make up the GALAXY ePROMs and administered prospectively across 26 CF centers in the United States. The ePROMs were completed at enrollment visit and then electronically at weeks 1, 2 and 4. PwCF at least 2 years and older were eligible for the study. Reminders were only provided by the mobile application during the study window., Results: There were 402 participants enrolled in GALAXY. Of those, 169 (42%) were under 18 years old and 193 (48%) were female. The proportion of all follow-up weeks with at least 1 ePROM fully completed was 80%, slightly higher in those ≥18 years of age (82.5%) compared to those <18 years of age (76.5%). When assessing the completion for all 4 ePROMs, the percentage was 77.6%, also higher among those ≥18 year of age (81.5% versus 72.2% for < 18 years of age)., Conclusion: Using ePROMs, our study demonstrated that GI symptoms can be feasibly collected with good reproducibility and with minimal involvement of research coordinator time. This mechanism of symptom collection may provide an efficient tool for future CF trials., Competing Interests: Conflict of Interest None of the authors have conflicts of interest related to the material in this paper. All of the authors receive funding from CFF with 5 of the authors being employed by CFF (PTV, UK, SLH, CHG)., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: The cystic fibrosis transmembrane conductance regulator (CFTR) potentiator, ivacaftor, was first approved for people with CF and the G551D CFTR mutation. This study describes the long-term clinical effectiveness of ivacaftor in this population., Methods: We conducted a multicenter, prospective, longitudinal, observational study of people with CF ages ≥6 years with at least one copy of the G551D CFTR mutation. Measurements of lung function, growth, quality of life, and sweat chloride were performed after ivacaftor initiation (baseline, 1 month, 3 months, 6 months, and annually thereafter until 5.5 years)., Results: Ninety-six participants were enrolled, with 81% completing all study measures through 5.5 years. This cohort experienced significant improvements in percent predicted forced expiratory volume in 1 second (ppFEV1) of 4.8 [2.6, 7.1] (p < 0.001) at 1.5 years, that diminished to 0.8 [-2.0, 3.6] (p = 0.57) at 5.5 years. Adults experienced larger improvements in ppFEV1 (7.4 [3.6, 11.3], p < 0.001 at 1.5 years and 4.3 [0.6, 8.1], p = 0.02 at 5.5 years) than children (2.8 [0.1, 5.6], p = 0.04 at 1.5 years and -2.0 [-5.9, 2.0], p = 0.32 at 5.5 years). Rate of lung function decline for the overall study cohort from 1 month after ivacaftor initiation through 5.5 years was estimated to be -1.22 pp/year [-1.70, -0.73]. Significant improvements in growth, quality of life measures, sweat chloride, Pseudomonas aeruginosa detection, and pulmonary exacerbation rates requiring antimicrobial therapy persisted through five years of therapy., Conclusions: These findings demonstrate the long-term benefits and disease modifying effects of ivacaftor in children and adults with CF and the G551D mutation., Competing Interests: Declaration of Competing Interest SMR and MJ serve as investigators and/or consultants on the design and conduct of CF clinical trials to Vertex Pharmaceuticals, the manufacturer of ivacaftor. A.P. declares a previous (within 36 months) equity interest in AbbVie, Inc. All other authors declare no conflicts of interest., (Copyright © 2020. Published by Elsevier B.V.)

Background Antimicrobial susceptibility testing (AST) of bacterial isolates is a time- and resource-intensive procedure recommended by cystic fibrosis (CF) treatment guidelines for antimicrobial selection for pulmonary exacerbation (PEx) treatment. Methods We studied relationships between Pseudomonas aeruginosa (Pa) isolate AST results, antipseudomonal PEx treatments, and treatment responses as change in weight and percent predicted forced expiratory volume in 1 s (ppFEV 1 ) as well as future antimicrobial treatment hazard for PEx occurring at a CF care center from 1999 through 2018. Treatments were categorized by "Pa coverage" as complete (all Pa isolates susceptible by AST to at least one administered agent), none (no isolates susceptible), incomplete (some, but not all isolates susceptible), and indeterminant (administered antipseudomonals not evaluated by AST). Weight and ppFEV 1 responses were compared across Pa coverage categories using unadjusted and adjusted general estimating equations; hazard of future treatment was assessed by Cox and logistic regression. Results Among 3820 antimicrobial PEx treatment events in 413 patients with Pa, 62.6% (2390) had complete Pa coverage; 8.9% (340), 2.4% (99), and 26.2% (1000), had no, incomplete, and indeterminant Pa coverage, respectively. Mean baseline to follow-up weight change was +0.74 kg [95% CI 0.63, 0.86]; ppFEV 1 change was +1.60 [1.29, 1.90]. Pa coverage category was not associated with significant differences in weight or ppFEV 1 change or with future antimicrobial treatment hazard. Conclusions We did not observe superior responses for AST-defined complete Pa coverage treatments versus lesser coverage treatments, suggesting that AST may be of little utility in choosing antimicrobials for CF PEx treatment., Competing Interests: Declaration of Competing Interest None., (Copyright © 2020 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.)

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.)

Introduction: Biomarkers of inflammation in blood and sputum can play a critical role in anti-inflammatory drug development in cystic fibrosis (CF). The objectives of this analysis were to examine relationships between airway and systemic measurements of inflammation, associations between inflammatory biomarkers and FEV 1 , differences in airway and systemic inflammation by baseline covariates, reproducibility of serum biomarkers, and to assess the effects of freezing and delayed processing on sputum analyte measurements., Methods: We analyzed baseline and serial concentrations of inflammatory markers in blood and induced sputum collected from individuals with CF ages 10 years and older who participated in a multicenter clinical trial., Results: Among circulating biomarkers, serum high sensitivity C-reactive protein (hsCRP) and serum amyloid A (SAA) correlated most strongly with each other (r s  = 0.85). Comparing sputum-based inflammation measurements, sputum neutrophil elastase and myeloperoxidase (MPO) were the most highly correlated (r s  = 0.88). Markers most strongly correlated with ppFEV 1 were serum hsCRP (r s  = -0.55), SAA (r s =-0.58), and sputum neutrophil elastase (r s  = -0.53). Within-subject standard deviation was consistently lower than between-subject standard deviation for all serum biomarkers. Serum calprotectin and MPO had the highest ratio of between-to-within subject variability. Freezing and delayed sputum processing were not associated with significant differences in measurements of sputum neutrophil elastase, IL-1β, or MPO., Conclusions: Among the biomarkers analyzed, serum hsCRP and sputum neutrophil elastase are promising candidates to include in CF anti-inflammatory clinical trials to avoid redundancy, minimize variation, and serve as correlates of lung disease severity and change., Competing Interests: Declaration of Competing Interest The authors report the following conflicts of interest relevant to this manuscript. A.B., R.J., U.K., and S.S. received grant support from the Cystic Fibrosis Foundation related to this project., (Copyright © 2020. Published by Elsevier B.V.)

Introduction: Symptom improvement was assessed as changes in the Chronic Respiratory Infection Symptom Score (CRISS) during intravenous antimicrobial exacerbation treatments among subjects from study NCT02109822., Methods: Median daily CRISS reduction (i.e., improvement) and covariates associated with CRISS reduction by Day 14 were assessed by logistic regression., Results: Among 173 subjects, median baseline CRISS was 49 [IQR 41, 56]; 93.6% had a CRISS reduction of ≥11 (minimal clinically important difference); median time to -11 reduction was 2 days [95% CI 2, 3]. The greatest median CRISS difference from baseline, on Day 17, was -26 [-29, -23]. Odds of -26 CRISS change by Day 14 were greater in subjects with higher baseline CRISS (P=.006) and younger ages (P=.041)., Conclusions: CRISS response has good dynamic range and may be a useful efficacy endpoint for PEx interventional trials. The optimal use of CRISS change as an endpoint remains uncharacterized., Competing Interests: Declaration of Competing Interest None, (Copyright © 2020 European Cystic Fibrosis Society. 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.)

Background: Circulating biomarkers reflective of lung disease activity and severity have the potential to improve patient care and accelerate drug development in CF. The objective of this study was to leverage banked specimens to test the hypothesis that blood-based biomarkers discriminate CF children segregated by lung disease severity., Methods: Banked serum samples were selected from children who were categorized into two extremes of phenotype associated with lung function ('mild' or 'severe') based on CF-specific data and were matched on age, gender, CFTR genotype, and P. aeruginosa infection status. Targeted inflammatory proteins, lipids, and discovery metabolite profiles were measured in these serum samples., Results: The severe cohort, characterized by a lower CF-specific FEV 1 percentile, had significantly higher circulating concentrations of high sensitivity C-reactive protein, serum amyloid A, granulocyte colony stimulating factor, and calprotectin compared to the mild cohort. The mild cohort tended to have higher serum linoleic acid concentrations. The metabolite arabitol was lower in the severe cohort while other CF relevant metabolic pathways showed non-significant differences after adjusting for multiple comparisons. A sensitivity analysis to correct for biased estimates that may result from selecting subjects using an extremes of phenotype approach confirmed the protein biomarker findings., Conclusions: Circulating inflammatory proteins differ in CF children segregated by lung function. These findings serve to demonstrate the value of maintaining centralized, high quality patient derived samples for future research, with linkage to clinical information to answer testable hypotheses in biomarker development., Competing Interests: Declaration of Competing Interests None of the study authors have any conflicts of interest to disclose beyond the grant funding listed., (Copyright © 2019. Published by Elsevier B.V.)

Background: Biologic pathways and metabolic mechanisms underpinning early systemic disease in cystic fibrosis (CF) are poorly understood. The Baby Observational and Nutrition Study (BONUS) was a prospective multi-center study of infants with CF with a primary aim to examine the current state of nutrition in the first year of life. Its secondary aim was to prospectively explore concurrent nutritional, metabolic, respiratory, infectious, and inflammatory characteristics associated with early CF anthropometric measurements. We report here metabolomics differences within the urine of these infants as compared to infants without CF., Methods: Urine metabolomics was performed for 85 infants with predefined clinical phenotypes at approximately one year of age enrolled in BONUS via Ultrahigh Performance Liquid Chromatography-Tandem Mass Spectroscopy (UPLC-MS/MS). Samples were stratified by disease status (non-CF controls (n = 22); CF (n = 63, All-CF)) and CF clinical phenotype: respiratory hospitalization (CF Resp, n = 22), low length (CF LL, n = 23), and low weight (CF LW, n = 15)., Results: Global urine metabolomics profiles in CF were heterogeneous, however there were distinct metabolic differences between the CF and non-CF groups. Top pathways altered in CF included tRNA charging and methionine degradation. ADCYAP1 and huntingtin were identified as predicted unique regulators of altered metabolic pathways in CF compared to non-CF. Infants with CF displayed alterations in metabolites associated with bile acid homeostasis, pentose sugars, and vitamins., Conclusions: Predicted metabolic pathways and regulators were identified in CF infants compared to non-CF, but metabolic profiles were unable to discriminate between CF phenotypes. Targeted metabolomics provides an opportunity for further understanding of early CF disease., Trial Registration: United States ClinicalTrials.Gov registry NCT01424696 (clinicaltrials.gov)., (Copyright © 2018 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.)