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Background: Effective detection of early lung disease in cystic fibrosis (CF) is critical to understanding early pathogenesis and evaluating early intervention strategies. We aimed to compare ability of several proposed sensitive functional tools to detect early CF lung disease as defined by CT structural disease in school aged children., Methods: 50 CF subjects (mean±SD 11.2 ± 3.5y, range 5-18y) with early lung disease (FEV 1 ≥70 % predicted: 95.7 ± 11.8 %) performed spirometry, Multiple breath washout (MBW, including trapped gas assessment), oscillometry, cardiopulmonary exercise testing (CPET) and simultaneous spirometer-directed low-dose CT imaging. CT data were analysed using well-evaluated fully quantitative software for bronchiectasis and air trapping (AT)., Results: CT bronchiectasis and AT occurred in 24 % and 58 % of patients, respectively. Of the functional tools, MBW detected the highest rates of abnormality: S cond 82 %, MBW TG RV 78 %, LCI 74 %, MBW TG IC 68 % and S acin 51 %. CPET VO 2 peak detected slightly higher rates of abnormality (9 %) than spirometry-based FEV 1 (2 %). For oscillometry AX (14 %) performed better than Rrs (2 %) whereas Xrs and R5-19 failed to detect any abnormality. LCI and S cond correlated with bronchiectasis (r = 0.55-0.64, p < 0.001) and AT (r = 0.73-0.74, p < 0.001). MBW-assessed trapped gas was detectable in 92 % of subjects and concordant with CT-assessed AT in 74 %., Conclusions: Significant structural and functional deficits occur in early CF lung disease, as detected by CT and MBW. For MBW, additional utility, beyond that offered by LCI, was suggested for S cond and MBW-assessed gas trapping. Our study reinforces the complementary nature of these tools and the limited utility of conventional oscillometry and CPET in this setting., Competing Interests: Declaration of competing interest The authors have no conflict of interests to declare, (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Following discovery of the cystic fibrosis transmembrane conductance regulator (CFTR) gene in 1989 and subsequent elucidation of the varied CFTR protein abnormalities that result, a new era of cystic fibrosis management has emerged-one in which scientific principles translated from the bench to the bedside have enabled us to potentially treat the basic defect in the majority of children and adults with cystic fibrosis, with a resultant burgeoning adult cystic fibrosis population. However, the long-term effects of these therapies on the multiple manifestations of cystic fibrosis are still under investigation. Understanding the effects of modulators in populations excluded from clinical trials is also crucial. Furthermore, establishing appropriate disease measures to assess efficacy in the youngest potential trial participants and in those whose post-modulator lung function is in the typical range for people without chronic lung disease is essential for continued drug development. Finally, recognising that a health outcome gap has been created for some people and widened for others who are not eligible for, cannot tolerate, or do not have access to modulators is important., Competing Interests: Declaration of interests In the last 36 months, unrelated to this work, JLT-C has received grants to her institution from the Cystic Fibrosis Foundation (CFF), the National Institutes of Health, Vertex Pharmaceuticals, Eloxx, and 4DMT; she has received fees from Vertex Pharmaceuticals related to consultation on clinical research design, participation on advisory boards, and speaking engagements; and has served on advisory boards or provided clinical trial design consultation for Insmed, 4DMT, and AbbVie. JLT-C has served as chair of a data monitoring committee for AbbVie. She serves as the adult patient care representative to the CFF board of trustees, and on the CFF's clinical research executive committee, clinical research advisory board, as immediate past chair of the Cystic Fibrosis Therapeutics Development Network's Sexual Health, Reproduction and Gender Research working group, and as co-chair of the Heath Equity Team Science Awards study section. She also serves on the scientific advisory board for Emily's Entourage, on the American Thoracis Society Respiratory Health Awards Working Group, and as chair-elect of the International Conference Committee. She is an associate editor for the Journal of Cystic Fibrosis and a member of the international advisory board for The Lancet Respiratory Medicine. She serves on the Clinical Trials Review (CTLR) Study section for the National Institutes of Health National Heart, Lung, and Blood Institute. PDR reports that his previous institution, The Children's Hospital at Westmead, Sydney, has received remuneration for services provided by the Australian Central Over-Reading Centre he established for pharmaceutical-sponsored and investigator-led studies in cystic fibrosis. This renumeration will also be the case for his current institution (the University of Queensland) moving forward. MS has received grants and research support from: GSK, Insmed, Novartis, Trudell Pharma, Tel Aviv League for Lung Diseases; consultation fees from AstraZeneca, Boehringer Ingelheim, Dexcel, GSK, Kamada, Syncrony Medical, Trumed, Zambon; and speaker's fees from AstraZeneca, Boeringer Ingelheim, GSK, Kamada, Novartis, PhysioAssist, Sanofi, and Teva. MS serves as a data and safety monitoring board member for Bonus Biotherapeutics. MS is a member of management board of EMBARC, a member of the executive committee of the Israel Society for TB and Mycobacterial Diseases, an associate editor for the American Journal of Respiratory and Critical Care Medicine, and an editorial board member for the European Respiratory Journal and Chest. DGD reports grants from Chiesi Farmaceutici, the CF Trust, and the CFF to his institution. He reports consulting fees from Vertex and Insmed; and payments from Chiesi and Gilead for presentations. DGD receives support from the European Cystic Fibrosis Society and CFF for travel to meetings. He participates on a data and safety monitoring board for the Nomab trial and CSL Behring. He serves on the research oversight scientific board for the UK Clinical Trials Accelerator Platform and is the Director of the European Cystic Fibrosis Society Clinical Trials Network., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Objectives: Telehealth and home spirometry feasibility for children has been established, but their impact on cystic fibrosis (CF) disease progression remains unassessed. We aimed to evaluate the effects of telehealth and home spirometry on CF disease progression and care., Methods: Children with CF aged 5-17 years from all Swedish CF centers were provided with home spirometers. A minimum of two in-person visits were replaced with telemedicine visits and participants were instructed to conduct home spirometry before visits. Linear mixed-effects models were used to compare annual CF disease trajectories during the intervention period and prepandemic period (1 January 2019 to 28 February 2020). Participants and caregivers completed study questionnaires., Results: A total of 59 individuals completed the study over a mean (SD) period of 6.8 (1.4) months, made 3.1 (1.0) physical visits and 2.2 (0.6) telehealth visits per patient year during the study period. The mean difference (95% CI) between the intervention and prepandemic period progression rate for FEV 1 %, lung clearance index and BMI were -0.4 (-1.3 to 0.5, p = 0.39), 0.11 (-0.07 to 0.28, p = 0.25) and -0.02 (-0.13 to 0.08, p = 0.70), respectively. There were no major shifts in the incidence of airway pathogens, sputum cultures, or antibiotics use between the periods (p > 0.05). The intervention did not increase stress. Almost all participants and caregivers expressed a desire to continue with home spirometry and telemedicine., Conclusion: Combining telehealth and physical visits with access to home spirometry demonstrated comparable effectiveness as exclusively in-person care with enhanced flexibility and personalization of CF care., (© 2024 The Author(s). Pediatric Pulmonology published by Wiley Periodicals LLC.)

Rationale: Lung T1 MRI is a potential method to assess cystic fibrosis (CF) lung disease that is safe, quick, and widely available, but there are no data in children with mild CF lung disease., Objective: Assess the ability of lung T1 MRI to detect abnormalities in children with mild CF lung disease., Methods: We performed T1 MRI, multiple breath washout (MBW), chest computed tomography (CT), and spirometry in a cohort of 45 children with mild CF lung disease (6-11 years of age)., Main Results: Despite mean normal ppFEV1 values, the majority of children with CF in this study exhibited mild lung disease evident in lung clearance index (LCI) measured by MBW, chest CT Brody scores, and percent normal lung perfusion (%NLP) measured by T1 MRI. The %NLP correlated with chest CT Brody scores, as did LCI, but %NLP and LCI did not correlate with each other. Analysis of the Brody subscores showed that %NLP and LCI largely correlated with different Brody subscores., Conclusions: T1 MRI can detect mild CF lung disease in children and correlates with chest CT findings. The %NLP from T1 MRI and LCI correlate with different chest CT Brody subscores, suggesting they provide complementary information about CF lung disease., (© 2024 The Authors. Pediatric Pulmonology published by Wiley Periodicals LLC.)

Haemoptysis occurs in up to 25 % of young people with Cystic fibrosis (CF) [1]. We undertook a literature review and described the management approach to haemoptysis in CF between 2010 and 2020 at an Australian tertiary paediatric centre, The Children's Hospital Westmead, Sydney, New South Wales, using a retrospective review of the medical records which identified 67 episodes. Sixty episodes met inclusion criteria, including 31 patients. Using the US CF Foundation guidelines, episodes were classified as scant (53.3 %), moderate (38.3 %) or massive (8.3 %). Fifty-two percent of patients were female, mean age at presentation was 15.4 years (SD+/- 2.4) and 58 % were homozygous for the Fdel508 genotype. Twelve episodes (9 patients) required bronchial artery embolization (BAE). BAE was used in all cases of massive haemoptysis 5/5 (100 %), 6/23 (22 %) episodes of moderate and 1/32 (3 %) episode of scant haemoptysis as an elective procedure for recurrent haemoptysis. Our literature review and institutional experience highlights the need for up-to-date management guidelines in the management of haemoptysis in Cystic Fibrosis. Based on our experience, we provide a proposed algorithm to help guide the management of haemoptysis in CF., Competing Interests: Conflict of Interest The authors have no conflict of interest to disclose., (Copyright © 2022. Published by Elsevier Ltd.)

Introduction: Multiple breath washout (MBW) is used for early detection of cystic fibrosis (CF) lung disease, with SF 6 MBW commonly viewed as the reference method. The use of N 2 MBW in infants and toddlers has been questioned for technical and physiological reasons, but a new correction of the N 2  signal has minimized the technical part. The present study aimed to assess the remaining differences and the contributing mechanisms for the differences between SF 6 and N 2 MBW,corrected-such as tidal volume reduction during N 2 washout with pure O 2 ., Method: This was a longitudinal multicenter cohort study. SF 6 MBW and N 2 MBW were performed prospectively at three CF centers in the same visits on 154 test occasions across 62 children with CF (mean age: 22.7 months). Offline analysis using identical algorithms to the commercially available program provided outcomes of N 2,original and N 2,corrected for comparison with SF 6 MBW., Results: Mean functional residual capacity, FRC N2,corrected was 14.3% lower than FRC N2, original , and 1.0% different from FRC SF6 . Lung clearance index, LCI N2,corrected was 25.2% lower than LCI N2,original , and 7.3% higher than LCI SF6 . Mean (SD) tidal volume decreased significantly during N 2 MBW corrected , compared to SF 6 MBW (-13.1 ml [-30.7; 4.6], p < 0.0001, equal to -12.0% [-25.7; 1.73]), but this tidal volume reduction did not correlate to the differences between LCI N2,corrected and LCI SF6 . The absolute differences in LCI increased significantly with higher LCI SF6 (0.63/LCI SF6 ) and (0.23/LCI SF6 ), respectively, for N 2,original and N 2,corrected , but the relative differences were stable across disease severity for N 2,corrected , but not for N 2,original ., Conclusion: Only minor residual differences between FRC N2,corrected and FRC SF6 remained to show that the two methods measure gas volumes very similar in this age range. Small differences in LCI were found. Tidal volume reduction during N 2 MBW did not affect differences. The corrected N 2 MBW can now be used with confidence in young children with CF, although not interchangeably with SF 6 ., (© 2022 Wiley Periodicals LLC.)

Cystic fibrosis (CF) lung disease is characterized by increased ventilation inhomogeneity (VI), as measured by multiple-breath washout (MBW). Lung clearance index (LCI) is the most reported VI outcome. This study aimed to evaluate historically published reference equations for sulfur hexafluoride (SF 6 ) MBW outcomes, to data collected using updated commercial SF 6 MBW equipment, and to produce device-specific equations if necessary. SF 6 MBW was performed in 327 healthy children aged 0.1-18.4 yr [151 (46%) girls], 191 (58.4%) <3 yr. z-Scores were calculated from published reference equations (FRC and LCI) and multivariate linear regression was performed to produce device-specific reference equations. Due to increasing residual standard deviations with increasing LCI values, investigation of methods for improvement were investigated, based on the relationship between VI and dead space ventilation (VD/VT; dead space volume/tidal volume) in a cohort of 59 healthy children, 26 children with CF ( n = 138 test occasions), and 49 adults with lung disease. Historical SF 6 MBW reference equations were unsuitable for EXHALYZER D data. In contrast to LCI and log 10 (LCI), 1/LCI (ventilation distribution efficiency; VDE) was linearly related to VD/VT, with z-scores linearly related to its absolute values. Reference equations were reported for VDE and log 10 (FRC). Significant predictors for VDE and log 10 (FRC), respectively, were log 10 (age) and sex, and log 10 (height), sex, and posture. VDE is potentially a better index of VI than LCI, particularly in more advanced CF lung disease and also for longitudinal monitoring. Further confirmatory clinical studies, particularly longitudinal imaging studies of structural or ventilatory changes, are warranted. NEW & NOTEWORTHY Lung clearance index (LCI) is the most used outcome from the multiple-breath washout test. As known for decades, the LCI is not linearly related to dead space ventilation, giving difficulties interpreting changes over time and in clinical trials. We present a new and improved outcome based on LCI, the ventilation distribution efficiency (VDE), which solves this problem by being linearly related to dead space ventilation. A pediatric age range reference equation for VDE is presented.

Background: Nontuberculous Mycobacterium infections, particularly Mycobacterium abscessus, are increasingly common among patients with cystic fibrosis and chronic bronchiectatic lung diseases. Treatment is challenging due to intrinsic antibiotic resistance. Bacteriophage therapy represents a potentially novel approach. Relatively few active lytic phages are available and there is great variation in phage susceptibilities among M. abscessus isolates, requiring personalized phage identification., Methods: Mycobacterium isolates from 200 culture-positive patients with symptomatic disease were screened for phage susceptibilities. One or more lytic phages were identified for 55 isolates. Phages were administered intravenously, by aerosolization, or both to 20 patients on a compassionate use basis and patients were monitored for adverse reactions, clinical and microbiologic responses, the emergence of phage resistance, and phage neutralization in serum, sputum, or bronchoalveolar lavage fluid., Results: No adverse reactions attributed to therapy were seen in any patient regardless of the pathogen, phages administered, or the route of delivery. Favorable clinical or microbiological responses were observed in 11 patients. Neutralizing antibodies were identified in serum after initiation of phage delivery intravenously in 8 patients, potentially contributing to lack of treatment response in 4 cases, but were not consistently associated with unfavorable responses in others. Eleven patients were treated with only a single phage, and no phage resistance was observed in any of these., Conclusions: Phage treatment of Mycobacterium infections is challenging due to the limited repertoire of therapeutically useful phages, but favorable clinical outcomes in patients lacking any other treatment options support continued development of adjunctive phage therapy for some mycobacterial infections., Competing Interests: Potential conflicts of interest. G. F. H. is a consultant for and receives grant support not directly related to this work from Janssen Pharmaceuticals (Collaborative Research Agreement); reports consulting fees from Janssen Inc and Tessera Inc; and reports presentation honoraria from the Pittsburgh Foundation and a leadership or fiduciary role with the Charles E. Kaufman Foundation scientific advisory board. R. M. De. and G. F. H. are co-inventors on patent applications related to the use of phages for treating nontuberculous mycobacterial (NTM) infections filed by the University of Pittsburgh of the Commonwealth System of Higher Education. D. v. D. is a consultant for Actavis, Tetraphase, Sanofi Pasteur, MedImmune, Astellas, Merck, Allergan, T2Biosystems, Roche, Achaogen, Neumedicine, Shionogi, Pfizer, Entasis, QPex, Wellspring, Karius, Melinta, and Utility; receives an editor’s stipend from British Society for Antimicrobial Chemotherapy; has received funding for unrelated projects from NIH, Merck, and Shionogi; reports payments for lectures, presentations, speaker’s bureaus, manuscript writing, or educational events from Pfizer and Entasis; reports paid participation on a data and safety monitoring board (DSMB) or advisory board for Utility, Union, Entasis, and Merck; and reports a paid leadership or fiduciary role with the British Society for Antimicrobial Chemotherapy. K. A. C. has received consulting fees from Insmed (clinical trial site), Hillrom (clinical trial site), Paratek, Microbion, and AN2, and reports honoraria for a presentation from Insmed. G. H. receives grant support unrelated to this study from Karius, Allovir, and AstraZeneca, and reports participation on a DSMB or advisory board with Karius. R. T. S. is a paid consultant to Vir Biotechnology and to LysNtech; holds stock options in Antiva Biosciences and CytoDyn and stock or stock options with NoniGenex and Arcturus; previously served as an uncompensated member of the AmpliPhi scientific advisory board; reports grants or contracts paid to institution from the National Institute of Allergy and Infectious Diseases; reports consulting fees from Pfizer, Sempra Energy, and Nurix; has patents planned, issued, or pending for orally bioavailable anti-coronavirus compounds; reports paid participation on DSMBs or advisory boards for Merck, VIr Biosciences, SNIPR Biome, and Pardes Biosciences; and holds leadership or fiduciary roles with the International Antiviral Society (IAS)–USA and Specialists in Global Health. C. A. B. reports contracts to institution for clinical trials from Gilead and DNAe; payment to author for educational lectures from IAS-USA, Practice Point Communications (Optimal Management of HIV Disease and Hepatitis Clinical Conference [OPMAN] conference), and University of Arizona; has received payment for travel to the OPMAN conference from Practice Point Communications; served on a DSMB for ViiV/GlaxoSmith Kline; has held unpaid volunteer roles with IAS-USA and the Conference on Retroviruses and Opportunistic Infections Foundation Board; and has served as Deputy Editor/Associate Editor for the Infectious Diseases Society of America. A. K. reports the following grants or contracts unrelated to this work: National Health and Medical Research Council (NHMRC, Australia) Investigator Grant at Emerging Leadership 1 level, Conquer CF, Innovation Grant from Cystic Fibrosis Australia, Research Establishment Fellowship from the Royal Australasian College of Physicians and Research Award from the Australasian Society for Infectious Diseases (all paid to institution); payment to institution for grant application review for the Italian Cystic Fibrosis Research Foundation; unpaid role as member of DSMB for FluBubs (Safety and Immunogenicity of Early Quadrivalent Influenza Vaccine); unpaid leadership or fiduciary roles as Deputy Director (Clinical) of Phage Australia, pediatric infectious diseases research representative on the Australian Society for Infectious Diseases Clinical Research Network Steering Committee and the Australia and New Zealand Paediatric Infectious Diseases Group Executive Committee, member of the Sydney Children’s Hospitals Network Human Research Ethics Committee Scientific Advisory Committee, and member of the Sydney Children’s Hospitals Network Advanced Therapeutics Steering Committee. A. W. B. reports a role as a part-time employee of the Cystic Fibrosis Foundation, which provides some grant support to G. F. H.’s laboratory and, for the purposes of this manuscript, is the treating physician of one of the NTM patients in the cystic fibrosis clinic at Inova Fairfax Hospital. C. B. G. reports consulting fees from Advisory Janssen. B. J. M. reports an NHMRC Investigator Grant and philanthropic grant from the Curing Homesickness Foundation, both paid to institution and unrelated to this work; unpaid participation as member of the DSMB for the PATRIC trial; and unpaid position as board director of the Australasian Society for Infectious Diseases. M. G. T. O. reports a Cystic Fibrosis Foundation Adult Center Award and Cystic Fibrosis Foundation Therapeutic Development Center Award, unrelated to this work; support for attending meetings and/or travel, paid to University of Miami, from the Cystic Fibrosis Foundation Adult Center Award for attending North American Cystic Fibrosis Conference and a Cystic Fibrosis Foundation Therapeutic Development Center Award for attending the Therapeutics Development Network spring meeting; and an unpaid position as Cystic Fibrosis Lifestyle Foundation board member. J. I. reports an Investigator Grant (personal support) unrelated to this work from NHMRC. A. M. reports consulting fees paid to author as a member of the Air Liquide Advisory Board. J. A. N. reports contracts or grants unrelated to this work from the Cystic Fibrosis Foundation. M. S. reports funding on a project to set up a phage therapy laboratory in Finland, unrelated to this work, from the Jane and Aatos Erkko Foundation. P. W. reports consulting fees from AstraZeneca, GlaxoSmithKline, Pfizer, Sanofi Regeneron, and Vertex; payment or honoraria for lectures, presentations, speaker’s bureaus, manuscript writing, or educational events from AstraZeneca, GlaxoSmithKline, Pfizer, Boehringer Ingelheim, and Vertex; and a leadership or fiduciary role with the Cystic Fibrosis Australia National Asthma Council of Australia. D. E. M. reports stock or stock options (no payments) with Moderna (1 share) and Pfizer (5 shares). R. M. Da. reports grants from the NIH unrelated to this work (grant number K01-AI125726 [principal investigator]). All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Infectious Diseases Society of America.)

Rationale: The triple-combination regimen elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) was shown to be safe and efficacious in children aged 6 through 11 years with cystic fibrosis and at least one F508del-CFTR allele in a phase 3, open-label, single-arm study. Objectives: To further evaluate the efficacy and safety of ELX/TEZ/IVA in children 6 through 11 years of age with cystic fibrosis heterozygous for F508del and a minimal function CFTR mutation ( F /MF genotypes) in a randomized, double-blind, placebo-controlled phase 3b trial. Methods: Children were randomized to receive either ELX/TEZ/IVA ( n  = 60) or placebo ( n  = 61) during a 24-week treatment period. The dose of ELX/TEZ/IVA administered was based on weight at screening, with children <30 kg receiving ELX 100 mg once daily, TEZ 50 mg once daily, and IVA 75 mg every 12 hours, and children ⩾30 kg receiving ELX 200 mg once daily, TEZ 100 mg once daily, and IVA 150 mg every 12 hours (adult dose). Measurements and Main Results: The primary endpoint was absolute change in lung clearance index 2.5 from baseline through Week 24. Children given ELX/TEZ/IVA had a mean decrease in lung clearance index 2.5 of 2.29 units (95% confidence interval [CI], 1.97-2.60) compared with 0.02 units (95% CI, -0.29 to 0.34) in children given placebo (between-group treatment difference, -2.26 units; 95% CI, -2.71 to -1.81; P  < 0.0001). ELX/TEZ/IVA treatment also led to improvements in the secondary endpoint of sweat chloride concentration (between-group treatment difference, -51.2 mmol/L; 95% CI, -55.3 to -47.1) and in the other endpoints of percent predicted FEV 1 (between-group treatment difference, 11.0 percentage points; 95% CI, 6.9-15.1) and Cystic Fibrosis Questionnaire-Revised Respiratory domain score (between-group treatment difference, 5.5 points; 95% CI, 1.0-10.0) compared with placebo from baseline through Week 24. The most common adverse events in children receiving ELX/TEZ/IVA were headache and cough (30.0% and 23.3%, respectively); most adverse events were mild or moderate in severity. Conclusions: In this first randomized, controlled study of a cystic fibrosis transmembrane conductance regulator modulator conducted in children 6 through 11 years of age with F /MF genotypes, ELX/TEZ/IVA treatment led to significant improvements in lung function, as well as robust improvements in respiratory symptoms and cystic fibrosis transmembrane conductance regulator function. ELX/TEZ/IVA was generally safe and well tolerated in this pediatric population with no new safety findings.

Background: Children with cystic fibrosis (CF) pulmonary exacerbations receive IV tobramycin therapy, with dosing guided by either log-linear regression (LLR) or Bayesian forecasting (BF)., Objectives: To compare clinical and performance outcomes for LLR and BF., Patients and Methods: A quasi-experimental intervention study was conducted at a tertiary children's hospital. Electronic medical records were extracted (from January 2015 to September 2021) to establish a database consisting of pre-intervention (LLR) and post-intervention (BF) patient admissions and relevant outcomes. All consecutive patients treated with IV tobramycin for CF pulmonary exacerbations guided by either LLR or BF were eligible., Results: A total of 376 hospital admissions (LLR = 248, BF = 128) for CF pulmonary exacerbations were included. Patient demographics were similar between cohorts. There were no significant differences found in overall hospital length of stay, rates of re-admission within 1 month of discharge or change in forced expiratory volume in the first second (Δ FEV1) at the end of tobramycin treatment. Patients treated with LLR on average had twice the number of therapeutic drug monitoring (TDM) blood samples collected during a single hospital admission. The timeframe for blood sampling was more flexible with BF, with TDM samples collected up to 16 h post-tobramycin dose compared with 10 h for LLR. The tobramycin AUC0-24 target of ≥100 mg/L·h was more frequently attained using BF (72%; 92/128) compared with LLR (50%; 124/248) (P < 0.001). Incidence of acute kidney injury was rare in both groups., Conclusions: LLR and BF result in comparable clinical outcomes. However, BF can significantly reduce the number of blood collections required during each admission, improve dosing accuracy, and provide more reliable target concentration attainment in CF children., (© The Author(s) 2022. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Can physiotherapy with a positive expiratory pressure (PEP) mask improve peripheral ventilation inhomogeneity, a typical feature of children with cystic fibrosis (cwCF)? To answer this question, we used the nitrogen multiple-breath washout (N 2 MBW) test to measure diffusion-convection-dependent inhomogeneity arising within the intracinar compartment (S acin *VT)., Methods: For this randomized, sham-controlled crossover trial, two N 2 MBW tests were performed near the hospital discharge date: one before and the other after PEP mask therapy (1 min of breathing through a flow-dependent PEP device attached to a face mask, followed by three huffs and one cough repeated 10 times) by either a standard (10-15 cmH 2 0) or a sham (<5 cmH 2 0) procedure on two consecutive mornings. Deception entailed misinforming the subjects about the nature of the study; also the N 2 MBW operators were blinded to treatment allocation. Study outcomes were assessed with mixed-effect models., Results: The study sample was 19 cwCF (ten girls), aged 11.4 (2.7) years. The adjusted S acin *VT mean difference between the standard and the sham procedure was -0.015 (90% confidence interval [CI]: -∞ to 0.025) L -1 . There was no statistically significant difference in S cond *VT and lung clearance index between the two procedures: -0.005 (95% CI: -0.019 to 0.01) L -1 and 0.49 (95% CI: -0.05 to 1.03) turnovers, respectively., Conclusion: Our findings do not support evidence for an immediate effect of PEP mask physiotherapy on S acin *VT with pressure range 10-15 cmH 2 0. Measurement with the N 2 MBW and the crossover design were found to be time-consuming and unsuitable for a short-term study of airway clearance techniques., (© 2024 The Authors. Pediatric Pulmonology published by Wiley Periodicals LLC.)

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

Background: Adding a slow vital capacity (SVC) to multiple breath washout (MBW) allows quantification of otherwise overlooked signal from under/un-ventilated lung units (UVLU) and may provide a more comprehensive assessment of airway disease than conventional lung clearance index (LCI 2.5 )., Methods: We conducted a pilot study on people undergoing MBW tests: 10 healthy controls (HC) and 43 cystic fibrosis (CF) subjects performed an SVC after the standard end of test. We term the new outcome LCI with Short extension (LCI ShX ). We assessed (i) CF/ HC differences, (ii) variability (iii) effect of pulmonary exacerbation (PEx)/treatment and (iv) relationship with CF computed tomography (CFCT) scores., Results: HC/ CF group differences were larger with LCI ShX than LCI 2.5 (P<0.001). Within the CF group UVLU was highly variable and when abnormal it did not correlate with corresponding LCI 2.5 . Signal showed little variability during clinical stability (n = 11 CF; 2 visits; median inter-test variability 2.6% LCI ShX, 2.5% LCI 2.5 ). PEx signal was significantly greater for LCI ShX both for onset and resolution. Both MBW parameters correlated significantly with total lung CT scores and hyperinflation but only LCI ShX correlated with mucus plugging., Conclusions: UVLU captured within the LCI ShX varies between individuals; the lack of relationship with LCI 2.5 demonstrates that new, additional information is being captured. LCI ShX repeatability during clinical stability combined with its larger signal around episodes of PEx may lend it superior sensitivity as an outcome measure. Further studies will build on this pilot data to fully establish its utility in monitoring disease status., Competing Interests: Declaration of Competing Interest Christopher Short, Clare Saunders, Dominic Hughes, Samantha Irving, Laura Gardener, Mark Rosenthal and Paul Robinson report no conflicts of interest. Thomas Semple reports speakers fees - Vertex Pharmaceuticals. Research grants – Chiesi Pharmaceuticals. Consultancy fees - Boehringer-Ingelheim and Calyx. Prof. Jane Davies has performed clinical trial leadership roles, educational and/ or advisory activities for the following: Abbvie, Algipharma AS, Bayer AG, Boehringer Ingelheim Pharma GmbH & Co. KG, Eloxx, Enterprise, Galapagos NV, ImevaX GmbH, Ionis, Nivalis Therapeutics, Inc., Novartis, ProQR Therapeutics III B.V., Proteostasis Therapeutics, INC., Pulmocide Raptor Pharmaceuticals, Inc, Vertex Pharmaceuticals., (Copyright © 2021. Published by Elsevier B.V.)

Structural and functional defects within the lungs of children with cystic fibrosis (CF) are detectable soon after birth and progress throughout preschool years often without overt clinical signs or symptoms. By school age, most children have structural changes such as bronchiectasis or gas trapping/hypoperfusion and lung function abnormalities that persist into later life. Despite improved survival, gains in forced expiratory volume in one second (FEV 1 ) achieved across successive birth cohorts during childhood have plateaued, and rates of FEV 1 decline in adolescence and adulthood have not slowed. This suggests that interventions aimed at preventing lung disease should be targeted to mild disease and commence in early life. Spirometry-based classifications of 'normal' (FEV 1 ≥90% predicted) and 'mild lung disease' (FEV 1 70%-89% predicted) are inappropriate, given the failure of spirometry to detect significant structural or functional abnormalities shown by more sensitive imaging and lung function techniques. The state and readiness of two imaging (CT and MRI) and two functional (multiple breath washout and oscillometry) tools for the detection and monitoring of early lung disease in children and adults with CF are discussed in this article.Prospective research programmes and technological advances in these techniques mean that well-designed interventional trials in early lung disease, particularly in young children and infants, are possible. Age appropriate, randomised controlled trials are critical to determine the safety, efficacy and best use of new therapies in young children. Regulatory bodies continue to approve medications in young children based on safety data alone and extrapolation of efficacy results from older age groups. Harnessing the complementary information from structural and functional tools, with measures of inflammation and infection, will significantly advance our understanding of early CF lung disease pathophysiology and responses to therapy. Defining clinical utility for these novel techniques will require effective collaboration across multiple disciplines to address important remaining research questions. Future impact on existing management burden for patients with CF and their family must be considered, assessed and minimised.To address the possible role of these techniques in early lung disease, a meeting of international leaders and experts in the field was convened in August 2019 at the Australiasian Cystic Fibrosis Conference. The meeting entitiled 'Shaping imaging and functional testing for early disease detection of lung disease in Cystic Fibrosis', was attended by representatives across the range of disciplines involved in modern CF care. This document summarises the proceedings, key priorities and important research questions highlighted., Competing Interests: Competing interests: TR reports personal fees from Vertex Pharmaceuticals during the conduct of the study; in addition, TR has a patent PCT/AU2016/000079 issued. JCD reports others from Algipharma AS, Bayer AG, Boehringer Ingelheim Pharma GmbH & Co. KG, Galapagos NV, ImevaX GmbH, Nivalis Therapeutics, Inc., ProQR Therapeutics III B.V., Proteostasis Therapeutics, Inc., Raptor Pharmaceuticals, Inc, Vertex Pharmaceuticals (Europe) Limited, Enterprise, Novartis, Pulmocide and Flatley; grants from CF Trust; and others from Teva, outside the submitted work. JSE reports grants from Ionis and the European Commission; personal fees and others from Vertex, during the conduct of the study. MM reports grants from the German Federal Ministry of Education and Research and Einstein Foundation Berlin, during the conduct of the study; personal fees and others from Boehringer Ingelheim and Vertex Pharmaceuticals; personal fees from Arrowhead Pharmaceuticals, Santhera, Galapagos, Sterna Biologicals, Enterprise Therapeutics and Antabio, outside the submitted work. FR reports non-financial support from Vertex during the conduct of the study and acts as a consultant to Vertex Pharmaceuticals, who was the sponsor of this meeting. ARS reports grants from Vertex and personal fees from Novartis, Teva and Vertex, outside the submitted work; and patent issued: 'Alkyl quinolones as biomarkers of Pseudomonas aeruginosa infection and uses thereof'. SS reports a patent licensed to Thirona, and a patent licensed to Resonance Health Ltd and Institutional reimbursement from Vertex Pharmaceuticals (Australia) Pty Ltd. for Steering Committee Member duties organising SHIFT at the Australasian Cystic Fibrosis Conference 2019, Perth. CEW reports institutional reimbursement from Vertex Pharmaceuticals (Australia) P/L for Steering Committee Member duties organising SHIFT at the Australasian Cystic Fibrosis Conference 2019, Perth; income on a per patient basis derived from Pharmaceutical Studies - Vertex Pharmaceuticals Inc., and Boehringer-Ingelheim; research grant from Novo Nordisk Pharmaceuticals P/L- CF-IDEA Study; other reimbursements from Vertex Pharmaceuticals P/L honorarium to attend CF International Advisory Board Meeting in February 2014, Vertex Pharmaceuticals P/L honorarium to attend CF Medical Advisory Board Meeting in Adelaide in April 2014, Novartis Pharmaceuticals P/L honorarium to present symposium at National Pediatric Congress in Lebanon in May 2014, European CF Conference in Gothenburg June 2014 Vertex Pharmaceuticals P/L return travel and honorarium for lecture and discussions, North American CF Conference Georgia October 2014 DKBmed, LLC honorarium to present symposium, Vertex Pharmaceuticals P/L honorarium to present as speaker in an educational meeting series in Brisbane and Sydney in April 2015, Vertex Pharmaceuticals P/L honorarium to attend the Vertex Steering Committee Meetings re VX15-770-123 Study in 2014, Vertex Pharmaceuticals P/L honorarium for Vertex Medical Advisory Board- Innovative endpoints in CF in August 2015, The University of Miami honorarium for meeting attendance in 2015, Thorax honorarium for associate editor duties Q3/Q4 2015, BMJ honorarium for work as reviewer, Vertex Pharmaceuticals 2015 Chicago return flight and accommodation as investigator in Lumacaftor study, Vertex Pharmaceuticals 2015–2017 honorarium as speaker at Vertex sponsored educational meeting series in Australia, Vertex Pharmaceuticals 2016 Phoenix return flight and accommodation as investigator in Next Gen study, Vertex Pharmaceuticals December 2016 honoraria as speaker at Vertex sponsored educational meeting in Liverpool, UK DKBmed eCF Review Issue honoraria in January 2017, Vertex Pharmaceuticals–March 2017 honoraria as speaker at TSANZ meeting Vertex Pharmaceuticals Inc. 2014–2018, honorarium for acting as consultant on the Vertex Orkambi 6-11 HTA Advisory Board, the Global Pediatric Advisory Committee, the Global Medical Advisory Board, and the VIA Grants Committee; Gilead Sciences Ltd. honorarium for meeting attendance on CF imaging; Honorarium for In Vivo Academy Limited for webcast meeting attendance at ECFC–2018; Vertex Pharmaceuticals P/L honorarium to present as speaker in an educational meeting at ECFC in Belgrade–2018; Vertex Pharmaceuticals Inc. honorarium to attend Next Gen Early Lifecycle Management Plan–London–2018; Vertex Pharmaceuticals P/L to act as consultant and to render such services in the form of documents, advice, meetings and conferences during the period October 2018; present Vertex Pharmaceuticals P/L to attend the EU Real World Evidence Steering Committee in Amsterdam–2019 Current Board Positions–International Advisory Board Vertex Pharmaceuticals P/L Deputy Editor Thorax /Associate Editor Respirology. PDR reports institutional reimbursement from Vertex Pharmaceuticals (Australia) Pty. Ltd for Steering Committee Member duties organising SHIFT at the Australasian Cystic Fibrosis Conference 2019, Perth., (© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Elexacaftor-tezacaftor-ivacaftor (ETI) is a highly effective cystic fibrosis (CF) transmembrane conductance regulator (CFTR) modulating therapy for people with CF and at least one F508del variant. However, there is limited data about the safety and efficacy of this therapy in pediatric populations and in real-world settings. This study aimed at evaluating the effectiveness, tolerability, and safety of ETI in children with CF., Methods: This was a prospective observational study including all children aged 6-11 years who initiated ETI therapy between October 2022 and March 2023 at the Pediatric CF Center of Milan (Italy). Study outcomes included changes in sweat chloride concentration, FEV 1 , LCI 2.5 , body mass index (BMI), tolerance, and safety. Mean changes in study outcomes from baseline through 24 weeks were estimated using mixed-effects regression models., Results: The study included 34 children with CF (median age: 8.3 years). At Week 12, we observed an average decrease in LCI 2.5 of 2.3 units (95% confidence interval [CI]: -3.1; -1.5). At Week 24, sweat chloride concentration decreased by 63 mEq/L (95% CI: -69; -58), FEV 1 increased by 8.8 percentage point (95% CI: 3.7; 13.9) and BMI increased by 0.15 standard deviation scores (95% CI: 0.04; 0.25). Skin rashes appeared in 6 patients which spontaneously resolved within a few days. One month after treatment initiation, one patient experienced an elevation in liver function test results, which subsequently decreased during follow-up visits without necessitating discontinuation of therapy., Conclusions: Our data indicate that ETI therapy is well tolerated by children with CF and is effective in improving signs of lung function abnormalities from early childhood., (© 2024 The Author(s). Pediatric Pulmonology published by Wiley Periodicals LLC.)

Gene therapy for CF has concentrated on targeting the lung. Here we took a different approach by injecting into the cephalic vein and spraying into the trachea of G551D, CF ferrets either AAV1 or 6 containing Δ27-264-CFTR, a truncated version of CFTR. Treatment with the potentiator VX-770 was halted for 7 days before instillation to induce a disease phenotype. Indeed, all ferrets were pancreas-insufficient when they entered the study. Four ferrets (three receiving AAV1 and one AAV6) were necropsied 48 days after vector delivery, and four (three receiving AAV6, one AAV1) were euthanized or died prior to the planned necropsy. AAV1 or AAV6 vector genomes, mRNA expression, and CFTR protein were detected in all tracheal and lung samples and in the liver, pancreas, and ileum of the treated ferrets. Surface and basal airway cells, pancreatic and bile ducts, and ileal crypts and villi were successfully transduced. Obstruction of the airways accompanied by pulmonary hemorrhaging, plugged pancreatic and bile ducts as well as mucous plugs in the ileum were noticed in untreated but absent from transduced ferrets necropsied at 48 days. Transduction of G551D ferrets suggests that a combination of systemic and airway application may be the preferred route of delivery for CF., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

The vast majority of people with cystic fibrosis (pwCF) have untreated secondary chronic rhinosinusitis (CRS). Whereas the introduction of the cystic fibrosis transmembrane conductance regulator modulator (CFTRm) treatment regime has improved the lung function of pwCF, few studies have been published examining the effect on sinonasal symptoms in children. Our aim was to explore the effect of double CFTRm treatment on CRS and olfaction in children with CF. pwCF were included in this non-randomized cross-sectional study, where an otolaryngologist performed a complete ENT examination before initiating treatment with elaxacaftor/tezacaftor/ivacaftor (ETI). Twenty-three pwCF aged 6-12 years were included. Eighteen of 23 patients were on a double CFTRm treatment, and 5 patients were CFTRm naive, respectively. Altogether, 19 had normal olfaction, 20 had none or mild CRS symptoms according to SNOT-22, and 14 had a normal endoscopy. None of the patients had symptoms of chronic rhinosinusitis lasting for more than 12 weeks, thus none of the patients fulfilled the criteria for CRS. Children with CF treated with double CFTRm have few to no symptoms of CRS and normal olfaction, which is an improvement compared with children following treatment modalities prior to CFTRm., (© 2024 The Authors. APMIS published by John Wiley & Sons Ltd on behalf of Scandinavian Societies for Pathology, Medical Microbiology and Immunology.)

Current cystic fibrosis (CF) treatment strategies are primarily focused on oral/inhaled anti-inflammatories and antibiotics, resulting in a considerable treatment burden for CF patients. Therefore, combination treatments consisting of anti-inflammatories with antibiotics could reduce the CF treatment burden. However, there is an imperative need to understand the potential drug-drug interactions of these combination treatments to determine their efficacy. Thus, this study aimed to determine the interactions of the anti-inflammatory agent Ibuprofen with each of the CF-approved inhaled antibiotics (Tobramycin, Colistin and its prodrug colistimethate sodium/Tadim) and anti-bacterial and anti-inflammatory efficacy. Chemical interactions of the Ibuprofen:antibiotic combinations were elucidated using High-Resolution Mass-Spectrometry (HRMS) and 1 H NMR. HRMS showed pairing of Ibuprofen and Tobramycin, further confirmed by 1 H NMR whilst no pairing was observed for either Ibuprofen:Colistin or Ibuprofen:Tadim combinations. The anti-bacterial activity of the combinations against Pseudomonas aeruginosa showed that neither paired nor non-paired Ibuprofen:antibiotic therapies altered the anti-bacterial activity. The anti-inflammatory efficacy of the combination therapies was next determined at two different concentrations (Low and High) using in vitro models of NuLi-1 (healthy) and CuFi-1 (CF) cell lines. Differential response in the anti-inflammatory efficacy of Ibuprofen:Tobramycin combination was observed between the two concentrations due to changes in the structural conformation of the paired Ibuprofen:Tobramycin complex at High concentration, confirmed by 1 H NMR. In contrast, the non-pairing of the Ibuprofen:Colistin and Ibuprofen:Tadim combinations showed a significant decrease in IL-8 secretion at both the concentrations. Importantly, all antibiotics alone showed anti-inflammatory properties, highlighting the inherent anti-inflammatory properties of these antibiotics., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: The lung clearance index (LCI), derived from the Multiple Breath Washout (MBW) test, is sensitive to treatment effects and compared with spirometry has higher feasibility in younger children and requires smaller sample sizes. As a result, the LCI has been endorsed by the European CF Society Clinical Trials Network for use as a primary outcome measure in CF clinical trials., Methods: Here we describe the implementation of standardised protocols for MBW test performance, data collection and quality control to successfully incorporate LCI as a novel outcome measure in a large multicentre phase III clinical trial., Results: Three regional (North America (NA), Europe (EU), Australia (AUS)) central over-reading centres (CORC) were established to provide a collaborative platform for MBW training, certification and quality control of data. One hundred and thirty-two naïve operators from 53 sites across NA, EU and AUS were successfully trained and certified to perform MBW testing.  Incorporation of a re-screening opportunity in the study protocol resulted a final screening feasibility rate of 93%, success remained high throughout the study resulting in an overall feasibility of MBW study data of 88.1% (1107/1257). MBW test acceptability was similar between geographical regions: NA (88%), EU (89%) and AUS (89%)., Conclusion: With this approach we achieved high MBW test feasibility and sustained collection of good quality data, demonstrating the utility of LCI as an effective primary endpoint in the first international phase III clinical trial to report LCI as the primary outcome., (Copyright © 2019. Published by Elsevier B.V.)

Introduction: No data are available on the values and role of lung clearance index (LCI) in cystic fibrosis (CF) Screen Positive Inconclusive Diagnosis (CFSPID) progressed to CF diagnosis (CFSPID > CF). This study aimed to assess the value of the LCI in correctly predicting the progression of CFSPID to CF., Methods: This is a prospective study carried out at the CF Regional Center of Florence, Italy from September 1, 2019. We compared LCI values in children with CF diagnosed for positive newborn screening (NBS), CFSPID or CFSPID > CF for pathological sweat chloride (SC). The Exhalyzer-D (EcoMedics AG, Duernten, Switzerland, software version 3.3.1) was used to conduct the LCI tests, every 6 months on stable children., Results: Forty-two cooperating children were enrolled (mean age at LCI tests: 5.4 years, range: 2.7-8.7): 26 (62%) had CF, 8 (19%) were CFSPID > CF for positive SC, while 8 (19%) kept the CFSPID label at last LCI test. The mean LCI value for patients with CF (7.39; 5.98-10.24) was statistically higher compared to both the mean LCI in the CFSPID > CF (6.62; 5.69-7.58) and in CFSPID (6.56; 5.64-7.21)., Conclusions: Most of asymptomatic CFSPID or progressed to CF have normal LCI. Further data on the longitudinal course of LCI during follow up of CFSPID and on larger cohorts is needed., (© 2023 Wiley Periodicals LLC.)

Background: Clinical and prognostic value of preschool Multiple Breath Washout (MBW) remains unclear., Methods: Initial MBW results (Exhalyzer® D, EcoMedics AG) in preschool Cystic Fibrosis (CF) subjects (age 2-6 years) at a time of clinical stability were compared to (1) concurrent clinical status measures and (2) later spirometry outcomes. Abnormal Lung Clearance Index (LCI) was defined using published reference data (ULN for LCI 8.0)., Results: LCI was abnormal in 56% (28/50), with mean (SD) LCI 8.61(1.85) at age 4.71(1.3) years. Abnormal LCI was associated with higher dornase alfa use, previous positive bacterial cultures and pF508.del homozygous genotype. Later spirometry (n = 44; mean (SD) 2.3(0.5) years after MBW) demonstrated that abnormal initial preschool LCI was a strong predictor of lower later spirometry outcomes., Conclusion: Abnormal preschool LCI was associated with concurrent measures of clinical status and later spirometry deficits, suggesting early prognostic utility of MBW testing in this age range., (Copyright © 2019. Published by Elsevier B.V.)

Non-tuberculous mycobacterial (NTM) (especially M. abscessus complex) infections pose a considerable challenge in the management of lung disease in patients with cystic fibrosis (CF). The apparent increase in prevalence is likely multifactorial. Emergent evidence of patient-to-patient transmission and isolation of highly resistant strains is a concern for all CF centers around the world. Treatment is often long and burdensome with multiple agents. Treatment side effects are frequent and can cause significant morbidity. Although consensus guidelines provide some direction, many units are faced with the challenges of: finding drug combinations for highly resistant strains; dealing with interruptions of treatment; discussing additional facilitating procedures in the form of gastrostomy and long-term vascular access devices; as well as supporting families emotionally and psychologically through the process., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: Elexacaftor in combination with Tezacaftor and Ivacaftor (ETI) became licensed in the United Kingdom in early 2022 for children aged 6-11 years with cystic fibrosis (CF) and an eligible mutation. Many in this age group have excellent prior lung health making quantitative measurement of benefit challenging. Clinical trials purport that lung clearance index (LCI 2.5 ) measurement is most suitable for this purpose., Objectives: This study aimed to understand the clinical utility of LCI 2.5 in detecting change after commencing ETI in the real world., Patient Selection/methods: Baseline anthropometric data were collected along with spirometry (forced expiratory volume in 1 s [FEV 1 ], forced vital capacityFV and LCI 2.5 measures in children aged 6-11 years with CF before starting ETI. Measures were repeated after a mean (range) of 8.2 (7-14) months of ETI treatment. The primary endpoint was a change in LCI 2.5 , with secondary endpoints including change in FEV 1 and change in body mass index (BMI) also reported., Results: Twelve children were studied (seven male, mean age 9.5 years at baseline). Our study population had a mean (SD) LCI 2.5 of 7.01 (1.14) and FEV 1 of 96 (13) %predicted at baseline. Mean (95% confidence interval) changes in LCI 2.5 [-0.7 (-1.4, 0), p = .06] and BMI [+0.7 (+0.1, +1.3), p = .03] were observed, along with changes in FEV 1 of +3.1 (-1.9, +8.1) %predicted., Conclusions: Real-world changes in LCI 2.5 (-0.7) are different to those reported in clinical trials (-2.29). Lower baseline LCI 2.5 as a result of prior modulator exposure, high baseline lung health, and new LCI 2.5 software analyses all contribute to lower LCI 2.5 values being recorded in the real world of children with CF., (© 2024 Wiley Periodicals LLC.)

Background: The introduction of modulator therapy for cystic fibrosis (CF) has led to an increased interest in the detection of small airway disease (SAD) as sensitive marker of treatment response. The particles in exhaled air (PExA) method, which records exhaled particle mass (PEx ng/L) and number (PExNR), detects SAD in adult patients. Our primary aim was to investigate if PExA outcomes in children with CF are different when compared to controls and associated with more severe disease. Secondary aims were to assess feasibility and repeatability of PExA in children with CF and to correlate PExA to multiple breath nitrogen washout (MBNW) as an established marker of SAD., Methods: Thirteen healthy children (HC), 17 children with CF with normal lung function (CF-N) (FEV 1 z-score ≥ -1.64) and six with airway obstruction (CF-AO) (FEV 1 z-score < -1.64) between 8 and 18 years performed MBNW followed by PExA and spirometry. Children with CF repeated the measurements after 3 months., Results: PEx ng/L and PExNR/L per liter of exhaled breath were similar between the three groups. The lung clearance index (LCI) was significantly higher in both CF-N and CF-AO compared to HC. All participants, except one, were able to perform PExA. Coefficient of variation for PEx ng/l was (median) 0.38, range 0-1.25 and PExNR/l 0.38, 0-1.09. Correlation between LCI and PEx ng/l was low, r s 0.32 (p = .07)., Conclusion: PExA is feasible in children. In contrast to LCI, PExA did not differentiate healthy children from children with CF suggesting it to be a less sensitive tool to detect SAD., (© 2024 The Authors. Pediatric Pulmonology published by Wiley Periodicals LLC.)

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

Background: Pulmonary exacerbations (PEx), pathogens colonizing the respiratory tract, and patients' age are associated with progressive worsening of lung function among patients with cystic fibrosis (CF). However, the effect of these factors on longitudinal changes of Lung Clearance Index (LCI) remains unclear., Aim: To assess the role of age, different types of bronchial infection, and PEx on LCI deterioration., Methods: We conducted a retrospective study assessing multiple-breath washout (MBW) and spirometry changes among CF patients evaluated at quarterly outpatient clinic visits over 8 years. MBW and spirometry were performed at each visit, sputum samples and/or cough swabs were obtained for culture, whereas respiratory symptoms and clinical examination findings were recorded. Patients who had ≥5 serial MBW measurements, one of which coincided with a pulmonary exacerbation, were reviewed., Results: Seventy-six patients were included in the study: mean age of 10.61 years (range 1.75-23.75). A total of 1152 MBW tests and 1047 spirometry tests were performed. LCI was significantly higher among CF patients aged 11-15, 16-20, and over 20 years than those under 5 years of age; ΔLCI: 1.16 (confidence interval [CI] 0.43-1.90) and 3.25 (CI 2.33-4.17), respectively. Furthermore, LCI was significantly elevated in CF patients with positive cultures for Pseudomonas aeruginosa (0.52 LCI [CI -0.12 to 0.71]) and Stenotrophomonas Maltophilia (1.41 LCI [CI 0.61-2.21]). Moreover, increased values of LCI in CF patients were significantly associated with increased risk of PEx (odds ratio [OR] 1.19, CI [1.14-1.25], p < 0.001)., Conclusion: LCI demonstrates a progression of lung disease and corresponds to changes in bacterial infections and PEx among patients with CF. LCI may be a valuable marker for tracking disease deterioration and may have a role in the routine clinical care of patients with CF., (© 2022 Wiley Periodicals LLC.)

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

Background: Data on long term variability of Lung Clearance Index (LCI) in Cystic Fibrosis (CF) is urgently needed to guide test result interpretation. Our aim was to evaluate LCI variability in clinically stable CF lung disease in school age children., Methods: Paediatric patients, aged 6 to 17years, attending the outpatient CF clinic performed Multiple Breath Nitrogen Washout (Exhalyzer® D) and spirometry every third month over a period of one year. Clinical stability was assessed by the Cystic Fibrosis Clinical Score (CFCS) at each visit., Results: Twentyfive children were recruited: baseline median (range) FEV 1 % pred. 91 (55-122)%, LCI 9.1 (6.4-18.6), CFCS 15 (12-23). A total of 107 visits were included in the study, of which 93% were defined as clinically stable. In clinically stable visits, within-subject variability of LCI and FEV 1 % pred. were 10% and 16%, respectively. The upper limit of normal (ULN, 95% percentile) of LCI variability during clinical stability was 17%., Conclusions: LCI within-subject variability was low and comparable to FEV 1 % pred. which strengthen the use of LCI to monitor lung disease progression in CF patients. An increase in LCI >17% compared to previous LCI-measurement in clinically stable CF patients may therefore indicate early lung disease progression., (Copyright © 2017 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.)

The identification of cystic fibrosis screening-positive, inconclusive diagnosis (CFSPID) in infants is a controversial outcome of newborn screening for cystic fibrosis (CF). Today, despite improvements in the knowledge of CFSPID and the description of several cohorts, little data are available on cohorts with a follow-up period of more than 6 years. In this study, we report the outcomes of an Italian cohort of CFSPID individuals with CFSPID or formerly CFTR-related disorders (CFTR-RD) (CFSPID > CFTR-RD) or diagnosed with CF (CFSPID > CF). This was an observational and multicentre Italian study collecting clinical data on CFSPID born between the period January 1, 2011, and December 13, 2019. A total of 268 participants were included: 243 with persistent CFSPID, 7 with CFSPID > CFTR-RD, and 18 with CFSPID > CF. The trend of sweat chloride (SC) values, percentage of definitive diagnoses, lung function in school-aged children, and development of CF-related complications were evaluated. At the end of the observation period, almost 80% of the individuals with CFSPID did not have a conclusive diagnosis. A total of 29 children (10.8%) transitioned to a diagnosis of CF for pathological SC values (≥ 60 mmol/L) or multi-organ involvement, and 18 (6.7%) to CFTR-RD. Children who were followed up for > 6 years (median age, 7.5 years; range, 6.04-10.5) had normal lung function and were pancreatic sufficient, and the evolution in CF was only present in two cases., Conclusion: Most Italian preschool and school-aged children with CFSPID did not have a conclusive diagnosis, and progression to CF was unlikely in children > 6 years of age. An annual follow-up could be indicated to identify early evolution in clinical features consistent with a CFTR-RD., What Is Known: • Cystic Fibrosis newborn screening identifies also subjects with an inconclusive diagnosis (CFSPID). • Over time a variable percentage of CFSPIDs will be diagnosed as CF. • Little data is available on CFSPIDs with a follow-up period of more than six years., What Is New: • 80% of Italian preschool and school-age CFSPIDs not have a conclusive diagnosis. • Italian preschool and school-age CFSPIDs have normal lung function and are pancreatic sufficient. • Annual follow-up after 6 years is recommended in CFSPID with abnormal LCI2.5 or with a CF-causing variant in trans with a VVCC., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Objectives: To investigate whether 3D phase-resolved functional lung (PREFUL)-MRI parameters are suitable to measure response to elexacaftor/tezacaftor/ivacaftor (ETI) therapy and their association with clinical outcomes in cystic fibrosis (CF) patients., Methods: Twenty-three patients with CF (mean age: 21; age range: 14-46) underwent MRI examination at baseline and 8-16 weeks after initiation of ETI. Morphological and 3D PREFUL scans assessed pulmonary ventilation. Morphological images were evaluated using a semi-quantitative scoring system, and 3D PREFUL scans were evaluated by ventilation defect percentage (VDP) values derived from regional ventilation (RVent) and cross-correlation maps. Improved ventilation volume (IVV) normalized to body surface area (BSA) between baseline and post-treatment visit was computed. Forced expiratory volume in 1 second (FEV 1 ) and mid-expiratory flow at 25% of forced vital capacity (MEF25), as well as lung clearance index (LCI), were assessed. Treatment effects were analyzed using paired Wilcoxon signed-rank tests. Treatment changes and post-treatment agreement between 3D PREFUL and clinical parameters were evaluated by Spearman's correlation., Results: After ETI therapy, all 3D PREFUL ventilation markers (all p < 0.0056) improved significantly, except for the mean RVent parameter. The BSA normalized IVV RVent was significantly correlated to relative treatment changes of MEF25 and mucus plugging score (all |r| > 0.48, all p < 0.0219). In post-treatment analyses, 3D PREFUL VDP values significantly correlated with spirometry, LCI, MRI global, morphology, and perfusion scores (all |r| > 0.44, all p < 0.0348)., Conclusions: 3D PREFUL MRI is a very promising tool to monitor CFTR modulator-induced regional dynamic ventilation changes in CF patients., Clinical Relevance Statement: 3D PREFUL MRI is sensitive to monitor CFTR modulator-induced regional ventilation changes in CF patients. Improved ventilation volume correlates with the relative change of mucus plugging, suggesting that reduced endobronchial mucus is predominantly responsible for regional ventilation improvement., Key Points: • 3D PREFUL MRI-derived ventilation maps show significantly reduced ventilation defects in CF patients after ETI therapy. • Significant post-treatment correlations of 3D PREFUL ventilation measures especially with LCI, FEV 1 %pred, and global MRI score suggest that 3D PREFUL MRI is sensitive to measure improved regional ventilation of the lung parenchyma due to reduced inflammation induced by ETI therapy in CF patients. • 3D PREFUL MRI-derived improved ventilation volume (IVV) correlated with MRI mucus plugging score changes suggesting that reduced endobronchial mucus is predominantly responsible for regional ventilation improvement 8-16 weeks after ETI therapy., (© 2023. The Author(s).)

Objectives: To describe the short- and medium-term repeatability of lung clearance index at 2.5% (LCI 2.5 ) in infants and calculate the number of patients needed to enroll in a study (N) using LCI 2.5 as a primary outcome., Methods: An 8-month follow-up observational study was employed for assessing short-term [coefficient of repeatability (CR) and intraclass correlation (ICC)] and medium-term repeatability (Bland-Altman method) of LCI 2.5 in infants with cystic fibrosis (CF) or recurrent wheeze (RW) measured by the nitrogen multiple-breath washout test (N 2 -MBW). Using these variability data, the N to reach 90% test power at the level of statistical significance (0.05) was calculated., Results: Forty infants with CF and 21 with RW were enrolled. Initial N 2 -MBW testing was successful in 33 and 17 patients, respectively. Follow-up data were available for 23 and 11 infants, respectively. Short-term repeatability of LCI 2.5 was high (CR = 1.10 and 1.04 in CF and RW patients, respectively; ICC = 0.88 and 0.83 in CF and RW patients, respectively). The between-subject standard deviation was <13% of the actual LCI 2.5 value. In clinically stable patients, LCI 2.5 did not significantly change during the 8-month follow-up. Mean LCI 2.5 change was -0.08 (1% of baseline) in CF and -0.05 (0.6%) in RW, with 95% limits of agreement being (-1.70; 1.53) in CF and (-1.51; 1.40) in RW patients. N = 23 infants if both intragroup differences of LCI 2.5 and minimal difference to be detected would be 2.0., Conclusion: N 2 -MBW may be a reproducible tool with reasonable test power to detect differences in infant studies., (© 2022 Wiley Periodicals LLC.)

Background: Pulmonary exacerbations (PE) tend to complicate the course of cystic fibrosis (CF) and worsen the disease prognosis. One of the diagnostic criteria for an exacerbation is the forced expiratory volume in the first second (FEV 1 ) decline. Not all children, however, are able to perform spirometry. Therefore, the aim of this study was to evaluate alternative lung function tests in the diagnosis of PE., Methods: We assessed retrospectively the results of impulse oscillometry (IOS) and lung clearance index in multiple breath washout (MBW) during 259 visits in 47 CF paediatric patients. The differences in the results were compared between patients diagnosed with PE (ΔPE) and those in stable condition (ΔS)., Results: Among the whole group of patients, we found significant differences between the changes during exacerbation (ΔPEs) and stable condition (ΔSs) values for lung clearance index (LCI), S acin , R5Hz, R5-20Hz, X10Hz, AX, and Fres. The predictive values of Fres and X10Hz in IOS (AUC ROC 0.71 both parameters) were higher than those of LCI (AUC ROC 0.67). There was no difference in the predictive values (AUC ROC ) of Δ LCI and IOS parameters in the subgroups of patients stratified based on FEV 1 z-score cut-off value of -1.64. In both groups of patients, predictive values of LCI were slightly lower than of IOS parameters (AUC 0.66 for LCI vs. 0.69 for both ΔX10Hz z-score and Δ Fres z-score in patients with FEV 1 z-score ≥-1.64 and AUC 0.67 for LCI vs 0.69 for both ΔX10Hz zscore and Δ Fres zscore in patients with FEV 1 <1.64., Conclusions: Both IOS and MBW measurements are useful in the assessment of pediatric CF patients with PE. LCI has a similar predictive value to IOS in children with CF independently of their FEV 1 value., (© 2022 Wiley Periodicals LLC.)

Background: Lumacaftor and ivacaftor combination treatment showed efficacy in patients aged 12 years or older with cystic fibrosis homozygous for F508del-cystic fibrosis transmembrane conductance regulator (CFTR) in placebo-controlled studies and patients aged 6-11 years with cystic fibrosis homozygous for F508del-CFTR in an open-label study. We report efficacy and safety of lumacaftor and ivacaftor in patients with cystic fibrosis aged 6-11 years homozygous for F508del-CFTR., Methods: In this phase 3, randomised, double-blind, placebo-controlled, multicentre study, patients were enrolled at 54 hospitals and medical centres in nine countries (the USA, Australia, Belgium, Canada, Denmark, France, Germany, Sweden, and the UK). Eligible patients weighed at least 15 kg, with a confirmed diagnosis of cystic fibrosis, percent predicted forced expiratory volume in 1 s (FEV 1 ) of 70 or more, and lung clearance index 2·5 (LCI 2·5 ) of 7·5 or more at screening (values less than these thresholds were permitted at day 1). All patients were tested for CFTR genotype at screening; eligible patients had to have the F508del-CFTR mutation on both alleles. Exclusion criteria included any comorbidity or laboratory abnormality that might confound the study results or pose additional risk to the patient. Patients were stratified by weight (<25 kg vs ≥25 kg) and ppFEV 1 severity (<90 vs ≥90) determined at the screening visit, and randomly assigned 1:1 to treatment using an interactive web response system to receive 200 mg lumacaftor and 250 mg ivacaftor every 12 hours or placebo for 24 weeks. Patients, all site personnel including the investigator and the site monitor, and the study team were blinded, with the exception of site personnel needing this information in the event of medical emergency or pregnancy and patient safety and regulatory affairs personnel to meet serious adverse event reporting requirements. The primary endpoint was the mean absolute change in LCI 2·5 from all on-treatment study visits up to and including week 24. All randomly assigned patients who were exposed to any amount of study drug, with treatment assignment as assigned were included in primary and other efficacy analyses. All patients who were exposed to any amount of study drug, with treatment assignment as treated, were included in the safety analysis. This study was registered with ClinicalTrials.gov, number NCT02514473., Findings: Between July 23, 2015, and Sept 20, 2016, a total of 206 patients were enrolled and randomly assigned to receive lumacaftor and ivacaftor (n=104) or placebo (n=102). Two randomly assigned patients were never dosed with study drug (one in the placebo arm due to ineligibility arising from a streptococcal throat infection and one in the lumacaftor and ivacaftor arm due to withdrawal based on refusal to provide blood tests) and were not included in the analyses. 103 patients received at least one dose of lumacaftor and ivacaftor and 101 patients received at least one dose of placebo. For the primary endpoint, the average absolute change in LCI 2·5 from baseline over all study visits up to and including the week 24 visit, least squares mean difference was -1·09 units (95% CI -1·43 to -0·75, p<0·0001) for lumacaftor and ivacaftor versus placebo. For the key secondary endpoint of sweat chloride concentration, the least squares mean difference versus placebo was -20·8 mmol/L (95% CI -23·4 to -18·2, average absolute change at day 15/week 4; p<0·0001). The least squares mean difference compared with placebo in absolute change in ppFEV 1 from all on-treatment study visits until week 24 was 2·4 (95% CI 0·4-4·4, p=0·0182). 196 (96%) of 204 patients reported adverse events, most of which were mild (87 [43%]) or moderate (98 [48%]). Treatment was discontinued due to adverse events in three (3%) of 103 patients in the lumacaftor and ivacaftor group and two (2%) of 101 patients in the placebo group. Serious adverse events were reported in 13 (13%) of 103 patients in the lumacaftor and ivacaftor group and 11 (11%) of 101 patients in the placebo group., Interpretation: Treatment with lumacaftor and ivacaftor was associated with statistically significant improvements in lung function, as measured by LCI 2·5 and ppFEV 1 , versus placebo in patients aged 6-11 years with cystic fibrosis homozygous for F508del-CFTR. The overall safety profile was consistent with previous phase 3 studies of lumacaftor and ivacaftor., Funding: Vertex Pharmaceuticals., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Purpose of Review: Cystic fibrosis is a genetic disease that increases risk of death from respiratory failure because of impairment in mucociliary clearance. Complex daily care regimens including medications and airway clearance techniques (ACTs) aim to preserve lung function and alleviate symptoms for people with cystic fibrosis (pwCF). The success of highly effective modulator therapy (HEMT) permits evaluation of treatment simplification. In this review, we evaluate adjustments made in daily respiratory care among pwCF taking HEMT and the feasibility of treatment simplification., Recent Findings: Treatment simplification has been identified as a top priority among pwCF, with recent studies showing pwCF are willing to sacrifice mild to moderate amounts of lung function and longevity to reduce treatment burden. Retrospective studies have shown that patients taking HEMT with better baseline lung function have lower adherence to and prescription of inhaled medications. A randomized, controlled trial found that short-term discontinuation of dornase alfa or hypertonic saline was clinically noninferior to continuation of these medications. Major knowledge gaps remain about withdrawing ACTs., Summary: This review highlights trials evaluating the feasibility of treatment simplification among pwCF taking HEMT. More data is needed to evaluate approaches to simplification in this phenotypically diverse patient population., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Effective work of breathing and bronchial hygiene requires synergy of inspiratory and expiratory muscles. Inspiratory muscle training (IMT) is a part of pulmonary rehabilitation in chronic obstructive pulmonary disease (COPD). There is some evidence of its efficacy in cystic fibrosis (CF) and, recently, in long COVID-19. We are not aware of studies on IMT in primary ciliary dyskinesia (PCD). Our aim was to assess the effect of IMT on respiratory muscle strength and pulmonary function in PCD and CF patients., Methods: A single center pilot study. Spirometry, lung clearance index (LCI), maximal inspiratory pressure (MIP), and maximal expiratory pressure (MEP) were measured at baseline (visit 1), after a month of IMT with ®POWERbreathe (visit 2), and at follow-up (visit 3)., Results: The cohort included 27 patients (19 PCD, 8 CF); mean age 18.4 ± 9.8 years. After a month of IMT, there was a significant increase in MIP and MIP% (6.19-7.44, p = .015; and 81.85%-100.41%, p = .046, respectively), which was sustained at visit 3. Compliance ≥90% led to higher improvement in MIP. In sub-group analysis, improvement in MIP and MIP% remained significant for PCD patients (p = .026 and p = .049, respectively). No significant changes were found in spirometry, MEP or LCI., Conclusions: IMT was well-tolerated and led to improved inspiratory muscle strength in PCD patients. The clinical implication of improved MIP should be further investigated. Larger, long-term studies are needed to evaluate long-term effects of IMT on pulmonary function, respiratory muscle strength, pulmonary exacerbations, and quality of life., (© 2023 The Authors. Pediatric Pulmonology published by Wiley Periodicals LLC.)

Background: The utility of the forced oscillations technique (FOT) in cystic fibrosis (CF) remains uncertain. The aim of this study was to explore the ability of lower-frequency FOT indices, alone and after adjustment for the lung volume, to assess the extent of ventilation inhomogeneity in CF patients with varying disease severity., Methods: Forty-five children, adolescents, and adults with CF (age 6.9-27 years) underwent spirometry, FOT, and nitrogen multiple-breath washout (N2-MBW) measurements. The respiratory resistance and reactance at 5 Hz (Rrs5 and Xrs5, respectively) were recorded, and a novel FOT index, the specific respiratory conductance (sGrs), was computed as the reciprocal of Rrs5 divided by the functional residual capacity., Results: The sGrs correlated well with the lung clearance index (LCI) (Spearman's r: -.797), whereas the correlation of Rrs5 and Xrs5 with the LCI, albeit significant, was weaker (r: .643 and -.631, respectively). The sGrs emerged as the most robust predictor of LCI regardless of the severity of lung disease, as reflected by patients' age and lung function measurements. Most importantly, the relationship between sGrs and LCI remained unaffected by lung hyperinflation, as opposed to that of the LCI with the spirometric and standard FOT indices., Conclusions: In CF patients, the FOT indices at 5 Hz and the novel, volume-adjusted parameter sGrs, reflect the extent of lung involvement and the underlying ventilation inhomogeneity in a way comparable to N2-MBW. Future research should explore the role of lower-frequency FOT in assessing the severity and monitoring the progression of CF lung disease., (© 2023 The Authors. Pediatric Pulmonology published by Wiley Periodicals LLC.)

Background: Multiple-breath washout (MBW) 129 Xe MRI (MBW Xe-MRI) is a promising technique for following pediatric cystic fibrosis (CF) lung disease progression. However, its repeatability in stable CF needs to be established to use it as an outcome measure for novel therapies., Purpose: To assess intravisit and intervisit repeatability of MBW Xe-MRI in healthy and CF children., Study Type: Prospective, longitudinal cohort study., Subjects: A total of 18 pediatric subjects (7 healthy, 11 CF)., Field Strength/sequence: A 3 T/2D coronal hyperpolarized (HP) 129 Xe images using GRE sequence., Assessment: All subjects completed MBW Xe-MRI, pulmonary function tests (PFTs) (spirometry, nitrogen [N 2 ] MBW for lung clearance index [LCI]) and ventilation defect percent (VDP) at baseline (visit 1) and 1-month after. Fractional ventilation (FV), coefficient of variation (CoV FV ) maps were calculated from MBW Xe-MRI data acquired between intervening air washout breaths performed after an initial xenon breath-hold. Skewness of FV and CoV FV map distributions was also assessed., Statistical Tests: Repeatability: intraclass correlation coefficients (ICC), within-subject coefficient of variation (CV%), repeatability coefficient (CR). Agreement: Bland-Altman. For correlations between MBW Xe-MRI, VDP and PFTs: Spearman's correlation. Significance threshold: P < 0.05., Results: For FV, intravisit median [IQR] ICC was high in both healthy (0.94 [0.48, 0.99]) and CF (0.83 [0.04, 0.97]) subjects. CoV FV also had good intravisit ICC in healthy (0.92 [0.42, 0.99]) and CF (0.79 [0.02, 0.96]) subjects. Similarly, for FV, intervisit ICC was high in health (0.94 [0.68, 0.99]) and CF (0.89 [0.61, 0.97]). CoV FV also had good intervisit ICC in health (0.92 [0.42, 0.99]) and CF (0.78 [0.26, 0.94]). FV had better intervisit repeatability than VDP. CoV FV correlated significantly with LCI (R = 0.56). Skewness of FV distributions significantly distinguished between cohorts at baseline., Data Conclusion: MBW Xe-MRI had high intravisit and intervisit repeatability in healthy and stable CF subjects. CoV FV correlated with LCI, suggesting the importance of ventilation heterogeneity to early CF., Evidence Level: 1., Technical Efficacy: Stage 2., (© 2023 The Authors. Journal of Magnetic Resonance Imaging published by Wiley Periodicals LLC on behalf of International Society for Magnetic Resonance in Medicine.)

The lung clearance index (LCI) is a lung function parameter derived from the multiple-breath washout (MBW) test. Although first developed 60 years ago, the technique was not widely used for many years. Recent technological advances in equipment design have produced gains in popularity for this test among cystic fibrosis (CF) researchers and clinicians, particularly for testing preschool-aged children. LCI has been shown to be feasible and sensitive to early CF lung disease in patients of all ages from infancy to adulthood. A workshop was convened in January 2014 by the North American Cystic Fibrosis Foundation to determine the readiness of the LCI for use in multicenter clinical trials as well as clinical care. The workshop concluded that the MBW text is a valuable potential outcome measure for CF clinical trials in preschool-aged patients and in older patients with FEV1 in the normal range. However, gaps in knowledge about the choice of device, gas, and standardization across systems are key issues precluding its use as a clinical trial end point in infants. Based on the current evidence, there are insufficient data to support the use of LCI or MBW parameters in the routine clinical management of patients with CF.

Background: Multiple-breath inert gas washout (MBW) is a sensitive technique to assess lung volumes and ventilation inhomogeneity in infancy. Poor agreement amongst commercially available setups and a lack of transparency in the underlying algorithms for the computation of infant MBW outcomes currently limit the widespread application of MBW as a surveillance tool in early lung disease., Methods: We determined all computational steps in signal processing and the calculation of MBW outcomes in the current infant WBreath/Exhalyzer D setup (Exhalyzer D device, Eco Medics AG; WBreath software version 3.28.0, ndd Medizintechnik AG; Switzerland). We developed a revised WBreath version based on current consensus guidelines and compared outcomes between the current (3.28.0) and revised (3.52.3) WBreath version. We analyzed 60 visits from 40 infants with cystic fibrosis (CF) and 20 healthy controls at 6 weeks and 1 year of age., Results: Investigation into the algorithms in WBreath 3.28.0 revealed discrepancies from current consensus guidelines, which resulted in a potential overestimation of functional residual capacity (FRC) and underestimation of lung clearance index (LCI). We developed a revised WBreath version (3.52.3), which overall resulted in 6.7% lower FRC (mean (SD) -1.78 (0.99) mL/kg) and 14.1% higher LCI (1.11 (0.57) TO) than WBreath version 3.28.0., Conclusion: Comprehensive investigation into the signal processing and algorithms used for analysis of MBW measurements improves the transparency and robustness of infant MBW data. The revised software version calculates outcomes according to consensus guidelines. Future work is needed to validate and compare outcomes between infant MBW setups., (© 2021 Wiley Periodicals LLC.)

Background: Data from clinical trials of lumacaftor-ivacaftor (LUM-IVA) demonstrate improvements in lung clearance index (LCI) but not in FEV 1 in children with Cystic Fibrosis (CF) aged 6-11 years and homozygous for the Phe508del mutation. It is not known whether LUM/IVA use in children can impact the progression of structural lung disease. We sought to determine the real-world impact of LUM/IVA on lung structure and function in children aged 6-11 years., Methods: This real-world observational cohort study was conducted across four paediatric sites in Ireland over 24-months using spirometry-controlled CT scores and LCI as primary outcome measures. Children commencing LUM-/IVA as part of routine care were included. CT scans were manually scored with the PRAGMA CF scoring system and analysed using the automated bronchus-artery (BA) method. Secondary outcome measures included rate of change of ppFEV 1 , nutritional indices and exacerbations requiring hospitalisation., Results: Seventy-one participants were recruited to the study, 31 of whom had spirometry-controlled CT performed at baseline, and after one year and two years of LUM/IVA treatment. At two years there was a reduction from baseline in trapped air scores (0.13 to 0.07, p = 0.016), but an increase from baseline in the % bronchiectasis score (0.84 to 1.23, p = 0.007). There was no change in overall % disease score (2.78 to 2.25, p = 0.138). Airway lumen to pulmonary artery ratios (A lumen A ratio) were abnormal at baseline and worsened over the course of the study. In 28 participants, the mean annual change from baseline LCI 2.5 (-0.055 (-0.61 to 0.50), p = 0.85) measurements over two years were not significant. Improvements from baseline in weight (0.10 (0.06 to 0.15, p < 0.0001), height (0.05 (0.02 to 0.09), p = 0.002) and BMI (0.09 (0.03 to 0.15) p = 0.005) z-scores were seen with LUM/IVA treatment. The mean annual change from baseline ppFEV 1 (-2.45 (-4.44 to 2.54), p = 0.66) measurements over two years were not significant., Conclusion: In a real-world setting, the use of LUM/IVA over two years in children with CF aged 6-11 resulted in improvements in air trapping on CT but worsening in bronchiectasis scores. Our results suggest that LUM/IVA use in this age group improves air trapping but does not prevent progression of bronchiectasis over two years of treatment., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Background: PCD is a genetic disease leading to a decline in pulmonary function. There is only little knowledge of factors determining the long-term pulmonary outcome. Especially adherence has not been addressed yet although being an independent risk factor for an increased loss of lung capacity in other chronic respiratory diseases., Objective: Assessing the impact of bacterial airway colonization and adherence on long-term lung function in patients with PCD., Methods: Data on colonization and lung function parameters like forced expiratory volume in the first second (FEV 1, Z-score) and lung clearance index (LCI 2,5% ) were collected for 7.01 ± 2.2 years (893 quarters) in 44 PCD patients. Adherence was classified as good, moderate or poor. The impact of both adherence and colonization was assessed for the long-term course of FEV1, the association of colonization with lung function also quarterly., Statistics: Kruskall-Wallis test, T test, ANOVA, linear regression, linear mixed model., Results: Chronic colonization did not show any impact on the for long-term course of FEV 1 , but adherence was a significant factor: patients with good adherence showed better FEV 1 at the end of the observation period than children with poor adherence (-0.15 ± 0.88 vs. -2.63 ± 1.79, p < 0.01)., Conclusion: Adherence has not yet been investigated for PCD. However, we found it to be a major significant factor affecting long-term FEV 1 in PCD. Thus, it should be taken into consideration in the treatment protocols for PCD., (© 2023 The Authors. Pediatric Pulmonology published by Wiley Periodicals LLC.)

Imaging studies describe significant ventilation defects across a wide range of cystic fibrosis (CF) related lung disease severity. These are unfortunately poorly reflected by phase III slope analysis-derived Scond and Sacin from multiple-breath washout (MBW). Methodology extending previous two-lung compartment model-based analysis is presented describing size and function of fast- and slow-ventilating lung compartments from nitrogen (N2) MBW and correlation to obstructive lung disease severity. In 37 CF subjects (forced expiratory volume in 1 s [FEV1] mean [SD] 84.8 [19.9] % predicted; abnormal lung clearance index [LCI] in 36/37, range 7.28-18.9) and 74 matched healthy controls, volume and specific ventilation of both fast and slowly ventilated lung compartments were derived from N2-based MBW with commercial equipment. In healthy controls lung emptying was characterized by a large compartment constituting 75.6 (8.4)% of functional residual capacity (FRC) with a specific ventilation (regional alveolar tidal volume/regional lung volume) of 13.9 (3.7)% and a small compartment with high specific ventilation (48.4 [15.7]%). In CF the slowly ventilated lung compartment constituted 51.9(9.1)% of FRC, with low specific ventilation of 5.3 (2.4)%. Specific ventilation of the slowly ventilated lung compartment showed stronger correlation with LCI (r2 = 0.70, P < 0.001) vs. Sacin (r2 = 0.44, P < 0.001) or Scond (no significant correlation). Overventilation of the fast lung compartment was no longer seen in severe CF lung disease. Magnitude and function of under- and overventilated lung volumes can be derived from routine N2 MBW in CF. Reported values agree with previous modelling-derived estimates of impaired ventilation and offer improved correlation to disease severity, compared with SnIII analysis., (Copyright © 2014 the American Physiological Society.)

One of the major complications of Cystic Fibrosis (CF) is CF-Related Diabetes (CFRD), which increases in incidence with age, from 1-2% below the age of 10 years to ∼20% of adolescents and 40-50% of adults. Multiple guidelines have been published over the last few years for the diagnosis and management of CFRD, from the American Diabetes Association (ADA) / US Cystic Fibrosis Foundation, International Society for Pediatric and Adolescent Diabetes (ISPAD) and the Thoracic Society of Australia and New Zealand-Australian Diabetes Society. However, little is published about the particular issues involved in transition of patients with CFRD from paediatric to adult care, nor the issues concerning the development of CFRD during the transition period. This document seeks to provide assistance to physicians, dieticians, nurses, diabetes educators, CF patients and their families by outlining the issues surrounding CFRD during transition from paediatric to adult care., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Despite early diagnosis of cystic fibrosis (CF) through newborn screening, a substantial proportion of infants and young children with CF still demonstrate physiologic and structural evidence of lung disease progression, such as obstructive airway disease and bronchiectasis. The growing availability of highly effective CF transmembrane conductance regulatory modulator therapy to the vast majority of people with CF has led to the potential to alter the natural history of CF lung disease, but to assess the full impact of these therapies on CF lung disease and to help guide treatment, sensitive measures of early and mild disease are needed. Chest imaging using computed tomography or magnetic resonance imaging is one approach, but technologic barriers and/or concern about exposure to ionizing radiation may limit its use. However, advances in physiologic measurement techniques and exhaled breath analysis offer another option for assessment of CF lung disease., (© 2020 Wiley Periodicals LLC.)