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Background: Cystic Fibrosis has historically been described as a disease that affects people of European ancestry. Consequently, much of what we know about CF is based on evidence generated from data collected in white individuals. This may lead to systematic bias in how non-white people with CF are diagnosed and treated. In this study we compared clinical outcomes between the white and non-white people with CF in Canada., Methods: Canadian CF Registry data collected between 2000 and 2019 were used in this population-based cohort study. Demographic characteristics and clinical outcomes of people with CF identified as white and those identified as non-white were compared. Analyses were adjusted for cohort effects but not socioeconomic status., Results: Between 2000 and 2019, 5516 people with CF in the Registry were identified as white and 323 were identified as non-white. At diagnosis, the white and non-white groups were similar with respect to sex at birth, age at diagnosis, prevalence of pancreatic insufficiency, and meconium ileus. The non-white group had similar rates of CF-related complications and bacterial infections compared to the white, but worse lung function, worse nutritional status, lower treatment rates, and higher rate of hospitalizations. During the 20-year study period, the non-white group had a 1.85 higher risk of death compared to the white group (HR 95 %CI 1.39; 2.47)., Interpretation: There is an urgent need understand why outcomes for Canadians with CF differ between white and non-white individuals, including the role of socioeconomic circumstances., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: SS receives consulting fees from ndd medical, Chiesi and speaker fees from Vyaire. SC is an employee of CF Canada., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Cystic fibrosis (CF) contributes a significant economic burden on individuals, healthcare systems, and society. Understanding the economic impact of CF is crucial for planning resource allocation., Methods: We conducted a scoping review of literature published between 1990 and 2022 that reported the cost of illness, and/or economic burden of CF. Costs were adjusted for inflation and reported as United States dollars., Results: A total of 39 studies were included. Direct healthcare costs (e.g., medications, inpatient and outpatient care) were the most frequently reported. Most studies estimated the cost of CF using a prevalence-based (n = 18, 46.2 %), bottom-up approach (n = 23, 59 %). Direct non-healthcare costs and indirect costs were seldom included. The most frequently reported direct cost components were medications (n = 34, 87.2 %), inpatient care (n = 33, 84.6 %), and outpatient care (n = 31, 79.5 %). Twenty-eight percent (n = 11) of studies reported the burden of CF from all three perspectives (healthcare system (payer), individual, and society). Indirect costs of CF were reported in approximately 20 % of studies (n = 8). The reported total cost of CF varied widely, ranging from $451 to $160,000 per person per year (2022 US$). The total cost depended on the number of domains and perspectives included in each study., Conclusions: Most studies only reported costs to the healthcare system (i.e., hospitalizations and healthcare encounters) which likely underestimates the total costs of CF. The wide range of costs reported highlights the importance of standardizing perspectives, domains and costs when estimating the economic burden of CF., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier B.V.)

Background: Understanding the pulmonary impact of changes in early life nutritional status over time in a paediatric CF population may help inform how to use nutritional assessment to guide clinical care. National registry data provides an opportunity to study patterns of weight gain over time at the level of the individual, and thus to gain detailed understanding of the relationship between early weight trajectories and later lung function in children with Cystic Fibrosis (CF)., Methods: Using data from the United Kingdom (UK) and Canadian CF Registries, a mixed effects linear regression model was used to describe children's weight and BMI z-score trajectories from age 1 to 5 years. The intercept (weight-for-age at age 1) and slope (weight-for-age trajectory) from this model were then used as covariates in a linear regression of first lung function measurement at age 6 years., Results: In both the UK and Canadian data, greater weight-for-age z-score at age 1 year and greater change in weight-for-age over time were associated with higher FEV 1 % predicted. A greater weight-for-age z-score at age 1 year was associated with a higher FEV 1 % predicted (UK: 3.78% (95% CI: 1.76; 4.70); Canada: 3.20% (95%CI: 1.76, 4.70)). These associations were reproduced for BMI z-scores and FVC% predicted., Conclusions: Early weight-for-age, specifically at age 1 year, and weight-for-age trajectories across early childhood are associated with later lung function. This relationship persists after adjustment for potential confounders. Current guidelines may need to be updated to place less emphasis on a specific cut-off (such as the 10th percentile) and encourage tracking of weight-for-age over time., Competing Interests: Declaration of Competing Interest CB, DJ and AM report no conflicts of interest. GD reports personal fees (speaker honoraria) from Vertex pharmaceuticals and Chiesi Limited, unrelated to the current work. SBC reports personal fees and other from Chiesi Pharmaceuticals, non-financial support and other from Vertex outside the submitted work. SS reports personal fees from Chiesi Pharmaceuticals unrelated to the current work., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: The availability of new diagnostic algorithms for cystic fibrosis (CF), changing population demographics and programs that impact family planning decisions can influence incidence rates. Thus, previously reported incidence rates in Canada and the United States (US) may be outdated. The objectives of this study were to estimate contemporary CF incidence rates in Canada and the US and to determine if the incidence rate has changed over time., Method: This population-based cohort study utilized data between 1995-2019 from the Canadian CF Registry (CCFR), Statistics Canada, US CF Foundation Patient Registry (CFFPR) data, and US Center for Disease Control (CDC) National Vital Statistics System. Incidence was estimated using the number of live CF births by year, sex, and geographic region using Poisson regression, with the number of live births used as the denominator. To account for delayed diagnoses, we imputed the proportion of diagnoses expected given historical trends, and varying rates of newborn screening (NBS) implementation by region., Results: After accounting for implementation of NBS and delayed diagnoses, the estimated incidence rate for CF in 2019 was 1:3848 (95% CI: 1:3574, 1:4143) live births in Canada compared to 1:5130 (95% CI:1:4996, 1:5267) in the US. There was substantial regional variation in incidence rates within both Canada and the US. Since 1995, incidence rates have decreased at a rate of 1.6% per year in both countries (p<0.001)., Conclusion: Contemporary CF incidence rates suggest CF incidence is lower than previously reported and varies widely within North America. This information is important for resource planning and for tracking how programs (e.g., genetic counselling, modulator availability etc.) may impact the incidence of CF moving forward., Competing Interests: Declaration of Competing Interest There are no conflicts to disclose., (Copyright © 2022. Published by Elsevier B.V.)

Children and young people with CF (CYPwCF) get advice about using positive expiratory pressure (PEP) or oscillating PEP (OPEP) devices to clear sticky mucus from their lungs. However, little is known about the quantity (number of treatments, breaths, or sets) or quality (breath pressures and lengths) of these daily airway clearance techniques (ACTs) undertaken at home. This study used electronic pressure sensors to record real time breath-by-breath data from 145 CYPwCF (6-16y) during routine ACTs over 2 months. ACT quantity and quality were benchmarked against individual prescriptions and accepted recommendations for device use. In total 742,084 breaths from 9,081 treatments were recorded. Individual CYPwCF maintained consistent patterns of ACT quantity and quality over time. Overall, 60% of CYPwCF did at least half their prescribed treatments, while 27% did fewer than a quarter. About 77% of pre-teens did the right number of daily treatments compared with only 56% of teenagers. CYPwCF usually did the right number of breaths. ACT quality (recommended breath length and pressure) varied between participants and depended on device. Breath pressures, lengths and pressure-length relationships were significantly different between ACT devices. PEP devices encouraged longer breaths with lower pressures, while OPEP devices encouraged shorter breaths with higher pressures. More breaths per treatment were within advised ranges for both pressure and length using PEP (30-31%) than OPEP devices (1-3%). Objective measures of quantity and quality may help to optimise ACT device selection and support CYPwCF to do regular effective ACTs., Competing Interests: Conflict of interest statement All authors declare that they have no conflicts of interest., (Copyright © 2022. Published by Elsevier B.V.)

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

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

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: Ivacaftor is a CFTR potentiator with demonstrated efficacy in clinical trials and has been rapidly adopted within the CF community. Given the uptake of ivacaftor in eligible people, identifying a comparator group not on modulators to measure effectiveness is difficult. We evaluated health outcomes in individuals with G551D and non-G551D genotypes on ivacaftor using real-world longitudinal data., Methods: This population-based observational study compared clinical trajectories pre-post ivacaftor using the Canadian CF Registry from 2006 to 01-01 through 2018-12-31. Piece-wise linear mixed-effects models were used to compare lung function, nutritional status, pulmonary exacerbations, and Pseudomonas colonization pre- and post-ivacaftor. Multivariable models were used to adjust for confounding factors., Results: Forced expiratory volume in 1 second (FEV1) increased significantly by 5.7 percent predicted (95% confidence interval (CI) 3.9, 7.5; p<0.001) after initiation of ivacaftor. FEV1 decline rate was attenuated to -0.30% (95% CI -0.9, 0.29; p = 0.32) predicted/year post-ivacaftor, compared with -0.75% (95% CI -1.12, -0.37; p<0.001) predicted/year pre-ivacaftor, although this difference did not reach statistical significance. BMI percentiles also increased post-ivacaftor (6.57 percentiles, 95% CI 3.91, 9.24; p<0.001). Pulmonary exacerbations showed a nonsignificant reduction of 18% (RR 0.82, 95% CI 0.61, 1.11; p = 0.19) and the odds of a positive sputum culture for Pseudomonas aeruginosa decreased in the post-ivacaftor period (odds ratio 0.44, 95% CI 0.30, 0.63; p<0.001)., Conclusions: This real-world, observational study demonstrated improvement in health outcomes in a broad population of people with CF. Additional studies are needed to evaluate the impact of ivacaftor on quality of life and survival., Competing Interests: Declaration of Competing Interest AS received grant funding from CF Canada unrelated to this study. AS received consultant fees for educational program unrelated to this study. SS received funding from Vertex unrelated to this study., (Copyright © 2021. Published by Elsevier B.V.)

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

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

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

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

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

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

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

Survival statistics, estimated using data collected by national cystic fibrosis (CF) patient registries, are used to inform the CF community and monitor survival of CF populations. Annual registry reports typically give the median age of survival, though different registries use different estimation approaches and terminology, which has created confusion for the community. In this article we explain how median age of survival is estimated, what its interpretation is, and what assumptions and limitations are involved. Information on survival from birth is less useful for individuals who have already reached a certain age and we propose use of conditional survivor curves to address this. We provide recommendations for CF registries with the aim of facilitating clear and consistent reporting of survival statistics. Our recommendations are illustrated using data from the UK Cystic Fibrosis Registry., (Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Forced expiratory volume in 1s (FEV 1 ) is an established marker of cystic fibrosis (CF) disease progression that is used to capture clinical course and evaluate therapeutic efficacy. The research community has established FEV 1 surveillance data through a variety of observational data sources such as patient registries, and there is a growing pipeline of new CF therapies demonstrated to be efficacious in clinical trials by establishing improvements in FEV 1 ., Results: In this review, we summarize from a statistical perspective the clinical relevance of FEV 1 based on its association with morbidity and mortality in CF, its role in epidemiologic studies of disease progression and comparative effectiveness, and its utility in clinical trials. In addition, we identify opportunities to advance epidemiologic research and the clinical development pipeline through further statistical considerations., Conclusions: Our understanding of CF disease course, therapeutics, and clinical care has evolved immensely in the past decades, in large part due to the thoughtful application of rigorous research methods and meaningful clinical endpoints such as FEV 1 . A continued commitment to conduct research that minimizes the potential for bias, maximizes the limited patient population, and harmonizes approaches to FEV 1 analysis while maintaining clinical relevance, will facilitate further opportunities to advance CF care., (Copyright © 2017 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.)

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

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

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

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

Background: Pulmonary exacerbations are associated with significant lung function decline from baseline in cystic fibrosis (CF) and it is not well understood why some patients do not respond to antibiotic therapy. The objective of this study was to identify factors associated with lung function response to antibiotic treatment of pulmonary exacerbations., Methods: As a secondary analysis of a randomized, controlled trial of intravenous antibiotic treatment for pulmonary exacerbations in CF patients, we investigated whether baseline factors and changes in sputum bacterial density, serum or sputum inflammatory markers were associated with recovery of lung function and risk of subsequent exacerbation., Results: In 36 of the 70 exacerbations (51%), patients' lung function returned to >100% of their baseline at day 14 of antibiotic treatment; 34 exacerbations were classified as non-responders. Baseline characteristics were not significantly different between responders and non-responders. Less of a drop in FEV1 from baseline to exacerbation (OR 1.09, 95% CI 1.0, 1.18, p=0.04) as well as a greater decrease in sputum neutrophil elastase (OR 2.94, 95% CI 1.07, 8.06, p=0.04) were associated with response to antibiotic treatment at day 14. In addition, higher CRP (HR 1.35 (95% CI: 1.01, 1.78), p=0.04) and sputum neutrophil elastase (HR 1.71 (95% CI: 1.02, 2.88), p=0.04) at day 14 of antibiotic therapy were associated with an increased risk of subsequent exacerbation., Conclusions: Inadequate reduction of inflammation during an exacerbation is associated with failure to recover lung function and increased risk of subsequent re-exacerbation in CF patients., (Copyright © 2015 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.)

Background: The lung clearance index (LCI) measured by multiple-breath washout (MBW) has been proposed as an outcome for clinical trials; however, MBW is time consuming and LCI can be affected by breathing pattern. We aimed to evaluate moment ratios and abbreviated LCI in school-aged children with mild-to-moderate CF lung disease., Methods: Using existing data from three studies we assessed the sensitivity of moment ratios and abbreviated LCIs to (i) detect mild-to-moderate CF lung disease and (ii) detect treatment effects after 4 weeks of hypertonic saline or dornase alfa inhalation. MBW was measured by respiratory mass spectrometry using 4% ""sulphur hexafluoride as a tracer gas., Results: Compared to the traditional LCI, moment ratios and abbreviated LCIs were similarly sensitive to detect CF lung disease. Moment ratios consistently demonstrated treatment effects, whereas abbreviated LCIs were less sensitive., Conclusions: Both moment ratios and abbreviated LCI are suitable to differentiate health from disease. Sensitivity is decreased for abbreviated LCIs in interventional studies in mild CF lung disease., (Copyright © 2014 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.)

This study aimed to determine whether antimicrobial susceptibility testing of Pseudomonas aeruginosa grown as a biofilm, rather than planktonically, improves efficacy of antibiotic treatment for pulmonary exacerbations. This was a multicenter randomized, double-blind controlled trial of 14 days of intravenous antibiotic treatment for pulmonary exacerbations chosen based on conventional vs. biofilm antimicrobial susceptibility results in CF patients with chronic P. aeruginosa infection. There were 74 exacerbations in 39 patients. A total of 46% (12/26) exacerbations in the conventional group compared to 40% (19/48) exacerbations in the biofilm group achieved a ≥3 log drop in P. aeruginosa sputum density (difference -0.03, 95% CI -0.5 to 0.4, p=0.9). Lung function improvements were similar in both groups. Biofilm antimicrobial susceptibility testing did not lead to improved microbiological or clinical outcomes compared to conventional methods in the treatment of pulmonary exacerbations in CF patients with chronic P. aeruginosa., (Copyright © 2014 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.)

Background: The Quanjer et al. Global Lung Function Initiative (GLI)-2012 multi-ethnic all-age reference equations for spirometry are endorsed by all major respiratory societies and are the new gold standard. Before the GLI equations are implemented for use in CF patients, the impact of changing equations from those currently used needs to be better understood., Methods: Annual review data submitted to the UK CF Trust Registry between 2007 and 2011 were used to calculate %predicted FEV1, FVC and FEV1/FVC using three widely used reference equations (Wang-Hankinson and Knudson) and the new GLI-2012 equations., Results: Overall, Knudson and Wang equations overestimated %predicted values in paediatric patients, such that a greater proportion of patients had lung function values in the normal range. Within individual patients, the impact of switching equations varied greatly depending on the patients' age, and which equations were used., Conclusions: A unified approach to interpreting spirometric lung function measurements would help facilitate more appropriate comparison both within and between centres and countries. Interpretation of longitudinal measurements using a continuous reference equation across all-ages, like the GLI, may further improve our understanding of CF lung disease., (Copyright © 2013 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.)

Background: Inhaled tobramycin therapy has been shown to be efficacious in clinical trials for the eradication of initial Pseudomonas aeruginosa infection in children with cystic fibrosis (CF). However, the effectiveness of different regimens in eradicating P. aeruginosa and preventing the development of chronic infection in actual clinical settings has yet to be determined., Methods: This was an observational study of children (<18 years of age) with CF with incident P. aeruginosa infection from 2005-2012 based on data collected from the Toronto CF Database and medical charts. Patients who received inhaled tobramycin (80 mg/2 ml twice daily for 365 days) were compared to those who received tobramycin inhalation solution (TIS) (300 mg/5 ml twice daily for 28 days) with respect to eradication and development of chronic infection. We also examined the risk factors for recurrence of infection., Results: During the study period, 65 patients were identified with incident P. aeruginosa, of which 7 (11%) failed eradication therapy. Eradication failure was similar between the two treatment groups. A total of 4 patients (6%) developed chronic P. aeruginosa infection in the 12 months following the end of therapy with no differences between treatment groups. Female gender, older age, pancreatic insufficiency, lower lung function and worse nutritional status were identified as risk factors for recurrence of P. aeruginosa infection., Conclusions: Both regimens of inhaled tobramycin have similar effectiveness in eradicating P. aeruginosa and preventing chronic P. aeruginosa infection in CF patients in clinical practice. Further work is needed, however, to identify patient characteristics and bacterial factors that play a role in eradication failure, in order to develop more effective antimicrobial rescue treatment strategies., (© 2013.)

Background: Stenotrophomonas maltophilia is one of the most common multi-drug resistant organisms causing pulmonary infections in CF patients. It is unknown whether S. maltophilia infection follows the same pattern and shares similar risk factors for acquisition as described for Pseudomonas aeruginosa., Methods: We examined all clinical events from 1997 to 2008 in the Toronto CF Database to identify risk factors for the acquisition of S. maltophilia and to define distinct patterns of infection., Results: We followed 601 patients over 12 years, during which time one quarter of subjects had at least one positive culture for S. maltophilia; the incidence rate was slightly higher in children (11.6/100 person years) compared with adults (10.6/100 person years). Using multi-variable Cox proportional hazards models, steeper rate of FEV1 decline was a significant risk factor for S. maltophilia acquisition, whereas new infections were less likely to occur with greater oral antibiotic use and a history of Burkholderia cepacia complex infection., Conclusions: This study illustrates the evolution of S. maltophilia infection over time in a large cohort of adults and children with CF. Younger CF patients, and those with greater lung function decline were at increased risk of S. maltophilia infection. The use of oral antibiotics to maintain lung function may be a way of decreasing the risk of infection. However, the optimal management of CF patients with persistent S. maltophilia infection is not yet known and requires further studies., (Copyright © 2013 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.)