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

Background and Objectives: Cystic fibrosis (CF) screen-positive infants with an inconclusive diagnosis (CFSPID) are infants in whom sweat testing and genetic analysis does not resolve a CF diagnosis. Lack of knowledge about the health outcome of these children who require clinical follow-up challenges effective consultation. Early predictive biomarkers to delineate the CF risk would allow a more targeted approach to these children., Methods: Prospective, longitudinal, multicenter, Canada-wide cohort study of CF positive-screened newborns with 1 to 2 cystic fibrosis transmembrane conductance regulator gene variants, of which at least 1 is not known to be CF-causing and/or a sweat chloride between 30 and 59 mmol/L. These were monitored for conversion to a CF diagnosis, pulmonary, and nutritional outcomes., Results: The mean observation period was 7.7 (95% confidence interval 7.1 to 8.4) years. A CF diagnosis was established for 24 of the 115 children with CFSPID (21%) either because of reinterpretation of the cystic fibrosis transmembrane conductance regulator genotype or because of increase in sweat chloride concentration ≥60 mmol/L. An initial sweat chloride of ≥40 mmol/l predicted conversion to CF on the basis of sweat testing. The 91 remaining children with CFSPID were pancreatic sufficient and showed normal growth until school age. Pulmonary function as well as lung clearance index in a subgroup of children with CFSPID were similar to that of healthy controls., Conclusions: Children with CFSPID have good nutritional and pulmonary outcomes at school age, but rates of reclassifying the diagnosis are high. The initial sweat chloride test can be used as a biomarker to predict the risk for CF in CFSPID., Competing Interests: POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose., (Copyright © 2021 by the American Academy of Pediatrics.)

Background: The safety and efficacy of 24 weeks of lumacaftor-ivacaftor combination therapy in children aged 6-11 years with cystic fibrosis homozygous for the F508del-CFTR mutation was previously shown in two phase 3 studies. Here, we report long-term safety and efficacy data., Methods: In this phase 3, open-label, multicentre, extension study (study 110), we examined the long-term safety, tolerability, and efficacy of lumacaftor-ivacaftor in children pooled from two phase 3 parent studies (open-label study 011B and randomised, placebo-controlled study 109). The study was conducted at 61 clinics in the USA, Australia, Belgium, Canada, Denmark, France, Germany, Sweden, and the UK. Children with cystic fibrosis homozygous for the F508del-CFTR mutation who had received lumacaftor-ivacaftor or placebo in the parent studies were treated with lumacaftor-ivacaftor for up to 96 weeks; those who had received the combination therapy in the parent studies (the treatment-to-treatment group) received up to 120 weeks of treatment in total. Participants aged 6-11 years at the start of the parent study received lumacaftor 200 mg-ivacaftor 250 mg orally once every 12 h; those aged 12 years or older received lumacaftor 400 mg-ivacaftor 250 mg orally once every 12 h. The primary endpoint was safety and tolerability in all children who had received at least one dose of the study drug. Secondary endpoints included change from baseline in lung clearance index 2·5% (LCI 2·5 ), sweat chloride concentration, body-mass index, and Cystic Fibrosis Questionnaire-Revised respiratory domain score. This extension study is registered with ClinicalTrials.gov, NCT02544451, and has been completed., Findings: The extension study ran from Aug 13, 2015, to Aug 17, 2018. Of 239 children who enrolled in the study and received at least one dose of lumacaftor-ivacaftor, 215 (90%) completed 96 weeks of treatment. Most children (236 [99%] of 239 children) had adverse events that were mild (49 [21%] of 239) or moderate (148 [62%] of 239) in severity, and there was a low rate of adverse events leading to treatment discontinuation. The most frequently reported adverse events were common manifestations or complications of cystic fibrosis, such as cough and pulmonary exacerbation, or were consistent with the known safety profile of lumacaftor-ivacaftor in older children and adults. No new safety concerns were identified with extended lumacaftor-ivacaftor treatment. Children in the placebo-to-treatment group had improvements in efficacy endpoints consistent with those observed in the parent studies. Improvements observed in children treated with lumacaftor-ivacaftor in the parent study were generally maintained in the extension study., Interpretation: Lumacaftor-ivacaftor therapy in children homozygous for F508del-CFTR who initiated treatment at age 6-11 years was generally safe and well tolerated, and efficacy was sustained for up to 120 weeks. These data support the long-term use of lumacaftor-ivacaftor to treat children aged 6 years and older who are homozygous for the F508del-CFTR mutation., Funding: Vertex Pharmaceuticals Incorporated., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Purpose: Cystic fibrosis (CF), caused by pathogenic variants in the CF transmembrane conductance regulator (CFTR), affects multiple organs including the exocrine pancreas, which is a causal contributor to cystic fibrosis-related diabetes (CFRD). Untreated CFRD causes increased CF-related mortality whereas early detection can improve outcomes., Methods: Using genetic and easily accessible clinical measures available at birth, we constructed a CFRD prediction model using the Canadian CF Gene Modifier Study (CGS; n = 1,958) and validated it in the French CF Gene Modifier Study (FGMS; n = 1,003). We investigated genetic variants shown to associate with CF disease severity across multiple organs in genome-wide association studies., Results: The strongest predictors included sex, CFTR severity score, and several genetic variants including one annotated to PRSS1, which encodes cationic trypsinogen. The final model defined in the CGS shows excellent agreement when validated on the FGMS, and the risk classifier shows slightly better performance at predicting CFRD risk later in life in both studies., Conclusion: We demonstrated clinical utility by comparing CFRD prevalence rates between the top 10% of individuals with the highest risk and the bottom 10% with the lowest risk. A web-based application was developed to provide practitioners with patient-specific CFRD risk to guide CFRD monitoring and treatment.

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.)

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: Inhaled hypertonic saline enhances mucociliary clearance, improves lung function, and reduces pulmonary exacerbations in people with cystic fibrosis older than age 6 years. We aimed to assess the effect of inhaled hypertonic saline on the lung clearance index (LCI 2·5 )-a measure of ventilation inhomogeneity-in children aged 3-6 years with cystic fibrosis., Methods: The Saline Hypertonic in Preschoolers (SHIP) Study was a randomised, double-blind, placebo-controlled trial at 25 cystic fibrosis centres in Canada and the USA. Eligible participants were aged 36-72 months; had a confirmed diagnosis of cystic fibrosis; were able to comply with medication use, study visits, and study procedures; and were able to complete at least two technically acceptable trials of multiple breath washout (MBW). Participants were randomly assigned (1:1) via a web-based data entry system that confirmed enrolment eligibility to inhaled 7% hypertonic saline or 0·9% isotonic saline nebulised twice daily (for no more than 15 min per dose) for 48 weeks. Permuted block randomisation was done separately for participants aged 36-54 months and those aged 55-72 months to ensure approximate balance by treatment group in the two age groups. The primary endpoint was the change in the LCI 2·5 measured by nitrogen MBW from baseline to week 48. All study sites were trained and certified in MBW. Analysis was by intention to treat. This study is registered with Clinicaltrials.gov, number NCT02378467., Findings: Between April 21, 2015, and Aug 4, 2017, 150 participants were enrolled and randomly assigned, 76 to the hypertonic saline group and 74 to the isotonic saline group. Overall 89% of the MBW tests produced acceptable data. At 48 weeks, treatment with hypertonic saline was associated with a significant decrease (ie, improvement) in LCI 2·5 compared with isotonic saline (mean treatment effect -0·63 LCI 2·5 units [95% CI -1·10 to -0·15]; p=0·010). Six participants in the hypertonic saline group had ten serious adverse events and eight participants in the isotonic saline group had nine serious adverse events. The serious adverse events reported were cough (two patients [3%] in the hypertonic saline group vs three [4%] in the isotonic saline group), gastrostomy tube placement or rupture (two [3%] vs one [1%]), upper gastrointestinal disorders (one [1%] vs two [3%]), distal intestinal obstruction syndrome (one [1%] vs one [1%]), and decreased pulmonary function (none vs one [1%]). None of these serious adverse events was judged to be treatment related., Interpretation: Inhaled hypertonic saline improved the LCI 2·5 in children aged 3-6 years, and could be a suitable early intervention in cystic fibrosis., Funding: Cystic Fibrosis Foundation., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

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

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

Background: The care of infants with recurrent wheezing relies largely on clinical assessment. The lung clearance index (LCI), a measure of ventilation inhomogeneity, is a sensitive marker of early airway disease in children with cystic fibrosis, but its utility has not been explored in infants with recurrent wheezing., Objective: To assess ventilation inhomogeneity using LCI among infants with a history of recurrent wheezing compared with healthy controls., Methods: This is a case-control study, including 37 infants with recurrent wheezing recruited from outpatient clinics, and 113 healthy infants from a longitudinal birth cohort, the Canadian Healthy Infant Longitudinal Development study. All infants, at a time of clinical stability, underwent functional assessment including multiple breath washout, forced expiratory flows and body plethysmography., Results: LCI z-score values among infants with recurrent wheeze were 0.84 units (95% CI 0.41 to 1.26) higher than healthy infants (mean (95% CI): 0.26 (-0.11 to 0.63) vs -0.58 (-0.79 to 0.36), p<0.001)). Nineteen percent of recurrently wheezing infants had LCI values that were above the upper limit of normal (>1.64 z-scores). Elevated exhaled nitric oxide, but not symptoms, was associated with abnormal LCI values in infants with recurrent wheeze (p=0.05)., Conclusions: Ventilation inhomogeneity is present in clinically stable infants with recurrent wheezing., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Background: Pulmonary function testing is commonly performed for diagnosis and clinical management of respiratory diseases. It is important to use appropriate reference equations from healthy subjects for interpretation of data from infants with lung disease. This study aimed to determine if published reference equations were similar to forced flow measures and plethysmographic infant pulmonary function testing data collected in the Canadian Healthy Infant Longitudinal Development (CHILD) Study., Methods: Reference equations for five pulmonary function variables (FEV 0.5 , FVC, FEF 25-75 , FEV 0.5 /FVC ratio and plethysmography (FRC pleth )) were developed using data from the nSpire system. New reference equations developed using healthy data from the CHILD Study were compared to previously published reference equations for forced flow and plethysmographic measures., Results: The current analysis included 131 infants (on 181 test occasions) with forced flow measures and 161 infants (on 246 test occasions) with plethysmography measures, aged 3-24 months. Age and length were major determinants of both forced flow and plethysmography measures. In addition, ethnicity (Caucasian vs non-Caucasian) was significantly associated with FEV 0.5 /FVC and FEF 25-75 measures. We found that the published reference equations based on custom-built equipment or commercially available systems provided poor fit to our current pulmonary function testing data, resulting in placing a large proportion of our healthy population outside the normal ranges., Conclusions: Our current data support the need for population and device specific reference data for infant pulmonary function studies. By deriving new equipment-specific reference equations for our healthy population, we provide normative data to other centers utilizing this equipment., (© 2018 Wiley Periodicals, Inc.)

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.)

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: Asthma is the most common disease in childhood. The prevalence of asthma is known to vary greatly between and within countries and among different ethnic groups. In this study, we aimed to determine the prevalence of asthma and wheezing symptoms in South Asian children living in Canada., Methods: In a cross sectional study, data from the Phase III International Study on Asthma and Allergies in Childhood (ISAAC) were analyzed. A surname algorithm to determine South Asian ethnic descent was used. Prevalence was calculated and compared to non-South Asian children from the same survey and to the reported prevalence from the Indian subcontinent ISAAC III survey for children ages 6-9 and 13-16., Results: The prevalence of asthma and wheezing did not differ between children of South Asian descent and non-South Asians living Canada. When compared to the children living in India, the prevalence of asthma, wheeze, and exercise induced wheeze was significantly higher in the South Asian children living in Canada. Higher body mass index of the child, parental smoking, and pet ownership were strongly associated with asthma and wheeze., Conclusions: In contrast to other studies these data suggest that South Asian children living in Canada have a similar asthma prevalence to non-South Asian children; both of whom had higher asthma prevalence compared with children residing in South Asia. This suggests that environmental and social factors play a role in asthma prevalence. Risk factors for asthma in children of South Asian descent living in Canada are similar to those of the overall population., (© 2013 Wiley Periodicals, Inc.)