Objective: The objective of this study was to analyze respiratory muscle function in children and adolescents with cystic fibrosis (CF) treated with Elexacaftor/Tezacaftor/Ivacaftor (ETI) compared to healthy individuals, based on the hypothesis that CFTR modulators may improve respiratory muscle strength. Methods: A descriptive, observational, cross-sectional study was conducted with patients with CF treated with ETI aged 6–18 years. Lung function, maximal expiratory and inspiratory pressures (MIP and MEP), diet quality (KIDMED), and physical activity levels (PAQ) were assessed. The student’s t-test or the Mann–Whitney U-test was used to compare differences between groups. The effect size was calculated with Cohen’s d. Significance level was set as a p-value < 0.05. Results: A total of 48 children and adolescents (60.4% male) were analyzed in this study (24 healthy and 24 with CF). The participants with CF had mild pulmonary involvement. No significant differences were found in respiratory muscle strength between groups (MEP_max p = 0.440, MIP_max p = 0.206). Patients with CF showed lower KIDMED (p = 0.022) and PAQ (p = 0.010) scores. However, the MIP and MEP values observed in CF participants were higher than those reported in previous studies conducted before the introduction of ETI modulators. Conclusions: Children and adolescents with CF treated with ETI showed respiratory muscle strength comparable to that of healthy controls. Despite differences in lifestyle factors, these findings may reflect a positive impact of CFTR modulators on respiratory muscle function, although further longitudinal and controlled studies are needed.

Introduction: Limited studies have explored the impact of cystic fibrosis (CF) transmembrane conductance regulator (CFTR) modulators on glucose tolerance and insulin secretion in patients with CF, yielding varied results. This study aims to assess alterations in glucose metabolism and insulin secretion over 24 and 52 weeks following CFTR modulator initiation in a cohort of pediatric and adult patients with CF. Materials and Methods: A prospective longitudinal study conducting oral glucose tolerance test (OGTT) with C-peptide and insulin levels. The insulin secretion rate at 60 min (ISR60) and the insulinogenic index (IGI) were calculated during the first 60 and 30 min of the OGTT, respectively. Glucose metabolism status was categorized as normal (NGT), indeterminate (INDET), impaired glucose tolerance (IGT), or cystic fibrosis-related diabetes (CFRD). Additionally, continuous glucose monitoring (CGM) was performed for 14 days at each visit. We employed a repeated-measures general linear model to assess changes in insulin secretion and CGM metrics, with glucose tolerance status as the between-subjects factor and visit (baseline, 24 and 52 weeks) as the within-subjects factor. Results: The study comprised 25 patients (11 adults and 14 pediatrics). At baseline, 2 patients (8%) had NGT, 8 (32%) had INDET, 10 (40%) had IGT, and 5 (20%) had CFRD. Overall, there were no significant changes in insulin and C-peptide area under the curve (AUC), IGI and DI after 52 weeks. However, we observed an increase in ISR60 among NGT patients (mean change: 1.766; 95% CI: 1.414; 2.118, p < 0.001). Consistently, average glucose exhibited a significant decrease in NGT patients between 24 and 52 weeks (mean change: −5.645; 95% CI: −4.233; −10.866, p = 0.028). Conclusions: Treatment with CFTR modulators potentially enhances insulin secretion in patients with CF NGT. Early initiation of treatment, as evaluated through long-term prospective trials, is essential to further investigate whether decreased glucose control is preventable or reversible.

Background: One of the most common genetic variants among individuals with cystic fibrosis screen-positive inconclusive diagnosis (CFSPID) is 5T;12TG. Classified as having “varying clinical consequences” (VVCC), it may produce a wide spectrum of CF phenotypes when combined in trans with a pathogenic variant on the other CFTR allele, ranging from asymptomatic cases to CFTR-related disorders (CFTR-RD) or classical cystic fibrosis (CF). The 5T;12TG variant is currently eligible for modulator treatment in the United States. Methods: We conducted a retrospective analysis of CFSPID children born between July 2009 and June 2023 in the Community of Madrid (Spain) who carried at least one 5T;12TG variant in trans with another CFTR variant. Data collected included trends in sweat chloride (SC) values, respiratory and digestive symptoms, lung function by spirometry, microbiological findings in nasopharyngeal aspirates, anthropometric data, and fecal elastase levels. Results: Twenty-one children (52.3% females; median age: 4.66 years [IQR 3.6–6.9]) were included. Eighteen had 5T;12TG in trans with a CF-causing variant (CFc), two had another VVCC variant, and one had a variant of unknown significance (VUS). After a median follow-up of 3.45 years [IQR 1.4–4.3], all the children remained asymptomatic. However, SC values rose to intermediate levels in nine (42.8%) of the children. No isolates of Pseudomonas aeruginosa were identified. Lung function and pancreatic markers remained normal. Conclusions: This is the first Spanish cohort of children with CFSPID and the 5T;12TG allele. Although clinical symptoms did not manifest during childhood, the SC value increased to intermediate values in 42.8% of the cohort, so these may require long-term follow-up to observe conversions to CFTR-RD or CF. The potential initiation of modulator therapy based solely on SC levels or emerging symptoms warrants careful consideration.