Sweat chloride concentrations are elevated in people with cystic fibrosis due to the absence or dysfunction of the cystic fibrosis transmembrane conductance regulator (CFTR) protein, an epithelial cell membrane ion channel. For many people with cystic fibrosis with responsive variants and drug access, treatment with CFTR modulators increases CFTR function, reduces sweat chloride concentrations, and improves lung health and quality of life. In clinical trials, average sweat chloride reduction is correlated with clinical efficacy across different modulators and study populations. Thus, for people with cystic fibrosis, larger reductions and lower absolute sweat chloride concentrations are often presumed to indicate greater clinical response and better prognosis. However, although true at the population level, at the individual level, a relationship between sweat chloride and clinical outcomes has not been definitively shown. This Personal View highlights how sweat chloride quantification informs our understanding of CFTR modulator therapeutic response while cautioning its ability to fully predict individual clinical response.

Background Evidence in clinical utility of impulse oscillometry (IOS) in muco-obstructive lung disease is limited. We compared IOS with nitrogen-multiple-breath washout (N 2 MBW), spirometry, and body plethysmography in cystic fibrosis (CF), primary ciliary dyskinesia (PCD), and humoral immunodeficiencies (HID). Method At routine follow-up, 111 patients (median age 19.7 years; 42.3% male) underwent same-day IOS, N 2 MBW, spirometry, body plethysmography. We evaluated feasibility, abnormality detection, cross-test associations in the total cohort and by disease group, and modelled predictors of elevated lung clearance index (LCI). Results IOS showed excellent feasibility (100.0%), followed by N 2 MBW (99.1%); body plethysmography and spirometry were less feasible, mainly due to poor cooperation in children and effort limits in advanced disease. IOS indices indicated air trapping and ventilation inhomogeneity. Reactance (Xrs5) and resonance frequency (Fres) achieved area under the curve (AUC)≥0.70 for predicting elevated LCI, with Fres demonstrating the highest specificity and negative predictive value, while reactance area (AX) showed the greatest sensitivity. IOS correlated with both, LCI and the body plethysmographic air-trapping marker residual volume/total lung capacity (RV/TLC). In PCD and HID, IOS-LCI correlations exceeded IOS-spirometry correlations and IOS related closely to RV and RV/TLC, indicating sensitivity to small-airway dysfunction when spirometry may be normal; CF showed similar but weaker patterns. Conclusion Across ages and diagnoses, IOS aligns with N 2 MBW and body plethysmography and complements spirometry. Given its low effort and minimal need for cooperation, IOS can complement existing methods for detecting and monitoring small airway disease in muco-obstructive lung disease, where evidence and child-friendly tools remain limited.

BACKGROUND:Elexacaftor/tezacaftor/ivacaftor(ELX/TEZ/IVA) was safe and efficacious in children with CF 2-5y with at least one F508del allele in 24-week phase 3 Trial 445-111. Children who completed 445-111 were eligible for the long-term safety and efficacy extension trial. METHODS:This 2-part (part A and B), open-label, phase 3, 192-week trial enrolled children ≥ 2y who completed 445-111. PRIMARY ENDPOINT:safety and tolerability. Secondary endpoints: absolute changes in sweat chloride(SwCl) concentration and lung clearance index 2.5(LCI2.5). 96-week analysis (Part A) is reported. RESULTS:Seventy children received ELX/TEZ/IVA and mean exposure was 89.9 (SD: 17.0) weeks. All children had ≥1 adverse event(AE), most AEs were mild (35.7%) or moderate (52.9%) in severity. Most AEs were generally consistent with known manifestations of CF in children. Fifteen children had ≥1 serious AE, of which 1 (DIOS) was considered related to ELX/TEZ/IVA. Three children discontinued due to AEs. Decreases in SwCl (-57.0 mmol/L [95%CI: -61.5, -52.6]) and LCI2.5 (-0.90 [95%CI: -1.14, -0.67]) were sustained from parent trial baseline, 80.8% of children achieved SwCl<60 mmol/L (below diagnostic threshold) and 28.8% achieved SwCl<30 mmol/L (normal). Growth remained in normal range throughout treatment period. Increases in fecal elastase-1 from parent trial baseline were maintained through Week 96, with 9 children above the pancreatic sufficiency threshold. CONCLUSIONS:ELX/TEZ/IVA remained generally safe and well-tolerated in this extension trial. SwCl and lung function improvements reported in parent trial were maintained through additional 96 w of treatment. These results demonstrate long-term safety and efficacy, and CF disease-modifying potential of ELX/TEZ/IVA in children ≥2y.

RATIONALE:Elexacaftor/tezacaftor/ivacaftor, a CF transmembrane conductance regulator (CFTR) modulator, stabilizes and restores F508del-CFTR function, which is the most common CFTR variant. In multiple clinical and real-world studies, elexacaftor/tezacaftor/ivacaftor was shown to be safe and highly effective in people with CF carrying at least one F508del-CFTR (∼80% of people with CF). OBJECTIVES:To characterize the response of rare, non-F508del CFTR variants to elexacaftor/tezacaftor/ivacaftor in vitro, and in clinical and real-world studies. METHODS:We engineered Fischer rat thyroid (FRT) cells each of which express 1 of 620 rare exonic CFTR variants present in public databases and evaluated their in vitro response to elexacaftor/tezacaftor/ivacaftor. We evaluated efficacy and safety of elexacaftor/tezacaftor/ivacaftor in a 24-week randomized, placebo-controlled, Phase 3 trial (445-124) in participants with 1 of 18 rare variants and no F508del and in a real-world study (CFD-016) in people carrying 82 rare variants and no F508del. MEASUREMENTS AND MAIN RESULTS:In FRT cells, 518 of 620 (84%) rare variants responded to elexacaftor/tezacaftor/ivacaftor. In 445-124, mean improvements were seen in the primary endpoint of percent predicted FEV1 (9.2 percentage points [95% CI: 7.2, 11.3; P < .0001]), and secondary endpoints of sweat chloride (-28.3 mmol/L [95% CI: -32.1, -24.5 mmol/L; P < .0001]) and CFQ-R RD (19.5 points [95% CI: 15.5, 23.5; P < .0001]). In CFD-016, improvements in lung function were seen after treatment initiation. CONCLUSIONS:In vitro, clinical, and real-world data support elexacaftor/tezacaftor/ivacaftor treatment in people carrying a range of CFTR variants and no F508del. The response of 84% of rare CFTR variants that produce protein to protein-stabilizing therapy suggests variants in many regions of the protein causes disease via protein destabilization.

Abstract To determine the relationship between mucus plugging and CT-derived parameters of sarcopenia in routine chest CT-scans. Patients with advanced Chronic Obstructive Lung Disease (COPD GOLD 3 or 4) were investigated. Mucus plug score (MPS) and cross-sectional muscle area (CSA) of pectoralis and erector spinae muscle of each patient was assessed by two radiologists. Statistics included non-parametric group comparison, multivariate analysis, and inter- and intrarater agreement. Median age of 123 patients (47 female) was 66 years. In 63 patients (15 females) no mucus plugging was found. 31 patients (15 females) had 1–2 mucus plugs and 29 patients (17 females) had a mucus plug of ≥ 3. PMCSA and ESMCSA were not independently associated with MPS; however, the association between PMCSA and MPS was modified by body weight, with a significant negative correlation between body weight and PMCSA in patients with higher MPS (≥ 3). Inter- and intrarater agreement was very good (ICC 0.899 or higher). Imaging based evaluation of MPS and CSA is reliable on routine chest CT-scans. Patients with more advanced COPD exhibited a higher MPS and larger PMCSA relative to body weight, possibly due to the greater muscular effort required for breathing.

Cystic fibrosis (CF) lung disease imposes a significant clinical, psychosocial, and economic burden on people with CF (pwCF), their caregivers, and healthcare systems. Although the introduction of CF transmembrane conductance regulator (CFTR) modulator therapies has led to significant improvements in symptoms, lung function, exacerbations, and quality of life, substantial burden remains. A subset of pwCF taking CFTR modulator therapy experience residual infection, neutrophilic inflammation (to levels seen in non-CF bronchiectasis), exacerbations, and pulmonary complications. Furthermore, 10%-15% of the global CF population is either ineligible for or intolerant to current CFTR modulator therapies, with some pwCF (although in the minority) experiencing adverse events that necessitate treatment discontinuation. For these people, the burden of disease remains. The worsening of mental health experienced by some pwCF on CFTR modulator therapy adds to the psychosocial burden. Although some evidence suggests a decrease in treatment burden, in general, CFTR modulators have been added to therapeutic regimens rather than replacing symptomatic treatments. While reductions in healthcare resource use have been reported, hospitalizations and emergency department visits, and their associated costs, have not been eliminated. Given the expected improvements in life expectancy following the introduction of these therapies, the burden is likely to continue into old age. A better understanding of the residual clinical, psychosocial, and economic burden that lung disease imposes on pwCF in the era of CFTR modulator therapy highlights the remaining unmet needs and could assist healthcare systems in better planning resource allocation.

BACKGROUND:Cystic fibrosis (CF) transmembrane conductance regulator modulators improve lung function, however, effects on cough frequency, physical activity, and sleep have not been assessed in clinical studies. METHODS:After a 12-week, phase 4 pilot feasibility study, we conducted a 13-week, phase 3b, open-label study in participants with CF aged ≥12 years previously naïve to elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) to assess the effects of ELX/TEZ/IVA on cough frequency, physical activity, and sleep using wearable cough monitors and actigraphy sensors (VX-445-126). RESULTS:In study VX-445-126 (N = 81), participants treated with ELX/TEZ/IVA experienced a 91.7% reduction in cough frequency (cough events per day) (95% CI, 89.2% to 93.6%; 241.3 coughs per day at baseline to 20.3 coughs per day) from baseline at the average of week 8 through week 12 (primary endpoint). Total steps per day (secondary endpoint) increased by 638 (95% CI, 298 to 977) at the average of week 8 through week 12. Time spent above sedentary physical activity per day, time spent on moderate-to-vigorous physical activity per day, and total mean activity count per day all increased from baseline at the average of week 8 through week 12 (other efficacy endpoints). While no changes in sleep activity patterns were observed in actigraphy data, patient-reported measures of sleep quality improved (other efficacy endpoints). ELX/TEZ/IVA was generally safe and well-tolerated. CONCLUSIONS:ELX/TEZ/IVA treatment led to a > 90% reduction in daily cough frequency, with sustained improvements in physical activity and better perceptions of sleep quality.

BackgroundChronic rhinosinusitis (CRS) contributes to morbidity in cystic fibrosis (CF), and sinus surgery serves as second-line treatment. Magnetic resonance imaging (MRI) was recently shown to differentiate CF-related CRS (CF-CRS) manifestations, and to monitor therapy response, but has not been used to investigate the effects of sinus surgery on CF-CRS.ObjectiveThe aim of this study was to systematically study the effects of sinus surgery on CF-CRS.MethodsTwenty controls with CF (median age 15 years, range 9-33 years) who had not undergone sinus surgery with annual MRI examinations were age-matched to the surgery group. The surgery group comprised 10 individuals with CF (median age 15 years, range 8-32 years) who underwent endoscopic sinus surgery between 2010 and 2018 and underwent MRI in median 2.5 months before (MRI1) and at least one (MRI2) or two (MRI3) annual MRIs after surgery. The median time difference between sinus surgery and MRI2 was 14 months, and between MRI2 and MRI3 it was 13 months. All patients were modulator-naïve. The established CRS-MRI score was used including sinus dimension measurement.ResultsIn controls, the median maxillary sinus width was stable from MRI1 through MRI3 (range 23.0-24.5 mm; P > .999). In the surgery group, the median maxillary sinus width decreased from MRI1 to MRI2 (-5.5 mm, P < .01), and remained stable from MRI2 to MRI3 (+3.0 mm; P = .544). The prevalence of maxillary sinus deformation decreased from MRI1 to MRI2 (-35%; P < .05) and was stable from MRI2 to MRI3 (+19%; P = .295). The CRS-MRI sum score was stable from MRI1 through MRI3 in controls (median 28, 23 and 34 at MRI1-2-3), and in the surgery group (36, 35 and 39, respectively) (P = .743-.999).ConclusionSinus surgery improves maxillary sinus width and deformation. The CRS-MRI score could not detect further benefits of surgery on CF-CRS. MRI supports the evaluation of sinus surgery in the era of modulator treatment strategies as some patients still suffer from CF-CRS despite optimized modulator treatment and there is a need to identify patients that still might profit from sinus surgery.

Background: Primary ciliary dyskinesia (PCD) is a rare genetic disorder characterized by deficient mucociliary clearance and development of chronic lung disease. Pulmonary exacerbations (PEx) in chronic lung diseases increase morbidity and lung function decline, but their frequency in PCD has been understudied. We aimed to prospectively determine the annual frequency of PEx in PCD and identify related risk factors. Methods: In a multicentre, observational study conducted in 11 centres from seven countries, we prospectively collected data from a well-described patient cohort with genetically confirmed PCD over a year via monthly telephone questionnaires and clinical visits. We assessed the annual PEx frequency using three definitions: i) clinical definition 1 (Def-1) when three out of seven clinical items were positive; clinical definition 2 (Def-2) if the patient started or changed antibiotic treatment; self-reported PEx by the patient. For paired statistical comparisons we used the Friedman test and the Wilcoxon matched-pairs test and tested their agreement (Cohen's kappa statistics). We also determined related risk factors using a mixed-effects model. Results: We recruited 271 individuals with PCD of all ages. Among patients with complete annual records (n = 248), approximately 80% experienced at least one PEx per year, as assessed by the three definitions used. Self-reported PEx per year (median 2, interquartile range (IQR) 1-5) were higher (p < 0.0001) than the PEx assessed by Def-1 (median 2, IQR 0-4) and Def-2 (median 1, IQR 0.25-3). Self-reported PEx had a substantial agreement with Def-1 [kappa (SE) = 0.61 (0.05)] and a moderate agreement with Def-2 [kappa (SE) = 0.51 (0.05)]. Female sex and autumn season were associated with higher number of PEx, independent of the definition used. Increasing age was correlated with higher annual PEx frequency by Def-1. Conclusion: In this multicentre study, we prospectively assessed the annual PEx frequency in patients genetically diagnosed with PCD, demonstrating the importance of the definition used in capturing the exacerbation burden of PCD, as well as the influence of sex, age and season on exacerbation frequency.

We present a detailed protocol for the training and application of an artificial intelligence (AI)-assisted workflow for automated analysis of pore and filament structures in scanning electron microscopy (SEM) images of human mucus from the respiratory tract and ileum. Our method leverages machine learning within the Fiji platform to classify image regions into pores and filaments, enabling precise and efficient quantification. The workflow includes preprocessing, pixel classification using a trained multilayer perceptron classifier, feature extraction, and data pooling. This approach significantly reduces analysis time compared with manual measurements while maintaining high precision. To validate our method, we compared manual and automated measurements on SEM images of airway and ileal mucus samples. High agreement was observed between datasets, with effect sizes indicating that AI-generated data variability is even less than human-to-human interobserver variation. In addition, we showed that increasing the counting frame area in automated analysis did not alter resulting distributions notably, confirming the robustness of the method. This AI-assisted tool supports high-throughput, comparative studies of biological network structures, enhancing accuracy and efficiency. Its application has the potential to accelerate research into structural and functional alterations of mucus in diseases such as cystic fibrosis and Crohn's disease, contributing to a deeper understanding of pathophysiology and the development of targeted therapeutic strategies.NEW & NOTEWORTHY Our study introduces a new artificial intelligence (AI)-assisted workflow for quantitative analysis of mucus network structures in scanning electron microscopy (SEM) images. By integrating machine learning with systematic uniform random sampling, this approach reduces variability and increases throughput compared with traditional manual methods. In our setup, the automated analysis was 40-120 times faster compared with manual analysis. The workflow is intended to be adapted by other biomedical research groups, particularly valuable for large-scale respiratory research.

BACKGROUND:Primary ciliary dyskinesia (PCD) and cystic fibrosis (CF) are muco-obstructive lung diseases that are caused by distinct genetically determined defects in mucociliary clearance; however, knowledge on the relative severity of airway mucus dysfunction and chronic inflammation remains limited. The aim of this study was therefore to compare sputum viscoelastic properties, inflammation markers and the proteome between patients with PCD and patients with CF before and under elexacaftor/tezacaftor/ivacaftor (ETI) therapy. METHODS:We compared sputum rheology, inflammation markers and the proteome in 42 clinically stable adolescent and adult patients with PCD, 40 patients with CF with at least one F508del allele before (baseline) and 3 months after initiation of ETI, and 15 age-matched healthy controls. RESULTS:The elastic modulus (G') and viscous modulus (G″) of PCD sputum was increased compared to healthy controls (p<0.001), lower than in CF at baseline (p<0.001) and similar to CF on ETI. Inflammation markers in PCD sputum including neutrophil elastase, free DNA, myeloperoxidase, interleukin (IL)-1β and IL-8 were also increased compared to healthy controls (all p<0.001), lower than in CF at baseline (p<0.05 to p<0.001) and comparable to CF on ETI. Similarly, changes in the sputum proteome were less pronounced in PCD compared to CF at baseline, but comparable between PCD and CF on ETI. CONCLUSIONS:Clinically stable patients with PCD show changes in sputum viscoelastic properties, inflammation markers and the proteome that are less severe than in patients with CF at baseline, but comparable to CF patients on ETI therapy.

Pulmonary exacerbations in people with cystic fibrosis receiving highly effective CFTR modulator therapy are largely similar to those in patients without modulator treatment and continue to represent clinically significant events in CF https://bit.ly/49Vq5Le