BACKGROUND:Cystic fibrosis (CF) is a progressive, life-shortening disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. CFTR modulator therapies targeting the common Phe508del mutation have been introduced in clinical practice. This study evaluates the real-world effects of 1 year of dual CFTR modulator therapy - lumacaftor/ivacaftor or tezacaftor/ivacaftor - in children homozygous for Phe508del. METHODS:A retrospective single-center (Belgium) study was conducted in children with CF aged 2-18 years who initiated dual modulator therapy. Clinical data from 1 year before and after treatment initiation were analyzed. Outcomes included changes in sweat chloride concentration (SCC), lung function (percent predicted forced expiratory volume in 1 s (ppFEV1)), frequency of exacerbations and hospitalizations, sputum microbiology, nutritional status (body mass index (BMI) z-score), liver function, vitamin levels, and ophthalmologic status. RESULTS:Fifty-four children (mean age 8.5 years) were included. After 1 year, SCC decreased significantly with a mean of 14 mmol/L (p < 0.001). Lung function showed a modest improvement with a mean increase of 2.3% in ppFEV1 (range: +16% to -15%, p = 0.023). No significant changes were observed in exacerbation or hospitalization rates, nor in sputum microbiology. Nutritional status and liver function remained stable, though vitamin A levels increased significantly. The therapy was generally well-tolerated. CONCLUSION:This real-world study demonstrates that dual CFTR modulators in children homozygous for Phe508del result in a significant reduction in SCC and modest improvements in ppFEV1. These findings support the efficacy and safety of dual modulator therapy in pediatric CF care.

INTRODUCTION:Cystic fibrosis (CF) can present prenatally as fetal hyperechogenic bowel (FEB) or meconium ileus (MI), indicating early CFTR dysfunction. Elexacaftor/tezacaftor/ivacaftor (ETI) partially restores CFTR function and limited reports suggest it may benefit fetuses when administered maternally. CASE PRESENTATION:We report four pregnancies in CF carrier mothers with confirmed or presumed fetal CF after FEB detection, treated off-label with ETI. Fetal bowel status was monitored via ultrasound and MRI, and maternal safety was assessed. In Case 1, ETI from 26-36 weeks normalized bowel appearance; the infant had normal meconium passage. In Case 2, ETI at 30 weeks improved bowel findings in a fetus with CF and congenital diaphragmatic hernia, but the neonate died from hernia complications. Case 3 involved a single ETI dose before preterm birth at 28 weeks; the infant had severe MI and died from neurological complications. In Case 4, ETI at 35 weeks briefly improved bowel status; delivery at 37 weeks was required for progressive distension, followed by MI surgery with full recovery. Maternal therapy was well tolerated. CONCLUSIONS:Prenatal ETI may improve fetal bowel abnormalities and reduce MI risk, particularly with early, sustained exposure. Imaging effectively monitored response. Further studies are required to define optimal timing, protocols, and long-term safety.

BACKGROUND:Post-infectious bronchiolitis obliterans (PIBO) may occur following childhood infections. Subsequent dysanaptic lung growth, with differential development of the alveolar compartment over the airways, remains elusive. We performed a morphological characterization of the whole airway tree in PIBO compared to bronchiolitis obliterans syndrome (BOS) after lung transplantation. METHODS:Lungs from matched PIBO (n=5), BOS (n=5), and non-diseased donors (n=5) were evaluated using ex vivo high-resolution computed tomography (CT) scans followed by three-dimensional (3D)-airway segmentation. Matched lung tissue samples (n=4 locations/lung) were scanned with micro-CT (resolution: 5-10 µm) for 3D terminal bronchiole assessment and histology. RESULTS:No significant difference in the number of airways per generation (until generation 11) was observed between groups (p=0.86). Airway diameters in PIBO (generations 6-11) and BOS (generations 7-10) were increased compared to controls (overall p=0.018), without significant differences between PIBO and BOS. More obstructed airways were present in BOS versus PIBO (p=0.016), but airway obstructions were larger in PIBO versus BOS (p=0.032). There were significantly fewer terminal bronchioles in PIBO compared to BOS and controls (PIBO: median 2934 terminal bronchioles/lung (IQR:2247-4115), BOS 8424 terminal bronchioles/lung (IQR:6207-10480), controls 10 903 terminal bronchioles/lung (IQR:7583-12 820), p=0.0009), but terminal bronchiole diameters were not significantly different (p=0.37). Obstruction of pre-terminal bronchioles was segmental (i.e., focal with normal distal terminal bronchiole) in BOS, but partly non-focal (non-reopening bronchiole) in PIBO. CONCLUSIONS:PIBO lungs display an almost threefold decrease in terminal bronchioles compared to BOS, with morphological differences in the type and location of airway obstructions, providing structural evidence supporting dysanaptic lung growth.

Primary ciliary dyskinesia (PCD) is a rare, hereditary disorder characterized by impaired motile ciliary function, resulting in abnormal mucociliary clearance (MCC). This leads to persistent infection and inflammation, progressive airway damage, and bronchiectasis. Physiotherapy, particularly airway clearance therapy (ACT), is considered a cornerstone of PCD management to compensate for the mechanical MCC deficit, aiming to reduce infection risk, prevent disease progression, and improve quality of life (QOL). However, evidence supporting specific physiotherapy regimens in PCD remains limited. Current practice varies widely across centers and countries, with no standardized guidelines. Common ACT methods include positive expiratory pressure (PEP) with or without oscillation, autogenic and postural drainage, active cycle of breathing technique (ACBT), intrapulmonary percussive ventilation (IPV), and high-frequency chest wall oscillation (HFCWO). Comparative studies show no clear superiority among techniques. Evidence for mucolytic therapy, such as hypertonic saline or rhDNAse, is weak or controversial. Scarce data demonstrate potential benefits of exercise interventions in improving ventilatory capacity and QOL. Age-specific considerations are crucial: ACT should be started early, be adapted to developmental stages, and be combined with strategies to enhance adherence. Despite physiotherapy being standard care, randomized controlled trials are challenging due to ethical constraints, potentially reducing a therapy that is already believed to be helpful. Future priorities include developing international guidelines and conducting high-quality studies to optimize treatment strategies. In conclusion, physiotherapy plays a crucial role in PCD management, but current recommendations rely largely on expert opinion and extrapolation from related conditions like cystic fibrosis (CF) and non-CF bronchiectasis (BRECT), underscoring the need for robust evidence.

Abstract Background Upper airway disease is common in primary ciliary dyskinesia (PCD), but management evidence is limited. We aimed to describe management practices and identify factors influencing management decisions. Methods Using data from the Ear-Nose-Throat (ENT) Prospective International Cohort of patients with PCD (EPIC-PCD) and an ENT-specialist survey across participating centres, we described management practices recorded at routine follow-up. We assessed clinical factors associated with practices via mixed-effects logistic regression models. In a subgroup of patients, we assessed factors associated with initiation or discontinuation of practices. Results We included 579 patients: median age 15 years, 46% female. Nasal rinsing (54%) and nasal corticosteroids (22%) were most frequently prescribed. Among 466 patients with available data, 47 had grommets (10%) and 42 hearing aids (9%). Nasal corticosteroids and rinsing were more frequently prescribed in patients with polyps (odds ratio [OR] 3.74, 95% confidence interval [CI] 1.80-7.76; OR 3.39, 95% CI 1.37-8.37) or turbinate hypertrophy (OR 1.89, 95% CI 1.03-3.47; OR 2.89, 95% CI 1.55-5.38), and upper airway nebulisation in patients with frequent nasal symptoms (OR 2.86, 95% CI 1.11-7.39). Management practices differed between centres, as seen also by the specialists’ survey responses. In 177 patients with multiple visits, initiation of nasal rinsing was associated with frequent nasal symptoms (OR 3.18, 95% CI 1.24-8.18) and turbinate hypertrophy (OR 3.21, 95% CI 1.20-8.59). Conclusion Upper airway disease management in PCD varies and is partly guided by symptom burden and clinical findings. This variation across centres highlights the need for care standardisation and PCD-specific management guidelines.

BACKGROUND:Cystic Fibrosis (CF) and primary ciliary dyskinesia (PCD) are congenital disorders characterized by impaired mucociliary clearance, resulting in chronic airway infection, inflammation, and progressive lung damage. CF lung disease involves defective CFTR function throughout the entire airway epithelium, whereas PCD originates from dysfunction of motile respiratory cilia located predominantly in proximal airways. Diagnostic tools such as FEV1 lack sensitivity to detect early peripheral lung damage. Lung clearance index (LCI), obtained via multiple breath washout (MBW), has emerged as a promising marker for early detection of lung abnormalities. OBJECTIVES:To compare LCI between age and FEV1-matched people with (pw) CF and PCD (without highly effective CFTR modulator treatment), hypothesizing more abnormal LCI in CF due to more peripheral airway involvement. Secondary objectives included comparing phase III slope parameters (Scond x VT, Sacin x VT) to explore ventilation inhomogeneity and localization of lung disease. METHODS:This retrospective cross-sectional study included pwCF and pwPCD aged 6-20 years with available MBW and spirometry data (2011-2024). RESULTS:PwCF (n23, median age 14.4 y) had similar FEV1 z-scores compared to 23 pwPCD (median age 14.4 y) (-0.1 vs. -1.1, p: 0.33). LCI values were more abnormal in the CF group compared to the PCD group (7.8 vs. 7.1; p: 0.04). FEF25-75%pred and phase III slope parameters were not significantly different, though a trend toward higher Scond x VT in CF was noted (0.08 vs. 0.06; p: 0.11). CONCLUSION:Despite similar FEV1 abnormalities, reflecting proximal airway impairment, pwCF exhibit greater peripheral airway involvement than pwPCD, as indicated by higher LCI values.

This case report presents a 14-month-old boy with a history of cystic fibrosis (CF) carrier status, diagnosed following a positive newborn screening for CF (CF-NBS), who developed symptoms suggestive of Pseudo-Bartter syndrome (PBS). Despite initial evaluations not meeting CF diagnostic criteria, subsequent investigations revealed an intermediate sweat chloride concentration, a second CFTR mutation, and CFTR dysfunction through rectal organoid morphology analysis (ROMA) consistent with CFTR-related disorder (CFTR-RD). This case raises important considerations regarding the diagnosis and management of CFTR-RD. PBS can be considered as a rare presentation of CFTR-RD and can occur in children with sweat chloride below the CF range. Functional testing of CFTR by ROMA enabled a more accurate diagnosis. Despite the negative work-up after CF-NBS, this infant developed CFTR-RD, but this should not be considered as a screen failure. Follow-up of children with CFTR-RD at a CF centre is preferred, because of the risk of developing CF.

Background:The extent to which changes in lung function are due to natural variability in patients with primary ciliary dyskinesia (PCD) is unknown. We aimed to assess intra-individual variability in forced expiratory volume in 1 s (FEV1) derived from spirometry to define the extent to which the observed changes were due to test variability in clinically stable PCD patients. Methods:PROVALF-PCD (Prospective Observational Multicentre Study on Variability of Lung Function in Stable PCD Patients) was a large international prospective cohort conducted in 2017-2019. We included patients aged ≥5 years who were clinically stable at two or more consecutive visits and provided spirometry-derived lung function measurements. To calculate the upper limit of normal (ULN), we fitted an unadjusted multilevel mixed-effect model, and to determine the absolute change in FEV1 z-scores, we calculated the coefficient of repeatability (CR). We performed sensitivity analyses by stratifying relative change by age (adults versus children), number of measurements (at least four), and time between measurements (<4 months apart). Results:We included 252 participants from 12 countries with confirmed or highly likely PCD. We included 1028 FEV1 measurements from patients in stable state. The ULN for relative change between two measurements of FEV1 was 25%. Test variability remained high in all sensitivity analyses. The CR was 1.88 FEV1 z-score. Conclusions:Changes in intra-individual FEV1 >25% between visits in stable PCD patients lie beyond the expected test variability and therefore could be considered physiologically relevant. These findings inform the selection of end-points for pulmonary intervention trials in PCD, as they suggest that FEV1 is not a sensitive test for monitoring lung health in PCD.

Cystic fibrosis (CF) care has been revolutionized by CFTR modulators, particularly the triple combination elexacaftor/tezacaftor/ivacaftor (ETI). However, a subset of people with CF (pwCF) carrying ETI-unresponsive variants still lack effective therapies. A nextgeneration modulator combination, vanzacaftor/tezacaftor/deutivacaftor (VTD), shows promise in addressing this gap. Phase 3 trials report superior efficacy of VTD in reducing sweat chloride and suggest potential benefit for 31 CFTR variants previously deemed ETI-unresponsive based on limited in vitro data. Reassessment of these variants reveals that some demonstrate residual function or borderline ETI responsiveness, challenging their unresponsive classification. Differences in molecular interactions, particularly within NBD1 and modulator-binding sites, may account for variant-specific responses. Patient-derived intestinal organoid (PDIO) assays showed significant functional improvement with VTD, but not ETI, in 2 pwCF with G458V and G85R mutations, supporting the notion of distinct mechanisms of action. These findings underscore the need to refine CFTR variant classifications and highlight the limitations of current in vitro thresholds. While PDIOs offer physiologically relevant insights, clinical outcomes remain the ultimate determinant of therapeutic benefit. Broader access to raw data and individualized in vitro-clinical correlations are essential for informed therapeutic decisions. VTD offers new hope for pwCF with rare or previously unresponsive variants, reinforcing the importance of a personalized, datadriven approach to CF care.

Background: Patient-derived intestinal organoids (PDIOs) are an in vitro tool used to predict clinical responses to CFTR modulators in people with cystic fibrosis (pwCF). Although strong genotype-based correlations have been observed, individual responses among F508del homozygous pwCF remain variable. We aimed to assess this correlation specifically within this group. Methods: A retrospective multi-center study included 60 F508del homozygous pwCF from six Belgian CF centers. The 15 highest and 15 lowest PDIO responders to tezacaftor/ivacaftor (TI) and elexacaftor/tezacaftor/ivacaftor (ETI) were selected based on Forskolin-induced swelling (FIS) assay results. Clinical outcomes-sweat chloride concentration (SCC), spirometry, BMI, pulmonary exacerbations, and IV antibiotic use-were measured before and after treatment. Additionally, transcriptomics and 13 CFTR SNPs were compared between high and low responders to TI to assess whether variants within CFTR contribute to phenotypic variability. Results: Baseline characteristics were similar between low and high PDIO responders, except for lower pretreatment SCC in high TI responders. No significant differences in clinical outcomes were observed between groups after treatment. PDIO responses were higher with ETI than TI (p < 0.001). PDIO response magnitude was significantly associated with changes in SCC and ppFEV1 (p < 0.001). No differences in SNPs or transcriptomics were found. Conclusion: While high and low PDIO response groups did not differ in clinical outcomes individually, PDIO response magnitude was significantly associated with SCC and ppFEV1 changes when TI and ETI data were combined, suggesting its potential as a biomarker for modulator treatment efficacy.

Background Pulmonary hypertension (PH) is an important, life-limiting co-morbidity in cystic fibrosis (CF), where multiple mechanisms such as hypoxia, inflammation and primary CF-transmembrane regulator (CFTR) dysfunction may affect vascular integrity. We aimed to characterize the structural impact of vascular wall changes in the pulmonary microcirculation, to uncover the potential need for therapeutic strategies targeting vascular disease. Methods End-stage inflated CF (n=6), and control (n=4) lungs were processed to lung cores (2.8cm³) and scanned with micro-computed tomography (resolution: 8.5µm). The diameter and number of distal pulmonary arteries (dPA), distal airways (DA) and open terminal bronchioles (TB) were measured on 3D models (n= 2 cores/lobe) and compared per generation and within pairs. Morphometric assessment was paired with histological analysis (n= 1/lobe) to assess tissue morphology, collagen and connective tissue components. Results dPA in CF were narrowed and disappeared in the last generations of dichotomous branching, resulting in a decreased total diameter per generation. While narrowing was already present where TB remained open, dPA disappearance was only present where no TB were left. dPA narrowing increased when DA collapsed. Histologically, fibrotic dPA changes were present in areas without distal airway disease. Conclusion We showed for the first time the presence of dPA lumen narrowing and disappearance with fibrotic vascular wall changes in end-stage CF. Narrowing was present diffusely and fibrosis was also present in areas without airway disease. These findings suggest that vascular dysfunction in CF may not solely be secondary to hypoxic vasoconstriction and inflammation but may represent a distinct pathophysiological process related to CFTR dysfunction in the endothelium, warranting further study.

Background Primary ciliary dyskinesia (PCD) is a rare genetic disorder characterised by dysfunction of motile cilia. Symptoms include recurrent and chronic airway infections which can lead to deteriorating lung function and inflammatory destructive lung disease in the form of persistent atelectasis and bronchiectasis. Routine blood testing may be used as a tool for disease monitoring and management. However, currently there are no consensus-based guidelines within the field of PCD. BEAT-PCD together with the ERN-LUNG PCD-Clinical Trial Network aimed to develop an international expert consensus statement on which routine blood tests should be conducted in patients with PCD. Methods An international panel of 33 PCD experts from 17 countries was established to generate consensus on routine blood testing in PCD. A modified Delphi technique with three e-survey rounds was used to reach consensus, which was defined as ≥80% agreement for each statement. Two patient representatives were included in the consensus process. Results The expert panel reached consensus on 51 out of 101 statements (50%) on routine blood testing in children and adults with PCD to be performed at diagnosis, annually and on exacerbation. The statements include biomarkers for inflammation, haemoglobin, iron status, vitamin D, immune function, inhalant allergies, liver and kidney function, and allergic bronchopulmonary aspergillosis. Conclusions This is the first international consensus on routine blood testing in PCD. It highlights blood tests that may be relevant to perform at diagnosis, annually and on exacerbation in people with PCD. Further research on the clinical usefulness of routine blood testing in PCD is needed.

Due to the craniofacial anatomy of people with achondroplasia, sleep-disordered breathing (SDB) occurs more frequently than in the average stature population. SDB, which comprises obstructive sleep apnoea (OSA), more rarely central sleep apnoea (CSA), and nocturnal alveolar hypoventilation (NH), may present at any age in patients with achondroplasia. Untreated SDB is associated with neurocognitive dysfunction, cardiovascular, and metabolic complications in children and adults. There continues to be debate on the optimal assessment and management of SDB in achondroplasia. To help address this, the European Achondroplasia Forum (EAF), a network of clinicians and patient advocates representative of the achondroplasia clinical community, organised a virtual workshop in October 2023 to scrutinise, vote and agree upon five guiding principles for managing SDB in achondroplasia. This workshop was attended by 40 healthcare professionals, including clinical geneticists, general practitioners and consultants, orthodontic and orthopaedic surgeons, paediatricians, paediatric endocrinologists and pulmonologists, sleep researchers and specialists, and two patient advocacy group representatives. The five guiding principles focus on lifelong assessment and proactive management, incorporating individualised sleep studies, screening, and a stepwise approach to therapeutic management. The EAF was in favour of all guiding principles, with all achieving 100% consensus with high levels of agreement (range 8.9-9.7/10). In developing guiding principles for the management of SDB in achondroplasia, the EAF aims to facilitate optimal screening and management of SDB in infants, young children, and adults with achondroplasia.