BACKGROUND AND OBJECTIVE:Children with severe neurological disorders are at risk of secondary respiratory morbidity due to impaired airway clearance and dysphagia, but systematic data on structural lung changes remain scarce. METHODS:We retrospectively analyzed all clinically indicated chest CT examinations at a tertiary care center (2015-2025) in 34 children with severe neurological disorders (median age 10 years), excluding those with primary lung disease. Exploratory hierarchical clustering identified clinical phenotypes based on disease etiology, respiratory support, dysphagia, and mobility. RESULTS:Structural abnormalities were common. Lobar consolidation (76%) and bronchial wall thickening (62%) were the most frequent CT findings. Cluster analysis identified three phenotypes: a stable neuromuscular phenotype without bronchiectasis or Pseudomonas aeruginosa colonization, an advanced neuromuscular-dysphagic phenotype with the highest bronchiectasis prevalence (64%, p = 0.005), and a neurologic-dysphagic phenotype characterized by frequent consolidations (86%) and ground-glass opacities (36%). Although most scans were elective (76%), CT prompted management changes in 91% of patients, mainly intensified airway clearance, antibiotic treatment, and escalated respiratory support. Among CT abnormalities associated with subsequent management change, 60% were not clearly identifiable on retrospectively reviewed preceding chest radiographs. CONCLUSION:In this selective cohort of children with severe neurological disorders undergoing clinically indicated chest CT, structural lung abnormalities were common despite the absence of a primary pulmonary diagnosis. Exploratory clinical phenotyping suggested distinct risk patterns linked to dysphagia, impaired airway clearance, and microbial colonization, and may help identify patients in whom CT provides clinically relevant additional information. Prospective studies are warranted before broader CT-based strategies can be recommended.

BACKGROUND:Childhood interstitial lung diseases (chILDs) are rare, heterogeneous chronic pulmonary disorders that are often underdiagnosed due to their low prevalence and nonspecific clinical presentation. Persistent tachypnea of infancy (PTI), often referred to as neuroendocrine cell hyperplasia of infancy (NEHI), is 1 of the most frequent forms of chILD, although its underlying etiology remains unknown. RESEARCH QUESTION:Can comprehensive genetic testing significantly improve diagnostic yield in patients with PTI/NEHI compared with limited testing of established genes? STUDY DESIGN AND METHODS:We conducted a comparative genetic analysis, using exome sequencing, in a multicenter cohort of patients who had received diagnoses of PTI/NEHI and contrasted their findings with those of patients with chILD who did not meet the diagnostic criteria for PTI/NEHI (referred to as the non-PTI/NEHI group). Diagnostic yield was assessed in both groups, and patients were further stratified into subgroups to evaluate whether clinical characteristics or comorbidities differed between those with and without genetic diagnosis. RESULTS:In 12 patients with PTI/NEHI, broad genetic testing identified potentially pathogenic variants associated with known human conditions. Notably, the same genes were identified across multiple individuals exclusively in the PTI/NEHI subgroup, including SRRM2 (n = 5) and NAA10 (n = 3). Both genes are associated with complex disorders primarily manifesting neurodevelopmental delay, as are the 4 other genes (BRWD3, DEPDC5, NKX2-1, UBE3B) identified in the children with PTI/NEHI. Among 79 patients with PTI/NEHI, those with neurodevelopmental comorbidity had a significantly higher likelihood of receiving a genetic diagnosis (11 of 24; 45.8%) than those without (1 of 55; Fisher exact test, P < .001). INTERPRETATION:Our data further support the view that PTI/NEHI represents a phenotype rather than a disease entity and may occur in the context of various genetic conditions, including, but probably not limited to, neurodevelopmental disorders. Early genetic testing may help reduce diagnostic delays, and exome sequencing is particularly recommended in patients with PTI/NEHI with neurodevelopmental involvement.

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.

BACKGROUND:Malnutrition is a recognized but insufficiently investigated concern in children with childhood interstitial lung diseases (chILD). The relationship between nutritional status and pulmonary function in this population remains poorly understood. This study aimed to evaluate the frequency and impact of malnutrition in chILD and to identify associated clinical factors. METHODS:We analyzed baseline and follow-up data from the chILD-EU registry, including anthropometric measurements, disease severity scores, pulmonary function tests, and treatment information. Malnutrition was defined as a weight-for-age (WFA) z-score < -2. Multivariable linear regression models were used to assess the association between malnutrition and lung function after adjustment for potential confounders. Longitudinal mixed-effects models were applied to evaluate the relationship between time-varying nutritional status and lung function over time. RESULTS:A total of 3351 visits from 766 children were analyzed. At baseline, 38.9% of children were malnourished. Children with malnutrition had significantly lower lung function compared with those without malnutrition (both p < 0.001). In multivariable analyses adjusting for age, sex, prematurity, diagnostic category, and disease severity, malnutrition remained independently associated with reduced lung function (zFEV1 β = -0.83, p = 0.007; zFVC β = -1.35, p < 0.001). In longitudinal mixed-effects models including baseline and follow-up visits, improvements in WFA z-scores were associated with improved lung function over time (zFEV1 β = 0.33, p < 0.001; zFVC β = 0.37, p < 0.001). CONCLUSION:Malnutrition is common among children with chILD and is independently associated with impaired lung function and greater disease severity. Improvements in nutritional status are associated with improved pulmonary outcomes during follow-up, highlighting the importance of routine nutritional monitoring and multidisciplinary care.

The care and treatment of children and adolescents requiring long-term ventilation pursues several overarching goals and is ideally carried out through interdisciplinary collaboration within an experienced, multidisciplinary team.In children and adolescents, neuromuscular diseases resulting in respiratory insufficiency are the primary cause of long-term dependence on a ventilator. In addition to the diseases that necessitate long-term ventilation, airway obstructions, trauma, malformations associated with genetic syndromes, and, rarely, insufficient secretion clearance or severe dysphagia with aspiration in spontaneously breathing patients are indications for tracheotomy. For many of these congenital diseases, the disease course and prognosis do not inherently suggest any potential for weaning or decannulation.Consequently, some of the measures and examinations required by the German Federal Joint Committee's (GBA) guidelines on outpatient intensive care may be unnecessary or even contraindicated in children and adolescents.

The purpose of this study is to evaluate the feasibility, safety, and effectiveness of an individualized online exercise therapy (IOET) designed to improve physical capacity and quality of life in children and adolescents with long-COVID. In a prospective, randomized, single-center exploratory trial, 14 patients aged 9–17 years with long-COVID (median symptom duration: 21 months) received either 6 or 12 weeks of IOET. Sessions were held twice weekly via telemedicine and individually adapted to physical ability and symptoms. Primary outcomes were functional performance (6-minute walk test [6MWT], sit-to-stand test [STST], and handgrip strength test [HST]). Secondary outcomes included school attendance, quality of life (PedsQL), safety, and self-reported recovery. All participants showed clinically improvements. In the 12-week IOET group, 6MWT increased from 396.0 to 616.3 m (+ 220.3 m, 95

BACKGROUND:Childhood interstitial lung diseases (chILD) encompass a diverse group of rare, chronic respiratory disorders. While treatment options are limited, evaluating health-related quality of life (HRQoL) has become a vital approach for clinical monitoring. This study aims to enhance our understanding of the medical and sociodemographic factors influencing HRQoL in chILD. METHODS:This study used prospectively obtained data from the chILD-EU Register. Caregivers were handed validated, age-specific HRQoL questionnaires (the chILD-specific questionnaire and the generic Pediatric Quality of Life Questionnaire (PedsQL) 4.0 questionnaire). The scores were linearly transformed from a 5-point scale to a percentage scale ranging from 0% to 100%. We used exploratory univariate analyses and multivariable ordinary least squares (OLS) regression models on cross-sectional data to investigate the associations between subjects' clinical features and HRQoL scores. RESULTS:424 patients from 10 European countries and 48 study sites were included in the final analysis. The most relevant factors associated with lower HRQoL scores for the chILD-specific questionnaire and the PedsQL 4.0 Total Score, as identified in the univariate analysis and confirmed in the multivariable OLS regression model, were "inpatient medical care in the last 3 months" (-13.6%; p<0.0001 and -11.4%; p<0.0001, respectively) and "failure to thrive" (-9.1%; p=0.0014 and -12.1%; p<0.0001, respectively). Among subjects old enough for pulmonary function testing (PFT) (n=162), we observed only a weak correlation between PFT results and different HRQoL scores. CONCLUSIONS:The main factors linked to reduced HRQoL scores were prior inpatient treatment and failure to thrive. Further interventional studies should determine whether addressing these factors can enhance HRQoL scores and potentially improve quality of life in chILD.

Physical activity (PA) and structured exercise are established cornerstones of cystic fibrosis (CF) management. While CFTR modulators have transformed treatment, the psychological factors affecting sustained PA adherence, particularly motivational regulation and PA enjoyment, require further investigation. This study aimed to determine whether percent predicted forced expiratory volume in one second (ppFEV₁) is independently associated with autonomous motivation and PA enjoyment in adults with CF, after adjusting for CFTR modulator therapy status and sex. A cross-sectional study was conducted at a specialised CF centre (N = 200). Participants completed validated questionnaires assessing motivational regulation (Behavioural Regulation Questionnaire-2, BREQ-2) and PA enjoyment (Physical Activity Enjoyment Scale, PACES). Clinical data, including the ppFEV₁, were obtained from medical records. Multivariate general linear models (GLM), partial correlations, and hierarchical regression analyses were utilised. Cross-sectional analyses showed that ppFEV₁ was independently associated with intrinsic motivation (β = .233, p < .001), the relative autonomy index (RAI) (β = .203, p = .004) and the PACES total score (β = .201, p = .004). After CFTR modulator therapy status and sex were accounted for, the additional variance explained by the ppFEV₁ was statistically significant but modest (ΔR2 = .054, .041, and .040, respectively). Neither the CFTR modulator therapy status nor sex was significantly associated with the assessed motivational or enjoyment outcomes. Although ppFEV₁ showed small, independent associations with autonomous motivational regulation and PA enjoyment in adults with CF, lung function should not be used as a proxy for motivational support needs. To provide person-centred, SDT-informed support that encourages sustained participation in PA, the motivational regulation and enjoyment of PA should be assessed directly in adults with CF.

BACKGROUND:Tracheostomies are increasingly performed in children. The treatment of infections in tracheostomized patients is challenging because of the distinction between chronic colonization and acute infection. Next-generation sequencing (NGS) is a promising alternative for identifying and quantifying pathogens in a short period. This study investigated the utility of NGS of tracheal aspirates from healthy and tracheostomized children (TC). METHODS:This monocentric prospective case-control study recruited children with long-term TC and compared the colonization of the lower airways with a control group of children who had undergone elective general surgery. Tracheal aspirates were analyzed using three methods: bacterial culture, polymerase chain reaction (PCR), and NGS. RESULTS:In total, 107 children were recruited for this study. Sixty-two samples were excluded due to acute exacerbation, lack of tracheal secretion, or insufficient cfDNA concentration (< 0.3 ng/µl). Consequently, 45 samples (17 controls and 28 tracheotomized samples) were analyzed. Tracheal aspirates analyzed using NGS revealed a significantly higher prevalence of Pseudomonas aeruginosa (p = 0.0001), Staphylococcus aureus (p = 0.002), Stenotrophomonas maltophilia (p = 0.004), and Moraxella catarrhalis (p = 0.03) in TC. Through NGS, we were able to demonstrate that Pseudomonas aeruginosa was the dominant bacterium in 44% of the samples in which it was detected. CONCLUSIONS:NGS can effectively identify a wide spectrum of DNA-based pathogens (bacteria, viruses, and fungi) in the tracheal aspirates of children. Tracheostomized children were significantly more likely to be colonized by difficult-to-treat bacteria. Future research is required to evaluate the clinical benefits of NGS compared with standard microbiological procedures.

Background:This study aimed to investigate the mediating effect of physical activity enjoyment (PAE) on various physical activity (PA) levels in adult people with cystic fibrosis (pwCF) concerning disease-specific and non-disease-specific factors. Methods:A total of 168 adult pwCF (39.3% females; mean age 36.7 ± 11.9 years) completed questionnaires assessing PAE (Physical Activity Enjoyment Scale, PACES) and PA levels (7-day Physical Activity Recall, PAR). Participants' demographics (age, sex) and clinical characteristics [ppFEV1; percent predicted forced expiratory volume in 1 s, and BMI; body mass index (kg/m2)]) were extracted from medical records. Mediation analysis was used to examine the direct and indirect effects of disease-specific and non-disease-specific factors on PA, considering PAE as a potential mediator. Results:Correlation analyses indicated a weak but statistically significant association between ppFEV1 and very vigorous physical activity (VVPA) (r = 0.177; p = 0.021) and PAE (r = 0.221; p = 0.004). PAE was linked to time spent in vigorous physical activity (VPA) (r = 0.202; p = 0.009), VVPA (r = 0.238; p = 0.002), and moderate-to-vigorous physical activity (MVPA) (r = 0.152; p = 0.049). Mediation analysis revealed that PAE fully mediated the association between lung function (ppFEV1) and vigorous PA (VPA), very vigorous PA (VVPA), and moderate-to-vigorous PA (MVPA) but not moderate PA (MPA). PpFEV1 and PAE together accounted for 26-49.3% of the variance in PA, suggesting the presence of other influential factors. No mediation effect was observed between PAE and age and BMI on any of the PA levels. Conclusions:Our findings underscore the importance of both physiological and psychological factors in shaping PA among adults with CF. Beyond traditional clinical management, strategies that enhance PAE may be crucial for promoting sustained PA engagement. Future research should examine additional psychological and environmental factors influencing PAE and develop comprehensive approaches to support active lifestyles in this population.

Objective: To assess whether chronic rhinosinusitis (CRS) severity is associated with obstructive sleep apnea (OSA) in adult people with cystic fibrosis (pwCF). Methods: We conducted a retrospective single-center study of 44 adults with CF who underwent overnight polysomnography (PSG), Epworth Sleepiness Scale (ESS) assessment, and sinus computed tomography (CT). CRS severity was quantified using the Lund–Mackay score (LMS) and the main nasal cavity score (MNCS). OSA was defined by Apnea–Hypopnea Index (AHI) thresholds per American Academy of Sleep Medicine criteria. Results: Participants had a mean age of 31.1 ± 8.4 years and a mean percent predicted FEV1 of 51.8 ± 15.7. Sinus CT showed radiological evidence of CRS in all participants. Mean AHI was 5.3 ± 4.4/h; 48% had AHI ≥ 5/h. There were no significant differences between pwCF with and without OSA in age, sex, BMI, lung function, total sleep time, sleep efficiency, or ESS score (all p > 0.05). Mean LMS and MNCS did not differ between OSA and non-OSA groups (both p > 0.05), and neither score correlated with PSG parameters or ESS (all p > 0.05). Receiver operating characteristic (ROC) analysis demonstrated low discriminative ability of LMS and MNCS for predicting OSA (AUCs < 0.70, p < 0.05). Conclusions: In this cohort of adults with CF, CT-based CRS severity was not associated with OSA. Given the substantial prevalence of OSA observed, PSG screening should be considered irrespective of CRS severity.

BACKGROUND:Persistent tachypnea of infancy (PTI), also known as neuroendocrine cell hyperplasia of infancy (NEHI), represents 1 of the most common childhood interstitial lung diseases. Despite its frequency, standardized management protocol is lacking, and long-term outcome data remain limited. RESEARCH QUESTION:What treatment is used for patients with PTI/NEHI, how does clinical management vary across European countries, and what are the long-term outcomes in affected patients? STUDY DESIGN AND METHODS:This was a European multicenter, retrospective, observational study. Clinical characteristics, therapeutic interventions, and long-term follow-up data were collected and analyzed. Treatment strategies were compared among countries that contributed at least 10 patients. RESULTS:A total of 378 children (63.5% male [240 of 378]) from 73 centers across 17 countries were enrolled, with a median age at diagnosis of 9 months (interquartile range [IQR], 6-13 months). Therapeutic interventions included oxygen supplementation (75.9% [287 of 378]); inhaled bronchodilators, inhaled glucocorticoids, or both (62.4% [236 of 378]); systemic glucocorticoids (37.0% [140 of 378]); and nutritional support (33.8% [128 of 378]). Of the children who received oxygen therapy, 53.6% (154 of 287) were reported to have been weaned off, with a median age at weaning of 24 months (IQR, 16-36 months). Marked variability in treatment practices was observed across participating countries (P < .05). Longitudinal data were available for 48.9% of patients (185 of 378) with a median follow-up of 19 months (IQR, 16-57 months). The proportion of symptomatic children declined over time, with the most marked improvement observed at 4 years of age. Resolution of imaging and pulmonary function abnormalities also was reported; however, a subset of patients continued to demonstrate persistent hypoxemia, crackles, and exercise intolerance, as well as abnormal imaging and pulmonary function test findings into adolescence. INTERPRETATION:Our results show that significant differences in treatment strategies for PTI/NEHI were observed across European countries, highlighting the need for evidence-based guidelines. Although long-term prognosis generally is favorable, residual symptoms remain in some patients, warranting continued follow-up.

BACKGROUND:Pulmonary fibrosis is of critical importance in childhood interstitial lung disease (chILD), yet fibrosis prevalence, impact on clinical progression, and survival have not been systematically evaluated. Therefore, we aimed to determine the prevalence of pulmonary fibrosis and its impact on lung function as well as survival in individuals aged 0-18 years. METHODS:Data were extracted from the chILD-EU register, a multicentre cohort study of children and adolescents with chILD from 23 European countries. Data collection included centralised peer review and systematic scoring of CT scans and lung biopsies. The primary outcome was the presence or absence of fibrosing lung disease. Pulmonary fibrosis was determined based on predefined criteria used in the register (fibrosisregister) or in clinical trials (fibrosistrial). Clinical characteristics, disease categories, pulmonary function data, and survival were assessed. This study was registered with ClinicalTrials.gov (NCT02852928) and is ongoing. FINDINGS:Data were collected prospectively between March 3, 2004 and July 23, 2025. Among the 1071 children diagnosed with chILD, 220 of 1071 fulfilled the criteria of fibrosisregister (20·5% [95% CI 18·1-23·0]) and 62 of 534 fulfilled the criteria of fibrosistrial (11·6% [8·9-14·3]). Median age at inclusion was 2·4 years (IQR 0·6-9·2), 570 (53·2%) participants were male and 501 (46·8%) were female, and 882 (76·8%) were European. Pulmonary function, assessed as percent predicted forced vital capacity (ppFVC), in children with fibrosis under both fibrosis definitions was consistently 15-20% lower across all follow-up visits up to 8 years compared with individuals without fibrosing lung disease. Survival after enrolment was lower in children who fulfilled fibrosisregister criteria than in those who did not fulfil fibrosisregister criteria (log-rank p=0·0029; unadjusted hazard ratio (HR) for death or lung transplantation 1·64 [95% CI 1·18-2·28]). The increased hazard of fibrosisregister remained after adjusting for sex, age category, and BMI z-score. A higher BMI z-score was protective for survival with fibrosisregister (HR 0·80). While not statistically significant, children with fibrosistrial criteria had survival and HR trends in the same direction as those with fibrosisregister criteria. INTERPRETATION:The application of standardised criteria for diagnosing pulmonary fibrosis enables identification of affected children among patients with chILD. These children have lower pulmonary function, an increased risk of death, and could benefit from antifibrotic therapies. FUNDING:Deutsche Forschungsgemeinschaft and Boehringer Ingelheim, Germany.

Rationale: The mucoid phenotype of Staphylococcus aureus is caused by adaptation. Excessive biofilm formation associated with a protective effect for mucoid S. aureus was observed in isolates from respiratory samples of people with cystic fibrosis (pwCF). Objectives: There is little knowledge about the prevalence of mucoid S. aureus in pwCF and a potential association with CF lung disease. Methods: A prospective multicenter study was conducted (cross-sectional and longitudinal). Specimens and case report forms were sent to the central study laboratory for characterization of S. aureus and analysis of clinical parameters. Measurements and Main Results: In the cross-sectional study, in 41 (9.1%) of 451 S. aureus-positive pwCF from 13 CF centers, mucoid S. aureus was cultured. In the longitudinal study, the distribution of CFTR genotypes and the number of pwCF with highly effective modulator therapy and coinfection with Pseudomonas aeruginosa were equivalent in the mucoid group (35 pwCF) versus the control group (only nonmucoid S. aureus; 36 pwCF). Although lung function did not differ between groups as a whole, a subgroup analysis revealed significantly worse lung function for female pwCF with mucoid S. aureus as well as for pwCF if P. aeruginosa coinfection was excluded. Conclusions: In the era of highly effective modulator therapy, worse lung function was associated with female and P. aeruginosa-negative pwCF with mucoid S. aureus compared with pwCF with only nonmucoid S. aureus. Therefore, appropriate culture conditions should be established to detect mucoid S. aureus. Further investigations are needed to elucidate the relationship between mucoid S. aureus and CF lung disease. Clinical trial registered with www.clinicaltrials.gov (NCT04171583).

Die Adoleszenz ist eine Umbruchphase für Jugendliche mit chronischen Erkrankungen wie Mukoviszidose (zystische Fibrose [CF]) und Asthma. Dank großer Fortschritte in der hocheffektiven Cystic-fibrosis-transmembrane-conductance-regulator(CFTR)-Modulator-Therapie erreichen fast alle Patienten mit CF das Erwachsenenalter und bedürfen einer fortgesetzten interdisziplinären Betreuung. Dagegen haben etwa 70

Background Pulmonary fibrosis is of critical importance in childhood interstitial lung disease (chILD), yet fibrosis prevalence, impact on the clinical progression, and survival have not been systematically evaluated. Methods Data were extracted from the chILD-EU register, a European prospective multicenter cohort study with centralized peer-review on patient inclusion and systematic scoring of computed tomography (CT) scans and lung biopsies. Pulmonary fibrosis was determined based on predefined criteria (fibrosis register) or criteria used in clinical trials (fibrosis trial). We calculated fibrosis rates of chILD entities, evaluated fibrosis criteria and assessed longitudinal pulmonary function testing and survival rates of children with or without fibrosis. Results 1,071 children diagnosed with chILD were included in the final analysis. The childhood prevalence of fibrosis was for 20.5% (220/1071) according to a single time point, register definition and 11.6% (62/534) according to the dual time point, trial definition. At the age when the children were able to perform pulmonary function tests, those with fibrosis had 15-20% worse predicted forced vital capacity (ppFVC), were older and diagnosed later. Throughout childhood, the disease trajectories assessed as decline in ppFVC and survival did not differ between children with or without pulmonary fibrosis or between the two fibrosis definitions. Overall, survival until the age of 20 years was about 70%. Conclusions This study assesses the prevalence, pulmonary function progression and survival of pulmonary fibrosis in chILD. The application of standardized criteria for pulmonary fibrosis enables identification of affected children among patients and may support early selection for anti-fibrotic therapies. ### Competing Interest Statement MG reports personal fees for advisory and adjudication board work from Boehringer Ingelheim, outside the submitted work; grant support from Boehringer to the institution. AM-G reports fees to the institution for work as local principal investigator in a study by Boehringer, AM reports personal fees from Vertex for consulting, JL reports fees to the institution from Boehringer for work as a sub-investigator, HM reports fees to the institution from Boehringer, JLZ reports personal honoraria for lectures and consultation from Boehringer and from Bayer for study evaluation. FP reports personal fees for lectures from Sanofi/Regeneron, Allergopharma, Takeda Pharma, BioCryst, Vertex Pharmaceuticals, Nutricia-Milupa, Stallergenes Greer, ALK-Abello and for participation in an advisory board from Takeda Pharma and Sanofi/Regeneron. FS reports personal fees for attending meetings and for lectures by Vertex and to the institution by Vertex. FP is founder and partner of RPACT GbR, a company proving statistical analysis for the University of Munich. KK reports personal fees and payments to the institution from Boehringer, NS reports personal fees and payments to the institution from Boehringer. ### Funding Statement Relevant funding for this study was provided by the Deutsche Forschungsgemeinschaft (DFG, Gr970/9-1 and 9-2) and Boehringer-Ingelheim, Germany. The funders had no role in study design, conduct or interpretation, nor in writing or submitting the manuscript for publication. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Participating centers adhered to all contractual, legal, and ethical standards before enrolling patients. Each patient and/or caregiver provided age-appropriate verbal assent and written informed consent. The study was approved by the lead Ethics committee of the University Hospital Munich (20-0329, 22-0133) and all local committees. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Anonymized aggregated data from the chILD-EU register are available upon reasonable request. Research proposals using such aggregated data can be submitted to the corresponding author (matthias.griese{at}med.uni-muenchen.de). The proposals will be assessed by the chILD-EU register coordination team, and aggregated data will be shared if the proposal addresses relevant research questions. Requests for anonymized individual patient data can be sent to the corresponding author, who will facilitate contact with the responsible physicians who will discuss the legal and administrative feasibility of sharing those data.

Background: Despite the well-documented physical and psychological benefits of regular physical activity (PA) and exercise, participation remains insufficient in adults with cystic fibrosis (pwCF). In the general population, PA enjoyment is a key determinant of sustained engagement, yet its predictors in CF populations remain underexplored. Objective: We aimed to examine associations between clinical parameters, health-related quality of life (HRQoL), motivation and PA enjoyment in adult pwCF. We hypothesised that higher intrinsic motivation and better HRQoL would predict greater enjoyment, independent of clinical parameters. Methods: In this cross-sectional study, 197 adult pwCF (mean age = 36.6 ± 11.9 years) from a single centre completed validated questionnaires assessing PA and exercise enjoyment (Physical Activity Enjoyment Scale, PACES), motivation (Behavioral Regulation in Exercise Questionnaire-2, BREQ-2), and HRQoL (Cystic Fibrosis Questionnaire-Revised, CFQ-R). Hierarchical regression was conducted in three steps: clinical variables (Model 1), added HRQoL domains (Model 2), and motivational variables (Model 3). Results: The complete model explained 68.4% of the variance in PA and exercise enjoyment (R2 = 0.684, p < 0.001). Intrinsic motivation was the strongest positive predictor (β = 6.228, p < 0.001), while external regulation negatively predicted enjoyment (β = −1.932, p = 0.030). Among HRQoL domains, only health perception remained significant (β = 0.081, p = 0.038). Clinical variables alone accounted for minimal variance (R2 = 0.023, p = 0.370). Conclusions: Intrinsic motivation was the most robust predictor of PA and exercise enjoyment, outweighing clinical and most HRQoL factors. These findings support autonomy-supportive strategies to foster internal motivation and enhance long-term PA and exercise participation in adult pwCF.

Background: This study aimed to investigate longitudinal changes in muscle mass, quality, and composition (sarcopenia and myosteatosis) in adult people with cystic fibrosis (pwCF) using artificial intelligence (AI)-assisted body composition analysis (BCA) with chest computed tomography (CT) at the T12 level and to examine the influence of CFTR modulator therapy with elexacaftor/tezacaftor/ivacaftor (ETI). Methods: A retrospective observational study was conducted on 102 adult pwCF (42 females (41%), mean age 33.9 ± 11.1 years) who underwent routine chest CT scans with a minimum of six months between scans. PwCF were categorized into ETI and no ETI groups. AI-assisted BCA was performed on chest CT images at the T12 level to measure skeletal muscle area (SMA), inter- and intramuscular adipose tissue (IMAT), and low-attenuation muscle area (LAMA). IMAT/SMA ratio and height- and weight-related skeletal muscle indices (SMI) were calculated. Results: The ETI group showed a significant increase in SMA over time (p < 0.001), whereas the IMAT, LAMA, and IMAT/SMA ratio increased in both groups (all p < 0.05). SMI showed alterations only in the ETI group, with an increase in SMA/m2 (p < 0.001) and a decrease in SMA/kg (p = 0.003) and SMA/BMI (p = 0.006). Sex-specific analysis showed that SMA and myosteatosis increased regardless of sex (all p < 0.05). Weight-adjusted SMI decreased only in females receiving ETI therapy (p < 0.05). Conclusions: Adult pwCF, particularly those undergoing ETI therapy, experience significant changes in body composition, including increased muscle mass and myosteatosis. Trends in the development of sarcopenic obesity have been observed, particularly in female pwCF. These findings emphasize the importance of comprehensive body composition assessments and targeted interventions in pwCF treated with ETI to optimize muscle mass and quality while managing adipose tissue accumulation.