BACKGROUND:People with cystic fibrosis (pwCF) have complex treatment regimens with cystic fibrosis transmembrane conductance regulator (CFTR) modulators and supportive therapies. Evidence on adherence across cystic fibrosis (CF) therapies using different assessment methods and the added value of medication reviews remains limited. OBJECTIVE(S):This study compared adherence across CF therapies using three assessment methods and evaluated the contribution of medication reviews. METHODS:This cross-sectional study (February to April 2025) included pediatric and adult pwCF at Maastricht University Medical Centre+. Adherence to CFTR modulators and supportive therapies (vitamin supplements, pancreatic enzymes, inhalers, and nebulizers) was assessed with pharmacy refill data (medication possession ratio, MPR); self-reported adherence (Medication Adherence Report Scale-5, MARS-5), and structured medication reviews. The primary outcome was the proportion of pwCF adherent to CF medication per assessment method. Secondary outcomes were the within-patient differences in adherence between CFTR and supportive therapies (McNemar's exact test) based on MPR and the number and acceptance of DRP-interventions in the medication review. RESULTS:Forty-three pwCF (17 children, 26 adults; 39.5% female) were included. For CFTR modulators, adherence was 91.7% (MPR), 91.2% (MARS-5), and 72.2% (medication review). For supportive therapies, adherence was 56.3%, 77.7%, and 77.4%, respectively. Four nonadherent pwCF were identified exclusively through medication review. Within-patients, adherence was higher for CFTR modulators than for supportive therapies (p < 0.001). Medication reviews identified 51 DRPs in 41 pwCF (including nonadherence in 12 pwCF), all proposed interventions were accepted by the treating physician. CONCLUSION:Adherence varied by medication class and assessment method. Medication reviews provided clinically relevant information in addition to refill-based and self-reported measures.

Uncontrolled asthma in children impairs quality of life, emphasizing the need for effective symptom monitoring. Traditional follow-up visits may miss episodes of poor asthma control. This study aimed to evaluate if digital home monitoring including non-invasive vital parameter measurements via a smartwatch, medical feedback, and coaching can detect early signs of disease deterioration and improve asthma control. In this twelve-week prospective single-arm intervention study, 40 children with asthma (ages 6-18) were monitored at home using an app, smartwatch, and spirometer. Continuous vital parameters, monthly (Childhood) Asthma Control Test ((C)-ACT) scores, and weekly home lung function measurements were collected. Medical feedback was provided based on specific cut-off values. Changes in asthma control were analyzed using multivariable logistic regression. An increase in nocturnal heart rate was significantly associated with worsening (C)-ACT scores (OR: 2.11, CI: 1.068-4.168, p = 0.032), even after adjusting for Salbutamol use. Although C-ACT scores showed a trend towards improvement (baseline: 22.5, study end: 24, p = 0.063), no significant change in lung function was observed. Additionally, a higher frequency of lung function testing was linked to worsening (C)-ACT scores. Increased nocturnal heart rate was significantly associated with deteriorating (C)-ACT scores. These findings suggest that non-invasive home monitoring has potential in managing paediatric asthma.

Asthma is the most common chronic disease in children, yet adherence to treatment remains poor due to barriers in communication and self-management. Shared decision-making (SDM) can improve adherence, but no decision aid currently exists for paediatric asthma. This gap limits children’s engagement in treatment decisions, highlighting the need for a tailored patient decision aid. The aim was to develop a decision aid to support SDM between children with asthma, their parents, and healthcare providers (HCPs), followed by an evaluation of its acceptability and usability. A user-centred, iterative co-design approach was used, involving children aged 6–18 years with physician-diagnosed asthma, their parents, and healthcare providers (including paediatricians, asthma nurses, and general practitioners). An initial needs assessment identified key challenges in asthma-related decision-making. These insights informed eight structured co-creation sessions focusing on identifying decision points, exploring preferences, and shaping content and format of the decision aid. Usability and acceptability were tested with end-users, and the final version was independently reviewed against the IPDAS checklist by two researchers to assess quality and completeness. A needs assessment (n = 37) with HCPs, patients, and caregivers identified substantial information gaps, with many patients and parents unaware of treatment options or potential side effects. HCPs emphasised the potential value of a decision aid in improving information delivery and encouraging SDM. In eight co-creation sessions, a multidisciplinary group (n = 18) collaborated to develop and refine two complementary decision aids. Feedback highlighted improved clarity, age-appropriate design, and relevance for real-life consultations. In the final phases, both decision aids were tested for acceptability and usability, showing high user satisfaction with minor revisions made (n = 32). A quality assessment was conducted by two independent reviewers. Both tools met all 12 IPDAS criteria. These results confirm their quality and suitability for implementation in practice. The decision aids were well received by patients, parents and HCPs and met IPDAS criteria. They address critical unmet needs in paediatric asthma care by supporting informed decision-making. These tools have the potential to improve the quality of clinical consultations and promote more patient-centred care in the treatment of childhood asthma. Not applicable.

(1) Background: In recent years, cystic fibrosis transmembrane regulator (CFTR) modulating therapy has made it possible to treat the underlying pathophysiological defect in children with cystic fibrosis (CF). Response to therapy varies among patients. We investigated the immune responses and exhaled breath profile changes after the initiation of CFTR modulator therapy to explore their potential as markers of therapy response. (2) Methods: We performed a prospective, longitudinal proof-of-principle study, investigating immune responses and exhaled breath volatile organic component (VOC) profiles prior to and during the initiation of therapy with Lumacaftor/Ivacaftor in a cohort of 17 patients with CF aged 2 to 6 years old. Response to therapy was assessed based on clinical markers and the decrease in sweat chloride. Whole blood stimulation assays were performed at t = 0, 6 and 18 weeks, while VOC analysis was performed at t = 0 and 18 weeks. (3) Results: A pattern of immune reconstitution was found in the first 4 months of therapy. The same pattern was found in responders and non-responders. Exhaled breath VOC profiles were significantly affected by therapy. A trend toward a significant difference was found between responders and non-responders. (4) Conclusions: Pediatric CF patients show a pattern of immune reconstitution after the initiation of CFTR modulating therapy. We hypothesize that this could be explained by the need for a pro-inflammatory profile for a more effective clearance of latent airway pathogens in the initial phase. The exhaled breath profile also clearly changes after the initiation of therapy, indicating the therapy’s influence on airway inflammation and oxidative stress; thus, it might predict the response to therapy.

Asthma affects 7% of Dutch children and poses an increasing challenge, highlighting the need for effective paediatric asthma care. Achieving optimal asthma control is crucial given the potentially negative long-term effects of bad asthma control on lung development and quality of life in young children. The aim was to understand the challenges and requirements of existing asthma management practices in children. In a qualitative explorative study design, semi-structured, in-depth interviews were held among 37 Dutch stakeholders. A total of 15 patients/parents, 10 general practitioners (GPs), 5 paediatricians/paediatric pulmonologists and 7 nursing specialist/pulmonary nurses participated. Analysis was based on a thematic inductive analysis, using open and axial coding. GPs tended to emphasise the treatment of patients/parents with acute symptoms and underestimate the diagnosis and management of chronic symptoms, leading to possible over- and undertreatment. Asthma care between primary and secondary healthcare is fragmented and worsens these challenges. Moreover, the absence of well-established follow-up structures in primary care contributes to insufficient self-management skills among patients. Shared Decision-Making in children lacks a tailored approach, with variable engagement levels among healthcare providers. Limited focus on preventive strategies leads to little attention to, for example, promoting healthy lifestyles. Moreover, children are often not actively involved in decision-making. The study provides valuable insights to improve the quality and continuity of care for children with asthma and their parents. It underlines the need for a comprehensive and integrated care pathway to minimise the long-term negative effects of uncontrolled asthma.

To the editor, Asthma is a chronic disease and a notable cause of morbidity, affecting approximately 10% of all children worldwide 1 .The main goal of asthma treatment in children is to achieve good asthma control.The Global

Background The prevalence of asthma-like symptoms in preschool children is high. Despite numerous efforts, there still is no clinically available diagnostic tool to discriminate asthmatic children from children with transient wheeze at preschool age. This leads to potential overtreatment of children outgrowing their symptoms, and to potential undertreatment of children who turn out to have asthma. Our research group developed a breath test (using GC-tof–MS for VOC-analysis in exhaled breath) that is able to predict a diagnosis of asthma at preschool age. The ADEM2 study assesses the improvement in health gain and costs of care with the application of this breath test in wheezing preschool children. Methods This study is a combination of a multi-centre, parallel group, two arm, randomised controlled trial and a multi-centre longitudinal observational cohort study. The preschool children randomised into the treatment arm of the RCT receive a probability diagnosis (and corresponding treatment recommendations) of either asthma or transient wheeze based on the exhaled breath test. Children in the usual care arm do not receive a probability diagnosis. Participants are longitudinally followed up until the age of 6 years. The primary outcome is disease control after 1 and 2 years of follow-up. Participants of the RCT, together with a group of healthy preschool children, also contribute to the parallel observational cohort study developed to assess the validity of alternative VOC-sensing techniques and to explore numerous other potential discriminating biological parameters (such as allergic sensitisation, immunological markers, epigenetics, transcriptomics, microbiomics) and the subsequent identification of underlying disease pathways and relation to the discriminative VOCs in exhaled breath. Discussion The potential societal and clinical impact of the diagnostic tool for wheezing preschool children is substantial. By means of the breath test, it will become possible to deliver customized and high qualitative care to the large group of vulnerable preschool children with asthma-like symptoms. By applying a multi-omics approach to an extensive set of biological parameters we aim to explore (new) pathogenic mechanisms in the early development of asthma, creating potentially interesting targets for the development of new therapies. Trial registration Netherlands Trial Register, NL7336, Date registered 11–10-2018.

ABSTRACTBackgroundPreclinical cell-based assays that recapitulate human disease play an important role in drug repurposing. We previously developed a functional forskolin induced swelling (FIS) assay using patient-derived intestinal organoids (PDIOs), allowing functional characterization of CFTR, the gene mutated in people with cystic fibrosis (pwCF). CFTR function-increasing pharmacotherapies have revolutionized treatment for approximately 85% of people with CF, but a large unmet need remains to identify new treatments for all pwCF.MethodsWe used 76 non-homozygous F508del-CFTR PDIOs to test the efficacy of 1400 FDA-approved drugs on improving CFTR function, as measured in FIS assays.ResultsBased on the results of a secondary validation screen, we investigated CFTR elevating function of PDE4 inhibitors and currently existing CFTR modulators in further detail. We show that PDE4 inhibitors are potent CFTR function inducers in PDIOs and that CFTR modulator treatment rescues of CF genotypes that are currently not eligible for this therapy.ConclusionsThis study exemplifies the feasibility of high-throughput compound screening using PDIOs and we show the potential of repurposing drugs for pwCF that are currently not eligible for therapies.One-sentence SummaryWe screened 1400 FDA-approved drugs in CF patient-derived intestinal organoids using the previously established functional FIS assay, and show the potential of repurposing PDE4 inhibitors and CFTR modulators for rare CF genotypes.

Exhaled breath analysis has great potential in diagnosing various respiratory and non-respiratory diseases. In this study, we investigated the influence of inhaled corticosteroids (ICS) on exhaled volatile organic compounds (VOCs) of wheezing preschool children. Furthermore, we assessed whether exhaled VOCs could predict a clinical steroid response in wheezing preschool children. We performed a crossover 8-week ICS trial, in which 147 children were included. Complete data were available for 89 children, of which 46 children were defined as steroid-responsive. Exhaled VOCs were measured by GC-tof-MS. Statistical analysis by means of Random Forest was used to investigate the effect of ICS on exhaled VOCs. A set of 20 VOCs could best discriminate between measurements before and after ICS treatment, with a sensitivity of 73% and specificity of 67% (area under ROC curve = 0.72). Most discriminative VOCs were branched C11H24, butanal, octanal, acetic acid and methylated pentane. Other VOCs predominantly included alkanes. Regularised multivariate analysis of variance (rMANOVA) was used to determine treatment response, which showed a significant effect between responders and non-responders (p < 0.01). These results show that ICS significantly altered the exhaled breath profiles of wheezing preschool children, irrespective of clinical treatment response. Furthermore, exhaled VOCs were capable of determining corticosteroid responsiveness in wheezing preschool children.

ABSTRACTPatient-derived organoids hold great potential as predictive biomarker for disease expression or therapeutic response. Here, we used intestinal organoids to estimate individual cystic fibrosis transmembrane conductance regulator (CFTR) function of people with cystic fibrosis, a monogenic life-shortening disease associated with more than 2000 CFTR mutations and highly variable disease progression. In vitro CFTR function in CF intestinal organoids of 176 individuals with diverse CFTR mutations was quantified by forskolin induced swelling and was strongly associated with longitudinal changes of lung function and development of pancreatic insufficiency, CF-related liver disease and diabetes. This association was not observed when the commonly used biomarker of CFTR function sweat chloride concentration was used. The data strongly exemplifies the value of an organoid-based biomarker in a clinical disease setting and supports the prognostic value of forskolin induced swelling of intestinal organoids, especially for people with CF who have rare CFTR genotypes with unclear clinical consequences.

Background With the increased use of acid suppressants, significant potential complications such as community-acquired pneumonia (CAP) are becoming more apparent. Paradoxically, in spite of an increased focus on potential complications, there is an increased use of acid suppressants in children and a lack of data specifically targeting the association between acid suppressants and CAP. Our main objective was to evaluate the risk of CAP in children using acid suppressants (proton pump inhibitors (PPIs) and/or histamine-2 receptor antagonists (H2RAs)). Methods We performed a cohort study using data from the UK Clinical Practice Research Datalink. All patients aged 1 month to 18 years with a prescription of acid suppressants were included and matched to up to four unexposed children. Time-varying Cox proportional hazards models were used to estimate the risk of CAP. The cohort consisted of 84868 exposed and 325329 unexposed children. Results Current use of PPIs and H2RAs was associated with an increased risk of CAP (adjusted hazard ratio 2.05 (95% CI 1.90-2.22) and 1.80 (95% CI 1.67-1.94), respectively). The risk was even greater in patients with respiratory disease. Long-term use (>= 211 days) of PPIs and H2RAs led to a significantly greater risk of CAP compared with short-term use (<31 days). After cessation of therapy, the risk remained increased for the following 7 months. Conclusion The use of acid suppressants in children was associated with a doubled risk of CAP. This risk increased with chronic use and respiratory disease, and remained increased after discontinuation of therapy.

Selected-Ion Flow-Tube Mass Spectrometry (SIFT-MS) has been applied in a clinical context as diagnostic tool for breath samples using target biomarkers. Exhaled breath sampling is non-invasive and therefore much more patient friendly compared to bronchoscopy, which is the golden standard for evaluating airway inflammation. In the actual pilot study, 55 exhaled breath samples of children with asthma, cystic-fibrosis and healthy individuals were included. Rather than focusing on the analysis of target biomarkers or on the identification of biomarkers, different data analysis strategies, including a variety of pretreatment, classification and discrimination techniques, are evaluated regarding their capacity to distinguish the three classes based on subtle differences in their full scan SIFT-MS spectra. Proper data-analysis strategies are required because these full scan spectra contain much external, i.e. unwanted, variation. Each SIFT-MS analysis generates three spectra resulting from ion-molecule reactions of analyte molecules with H3O+, NO+ and O2+. Models were built with Linear Discriminant Analysis, Quadratic Discriminant Analysis, Soft Independent Modelling by Class Analogy, Partial Least Squares - Discriminant Analysis, K-Nearest Neighbours, and Classification and Regression Trees. Perfect models, concerning overall sensitivity and specificity (100% for both) were found using Direct Orthogonal Signal Correction (DOSC) pretreatment. Given the uncertainty related to the classification models associated with DOSC pretreatments (i.e. good classification found also for random classes), other models are built applying other preprocessing approaches. A Partial Least Squares - Discriminant Analysis model with a combined pre-processing method considering single value imputation results in 100% sensitivity and specificity for calibration, but was less good predictive. Pareto scaling prior to Quadratic Discriminant Analysis resulted in 41/55 correctly classified samples for calibration and 34/55 for cross-validation. In future, the uncertainty with DOSC and the applicability of the promising preprocessing methods and models must be further studied applying a larger representative data set with a more extensive number of samples for each class. Nevertheless, this pilot study showed already some potential for the untargeted SIFT-MS application as a rapid pattern-recognition technique, useful in the diagnosis of clinical breath samples.