Karin M. de Winter – de Groot

Cystic Fibrosis Screen Positive Inconclusive Diagnosis/CFTR-related Metabolic Syndrome (CFSPID/CRMS) presents a significant clinical challenge due to its variable diagnostic outcomes and uncertain disease progression. Current diagnostic strategies, including sweat chloride testing and genetic analysis fall short in delivering clear guidance for clinical decision-making and risk assessment. Here, we comment on the potential of CFTR functional tests in patient-derived intestinal organoids (PDIOs) to enhance early risk stratification in CFSPID/CRMS cases. Using four hypothetical cases based on real-world data, we illustrate diverse clinical trajectories: diagnosis of cystic fibrosis (CF), reclassification as a CFTR-related disorder (CFTR-RD), non-CF designation, and persistent diagnostic uncertainty. Organoid-based assays—such as forskolin-induced swelling (FIS), steady-state lumen area (SLA) analysis, and rectal organoid morphology analysis (ROMA)—offer functional insights into CFTR activity and drug responsiveness. Compared to existing CFTR functional tests, such as Intestinal Current Measurement (ICM) and Nasal Potential Difference (NPD), these assays are more accessible, highly reproducible, and when needed support personalized medicine approaches. PDIO-based assays could help identify infants at high risk of disease progression, facilitating earlier interventions while minimizing unnecessary follow-ups for those unlikely to develop CF-related symptoms. Although not yet widely implemented, these assays hold promise for refining CFSPID diagnostics and management. Future research should focus on establishing standardized protocols allowing validation of clinical utility.

Repeated European surveys of newborn bloodspot screening (NBS) have shown varied strategies for collecting missed cases, and information on data collection differs among countries/regions, hampering data comparison. The ECFS Neonatal Screening Working Group defined missed cases by NBS as either false negatives, protocol-related, concerning analytical issues, or non-protocol-related, concerning pre- and post-analytical issues. A questionnaire has been designed and sent to all key workers identified in each NBS programme to assess the feasibility of collecting data on missed cases, the stage of the NBS programme when the system failed, and individual patient data on each missed case.

Ivacaftor has been shown to restore the functionality of the S1251N (also known as c.3752G>A) mutated CFTR, which may cause alterations in both airway and gut physiology and micro-environment, resulting in a change of microbiota in these organs. The aim of the present study was to analyze the effects of ivacaftor on the microbial community composition of both airway and gut in subjects with CF carrying one S1251N mutation, using a 16S rRNA gene-based sequencing approach. In 16 subjects with CF, repetitive samples from airways and gut were collected just before, and 2 months after, and, for 8 patients, also 9 and 12 months after, start of ivacaftor. 16S rRNA based sequencing identified 344 operational taxonomical units (OTUs) in a total of 139 samples (35 nasopharyngeal, 39 oropharyngeal, 29 sputum, and 36 fecal samples). Ivacaftor significantly enhanced bacterial diversity and overall microbiota composition in the gut (p < 0.01). There were no significant changes in the overall microbial composition and alpha diversity in upper and lower airways of these patients after ivacaftor treatment. Treatment with ivacaftor induces changes in gut microbiota whereas airway microbiota do not change significantly over time.

There are limited data on health-related quality of life (HRQoL) changes over time in children with cystic fibrosis (CF). We investigated associations between clinical and treatment variables with changes in HRQoL during 1 year. Forty-nine children with CF aged 6–18 years were followed in this multicentre, observational cohort study during 1 year. HRQoL was measured by the validated disease specific cystic fibrosis questionnaire-revised (CFQ-R). The CFQ-R total score as well as most domain scores improved significantly (8.0 points and [3.3–31.7] points respectively) during the one-year follow-up. Age at baseline demonstrated a strong longitudinal association with the change of CFQ-R total score (2.853 points decrease of CFQ-R total score per year increase in age) and several domain scores. Below 12 years of age, CFQ-R total score improved in most children, whereas a deterioration was observed in most children above 12 years. The number of PEx was associated with an increase of treatment burden score (4.466 points decrease per extra PEx). Conclusion: In the group as a whole, HRQoL improved significantly over time. However, changes over time were significantly influenced by age: below 12 years of age, HRQoL improved in most patients whereas a deterioration was observed in most children >12 years. Strategies how to preserve or ideally to improve HRQoL in adolescence should be developed. What is known: • Quality of life in patient with CF is diminished • Although CF is a chronic disease, longitudinal data on QoL in children with CF are scarce. What is new: • Below 12 years of age, quality of life improved in most children during the 1-year follow-up whereas a deterioration in quality of life was observed in most children above 12 years. • the treatment burden score of QoL correlated with the exacerbation rate

Research from JAMA Otolaryngology–Head & Neck Surgery — Nasal Nitric Oxide Levels and Nasal Polyposis in Children and Adolescents With Cystic Fibrosis