Journal of Cystic Fibrosis最新文献

Background: Broncho-Alveolar Lavage (BAL) is the reference standard for airway surveillance in clinical management of cystic fibrosis (CF), but is invasive and requires general anaesthesia in children. Non-invasive alternatives can lack specificity (Oropharyngeal swabs; OPS), or evaluation in paediatric CF (Middle meatus sampling; MMS). We sought to determine if MMS via nasal-swabs performed better than OPS at representing the microbiological attributes of BAL.

Methods: In a stable preschool CF cohort attending a single specialist centre, we evaluated the microbiological yield of BAL, MMS, and OPS sampling using both standard clinical culturing, and shotgun metagenomic sequencing (Illumina NextSeq 500).

Results: Matched BAL, MMS, and OPS from 30 preschool children provided 88 samples. While both culture and metagenomic surveillance performed well at detecting S. pneumoniae in BAL, MMS performed better at detecting S. aureus, M. catarrhalis and Escherichia coli, while OPS performed better at detecting H. Influenzae. Metagenomics revealed a significantly more diverse microbiome in OPS than BAL or MMS. While agreement on pathogen profiles varied widely between metagenomics and culture methods, MMS more accurately represented BAL, particularly for Streptococcus, M. catarrhalis, and Escherichia.

Conclusions: MMS and OPS cultures performed well as proxies for BAL in relation to certain pathogens. Metagenomics detected pathogens in many samples that were unobserved in culture, and showed the oropharynx microbiome to be much more diverse. Lung and nares microbiomes were more similar in composition and diversity. Our data suggest that nasal sampling of the middle meatus may be a more accurate surrogate for lower airway samples.

As life expectancy for people with cystic fibrosis continues to improve due to advances in care and CFTR modulator therapies, age-related comorbidities are emerging as new clinical challenges. This short review summarizes insights from a symposium focusing on ageing and CF at the 20th ECFS Basic Science Conference in March 2025 in Pisa, Italy. Mechanisms of ageing and their involvement in CF disease are first outlined. We then highlight two age-associated comorbidities in CF, cardiovascular disease and colorectal cancer, and outline future research directions to clarify how CF-specific and general ageing mechanisms intersect. Understanding these processes will be crucial for tailoring long-term care strategies in the ageing CF population.

Background: CFTR modulating therapies have advanced significantly but remain ineffective for people with CF (pwCF) with mutations preventing CFTR protein production. PwCF carrying non-canonical splicing mutations show modest benefits. SPL84, an antisense oligonucleotide (ASO) developed by Splisense, targets the non-canonical CFTR splicing mutation 3849+10 kb C→T (3849) and is currently in Phase2 trials. SPL84-23, a longer SPL84 variant, was shown to modulate splicing and rescue CFTR activity in patient-derived respiratory epithelial cells carrying the 3849 mutation. Here, we investigated intestinal organoids as a platform to assess ASO-based splicing modulation.

Methods: SPL84-23 effect on CFTR splicing was measured using RT-PCR and RT-qPCR. Functional rescue was assessed in 3D-organoids by forskolin-induced swelling, and in 2D-monolayers by short-circuit current assays.

Results: We established a novel free-uptake ASO delivery protocol into 3D-intestinal organoids and 2D-monolayers from 3849 pwCF. All cultures showed high basal levels of correctly spliced transcripts, leading to high residual CFTR activity. SPL84-23 treatment reduced aberrant splicing by 78 %, in both 3D and 2D systems, resulting in significant improvements in CFTR function across all organoid cultures.

Conclusion: Intestinal organoids, both 3D and monolayers, provide a suitable platform for assessing ASO-based splicing modulation. Our study further implies that the high level of correctly spliced 3849 CFTR transcripts in intestinal epithelial cells may contribute to the mild intestinal symptoms in pwCF carrying non-canonical splicing mutations.

Introduction: Interpreting lung function trends in cystic fibrosis (CF) is challenging due to biological variability, irregular measurement intervals, and difficulties in establishing an individual baseline. Reliance on visual inspection alone may misclassify true change and delay recognition of clinically meaningful decline.

Methods: We developed a real-time graphical application, integrated into the Swedish CF registry, which captures spirometry measurements collected in routine clinical care. Individual lung function trends were visualised using locally estimated scatterplot smoothing (LOESS), and annual trends were estimated using linear mixed-effects models fitted to continuously updated data from the Swedish CF cohort. Each individual's lung function trend was compared with an age-based reference group, which included all individuals aged 5-17 years for paediatric assessments and all individuals within ±5 years of the patient's current age for adults.

Results: The application displays observed lung function values alongside dynamic LOESS curves, individual linear trends, and the population mean trend. Clinicians can estimate and visualise individual linear trends with 95% confidence intervals over the past 1, 3, or 5 years. The tool also provides estimated values, Z-scores, and deviations from each individual's estimated baseline, facilitating detailed assessment of both short- and long-term changes in lung function.

Conclusion: Integrating real-time FEV₁ analysis into the Swedish CF registry provides clinicians and patients with a practical tool for continuous evaluation of short- and long-term lung function trends, facilitating the monitoring of disease progression and supporting clinical decision-making.