Journal of Cystic Fibrosis最新文献

Background: In individuals with cystic fibrosis (CF), respiratory viral infections frequently result in hospitalization and have been linked to secondary bacterial infection and colonization, highlighting viral infections as possible contributors to CF lung disease progression. We hypothesized that expression of antiviral host defense genes is dysregulated in CF airway epithelia.

Methods: We infected primary CF and Non-CF airway epithelia with respiratory syncytial virus (RSV) and characterized their responses at 12 hr, 24 hr, 48 hr, 72 hr, and 120 hr post infection (hpi) by RNA sequencing (RNAseq).

Results: Our analysis revealed strikingly different gene expression profiles for the CF and Non-CF epithelia over the course of the infection. While both CF and Non-CF cells exhibited an early signature for interferon signaling and antiviral defense pathways, this response was relatively exaggerated and sustained in CF epithelia. We also observed, in both genotypes, a transient downregulation of cilia-associated genes and loss of ciliary activity by 72 hpi. Interestingly, recovery of cilia activity was delayed in the CF epithelia.

Conclusions: These findings further our understanding of innate immune dysfunction in the CF airway epithelium and suggest that virus-induced cilia injury may further compromise host defenses in CF airways.

Background: Cystic fibrosis (CF) has been associated with impaired cardiovascular and endothelial function. CF transmembrane conductance regulator (CFTR) modulator therapy, most recently Elexacaftor/Tezacaftor/Ivacaftor (ETI), has led to improved CFTR function and life expectancy. However, the rising prevalence of obesity in adults is concerning. This study assessed the micro- and macrovascular endothelial function, cardiovascular disease (CVD) risk factors, and physical activity (PA) profiles in people with CF (pwCF) on ETI compared to healthy matched controls.

Methods: In 15 pwCF and 15 age- and sex-matched controls, microvascular endothelial function (via transdermal delivery of insulin [INS] and acetylcholine [ACh] on the forearm), macrovascular endothelial function (via flow-mediated dilation [FMD] of the brachial artery), central haemodynamic parameters, including heart rate (HR), stroke volume index (SVi) and cardiac output index (Q̇I) (via thoracic impedance cardiography), body mass index (BMI), blood pressure (BP), and accelerometer-assessed PA were measured.

Results: There were no differences in INS or FMD-mediated vasodilation between the groups (P > 0.05). However, a reduced vasodilatory response was evident in pwCF following ACh-mediated vasodilation (P = 0.01) and FMD normalised for shear rate (P = 0.03). No differences in resting HR, SVi, Q̇I, BP, BMI or PA were found (P > 0.05).

Conclusion: This study demonstrated reduced micro- and macrovascular function in pwCF. This dysfunction may have potential health implications, particularly regarding long-term cardiovascular risk and further longitudinal assessments are warranted.

Background & aims: Cystic fibrosis hepatobiliary involvement is a heterogeneous and systemic entity. The primary objective was to determine the prevalence of steatosis, by magnetic resonance-proton density fat fraction (MR-PDFF), and liver fibrosis, by magnetic resonance elastography (MRE), in a cohort of adults with cystic fibrosis. The secondary objective was to determine the diagnostic yield of widely available non-invasive liver markers for steatosis and fibrosis, and vibration controlled transitional elastography (VCTE) releasing Control Attenuation Parameter (CAP) (dB/m) and stiffness (kPa), with the aim of proposing a diagnostic algorithm.

Methods: We conducted a cross-sectional study including 101 adult patients with cystic fibrosis seen in a multidisciplinary unit. The study encompassed a clinical evaluation, morpho-functional assessment, VCTE, non-invasive liver markers and MR-PDFF and MRE. Diagnostic accuracy was assessed using ROC curves and 2 × 2 tables.

Results: MR-PDFF detected hepatic steatosis in 18 of 101 (17.8 %) patients, while MRE detected significant liver fibrosis in 15 of 101 (14.9 %). The VCTE cut-off with the best diagnostic yield, determined by the Youden index, was 222 dB/m for the presence of steatosis (AUC 0.864 (95 % CI 0.768-0.961; p < 0.001) and the VCTE cut-off was 6.65 kPa for liver fibrosis (AUC 0.951(95 % CI 0.81-1; p = 0.053). A screening algorithm for hepatic steatosis was developed using the fatty liver index (FLI) and CAP, with a negative predictive value of 83.3 %. For liver fibrosis, it was outperformed by the Hepamet Fibrosis Score (HFS) and VCTE, with a negative predictive value of 100 %.

Conclusions: The prevalence of hepatic steatosis and liver fibrosis was 17.8 % and 14.9 %, respectively. VCTE alone or in combination with FLI for steatosis or HFS for fibrosis demonstrated high diagnostic accuracy. This approach effectively allows for the exclusion of steatosis and fibrosis, thereby reducing the need for MR-PDFF and MRE studies.

Background: Chronic pulmonary inflammation strongly contributes to respiratory failure and mortality in patients with cystic fibrosis (pwCF). Effective anti-microbial immunity and maintaining lung homeostasis require continuous structural-immune cell communication. Whether and how this crosstalk is altered in CF remains poorly understood, obscuring potential new angles for therapy development to restore airway homeostasis in pwCF.

Methods: We performed droplet-based single cell RNA-sequencing on bronchial biopsies from pwCF to investigate structural-immune cell crosstalk. Computational analyses were used to compare these data to samples obtained from healthy controls.

Results: CF airway wall biopsies showed lower proportions and altered transcriptomes of basal cells, submucosal gland cells and endothelial cells, and a higher abundance of ciliated cells, monocytes, macrophages and T cells. Both B and T lymphocytes displayed aberrantly activated phenotypes with transcriptional changes linked to hypoxia and vascular endothelial growth factor signaling, indicative of crosstalk with endothelial cells. The CF lung displayed unique changes in intercellular communication potential involving ionocytes, macrophages, endothelial cells and lymphocytes. This included interactions between HLA-E on structural cells and the druggable CD94/NKG2A immune checkpoint on CD8⁺T cells.

Conclusions: We report the first single cell transcriptome atlas of the CF lung containing the full spectrum of structural and immune cells, providing a valuable resource for investigating changes to cellular composition, phenotypes and crosstalk linked to CF. Our analyses highlight dysregulated basal cell function and adaptive immunity in pwCF - despite favorable responses to CFTR modulator therapy. We identify novel aspects of CF pathophysiology and potential entry points for therapeutic strategies.

Background: Increased variability in forced expiratory volume in 1 s of % predicted (FEV₁pp) has been associated with accelerated lung function decline in individuals with cystic fibrosis (CF). Lung function variability is a leading predictor of decline, but the association between ivacaftor initiation and FEV₁pp variability has not been characterized.

Methods: We utilized the Cystic Fibrosis Foundation Patient Registry (2008-2020) to quantify this association and identify risk factors of increased variability. Linear mixed effects models were used to compare pre- and post-ivacaftor initiation periods for established outcome measures of FEV₁pp variability: i) maximum and ii) median deviations from the best (highest) FEV₁pp during each period; iii) maximum, iv) median, and v) standard deviation about the trendline of the FEV₁pp trajectory in each period.

Results: The analysis cohort included 527 individuals. Across outcomes, FEV₁pp variability was reduced after ivacaftor initiation (median reduction: 1.85 % predicted). Reductions were robust with highest magnitudes of effect identified using maximum deviation from the best FEV₁pp while most consistent findings were reached with trendline measures, particularly median deviation. Risk factors for increased FEV₁pp variability differed between children and adults but were consistent between G551D and R117H subgroups. F508del homozygous patients followed contemporaneously exhibited minimal change in variability (median change: 0.25 % predicted). Reduced variability weakly correlated with changes in FEV₁pp and slope, but higher levels of pre-ivacaftor variability were associated with greater reductions.

Conclusions: There was evidence that ivacaftor initiation reduces FEV₁pp variability in people with CF. Quantifying FEV₁pp variability may have utility as a marker of therapeutic effectiveness.

Background: Pulmonary infections with multidrug-resistant nontuberculous mycobacteria (NTM), particularly Mycobacterium abscessus (MAB), are increasingly more prevalent in individuals with lung disease such as cystic fibrosis and are extremely difficult to treat. Protracted antibiotic therapies consist of multidrug regimens that last for months to years. Despite these intense protocols, failure rates are high with 50%-60% of patients not achieving a sustained culture-negative status. A major contributor to the difficult medical management of NTM infections is formation of pulmonary aggregate MAB biofilms which protect the resident bacteria from antimicrobials and host immune effectors. Thereby, novel and more effective approaches to combat recalcitrant NTM infections are urgently needed.

Methods: We developed an epitope-targeted monoclonal antibody-based technology to rapidly disrupt biofilms and release resident bacteria into a transient yet highly vulnerable phenotype that is significantly more sensitive to killing by both antibiotics and host innate immune effectors (e.g., PMNs and antimicrobial peptides). Herein, we tested this technology in a pre-clinical murine lung infection model to determine whether this treatment would mediate clearance of MAB from the lungs and speed return to homeostasis.

Results: As early as 48 h after a single treatment, bacterial loads were reduced to below the level of detection and histopathologic analysis showed markedly decreased inflammation and rapid eradication of aggregate biofilms compared to controls.

Conclusions: These new data add to those from multiple prior published studies which show the significant efficacy of this novel therapeutic approach to resolve recalcitrant bacterial biofilm diseases, now potentially including those induced by NTM.

Background: Elucidating the molecular and cellular effects caused by CFTR variants is crucial to understand Cystic Fibrosis (CF) disease pathophysiology, but also to predict disease severity, to provide genetic counselling, and to determine the most adequate therapeutic strategy for people with CF (pwCF). While the current CFTR modulator drugs (CFTRm) are approved mainly for pwCF with the most prevalent variant, p.Phe508del, pwCF carrying rare and/or uncharacterized CFTR variants are not eligible. However, previous studies have shown that such rare variants can be rescued by the approved CFTRm, suggesting clinical benefit for those pwCF. Here, we characterized the rare and non-eligible p.Ile148Asn CFTR variant found in Portuguese pwCF, regarding CFTR processing, traffic and function, and response to existing CFTRm.

Methods: We used the forskolin-induced swelling (FIS) assay in intestinal organoids (IOs) from 2 CF individuals carrying p.Ile148Asn in heterozygosity with p.Phe508del and p.Gly542Ter, respectively. Additionally, a Cystic Fibrosis Bronchial Epithelial (CFBE) cell line expressing p.Ile148Asn-CFTR was generated to study the molecular defect of this variant individually.

Results: Our results show that p.Ile148Asn is a CF-causing variant, impairing both CFTR plasma membrane (PM) traffic and function, albeit partially. Moreover, p.Ile148Asn-CFTR can be rescued by approved CFTRm in CFBE cells and IOs, suggesting potential clinical benefit for these individuals.

Conclusion: The work emphasizes the importance of testing CFTRm for rare variants not included in the drug label. It also shows that the 'theranostic' approach using IOs from pwCF, which captures the genetic background of each individual, complements theratyping in cell lines that focuses only on CFTR variants.

Objective: Access to highly effective modulator therapies (HEMT) in resource-limited countries is limited by prohibitive cost and restrictive patents. We report the clinical outcomes of a cost-reduction strategy in South Africa (SA), where generic elexacaftor/tezacaftor/ivacaftor (gETI) was pharmacokinetically enhanced with clarithromycin (gETI/c) for people with CF (pwCF) eligible for HEMT.

Methods: A multi-center observational study from December 2021 to May 2024. Analysis of variance (ANOVA) and linear mixed effects analyses were conducted to describe and compare change in sweat chloride (SC), FEV1pp, BMI (m/kg²) and adverse events (AE) over 18-months follow-up for different gETI dose categories: a) standard, full or b) modulator sparing dose (gETI/c at 25-50 % recommended dose, twice/thrice weekly).

Results: 70/413 (17 %) eligible pwCF [median age 27 years (range 6-52); 68 (97 %) with ≥ one copy F508del] received gETI with standard (n = 38) or modulator-sparing doses (n = 32); 29 changed dosing regimens across the study period. The overall mean (SD) reduction in SC after 1-month of treatment was -52.9 (16.9) mmol/L (p < 0.001), with no evidence of difference between dose groups (p = 0.2). Overall mean (SD) FEV1pp and BMI increased at 1-month by 14.9 (95 % CI 11.49-18.40) and 0.84 (95 % CI 0.16-1.49), respectively. Improvements in FEV1pp and BMI were sustained throughout follow-up, with no evidence of difference between dosing groups. No serious AEs were reported.

Conclusion: Our experience with gETI is similar to real-world reports using the originator product. Boosting ETI with CYP3A-inhibitors is a safe and effective strategy to increase access to ETI in settings where access to HEMT is restricted.