Journal of Cystic Fibrosis最新文献

Background: Vanzacaftor/tezacaftor/deutivacaftor (VNZ/TEZ/D-IVA) was shown to provide greater restoration of cystic fibrosis transmembrane conductance regulator (CFTR) function than prior CFTR modulators in people with cystic fibrosis (CF) aged ≥6 years. Here, we assessed the impact of VNZ/TEZ/D-IVA on health-related quality of life (HRQoL) in children, adolescents, and adults with CF.

Methods: Post-hoc analyses were conducted using VNZ/TEZ/D-IVA Phase 3 studies in adolescents and adults with F508del/minimal function variant (F/MF) genotypes (SKYLINE 102) or F/F and other responsive genotypes (SKYLINE 103) and children aged 6-11 years across all responsive genotypes (RIDGELINE 105). For participants aged ≥14 years, CF Questionnaire-Revised-8 Dimensions (CFQ-R-8D) utility scores, a CF-specific, preference-based scoring algorithm based on CFQ-R data, were compared for VNZ/TEZ/D-IVA and ELX/TEZ/IVA treatment through Week 52. For children aged 6-11 years, absolute changes in CFQ-R non-respiratory domain (CFQ-R non-RD) scores from baseline, following an ELX/TEZ/IVA run-in period, were assessed through Week 24.

Results: CFQ-R-8D utility scores were higher in adolescents and adults given VNZ/TEZ/D-IVA compared to ELX/TEZ/IVA (pooled 0.017; nominal P = 0.01); participants with F/MF genotypes had larger changes (0.031; nominal P = 0.004) compared to non-F/MF genotypes (0.008; nominal P = 0.35). Children treated with VNZ/TEZ/D-IVA had improvements in 6 out of 7 CFQ-R non-RD scores, ranging from 3.7 [95 % CI: 1.0, 6.3] points in emotional functioning to 7.2 [95 % CI: 3.8, 10.5] points in social functioning.

Conclusions: VNZ/TEZ/D-IVA was associated with higher HRQoL in adolescents and adults aged ≥14 years compared to ELX/TEZ/IVA, with largest changes in participants with F/MF genotypes, and in children aged 6-11 years compared to ELX/TEZ/IVA baseline. These results highlight potential HRQoL benefits from greater CFTR function restoration with VNZ/TEZ/D-IVA.

Background: Limited data exist on the real-world impact of elexacaftor/tezacaftor/ivacaftor (ETI) on use of chronic respiratory therapies. This post-hoc analysis evaluated long-term changes in use of chronic respiratory therapies following ETI initiation among people with (pw)CF aged ≥6 years in the United States and examined characteristics of those who were taking ≥2 chronic therapies at baseline and post-ETI.

Methods: PROMISE is a prospective, multicenter, observational study. Self-reported use of inhaled antibiotics (cycled or continuous), hypertonic saline, dornase alfa, and oral azithromycin were captured before and through 54 months post-ETI initiation in 479 participants ≥12 years and through 36 months post-ETI in 124 participants aged 6-11 years.

Results: ETI was associated with reductions in use of four chronic respiratory therapies through 54 months in participants ≥12 years (mean number of therapies decreasing from 2.6 [baseline] to 1.4 [54 months post-ETI]) and 36 months post-ETI in participants aged 6-11 years (mean number of therapies decreasing from 1.9 [baseline] to 1.3 [36 months post-ETI]). Consistent downward trends in use of all four therapies were observed among subgroups based on baseline age strata, sex at birth, prior CFTR modulator use, and ppFEV₁. Mean improvements in ppFEV₁ and mean changes in respiratory symptoms post-ETI did not differ between participants who remained on ≥2 therapies and participants taking <2 therapies.

Conclusions: ETI was associated with long-term reductions in use of chronic respiratory therapies (inhaled antibiotics, hypertonic saline, dornase alfa, azithromycin) among pwCF ≥6 years, indicating a sustained decrease in respiratory treatment burden among those on ETI therapy.

Background: Studies of CF therapies intended to reduce pulmonary exacerbations (PEx) balance future PEx risks across treatment groups. Recent PEx definitions capture any antimicrobial treatments, but future PEx risks using newer definitions and among people with CF (pwCF) receiving elexacaftor/tezacaftor/ivacaftor (ETI) remain undescribed.

Methods: PwCF 12+ years followed in the CF Foundation Patient Registry (CFFPR) receiving either no modulators or ETI in 2022-2023 were studied. 2022 PEx frequency was stratified (zero, one or two, or three+); mean 2023 PEx frequencies and time to first 2023 PEx were determined. 2023 PEx hazards were modeled using 2022 PEx frequency, lung disease stage, age, sex, Pseudomonas aeruginosa infection status, and treatment (no modulator, ETI).

Results: Among 2188 not receiving modulators, 62.7 %, 28.1 %, and 9.2 % had no, one or two, and three+ PEx in 2022, respectively, as did 73.1 %, 23.6 %, and 3.2 % of 14,964 receiving ETI. Mean 2023 PEx frequencies were strongly associated with 2022 PEx frequencies. Time to first 2023 PEx varied by 2022 PEx frequency (P < 0.0001). After adjustment, pwCF with three+ 2022 PEx had a 7.11-fold higher hazard [95 % CI 6.44, 7.86]) and those with one or two 2022 PEx had a 2.89-fold higher hazard [2.72, 3.08] of PEx in 2023 than those with no PEx in 2022.

Discussion: Prior-year PEx frequency (treated by any route) was strongly associated with future PEx risk independent of modulator use. Although ETI reduces PEx rates, agents intended to further reduce rates can be studied in pwCF receiving ETI having experienced higher numbers of prior-year PEx.

Background: Clarity and consistency of required knowledge and skills is crucial in supporting the development of members of cystic fibrosis (CF) multidisciplinary teams. Syllabi are effective frameworks for delivering a more uniform and evidence-based approach to high quality holistic care and research.

Method: Expert group representatives of the European Cystic Fibrosis Society (ECFS) Education Committee developed multiple speciality focused syllabi to define relevant core knowledge and skills. Contributors from a range of CF disciplines and countries reviewed each syllabus, which were further edited by members of the relevant ECFS speciality / working groups.

Results: Nine syllabus frameworks were developed and ratified for medicine, physiotherapy, nursing, pharmacy, psychosocial, exercise, nutrition, clinical trials and fundamental and translational science.

Discussion: Multiple challenges exist when developing and applying international syllabi. Examples include disparities in economics, health care infrastructure, available resources, and differing roles and responsibilities. By tapping into a broad international knowledge base, we were able to develop a clear framework for both comprehensive training and ongoing continuous professional development. These syllabi will support the further harmonisation of training and enhance education for both clinical and academic CF health care professionals across Europe.

Background: The introduction of CFTR modulators has been transformative for many people with cystic fibrosis (CF). The drugs are generally well tolerated although adverse reactions such as delayed-type T-cell mediated hypersensitivity and drug-induced liver injury (DILI) have been reported. Here, we characterise a novel underlying immunological mechanism driving DILI post Elexacaftor/Tezacaftor/Ivacaftor (ETI) administration.

Methods: Liver-infiltrating T-cells were isolated, post liver biopsy, using a collagenase digestion protocol. Phenotypic analysis of isolated T-cell populations was conducted using flow cytometry and mass cytometry (CyTOF). Lymphocyte transformation tests (LTT) were conducted to detect CFTR modulator-specific T-cell proliferation ([3H]-thymidine). Cytokine analysis was performed using intracellular cytokine staining and enzyme-linked immunospot assays.

Results: Liver function tests and histological examination of liver tissue revealed elevated alanine transaminase levels and evidence of perivenular zone three confluent necrosis and hepatocyte loss with mixed inflammatory infiltrate of lymphocytes. T-cells isolated from a percutaneous liver punch biopsy were associated with a dominant CD8+ cellular phenotype. Phenotypic analysis also revealed a CD45RO+ memory phenotype alongside expression of trafficking and migratory markers, such as CXCR3 and LFA-1. In vitro antigen specificity testing demonstrated significant proliferative T-cell responses after exposure to Ivacaftor, Ivacaftor M1 and Ivacaftor M6 metabolites within populations of CD3+ liver-infiltrating T-cells, but not peripheral blood mononuclear cells.

Conclusions: CFTR modulator-specific T-cells appear to be localised to sites of liver injury and not present at high frequencies within peripheral blood. Our findings align with pathomechanisms of immune-mediated DILI, during which drug-activated T-cells migrate towards sites of inflammation, infiltrate tissues and induce hepatotoxicity.

The Cystic Fibrosis Transmembrane conductance Regulator (CFTR) modulator VX-445 (Elexacaftor) used to treat cystic fibrosis presents both corrector and potentiator activities. This drug binds to a pocket within the CFTR membrane-spanning domain (MSD) assembly, in contact with the lasso motif. We have previously shown that the corrector activity of VX-445 is modulated by mutations within MSD1 and the nucleotide binding domain NBD1. Here, we evaluate if mutations affecting VX-445's corrector activity also affect its potentiator activity. Responses to increasing concentrations of VX-445 were measured using the halide sensitive fluorescent assay after transfection of CFTR mutants in HEK293 cells. Results show that VX-445 potentiated gating mutants causing cystic fibrosis located in the NBDs (NBD1 G551D and NBD2 G1349D) and in the IntraCellular Loops (ICL1 G178R and ICL3 G970R). Mutations within the VX-445 binding site inhibited potentiation of G551D, contrary to some mutations located outside this site that affected its corrector activity, two of which (M212A and F224A) were found to induce CFTR gain-of-function. Potentiation of G551D was also observed with correctors VX-809 and VX-121. In conclusion, CFTR modulator VX-445 can promote channel activity of gating mutants, an effect which is dependent on the integrity of its binding site. Potentiation could also be observed with correctors VX-809 and VX-121, indicating that more generally, CFTR correctors can promote channel activity.

Background: Systematic screening for cystic fibrosis related diabetes (CFRD) is recommended for all people living with cystic fibrosis (pwCF) from the age of 10. However, adhering to these guidelines is challenging given the cumbersome nature and potential side effects of the current test of reference, the Oral Glucose Tolerance Test (OGTT). Continuous glucose monitoring (CGM) could become an alternative to OGTT, thanks to its ease of use and to the extensive information it provides.

Methods: We present the baseline data from a prospective observational multicentric French and Canadian cohort. Concomitant OGTT, CGM and collection of clinical data were performed in adult pwCF.

Results: Complete data were available in 107 participants (73 with normal glucose tolerance, 24 with impaired glucose tolerance and 10 with cystic fibrosis related diabetes), of whom 63 % were treated with Elexacaftor/Tezacaftor/Ivacaftor. Glycated hemoglobin (HbA1c), time above 7.8mmol/L and time above 10mmol/L were lower in participants with normal glucose tolerance than in those with CFRD. Several CGM parameters associated more strongly with diagnosis of CFRD at OGTT than HbA1c (Area under the ROC curves: 0.88 for time above 10mmol/L and 0.87 for time above 7.8mmol/L, vs 0.61 for HbA1c). Spending more than 10 % of the time above 7.8mmol/L detected CFRD with 100 % sensitivity and 46% specificity.

Conclusions: Certain CGM parameters correlated more closely with diagnosis of CFRD at OGTT than HbA1c in adult pwCF, with or without treatment by Elexacaftor/Tezacaftor/Ivacaftor. If future studies confirm these results prospectively, CGM could be used as a first step to screen for CFRD.

Background: People with Cystic Fibrosis (pwCF) often exhibit impaired insulin secretion, which may lead to Cystic Fibrosis-Related Diabetes (CFRD). The impact of CF variants in the complex relationship between CFTR channel function, pancreatic function, and glucose metabolism remains only partially understood.

Methods: In this multicenter study, 341 pwCF (57 % females, 79 % with pancreatic insufficiency; median age 19 yrs.) underwent an oral glucose tolerance test (OGTT) sampling glucose, insulin, and C-peptide every 30 min for 2 h to assess β-cell function, expressed by β-cell glucose sensitivity. Participants were grouped by having either a minimal function (MF) mutation on both alleles (256 pts, 75 %) or at least one residual function (RF) mutation (85 pts, 25 %). Each variant was then associated to the CFTR-chloride conductance (CC) values from the CFTR2 database. The highest CC value (from each allele) was selected as the patient' representative CC, and used to assess its relationship with β-cell glucose sensitivity.

Results: 162 pwCF (84 % of MF group) carried variants on both alleles with CC data available in the CFTR2 database. PwCF in the RF group exhibited better glucose tolerance and β-cell glucose sensitivity (p ≤ 0.001). After adjustment for sex and age, a strong positive linear association was found between CFTR-CC values and β-cell glucose sensitivity (p < 0.001), without a significant interaction with pancreatic status.

Conclusions: Clinical data, OGTT results, and in vitro CC analysis demonstrate an independent relationship between the extent of CFTR channel dysfunction and β-cell function.

Background: Prevotella melaninogenica is enriched in the lungs of people with cystic fibrosis (pwCF), yet its functional impact on respiratory tract homeostasis remains incompletely understood. Prior studies identified immune modulatory effects following lung exposure to Prevotella, but the relevance of these findings for CF infections is unknown.

Methods: The impact of P. melaninogenica on infection with the CF pathogen Staphylococcus aureus was evaluated using a mouse lung infection model and by measuring S. aureus adherence to human respiratory tract cystic fibrosis transmembrane conductance regulator (CFTR) mutant and isogenic wild-type (WT)-corrected CFBE41o- epithelial cells. Epithelial cytokine/chemokine secretion and RNA-sequencing were performed to compare P. melaninogenica-induced signaling programs in WT-corrected versus CFTR mutant cells.

Results: P. melaninogenica significantly reduced S. aureus lung infection, associated with elevated S. aureus killing by lung neutrophils and impaired S. aureus adherence to epithelial cells. Live or killed P. melaninogenica were sufficient to mediate these effects, which were dependent on TLR2. P. melaninogenica impairment of S. aureus adherence required functional CFTR, as this effect was lost in CFTR mutant cells but restored by CFTR modulators. RNA-sequencing identified several antibacterial defense pathways selectively upregulated by P. melaninogenica in WT corrected epithelial cells, correlating with higher IL-8 and IL-6 cytokine production.

Conclusions: P. melaninogenica enhanced neutrophil and epithelial defense against S. aureus, but the benefits of epithelial cell regulation by P. melaninogenica were lost with CFTR dysfunction. CFTR modulators rescued P. melaninogenica responsiveness in epithelial cells, highlighting the potential for synergistic effects of host-microbiome interactions and CFTR targeted therapies.