Journal of Cystic Fibrosis最新文献

Background: Elexacaftor/tezacaftor/ivacaftor (ETI) has transformed cystic fibrosis (CF) therapy, yet observational clinical data in children with preserved spirometry remain limited. The lung clearance index (LCI) is used to monitor treatment response, but exhibits considerable short-term variability, affecting the interpretation of two-point comparisons.

Methods: We retrospectively analysed longitudinal clinical data from a typical pediatric CF cohort. Multiple measurements per patient within 12 months before and after ETI initiation enabled LCI variability assessment and comparison of mean LCI before and under treatment. We assessed the LCI response to ETI, its association with baseline LCI, FEV₁ z-score, sweat chloride, genotype, and changes in within-patient LCI variability.

Results: Mean LCI in 59 patients (median age 11.6y) decreased from 7.9 (IQR 6.9-9.4) to 6.4 (6.1-7.0) (p < 0.001), with a significant reduction in within-patient LCI variability from 7.9% (4.3-10.2%) to 4.9% (3.4-6.7%). LCI improvement strongly correlated with baseline LCI (r = 0.73) and weakly with baseline FEV₁ (r = -0.36). In multivariable analysis, baseline LCI, homozygous F508del genotype, baseline FEV₁ and sweat chloride were significant predictors of LCI change. LCI response was more variable in patients with baseline LCI >10.

Conclusions: ETI reduces ventilation inhomogeneity in children with CF, the magnitude of LCI reduction is strongly dependent on baseline disease severity. Within-patient LCI variability is reduced, indicating greater disease stability. LCI is a sensitive marker, improvements upon ETI treatment are well predictable particularly in early disease stages, observational data support its routine use in clinical monitoring of pediatric patients.

Nontuberculous mycobacteria (NTM) cause pulmonary disease in people with cystic fibrosis (pwCF). Recommended prolonged antibiotic therapy has significant toxicity. Non-antibiotic therapies for NTM pulmonary disease and supporting evidence were identified. Online databases and trials registries were searched for randomised or non-randomised studies (NRSIs). Primary outcomes were microbiology, quality of life (QoL), adverse events, lung function and pulmonary exacerbations. Bias was assessed using the relevant Joanna Briggs Institute tool. Seven NRSIs assessed: phage therapy, CF transmembrane conductance regulator (CFTR) modulator therapy (ETI: elexacaftor/tezacaftor/ivacaftor), inhaled nitric oxide (INO) and surgical lung resection. All had varying response definitions and very low-certainty evidence. The phage therapy study reported NTM culture conversion (n=4), partial conversion (n=4), inconclusive response (n=4) or no response (n=4). In one study of ETI with antibiotics (n=7) or without (n=8), nine participants eradicated NTM after a year, with positive cultures decreasing during treatment compared to pre-treatment. In another study (n=91) NTM infection fell by approximately 75% after at least two months of ETI (no information on concomitant treatment). In three INO studies (n=16), NTM was eradicated (n=2), showed transient negative cultures (n=6) and reductions in bacterial burden (n=11). Comparing lung resection (n=3) to antibiotic therapy (n=6), all surgical patients cleared M abscessus remaining negative at 24 months; 4 patients taking antibiotics cleared NTM. All M avium complex (MAC)-positive patients (surgery, n=1; antibiotic, n=2) cleared infection. Currently, non-antibiotic therapies are considered case by case. Randomised studies are needed to increase evidence quality and inform clinical practice for interventions appearing safe and feasible in pilot studies.

Introduction: While antibiotics are routinely prescribed for cystic fibrosis (CF) pulmonary exacerbation (PEx) treatment, little evidence exists informing optimal antibiotic selection. This study aimed to determine whether broader-spectrum antibiotics were associated with improved clinical outcomes compared to narrower-spectrum antibiotics for PEx treatment.

Methods: A secondary analysis of the Standardizing Treatment of Pulmonary Exacerbation-2 (STOP-2) clinical trial was completed. Antibiotic spectrum was defined using the CF antibiotic spectrum index (CF-ASI), a tool that classifies each antibiotic's expected spectrum of antibacterial activity, and was categorized into quartiles (<14, 14-17, 18-22, and >23). Multivariable generalized linear and inverse probability weighted models were constructed to describe the association between ASI and relevant clinical outcomes, including pre- to post-PEx changes in lung function, weight, and CF symptoms scores.

Results: A total of 982 people with CF with a mean age of 30.3 years (SD 9.7) were available for analysis. The median CF-ASI score for the entire cohort was 17 (IQR 13-22). The mean ppFEV₁ (difference 0.4, 95% CI -1.4, 2.2, p = 0.80) and CRISS (difference 1.3, 95% CI -2.5, 2.5, p = 0.75) changes from baseline did not differ between the lowest and highest CF-ASI quartiles. In the multivariable analysis, a higher CF-ASI quartile score was not statistically significantly associated with improvements in lung function, symptom score or weight compared to a lower CF-ASI quartile score. Adverse events did not differ in frequency between CF-ASI quartiles.

Conclusions: Opportunities exist to select narrower-spectrum antibiotics for PEx treatment in CF to minimize the risks of antibiotic toxicities.

Background: Forced expiratory volume in 1 second (FEV₁) is commonly decreased in pulmonary exacerbations (PEx) of cystic fibrosis and often does not fully recover to the pre-PEx value after treatment. The CF subpopulations at risk for large PEx-associated FEV₁ deficits, and the relationships between deficit magnitude and clinical outcomes, remain undefined.

Methods: We performed a secondary analysis of STOP2 (NCT02781610), a multicenter randomized trial of intravenous antimicrobial treatment durations for CF PEx (n = 982). Factors associated with large FEV₁ decreases from baseline were identified by multivariable logistic regression. Differences in clinical outcomes were assessed via propensity score matching.

Results: The mean absolute decrease in percent-predicted FEV₁ (ppFEV₁) from baseline was 5.6 ± 8.0, a relative 10.0 ± 13.7% loss of the pre-PEx value. Large absolute ppFEV₁ deficits (ppFEV₁ decreases from baseline at the 75th percentile or higher) were associated with higher pre-PEx FEV₁, Pseudomonas aeruginosa in airway cultures and serum C-reactive protein (CRP) concentration ≥30mg/L, but not CFTR modulator use. Participants with large initial FEV₁ deficits demonstrated a greater absolute FEV₁ improvement following intravenous antibiotics, but also had greater residual FEV₁ deficits after completing treatment. Change in symptoms and weight recovery did not differ by initial FEV₁ decrease. Large FEV₁ deficits at PEx diagnosis were associated with an increased hazard of subsequent PEx over a 1-year follow-up period.

Conclusions: These data may help identify those at risk for incomplete spirometric resolution following PEx and future PEx hazard. The presence of systemic inflammation serves as a marker of PEx severity.

Background: Nontuberculous mycobacteria (NTM) infections in people with cystic fibrosis (CF) can lead to pulmonary disease (NTM-PD), impacting lung function and quality of life. This study aimed to assess the prevalence, time to clearance and impact on lung function of NTM-PD in the Danish CF Cohort over time, including the period before and after the introduction of highly effective modulator therapy (HEMT).

Methods: This cohort study used data from the Danish CF Registry, microbiological culture data, and medical records from 2007 to 2023. Epidemiological analyses covered the period 2012-2023, and spirometry data were available from 2010 to 2023.

Results: For all people with CF in Denmark, the prevalence of NTM-PD decreased from 5.4 % in 2012 to 1.5 % in 2023, with a notable decline following the introduction of HEMT in 2020. Among 52 individuals diagnosed with NTM-PD in the study period, the median NTM clearance time was 3.6 years. Thirteen (25 %) received short NTM treatment (< 1 year), however, their time to clearance was similar to those with longer treatment. Throughout the study period, lung function was lower in those with NTM-PD compared to those without, although lung function for all rose after the introduction of HEMT.

Conclusion: While causality cannot be demonstrated, declining incidence and prevalence rates of NTM were observed during the study period in which HEMT was introduced. Improved respiratory outcomes were observed in those with NTM-PD. These findings support reconsideration of current treatment thresholds for NTM-PD in CF in the context of the HEMT era.

Multiple breath washout (MBW) and its primary output, lung clearance index (LCI), sensitively measure ventilation inhomogeneity in cystic fibrosis (CF). This study aimed to characterize real-world MBW use in Europe through retrospective analysis of 2023 data from the European Cystic Fibrosis Society Patient Registry (ECFSPR). We determined the proportions of people with (pwCF) with one MBW measurement in 2023 by age group, lung function, country and device used. We analysed data from 39,986 non-transplanted paediatric and adult pwCF from 40 countries. Overall, 10 % of pwCF had an MBW measurement in 2023. MBW was performed in 22 countries and in 12 % of pwCF in those countries. Austria had the highest overall MBW use (39 % of pwCF). The highest proportions of pwCF who had MBW were aged 6-11 years (23 %) and 12-17 years (23 %). MBW was mostly used in pwCF with normal (19 %) or mildly impaired (10 %) percent predicted forced expiratory volume in one second. The Eco Medics Exhalyzer® D N2 was the most commonly used device (83 %). MBW is not yet routinely used in CF care in many European countries, presenting a window of opportunity to standardise MBW devices, software, and data quality control processes. This will ensure the accuracy and reliability of LCI measurements across different centres and devices, and facilitate MBW implementation in research and in care.

Background: Inhibition of the epithelial sodium channel, ENaC, in the airways of people with cystic fibrosis, represents an approach to restore airway mucus hydration and clearance. ETD001 is a novel inhaled ENaC blocker that has been designed to provide long-lasting efficacy.

Methods: A Phase 1 study was conducted in healthy people evaluating safety, tolerability and pharmacokinetics of ETD001 following single and multiple inhaled ascending doses.

Results: ETD001 was tolerated at single inhaled doses (0.06 - 10.8 mg), and on repeat dosing for up to 14 days (0.6 - 4.65 mg) twice daily. Adverse events (AE) were balanced across treatment groups, were of mild or moderate severity and had resolved by study completion. Two participants were withdrawn from the study for non-drug related AEs (COVID-19 infection, atrial fibrillation). Two AEs of mild severity were considered possibly related to the study drug: dizziness (placebo participant) and chest discomfort (ETD001; 1.55 mg BID). There was no evidence for ETD001-induced changes in blood potassium levels at any of the doses evaluated. The pharmacokinetic profile of ETD001 was consistent with a slow, sustained absorption out of the lung into the circulation with renal clearance representing a significant pathway for elimination (up to 25% of the nominal dose).

Conclusions: ETD001 at doses up to and including 4.65 mg twice daily for 14 days was well tolerated in healthy people. The drug was slowly absorbed out of the lung and into the systemic circulation, consistent with prolonged retention in the lung, supporting twice daily dosing during further development.

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.