Journal of Cystic Fibrosis最新文献

Background: Triple modulator therapy elexacaftor/tezacaftor/ivacaftor (ETI) improves lung function and impacts upon the respiratory microbiome in people with Cystic fibrosis (pwCF) with advanced lung disease. However, adolescents with cystic fibrosis (CF) are less colonized with bacterial pathogens than adult pwCF but their microbiota already differs from healthy individuals. The aim of this study was to longitudinally analyze the impact of ETI on the respiratory metagenome in adolescents with predominantly mild CF lung disease.

Methods: In this prospective observational study, we included pwCF aged 12-20 years with at least one F508del mutation, who collected oropharyngeal swabs before and after initiation of ETI therapy twice per week to biweekly over three months. We performed whole metagenome shotgun sequencing, followed by host DNA filtering and taxonomic profiling. We used linear and additive mixed effects models adjusted for known confounders and corrected for multiple testing to study longitudinal development of the microbiome. We analyzed bacterial diversity, abundance, and strain-level phylogeny.

Results: We analyzed the metagenomic data of 297 swabs of 20 pwCF. Microbiome composition changed after initiation of ETI therapy. We observed a slight diversification of the microbiome over time (Inv Simpson, Coef 0.085, 95 %CI 0.003, 0.17, p = 0.04). Strain-level analysis and clustering showed that strain retention of the most frequent bacterial species is predominant even during ETI therapy.

Conclusions: During three months of ETI therapy, commensal bacteria increased, which may help to prevent overgrowth of bacterial pathogens.

Rationale: CF care guidelines recommend chronic inhaled antibiotics for chronic Pseudomonas aeruginosa (Pa) lung infection. These medications are costly, time consuming and prescription needs may change with improved outcomes.

Objectives: We determined the proportion of pwCF with chronic, intermittent or negative Pa infection categories, their clinical and demographic characteristics, factors associated with inhaled antibiotic prescription and changes between 2011 and 2019.

Methods: This cohort study using the U.S. CF Foundation patient registry for pwCF >2 years, no prior lung transplant, and with ≥3 respiratory cultures/year determined chronic inhaled antibiotics (≥3 months per calendar year) and Pa infection status from encounter level data. Outcomes and odds of prescription for relevant clinical factors were evaluated using generalized estimating equation models with additional interaction between the predictor and the calendar year to examine changes of predictors over time.

Results: Proportion of pwCF with chronic and intermittent Pa decreased and antibiotic prescription rates increased for these groups and decreased for Pa negative pwCF. Hispanic ethnicity, female sex, pancreatic insufficiency, CF diabetes, and ivacaftor/lumacaftor were associated with higher antibiotic prescriptions for each Pa status. Among Pa-negative pwCF prescriptions were higher with Burkholderia spp. (1.17, (CI₉₅ 1.03,1.34)) or MRSA (OR 1.45, (1.26,1.68)) but decreased between 2011 and 2019. For Aspergillus OR increased to 1.6,(1.3,1.8) in 2019. Prescriptions for pwCF on ivacaftor decreased, becoming lower in 2019 for chronic (OR 0.7, (0.5,0.8)) and Pa-negative pwCF (OR 0.7, (0.5,0.8)).

Conclusions: Factors predicting inhaled antibiotic prescription differed between 2011 and 2019 indicating changes in health and care for pwCF even prior to triple-modulators.

Background: The Cystic Fibrosis Foundation Patient Registry (CFFPR) maintains clinical data, including history of solid organ transplant, on people with cystic fibrosis (CF) who obtain care at CF Foundation-accredited care centers. The Scientific Registry of Transplant Recipients (SRTR) database is a collection of national data related to organ transplantation that supports research to evaluate solid organ transplant candidate and recipient outcomes.

Methods: Individuals in the CFFPR were matched to SRTR records using an algorithm that compared names, last four digits of social security numbers, date of birth and date of death. We evaluated match quality by summarizing the extent to which transplant status agreed between the two data sources by organ and year of listing or transplant. We summarized CFFPR-reported characteristics for lung and liver transplants in the year prior to transplant.

Results: A total of 7,594 individuals who participated in the CFFPR matched SRTR records with approximately 75% having at least one transplant record in SRTR. Over 97% of the matched population had a CF diagnosis reported to SRTR. In total, 5,253 people were identified as lung transplant recipients and 499 as liver transplant recipients in SRTR. Clinical characteristics for lung and liver transplants were consistent with the epidemiology of transplantation for people with CF.

Conclusions: Linkage of the two data sources was successful, with high agreement between them supporting the use of the matched population as a valid resource to study transplantation in CF, particularly leveraging pre-transplant characteristics (collected in CFFPR) with detailed transplant data (collected in SRTR).

Background: Monitoring multiple-breath washout (MBW) of a xenon tracer using magnetic resonance imaging (MBW Xe-MRI) provides quantitative regional measures of gas washout (fractional ventilation, FV) and spatial ventilation heterogeneity (coefficient of variation, CoV_FV) in pediatric CF lung disease, but has yet to be evaluated in an interventional setting.

Methods: 12 pediatric CF participants (median age 15.3 ± 2 years) completed MBW Xe-MRI, pulmonary function tests (PFTs) (spirometry, N₂ MBW for lung clearance index (LCI)) and single-breath Xe-MRI ventilation defect percent (VDP) measurements at baseline and 1-month post-initiation of elexacaftor/tezacaftor/ivacaftor (ETI) therapy. FV maps were calculated from MBW Xe-MRI washout images, and CoV_FV maps were derived from FV maps. Significant changes between visits were determined using a paired Wilcoxon signed-rank test. For correlations between absolute changes, Pearson's correlation was used.

Results: All measures changed significantly 1-month post-ETI therapy compared to baseline. For MRI metrics, median [IQR] VDP was significantly (P < 0.001) lower at 1 month (8.0 [3.7 12.4]) compared to baseline (17.8 [8.3 22.5]), FV was significantly (P < 0.05) higher at 1 month (0.42 [0.41 0.46]) compared to baseline (0.38 [0.33 0.44]), and CoV_FV was significantly (P < 0.001) lower at 1 month (0.06 [0.05 0.07]) compared to baseline (0.09 [0.08 0.12]). Both absolute and relative differences in CoV_FV and LCI were found to correlate highly (R = 0.92, P < 0.0001 and R = 0.91, P < 0.0001, respectively).

Conclusions: Functional information derived from MBW Xe-MRI, particularly CoV_FV, can be used to assess regional lung function in pediatric CF patients in an interventional setting and may be complementary to VDP and pulmonary function tests.

Background: The extent of cardiac involvement in cystic fibrosis (CF) remains to be determined. The remarkable therapeutic advancements with new highly effective cystic fibrosis transmembrane conductance regulator (CFTR) modulator treatment and subsequent increase in life expectancy substantiates further research. We aimed to explore the prevalence of cardiac alterations in people with CF (pwCF) compared to matched controls and investigate potential cardiovascular risk factors.

Methods: In this cross-sectional study, 104 pwCF underwent clinical and echocardiographic assessment. All participants were matched 1:1 with controls from the general population.

Results: Of 104 pwCF, 44 % were female, mean age was 34 years, and 93 % received CFTR modulator treatment. The prevalence of abnormal cardiac function in pwCF was 44 %, more than double the prevalence in controls. PwCF were found to have smaller left ventricular (LV) dimensions, worse LV diastolic function, and reduced right ventricle (RV) as well as LV systolic function. After multivariable adjustment, LV diastolic function as well as LV and RV systolic function remained poorer in pwCF as compared to controls. Male sex and decreasing FEV1/FVC ratio remained independently associated with abnormal cardiac function in pwCF (male sex: OR 3.94 (1.56; 9.95), p = 0.004 and FEV1/FVC ratio: OR 2.05 per 0.1 unit decrease (1.21; 3.52), p = 0.008, respectively).

Conclusions: Both left- and right-sided cardiac alterations were found in pwCF. After adjustments for risk factors, both RV and LV systolic measures remained altered in pwCF, compared to controls. Male sex and decreasing pulmonary function evaluated by FEV1/FVC-ratio were associated with abnormal cardiac function in pwCF.

Treating all people with Cystic Fibrosis (pwCF) to the level of benefit achieved by highly efficient CFTR modulator therapies (HEMT) remains a significant challenge. Theratyping and theranostics are two distinct approaches to advance CF treatment. Both theratyping in cell lines and pwCF-derived biomaterials theranostics have unique strengths and limitations in the context of studying and treating CF. The challenges, advantages and disadvantages of both approaches are discussed here. While theratyping in cell lines offers ease of use, cost-effectiveness, and standardized platforms for experimentation, it misses physiological relevance and patient-specificity. Theranostics, on the other hand, provides a more human-relevant model for personalized medicine approaches but requires specialized expertise, resources, and access to patient samples. Integrating these two approaches in parallel and leveraging their respective strengths may enhance our understanding of CF and facilitate the development of more effective therapies for all pwCF.

Interdisciplinary teams care for people with cystic fibrosis (pwCF) at specialized treatment centers. These teams have laid the foundation for the cystic fibrosis (CF) care model responsible for gains in health outcomes and quality of life within the CF community. However, the landscape of CF care is transforming, invigorated by new technologies, accessibility of cystic fibrosis transmembrane conductance regulator (CFTR) therapies, and increased utilization of telemedicine. In light of these advances, it is appropriate to re-evaluate the CF care team structure. This position paper offers guidance for the structure of a CF care center designed to meet the evolving needs of the CF community. Fundamental to the proposed center structure is recognition of pwCF and their families as integral members of their care teams, underpinning the necessity for shared decision making, awareness of social determinants of health, and active partnership between all healthcare professionals involved in the care of pwCF.