BACKGROUND:Among people with cystic fibrosis (CF), limited data exists describing how area-level socioeconomic factors influence in-hospital, emergency room, and ambulatory surgery healthcare utilization. Using the Childhood Opportunity Index (COI) as an area-level composite measure, we aimed to describe the healthcare utilization patterns among children with CF (CwCF) by COI and determine if COI is associated with increased healthcare utilization. METHODS:Retrospective cohort study that utilized the CF Foundation Patient Registry-Pediatric Health Information System dataset. The COI version 3.0 was used. Primary study outcomes included the number of hospital encounters (hospitalizations, emergency room visits, and ambulatory surgeries) between 2009-2022, compared among five COI quintiles. Generalized estimating equations were used to regress hospital encounter on COI quintile with a Poisson distribution and clustered on hospital. RESULTS:8177 CwCF <22 years contributed 65,038 hospital encounters for analysis. Compared to the very high quintile, CwCF in the very low, low, and moderate quintiles had a higher hospitalization risk (very low Relative Risk (RR) 1.31, 95% Confidence Interval (CI) 1.17-1.47; p < 0.001, low RR 1.16, 95%CI 1.04-1.30; p = 0.008, and moderate RR 1.15, 95%CI 1.05-1.25; p = 0.001). In addition, CwCF in the very low group had a higher respiratory-related hospitalization risk (RR 1.60, 95%CI 1.30-1.90; p < 0.01). CONCLUSIONS:CwCF in the lower COI quintiles had a higher hospitalization risk. Future research should focus on underlying area-level drivers of hospitalizations to reduce inpatient utilization.
Background The airways of people with cystic fibrosis (pwCF) are often colonized by a variety of different microbes. Although much effort has been put into cataloguing the impact of medication on the identities and abundances of these microbes, far less has been directed towards examining this from an ecological perspective, i.e., examining how medications affect the network and types of interactions between microbes. Methods In the current work, we generated an ecological model of the CF airway microbiome and examined how medications affect interactions between co-habiting airway microbiota in six pwCF. Ecological interactions were inferred from a generalized Lotka-Volterra model, and the impact of medications was determined by principal component(s) regression analysis. Results For the majority of the subjects studied, antimicrobial interventions had relatively little impact on the CF airway microbial ecology, and even appeared to stabilize ecological interactions between the microbiota. However, the microbial ecosystem in some individuals was more sensitive to external perturbations. More surprisingly, we found that some non-antimicrobial medications, and also certain carriers and excipients affect the ecosystem. Conclusions Medications affect the ecology of the CF airway microbiota. These impacts appear to be very patient-specific. We also note that some nominally non-bioactive ingredients in medications can also potentially impact the CF airway ecosystem. Our data highlight the importance of collecting patient-specific data and in employing suitable computational frameworks for disentangling medication-microbiota interactions in vivo.
Background Gut dysbiosis is a hallmark of cystic fibrosis (CF), typically characterised using non-specific diversity metrics and study-specific taxonomic lists, limiting comparability across studies. We aimed to develop a metagenomic, species-level CF Gut Microbial Dysbiosis Index (CF-GMDI) to standardise measurement of gut microbial imbalance in children with CF (cwCF) Methods CF-GMDI was derived using stool metagenomic data from the PEARL-CF study (70 cwCF; 67 healthy controls (HC); 0-6 years). Differentially abundant taxa were identified between cwCF and HC using MaAsLin2. The index was calculated as the log10 ratio of the summed relative abundances of taxa enriched in CF vs HC to those depleted in CF vs HC. Reproducibility was assessed in the independent EARTH cohort (56 cwCF; 56 HC; 0-18 years). Responsiveness to therapy was evaluated using publicly available metagenomic data from an Elexacaftor/Tezacaftor/Ivacaftor (ETI) study (39 cwCF; 6-18 years). Results CF-GMDI was significantly higher in cwCF than HC (p < 0.001), inversely correlated with species richness (ρ = -0.74, p < 0.001), and higher in pancreatic-insufficient vs pancreatic-sufficient cwCF in the PEARL-CF cohort (p = 0.01). Key ecological and clinical associations were replicated in the EARTH cohort. In the ETI study, CF-GMDI decreased significantly at 6 and 12 months post-treatment, whereas alpha diversity remained unchanged. Conclusions CF-GMDI is a CF-associated metric that captures clinically relevant gut microbiome restructuring not detected by standard diversity measures in cwCF (0-18 years). It differentiates disease and pancreatic status and tracks therapeutic modulation, supporting its use as a novel endpoint in CF intervention studies.
BACKGROUND:Peripheral muscle dysfunction is a well-established extrapulmonary manifestation of cystic fibrosis (CF), contributing to exercise intolerance and reduced quality of life. However, its persistence in the era of highly effective CFTR modulator therapy (HEMT) remains unclear. METHODS:Fifty-six people with CF (age: 31 ± 13 years, BMI: 22 [20-24] kg·m-2; FEV1%: 77 ± 24; 95% treated with elexacaftor/tezacaftor/ivacaftor for 31 ± 11 months) were compared with 46 healthy controls of comparable age and sex distribution. Muscle function was assessed following international recommendations, including quadriceps strength (primary outcome), endurance and thickness, handgrip strength, and squat jump performance. Physical activity was assessed using accelerometry. RESULTS:Compared with controls, people with CF exhibited lower quadriceps strength (203 [161-304] vs. 284 [238-335] N·m, p = 0.001, rrb = 0.35) and endurance (p < 0.001, rrb = 0.47). Quadriceps thickness (p = 0.002, rrb = 0.34) and handgrip strength (p = 0.009, d = 0.48) were also lower. After normalisation to muscle thickness, quadriceps strength remained lower (p = 0.01, rrb = 0.27), whereas habitual physical activity levels did not differ significantly between groups. CONCLUSION:This is the first large controlled study to comprehensively assess peripheral muscle function in people with CF following long-term HEMT exposure. Despite this prolonged exposure, clinically relevant impairments remained evident across multiple dimensions of muscle function. Altered muscle performance cannot be explained solely by muscle deconditioning and lower muscle size, suggesting intrinsic muscle alterations. These findings support the need for comprehensive assessment of peripheral muscle function and the continued prioritisation of interventions aiming to optimise muscle health.
BACKGROUND:Fetal meconium ileus (MI) is a clinically relevant manifestation of cystic fibrosis (CF). We conducted a systematic review with meta-analysis to evaluate the efficacy of prenatal CFTRm therapy, administered to carrier mothers or mothers with CF, for the prevention or treatment of fetal MI. The primary outcome was the occurrence of MI requiring surgical intervention. METHODS:A systematic search was conducted in PubMed/MEDLINE, Embase, SCOPUS and the Cochrane Library. In-vitro and animal studies were excluded. Reporting quality and the risk of bias of the cohort studies was assessed using the NOS Scale and the CARE checklist, as appropriate, and the ROBINS-I V2, respectively. An individual patient data meta-analysis and meta-regression were performed. RESULTS:We included 18 studies. Among 42 fetuses antenatally diagnosed with MI and exposed to CFTRm, 12% (95% CI, 6%-25%) required surgery after birth. Comparison with a historical cohort suggested a possible 59.5% absolute reduction in the risk of surgery (95% CI, 44%-69%). None of the nine asymptomatic fetuses exposed to treatment developed MI. On meta-regression, the diagnosis of MI in second trimester was associated with lower odds of surgery (OR 0.05, 0.01-0.50; p = 0.011), whereas maternal treatment duration shorter than 5 weeks was associated with increased odds (OR 15.15, 1.41-162.73; p = 0.025). DISCUSSION:Prenatal exposure to CFTRm appears to be effective in treating or preventing MI in fetuses with CF. However, the evidence is limited to case reports or small observational studies and prospective controlled studies are needed.
BACKGROUND:Persons with advanced cystic fibrosis lung disease (ACFLD) are a subpopulation with specific care needs and unique clinical challenges. In 2019, the Cystic Fibrosis Foundation Patient Registry (CFFPR) introduced new case report forms related to ACFLD. The objective of this study was to estimate the prevalence and incidence of ACFLD 2015-2023. METHODS:ACFLD cases were identified by summarizing individuals with report of supplemental oxygen use, pneumothorax, massive hemoptysis, ppFEV1 < 40, and transplant status. We estimated the incidence of ALD annually, and quantified prevalence accounting for deaths and transplants, compared to case identification using the additional ACFLD case report forms. Kaplan-Meier estimates were used to calculate survival proportions by calendar period and ACFLD qualifying condition. RESULTS:There were 19,117 people who met inclusion criteria; 3,590 incident cases were identified between 2015-2018 and 2,161 incident cases between 2019-2023. Prevalence of ACFLD fell from 6.1% in 2015 to 1.5% in 2023. There were 745 deaths among people meeting ACFLD criteria in 2015-2018 and 158 deaths among incident ACFLD cases 2019-2022. People identified as ACFLD with multiple qualifying conditions had worse survival in both time periods. CONCLUSIONS:Incidence of ACFLD and risk of death has declined from 2015-2023, but 1- and 2-year survival estimates reveal an ongoing need for attention to risk factors for death without lung transplant in this vulnerable population, as those with both ppFEV1 <40 and complications at ACFLD onset have the highest risk of death.
BACKGROUND:An unintended consequence of cystic fibrosis (CF) newborn bloodspot screening (NBS) is the identification of infants who have an abnormal NBS but do not meet the clinical diagnostic criteria for CF, known as CFTR-related metabolic syndrome (CRMS) in the US or CF screen positive, inconclusive diagnosis (CFSPID) in other countries. Many children with CRMS/CFSPID harbor at least one CFTR variant of varying clinical consequences (VVCC), a category associated with varying penetrance for CF. We sought to determine whether particular VVCCs are associated with differing risks of diagnostic transition (or conversion) from CRMS/CFSPID to CF. METHODS:We performed a meta-analysis of published CRMS/CFSPID cases and examined CF penetrance (i.e. conversion from CRMS/CFSPID to CF) associated with specific VVCCs. We examined expressivity by evaluating the symptoms associated with CF conversion for each individual VVCC and by overall group. RESULTS:There were 606 children with CRMS/CFSPID in 25 manuscripts. Of 268 children with CRMS/CFSPID harboring one VVCC and one CF-causing variant, 78 (28%) converted to CF. There was wide variability in VVCC penetrance; some variants (5T;TG13, Q1476X, P5L) were associated with a high risk of CF conversion (≥50%) whereas others (F1052V, R117H;7T, D1270N) were associated with a low risk. Expressivity associated with VVCCs varied substantially, with elevated sweat chloride concentration most commonly observed in CF conversions. CONCLUSIONS:There is significant variability in the penetrance and expressivity associated with VVCCs. Results can inform clinicians and families and guide policy regarding inclusion of VVCCs in CF NBS.
BACKGROUND AND AIMS:Pseudomonas (P.) aeruginosa is an opportunistic pathogen closely linked to Cystic Fibrosis (CF). Recent publications emphasize that an accumulation of bacterial derived extracellular vesicles within the circulation might be associated with the pathogenesis of various chronic inflammatory diseases and could potentially be used as diagnostic tool. METHODS:Bacterial extracellular vesicles (bEVs) were isolated and characterized via Nanoparticle Tracking Analysis (NTA) and Transmission Electron Microscopy (TEM) from plasma samples of persons with CF (pwCF) without infection with P. aeruginosa (PsA-, n = 31), pwCF with confirmed P. aeruginosa infection (PsA+, n = 29), and control individuals (HC, n = 30). Size and concentration of bEVs were evaluated and correlated with clinical parameters. Western blot analyses were implemented to study the species-specific origin of bEVs, using lysates and reference vesicles. RESULTS:bEVs could be detected in all samples from both, HC and pwCF. Relative NF‑κB induction, assessed via a TLR4 reporter assay, was significantly elevated in pwCF than in HC, with the strongest responses observed in PsA+ patients. emphasize bEV-associated activity. Surprisingly, CFTR modulator treatment (ETI) enhanced LPS concentration of bEVs in pwCF independent of P. aeruginosa colonization. Moreover, NF-kB induction correlated negatively with serum IgA levels in PsA+ patients. Direct detection of bEVs in plasma samples via Western blot was technically not possible. CONCLUSION:Our findings suggest a potential link between pulmonary P. aeruginosa colonization and increased systemic bEVs-associated activity as potential consequence of deficient mucosal barrier function. However, further research is required in order to validate our findings and to clarify the influence of ETI on bEV accumulation.
Cardiometabolic risk is increasingly recognised as a significant and evolving health concern within the cystic fibrosis (CF) population. Although nutrition has long been central to CF management, its broader influence on cardiometabolic health, well established in the general population, is only beginning to be understood in the context of CF. This narrative review seeks to synthesise emerging evidence and highlight the key research gaps relating to the role of nutrition in moderating cardiometabolic risk among people with CF (pwCF). Substantial gaps remain across several domains, including overweight and obesity, dysglycaemia and diabetes, cardiovascular disease, gut microbiota alterations and overall diet quality. Addressing these gaps is essential as pwCF live longer and encounter new health challenges. Future nutrition research must generate the robust, clinically relevant evidence needed to support clinical teams as they transition away from traditional dietary paradigms, enabling the development of updated guidance and the advancement of clinical practice toward metabolically informed, contemporary models of care.
BACKGROUND:There is evidence that antiviral defenses are impaired in airway epithelia derived from the lungs of people with cystic fibrosis (CF), however it is unclear whether this phenotype is an intrinsic feature of CF or an acquired trait that develops secondary to chronic airway infection and inflammation. To distinguish between these possibilities, we examined the antiviral responses of newborn CF pigs, prior to the onset of airway inflammation and chronic lung disease. METHODS:We performed an in vivo viral challenge experiment in newborn CF and non-CF pigs, using influenza A (IAV) as a model respiratory virus. To learn more about the contributions of epithelia in this setting, we carried out a parallel in vitro infection experiment using cultured airway epithelia derived from newborn CF and non-CF pig controls. RESULTS:We found that viral growth kinetics and host antiviral responses were relatively similar in the cultured epithelia from CF and non-CF pigs. However, we observed divergent host responses in the animal experiment, with the newborn CF pigs exhibiting comparatively increased innate immune activation and increased viral loads after IAV challenge. CONCLUSIONS:Our findings indicate a reduced effectiveness of antiviral host defense at birth in the CF pig model and suggest that this phenotype is not driven solely by altered airway epithelial cell function. These results highlight a likely contribution of early life viral infections in initiating CF lung disease.
BACKGROUND:Cystic fibrosis-related diabetes (CFRD) is a common comorbidity in cystic fibrosis (CF), significantly impacting morbidity and mortality. Recent advancements in therapy and diabetes technology have transformed the management of CF and diabetes. This study aims to assess the evolution of CFRD and its treatment over the past few decades in a large cohort receiving routine care. METHODS:Longitudinal data of 1039 persons with CFRD (median age at CFRD onset (Q1;Q3): 15.7 (13.2-19.9) years; 57.2% females) from the Diabetes Prospective Follow-up (DPV) database between 2000 and 2023 were analyzed. Changes in demographics, anthropometrics and diabetes therapy were studied using adjusted linear and logistic regression models. RESULTS:BMI-SDS at CFRD diagnosis increased from -0.62 (-1.78;+0.12) in 2000 to -0.45 (-0.81; +0.36) in 2023 (p = 0.002), while age at CFRD diagnosis decreased from 14.8 (13.4;19.1) years in 2000 to 12.5 (11.3;14.7) years in 2023 (p = 0.033). Pharmacological CFRD treatment has changed over the past years. Insulin monotherapy increased from 65.1% to 78.7% (p = 0.044), while OAD/GLP-1 RA-only use decreased (16.9% to 0.7%, p < 0.001). Insulin pump therapy was documented in 26.2% of people with CFRD (PwCFRD) in 2023. The use of CGM increased continuously since 2015, with 76.7% of participants using CGM in 2023 (p < 0.001). Proportion with underweight dropped from 34.3% in 2000 to 14.2% in 2023 (p < 0.001), while overweight increased during this period from 1.5% to 6% (p = 0.011). CONCLUSIONS:Insulin monotherapy and in particular diabetes technology is used more frequently. Improvements in CF therapy are reflected in increasing BMI-SDS and a decrease in the proportion of underweight people with CFRD.
BACKGROUND:As reduced exercise capacity and muscle weakness are common in people with cystic fibrosis (pwCF) and associated with worse life prognosis and quality of life, we aimed to evaluate the changes in functional exercise performance and peripheral muscle strength in pwCF after two years of elexacaftor/tezacaftor/ivacaftor (ETI). METHODS:The 6-Minute Walk Test (6MWT), 1-Minute Sit-to-Stand Test (1STST) and measurement of Maximal isometric Voluntary Contraction of the Quadriceps (MVCQ) with a dynamometer were performed before initiating ETI and after one and two years of ETI. RESULTS:82 pwCF (≥12y) were recruited. The 6MWT distance increased significantly after one and two years of ETI compared with baseline (608±73 m at baseline; 636±75 m after one year of ETI, p < 0.0001; 641±71 m after two years of ETI, p < 0.0001). The number of repetitions during the 1STST enhanced significantly after one and two years of ETI compared with baseline (51±15 at baseline; 55±14 after one year of ETI, p = 0.0022; 56±14 after two years of ETI, p = 0.0042). MVCQ also showed a significant improvement after one and two years of ETI compared with baseline (69±29Nm at baseline; 76±28Nm after one year of ETI, p = 0.0015; 82±29Nm after two years of ETI, p < 0.0001) as well as between one and two years (p = 0.0139). In contrast, no significant change was observed when comparing results in 6MWT and 1STST between one and two years of ETI. CONCLUSION:6MWT, 1STST and MVCQ improved after one year of ETI with improvements persisting at two years of treatment.
BACKGROUND:Cystic fibrosis (CF) is caused by mutations in the gene encoding the CF transmembrane conductance regulator protein. Since 2021, Argentina has provided a generic formulation of the triple modulator therapy elexacaftor/tezacaftor/ivacaftor (ETI). The aim of this study is to evaluate clinical effects on pulmonary function, nutritional status, sputum microbiology, sweat test (ST), respiratory exacerbations, and quality of life in patients using this generic formulation. METHODS:People with cystic fibrosis (PwCF), both sexes, aged ≥6 years, received the generic ETI formulation at Hospital de Pediatria Prof. Dr J.P. Garrahan. PRIMARY ENDPOINT:clinical variables were analyzed before and after one year of treatment. Secondary endpoint: pulmonary function was compared between groups with and without prior modulator therapy, both before and after treatment RESULTS: Fifty-five PwCF were included. The median age at ETI initiation was 11.6 years (IQR 8.9-14.5). Thirty-one (56.36%) had not previously received modulators. Baseline median ppFEV1 of the entire cohort was 80.7 (IQR 62.7-91), and after one year, ppFEV1 increased to101 (IQR 88.5-105.75). Median BMI z-score improved from -0.32 (IQR -0.77 to 0.35) to -0.09 (IQR -0.67 to 0.43) after one year. The median reduction in ST was 45 mEq/L. Pulmonary exacerbations showed significant decline. Pseudomonas aeruginosa decreased in sputum cultures, whereas the Burkholderia cepacia complex remained unchanged. Quality of life improved. No severe adverse effects were reported. After 12 months, lung function improved significantly in the group without previous modulator treatment. CONCLUSIONS:As previously reported for the original ETI formulation, the Argentine generic formulation showed similar results for clinical variables.
