J Immunoassay Immunochem. 2025 Feb 11:1-6. doi: 10.1080/15321819.2025.2462807. Online ahead of print.

ABSTRACT

Bacterial colonization of the cystic fibrosis (CF) airways is polymicrobial and several emerging microorganisms with a potential pathogenic role may be present. We report a case of three siblings with CF colonized by Pandoraea over a period of 10 years. Isolates identified as various non-fermentative Gram-negative bacilli from sputum cultures were successfully re-identified as Pandoraea vervacti (P. vervacti) by a combination of matrix-assisted laser desorption ionization - time of flight mass spectrometry (MALDI-TOF MS) and 16S rRNA and gyrB sequencing. Furthermore, the transcript expression of type I and type III interferon (IFN) genes was examined in the cells of respiratory samples from these patients and compared with a Pandoraea-negative group of CF individuals. Increased respiratory levels of IFNβ, IFNε and IL28R1 mRNA were found in the three siblings. Our results demonstrate that P. vervacti can chronically colonize CF patients and alter IFN response, likely contributing to immunopathogenesis and disease progression.

PMID:39935049 | DOI:10.1080/15321819.2025.2462807

Value Health Reg Issues. 2025 Feb 10;47:101085. doi: 10.1016/j.vhri.2025.101085. Online ahead of print.

ABSTRACT

OBJECTIVES: This study aimed to provide the first evidence of the socioeconomic burden of cystic fibrosis (CF) in Czechia.

METHODS: In a cross-sectional questionnaire-based primary data collection conducted from 2020 to 2021 among Czech patients with CF, we collected demographic, clinical, and healthcare resource use data, out-of-pocket and social transfer costs, and questionnaires: Cystic Fibrosis Questionnaire-Revised, Work Productivity and Activity Impairment, EQ-5D, and Zarit Burden Interview. Productivity loss/costs were assessed using the human capital approach with patient patient-assumed life expectancy of 45 years and caregiver retirement age of 64 years and discounted by 3%.

RESULTS: A total of 257 patients completed the questionnaires (37% of the Czech CF population). The average age was 17 years; most were females (59%), and the average forced expiratory volume in 1 second was 81.4% (SD 25.4%). A total of 107 patients had caregivers with an average age of 39 years and a significant caregiver time burden (extra 4.6 hours/day). The average Zarit Burden Interview score (25.4) was comparable with advanced cancer, dementia, or Duchenne muscular dystrophy. The proportion of unemployed caregivers was 10× higher than the general population (31% vs 3.2%). Total out-of-pocket family costs related to CF were €278/month, mainly for medicines (€105), foods (€73), and transport (€59); 25% received a disability pension and 18% other social security benefits. The work impairment of employed patients and caregivers was 25% and 15%, respectively, mostly due to presenteeism. Total lifetime productivity costs extrapolated to all Czech patients with CF (n = 687) and their caregivers were €155 181 286 (€225 883/person).

CONCLUSIONS: The societal burden imposed on Czech patients with CF and their caregivers is significant. Caregivers seem to be affected by higher disease activity more than patients.

PMID:39933437 | DOI:10.1016/j.vhri.2025.101085

Ther Drug Monit. 2024 Nov 12. doi: 10.1097/FTD.0000000000001267. Online ahead of print.

ABSTRACT

BACKGROUND: Ciprofloxacin (CIP) is effective against many Gram-negative pathogens and penetrates well into respiratory secretions and pulmonary tissues, thus making it useful for treating respiratory infections in patients with cystic fibrosis (CF).

METHODS: A 13-year-old patient with severe CF and an acute respiratory exacerbation from multidrug-resistant Pseudomonas aeruginosa was treated with 700 mg of CIP every 8 hours. Bronchial secretions confirmed that P. aeruginosa was sensitive to high doses of CIP. Pharmacokinetic monitoring using 2 blood samples estimated the AUC24 at 50 hours*mg/L. This led to an increase in CIP dosage to 850 mg three time a day (TID), then to 1000 mg TID, and finally to 1200 mg every 6 hours.

RESULTS: CIP pharmacokinetics can vary significantly, particularly in patients with CF due to increased clearance, ultimately resulting in shorter half-lives and higher risks of therapeutic failure and resistance. Therapeutic drug monitoring helps when adjusting dosages to maintain effective blood concentrations.

CONCLUSIONS: This case underscores the role of therapeutic drug monitoring in optimizing CIP dosing for patients with CF and highlights the necessity for close collaboration between clinicians and pharmacologists to ensure effective antibiotic exposure.

PMID:39933065 | DOI:10.1097/FTD.0000000000001267

Acta Med Port. 2025 Feb 3;38(2):117-118. doi: 10.20344/amp.21948. Epub 2025 Feb 3.

NO ABSTRACT

PMID:39932840 | DOI:10.20344/amp.21948

ERJ Open Res. 2025 Feb 10;11(1):00442-2024. doi: 10.1183/23120541.00442-2024. eCollection 2025 Jan.

ABSTRACT

BACKGROUND: Pulmonary gas exchange is assessed by the transfer factor of the lungs (T L) for carbon monoxide (T LCO), and can also be measured with inhaled xenon-129 (129Xe) magnetic resonance imaging (MRI). A model has been proposed to estimate T L from 129Xe MRI metrics, but this approach has not been fully validated and does not utilise the spatial information provided by three-dimensional 129Xe MRI.

METHODS: Three models for predicting T L from 129Xe MRI metrics were compared: 1) a previously-published physiology-based model, 2) multivariable linear regression and 3) random forest regression. Models were trained on data from 150 patients with asthma and/or COPD. The random forest model was applied voxel-wise to 129Xe images to yield regional T L maps.

RESULTS: Coefficients of the physiological model were found to differ from previously reported values. All models had good prediction accuracy with small mean absolute error (MAE): 1) 1.24±0.15 mmol·min-1·kPa-1, 2) 1.01±0.06 mmol·min-1·kPa-1, 3) 0.995±0.129 mmol·min-1·kPa-1. The random forest model performed well when applied to a validation group of post-COVID-19 patients and healthy volunteers (MAE=0.840 mmol·min-1·kPa-1), suggesting good generalisability. The feasibility of producing regional maps of predicted T L was demonstrated and the whole-lung sum of the T L maps agreed with measured T LCO (MAE=1.18 mmol·min-1·kPa-1).

CONCLUSION: The best prediction of T LCO from 129Xe MRI metrics was with a random forest regression framework. Applying this model on a voxel-wise level to create parametric T L maps provides a useful tool for regional visualisation and clinical interpretation of 129Xe gas exchange MRI.

PMID:39931664 | PMC:PMC11808933 | DOI:10.1183/23120541.00442-2024

Front Cell Dev Biol. 2025 Jan 27;13:1526306. doi: 10.3389/fcell.2025.1526306. eCollection 2025.

ABSTRACT

Rare diseases affect a small percentage of an individual country's population; however, with over 7,000 in total, rare diseases represent a significant disease burden impacting up to 10% of the world's population. Despite this, there are no approved treatments for almost 95% of rare diseases, and the existing treatments are cost-intensive for the patients. More than 70% of rare diseases are genetic in nature, with patient-specific mutations. This calls for the need to have personalised and patient-specific preclinical models that can lead to effective, speedy, and affordable therapeutic options. Complex in vitro models (CIVMs), including those using induced pluripotent stem cells (iPSCs), organoids, and organs-on-chips are emerging as powerful human-based pre-clinical systems with the capacity to provide efficacy data enabling drugs to move into clinical trials. In this narrative review, we discuss how CIVMs are providing insights into biomedical research on rare diseases. We also discuss how these systems are being used in clinical trials to develop efficacy models for rare diseases. Finally, we propose recommendations on how human relevant CIVMs could be leveraged to increase translatability of basic, applied and nonclinical research outcomes in the field of rare disease therapeutics in developed as well as middle-and low-income countries.

PMID:39931243 | PMC:PMC11807990 | DOI:10.3389/fcell.2025.1526306

Ther Adv Respir Dis. 2025 Jan-Dec;19:17534666251314706. doi: 10.1177/17534666251314706.

ABSTRACT

BACKGROUND: Cystic fibrosis (CF) is characterized by chronic neutrophilic inflammation in the airways. Elexacaftor/tezacaftor/ivacaftor (ETI) therapy has demonstrably improved clinical outcomes and quality of life in people with CF (pwCF), but its effects on systemic inflammatory parameters remain unclear.

OBJECTIVE: To evaluate the impact of ETI on systemic inflammation in children and adolescents with CF.

DESIGN: Retrospective, dual-center observational, propensity score-matching study of pediatric pwCF on ETI.

METHODS: PwCF aged ⩽ 18 years treated with ETI at two Italian reference centers were included in this study. Data on immunoglobulins (Ig) (A, G, and M), γ-globulin, leukocyte levels, percent predicted forced expiratory volume in the first second (ppFEV1), sweat chloride (SC) concentration, and sputum cultures were collected at baseline, 12, and 24 months of treatment. Laboratory data of a control group (pwCF, not in ETI therapy, same demographic characteristics as the study group) were also collected.

RESULTS: Sixty-six patients (30 males, median age: 12 years, F508del homozygous: 23) were included. Mean IgG levels (SD) significantly decreased (p = 0.001) from 1168.20 mg/dl (344.41) at baseline to 1093.05 mg/dl (258.73; 12 months) and 1092.87 mg/dl (232.42; 24 months). Similar reductions were observed for IgA and γ-globulin; IgM reduction was not statistically significant. Leukocyte levels also decreased significantly from 8.04 × 103/µl (3.23 × 103) at baseline to 6.61 × 103/µl (1.74 × 103) (12 months) and 6.45 × 103/µl (1.70 × 103; 24 months). As for the control group, no significant changes in the levels of Ig, leukocytes, and γ-globulin were detected throughout the study period (p > 0.05).The mean (SD) ppFEV1 and the overall mean (SD) SC concentration significantly decreased during the follow-up. Regarding cultures, 18 (27%) of the 27 patients positive (41%) for Staphylococcus aureus at baseline became negative during treatment. Three patients (4%) with persistently positive cultures for Pseudomonas aeruginosa during the first 12 months, became negative after 24 months. One patient (1.5%), with a baseline positive culture for Pseudomonas Aeruginosa, showed negative cultures after 12 months.

CONCLUSION: ETI treatment improved respiratory outcomes and significantly reduced values of IgG, IgA, γ-globulin, and leukocytes, suggesting an effect on the systemic inflammatory response. Further research is warranted to elucidate the role of inflammatory parameters in monitoring response to therapy.

PMID:39930791 | DOI:10.1177/17534666251314706

J Pediatr Gastroenterol Nutr. 2025 Feb 10. doi: 10.1002/jpn3.70010. Online ahead of print.

ABSTRACT

OBJECTIVES: Food insecurity (FI), limited or uncertain access to adequate food, impacts every state, county, and community in the United States. The goals of this quality improvement (QI) initiative were to first achieve greater than 90% compliance with FI screening for patients seen at pediatric GI clinics within 1 year and second increase the proportion of families identified as FI connected with resources to 50% at follow-up visits.

METHODS: Using plan-do-study-act cycles, interventions were implemented to (1) educate, (2) create a screening process, (3) optimize communication with EMR utilization, and (4) connect families to resources. Descriptive statistics on all variables collected were performed. Differences between the FI and food secure groups were assessed using the Mann-Whitney test for continuous variables and the Chi-squared test for categorical variables. QIMacros® Quality Improvement/SPC Software for Excel was used to create process control charts to show improvement.

RESULTS: During the timeframe from August 29, 2022, to February 29, 2024, 2946 visits were completed in the GI clinic, and 58% (1731 patients) were screened for FI. Of the patients that were screened for FI, 13% screened positive. Compliance with FI screening improved to 90%, and connection to resources improved to 75%. Race, ethnicity, preferred language, and insurance were all significantly associated with FI, p < 0.001 CONCLUSIONS: This QI initiative demonstrates standardized FI screening improves FI identification and connection to resources.

PMID:39930736 | DOI:10.1002/jpn3.70010

Thorac Res Pract. 2025 Jan 20. doi: 10.4274/ThoracResPract.2024.24047. Online ahead of print.

ABSTRACT

OBJECTIVE: Composite Model for End-Stage Liver Disease (MELD), an adapted version of the model score excluding international normalised ratio (MELD-XI), was reported to predict outcomes in patients with organ failure. Aim of study was to evaluate the prognostic significance of the MELD-XI score and compare it with the Sequential Organ Failure Assessment (SOFA) and Acute Physiology and Chronic Health Evaluation 2 (APACHE 2) scores in patients admitted to the intensive care unit (ICU) for respiratory failure.

MATERIAL AND METHODS: Out of 822 patients with respiratory failure between September 2020 and June 2023, a total of 727 patients with etiologies of chronic obstructive pulmonary disease exacerbation, cardiogenic pulmonary edema, pulmonary thromboembolism, pneumonia, bronchiectasis, kyphoscoliosis, neuromuscular diseases, obesity hypoventilation syndrome, and diffuse parenchymal lung disease were included.

RESULTS: A statistically significant correlation was found between MELD-XI, SOFA, and APACHE 2 scores. The cutoff value of the MELD-XI score was 11 on receiver operating characteristic analysis, indicating a higher risk of mortality in patients with a score of 11 or above. The APACHE 2 and SOFA scores of the MELD-XI ≥11 group were found to be higher and the Glasgow Coma Scale were lower than the MELD-XI <11 group. MELD-XI ≥11 was associated with an increased risk of mortality in overall [Hazard ratio (HR): 4.1, 95% confidence interval (CI): 2-6.4, P < 0.001] and subgroups with different etiologies in Cox regression analysis. In the multivariate analysis, MELD-XI was the most important independent variable indicating an increased risk of mortality, regardless of etiology (HR: 2.4, 95% CI: 2.0-2.5, P < 0.001).

CONCLUSION: MELD-XI is an important marker of ICU mortality in patients with respiratory failure due to different etiologies and is as effective as the SOFA and APACHE 2 in predicting mortality.

PMID:39930732 | DOI:10.4274/ThoracResPract.2024.24047

Drug Deliv. 2025 Dec;32(1):2463428. doi: 10.1080/10717544.2025.2463428. Epub 2025 Feb 10.

ABSTRACT

Nanoparticles-based gene delivery has emerged as a promising approach for the treatment of genetic diseases based on efficient delivery systems for therapeutic nucleic acids (NAs) into the target cells. For pulmonary diseases such as cystic fibrosis (CF), chronic obstructive pulmonary diseases (COPD), infectious disease or lung cancer, aerosol delivery is the best choice to locally deliver NAs into the lungs. It is, therefore, important to investigate the effects of nebulization conditions on the efficiency of delivery. To this purpose, the non-viral vector branched polyethyleneimine (b-PEI, 25 kDa) was investigated for plasmid delivery by aerosol. Two types of nebulizers, jet nebulizer and mesh nebulizer, were compared regarding the properties of the nanoparticles (NPs) formed, the efficiency of NAs delivery in vitro and in vivo models and the pulmonary deposition. The results indicate that the mesh nebulizer has a better gene delivery performance than the jet nebulizer in this application. This superiority was demonstrated in terms of size, concentration, distribution of NPs and efficiency of NAs delivery. However, pulmonary deposition appears to be similar regardless of the nebulizer used, and the difference between the two systems lies in the inhalable dose. These results underline the crucial role of nebulization techniques in optimizing aerosol-mediated gene delivery by b-PEI and highlight the potential of mesh nebulizers as promising tools to improved gene therapy. Therefore, the comparison must be performed for each gene therapy formulation to determine the most suitable nebulizer.

PMID:39930696 | DOI:10.1080/10717544.2025.2463428

J Cyst Fibros. 2025 Feb 9:S1569-1993(25)00047-5. doi: 10.1016/j.jcf.2025.01.014. Online ahead of print.

ABSTRACT

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.

PMID:39929763 | DOI:10.1016/j.jcf.2025.01.014

Thorax. 2025 Feb 10:thorax-2024-221634. doi: 10.1136/thorax-2024-221634. Online ahead of print.

ABSTRACT

BACKGROUND: Early-life inflammation has long been recognised as a key pathophysiological process in the evolution of cystic fibrosis (CF) lung disease. Despite this, no CF-specific anti-inflammatory treatments have been developed. This is crucial even in the era of highly effective modulator therapy as recent evidence suggests that modulators alter, but may not fully resolve, pulmonary inflammation.

METHODS: In this study, we used clinical microbiology data, high-dimensional flow cytometry and multiplex immunoassays to compare pulmonary (bronchoalveolar lavage (BAL)) and systemic immunity in 70 preschool children with CF and a total of 32 age-matched preschool controls.

RESULTS: We show that inflammation in the early-life CF lung is characterised by innate cell infiltration (neutrophils: 31.31 vs 1.8% of BAL in CF compared with controls, FDRp=0.0001; eosinophils: 0.55 vs 0.06%, FDRp=0.001, and monocytes: 1.91 vs 0.45%, FDRp=0.004) and widespread upregulation of both traditional and type 2 inflammatory soluble signatures (40 analytes significantly elevated in BAL of CF compared with controls, all FDRp<0.1). Key targetable features of this response included pulmonary interleukin (IL)-8 and IL-13 which were most significantly associated with neutrophilic and eosinophilic infiltration, respectively (IL-8 and neutrophils; Spearman rho=0.68, FDRp=0.002: IL-13 and eosinophils; Spearman rho=0.75, FDRp=0.01). Signatures of type 2 inflammation, as identified by REACTOME pathway analysis, including IL-4, IL-13 and FGF-2, were highly elevated in both the lungs and circulation in early CF. When exploring the efficacy of Cystic Fibrosis Transmembrane Conductance Regulator modulators to resolve pulmonary and systemic inflammation in early life, we showed that different classes of modulators have varying effects on inflammation, with ivacaftor showing a more significant effect in the lungs and circulation than lumacaftor/ivacaftor. Finally, we showed that CF children with pathogen colonisation had similar levels of pulmonary inflammation as CF children without pathogen colonisation (no significant differences), and that inflammation was evident during infancy even without evidence of colonisation (as observed by significant increases in levels of SDF-1alpha, M-CSF, IL-2, IL-9, IL-12p40, IL-17, MCP-1 and LIGHT/TNFSF14, all FDRp<0.1), highlighting a role for intrinsic dysregulation of inflammation that begins in early life.

CONCLUSIONS: We provide a rationale for targeted anti-inflammatory intervention in early-life CF.

PMID:39929713 | DOI:10.1136/thorax-2024-221634

BMJ Open Respir Res. 2025 Feb 10;12(1):e002606. doi: 10.1136/bmjresp-2024-002606.

ABSTRACT

Cystic fibrosis (CF) treatment has revolutionised care over the past three decades with major advances in survival. Despite these advances, CF continues to create psychological and social challenges for people with CF (PWCF) throughout their life and is associated with worse health outcomes and higher healthcare costs. Anxiety and depression screening and management protocols are widely implemented within CF care; however, a much broader scope of psychosocial challenges exist which lack a standardised screening and management approach. The advent of CF transmembrane conductance regulator modulator therapies is transforming the psychosocial landscape for PWCF with new challenges and evolving psychosocial needs. What it means to have CF, the expectations, hopes and stressors are rapidly changing, and psychosocial care must keep pace if health outcomes are to be fully optimised. A symposium of international CF and psychosocial experts was convened in November 2022 to explore current and emerging issues in psychosocial health and identify opportunities and approaches to optimise psychosocial care. This state-of-the-art review summarises key symposium proceedings and highlights priorities for clinical practice and research in psychosocial health across the lifespan among PWCF. It also summarises state-of-the-art initiatives for screening and intervention to optimise CF psychosocial healthcare and patient outcomes.

PMID:39929550 | DOI:10.1136/bmjresp-2024-002606

J Med Chem. 2025 Feb 10. doi: 10.1021/acs.jmedchem.4c02654. Online ahead of print.

ABSTRACT

Molecular-targeted therapies for the treatment of cystic fibrosis (CF) rely on small-molecule modulators that rescue the activity of the defective CF transmembrane conductance regulator (CFTR) anion channel. ARN23765 is a small molecule with subnanomolar potency in rescuing the function of mutant CFTR in bronchial epithelial cells from CF patients carrying the F508del-CFTR mutation. Considering the multifaceted interactions of CFTR with the plasma membrane and the complexity of the protein network within the cellular compartments, here we report the investigation of ARN23765's molecular mechanism in live cells. We used the photoaffinity labeling (PAL) approach to demonstrate the interaction of ARN23765-derived probes with CFTR in cells. We showed that ARN23765 contributes to F508del-CFTR rescue by stabilizing the membrane-spanning domain-1 and interacting with CFTR at the same site as other type I CFTR correctors. Our study characterizes ARN23765's mode of action and highlights the potential of studying the interactions between CFTR and its correctors in live cells.

PMID:39928576 | DOI:10.1021/acs.jmedchem.4c02654

Disabil Rehabil Assist Technol. 2025 Feb 10:1-8. doi: 10.1080/17483107.2025.2463548. Online ahead of print.

ABSTRACT

BACKGROUND: Cystic fibrosis (CF) is a genetic disorder affecting multiple organs, primarily the lungs. Rehabilitation is crucial in managing respiratory symptoms. Telerehabilitation, which provides remote rehabilitation services via digital platforms, gained importance during the COVID-19 pandemic. Despite its growing use, there is little clarity on the available tools and devices for CF telerehabilitation.

OBJECTIVE: This scoping review aims to map the existing tools and devices used in telerehabilitation for pediatric and adult CF patients.

METHODS: The review was conducted following the Joanna Briggs Institute methodology, using the PRISMA-ScR checklist. Comprehensive searches were performed across seven databases, alongside grey literature. Studies involving CF patients and telerehabilitation interventions were included. Data were extracted and analyzed both numerically and thematically.

RESULTS: Eighteen studies were included, involving 622 CF patients. The review identified 10 platforms, seven telemonitoring devices, and three rehabilitation devices. Most studies focused on motor rehabilitation with individual, synchronous sessions. Commonly used platforms included Zoom, Skype, and Google Meet, while only three studies used platforms specifically designed for CF.

CONCLUSIONS: Telerehabilitation for CF is in its early stages and less developed than for other conditions. There is a need for dedicated platforms and devices that address CF patients' specific motor and respiratory needs. Future efforts should focus on developing these tools to improve patient engagement and outcomes.

PMID:39928374 | DOI:10.1080/17483107.2025.2463548

Chron Respir Dis. 2025 Jan-Dec;22:14799731241310897. doi: 10.1177/14799731241310897.

ABSTRACT

OBJECTIVES: To assess real-world survival and healthcare resource utilization (HCRU) in US patients with non-cystic fibrosis bronchiectasis (NCFBE).

METHODS: This retrospective analysis, using data from the STATinMED RWD Insights database from Jan 2015-Oct 2022, included adults with NCFBE (from Jan 2015-Oct 2021) and non-NCFBE comparators (from Jan 2015-Aug 2020); baseline characteristics were balanced by inverse probability treatment weighting. Outcomes included survival through end of study. HCRU was assessed over 12 months.

RESULTS: 117,718 patients with NCFBE and 306,678 comparators were included. Patients with NCFBE had a 77% higher risk of death than comparators (hazard ratio [HR] 1.77 [95% CI 1.74-1.80]). Risk of death was higher among patients aged ≥65 years (vs 18-34 years; HR 11.03 [95% CI 10.36-11.74]), among Black patients (vs White; HR 1.53 [95% CI 1.50-1.55]), and among patients with comorbid COPD (HR 1.42 [95% CI 1.40-1.44]). Patients with NCFBE incurred higher all-cause and respiratory-related HCRU than comparators for outpatient office, outpatient hospital, emergency department (ED), inpatient and respiratory-related pulmonologist visits (all p < .0001); HCRU increased with exacerbations.

CONCLUSIONS: Patients with NCFBE have high mortality burden and incur high HCRU, both of which are further increased with exacerbations. Prevention and delay of exacerbations are key areas for improvement of disease management.

PMID:39925084 | DOI:10.1177/14799731241310897

Comput Biol Med. 2025 Feb 7;187:109748. doi: 10.1016/j.compbiomed.2025.109748. Online ahead of print.

ABSTRACT

BACKGROUND: Lung disease remains a leading cause of morbidity and mortality in individuals with cystic fibrosis (CF). Despite significant advances, the complex molecular mechanisms underlying CF-related airway pathology are not fully understood. Building upon previous single-cell transcriptomics studies in CF patients and healthy controls, this study employs enhanced analytical methodologies to deepen our understanding of CF-associated gene expression.

METHODS: We employed advanced single-cell transcriptomics techniques, integrating data from multiple sources and implementing rigorous normalization and mapping strategies using a comprehensive lung reference panel. These sophisticated methods were designed to enhance the accuracy and depth of our analysis, with a focus on elucidating differential gene expression and characterizing co-expression network dynamics associated with cystic fibrosis (CF).

RESULTS: Our analysis uncovered novel genes and regulatory networks that had not been previously associated with CF airway disease. These findings highlight new potential therapeutic targets that could be exploited to develop more effective interventions for managing CF-related lung conditions.

CONCLUSION: This study provides critical insights into the molecular landscape of CF airway disease, offering new avenues for targeted therapeutic strategies. By identifying key genes and networks involved in CF pathogenesis, our research contributes to the broader efforts to improve the prognosis and quality of life for patients with CF. These discoveries pave the way for future studies aimed at translating these findings into clinical practice.

PMID:39921941 | DOI:10.1016/j.compbiomed.2025.109748

Respir Med. 2025 Feb 5:107982. doi: 10.1016/j.rmed.2025.107982. Online ahead of print.

ABSTRACT

BACKGROUND/RATIONALE: Lung transplant (LTx) candidates with cystic fibrosis (CF) have ventilatory and musculoskeletal limitations and benefit from pulmonary rehabilitation (PR). Their training response has not been well characterized. The study aims to: 1) characterize the effect of outpatient PR and 2) evaluate the clinical characteristics associated with their PR response.

METHODS: Single-center retrospective cohort study of CF LTx candidates (July 2009-June 2019) with available pre-transplant exercise data, who participated in PR 2 to 3 times/week until transplantation. Demographics, CF-related characteristics, aerobic and muscle training volumes, and six-minute walk distance (6MWD) were characterized using descriptive statistics, paired t-tests and Spearman correlations to describe relationships between CF-related characteristics and training volumes.

RESULTS: In 86 CF LTx candidates (32±10 years, 49% males, FEV1: 23±5%; listing 6MWD 421±89 meters), the median PR time was 87 days (24-36 sessions). 78% had at least one exacerbation and 55% required hospitalization. 88% used supplemental oxygen and 37% required home non-invasive ventilation. Treadmill speed (1.7±0.5 mph); biceps (50 IQR [40-70] lbs*reps) and quadriceps (30 IQR [30-40] lbs*reps) training volumes improved with PR (p< 0.05), whereas 6MWD remained unchanged. The presence of ≥ 1 respiratory exacerbation was associated with a lower progression in treadmill speed [-0.36 mph 95%CI (-0.67 to -0.04), p=0.028].

CONCLUSION: CF LTx candidates participating in PR increased treadmill speed and muscle training volumes, with preservation of 6MWD. Respiratory exacerbations were prevalent and important determinants of aerobic training.

PMID:39921065 | DOI:10.1016/j.rmed.2025.107982

J Cyst Fibros. 2025 Feb 6:S1569-1993(25)00046-3. doi: 10.1016/j.jcf.2025.01.013. Online ahead of print.

ABSTRACT

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.

PMID:39919951 | DOI:10.1016/j.jcf.2025.01.013

J Cyst Fibros. 2025 Feb 6:S1569-1993(25)00048-7. doi: 10.1016/j.jcf.2025.01.015. Online ahead of print.

ABSTRACT

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.

PMID:39919950 | DOI:10.1016/j.jcf.2025.01.015