Ligand-free biodegradable poly(beta-amino ester) nanoparticles for targeted systemic delivery of mRNA to the lungs.

Non-viral nanoparticles (NPs) have seen heightened interest as a delivery method for a variety of clinically relevant nucleic acid cargoes in recent years. While much of the focus has been on lipid NPs, non-lipid NPs, including polymeric NPs, have the possibility of improved efficacy, safety, and targeting, especially to non-liver organs following systemic administration. A safe and effective systemic approach for intracellular delivery to the lungs could overcome limitations to intratracheal/intranasal delivery of NPs and improve clinical benefit for a range of diseases including cystic fibrosis. Here, engineered biodegradable poly (beta-amino ester) (PBAE) NPs are shown to facilitate efficient delivery of mRNA to primary human airway epithelial cells from both healthy donors and individuals with cystic fibrosis. Optimized NP formulations made with differentially endcapped PBAEs and systemically administered in vivo lead to high expression of mRNA within the lungs in BALB/c and C57 B/L mice without requiring a complex targeting ligand. High levels of mRNA-based gene editing were achieved in an Ai9 mouse model across bronchial, epithelial, and endothelial cell populations. No toxicity was observed either acutely or over time, including after multiple systemic administrations of the NPs. The non-lipid biodegradable PBAE NPs demonstrate high levels of transfection in both primary human airway epithelial cells and in vivo editing of lung cell types that are targets for numerous life-limiting diseases particularly single gene disorders such as cystic fibrosis and surfactant deficiencies.

Challenges in the care of cystic fibrosis in low-to-middle income countries.

Till few years ago cystic fibrosis (CF) was considered to be exclusively disease affecting Caucasian population. More recently CF has been reported from all over the world from different ethnic background. CF is an emerging illness in other parts of world (India with 1:2200 to 1:40,000 live birth). In low- and middle-income countries (LMICs) diagnosis of CF is missed due to ignorance and nonavailability of diagnostic tests. Diagnosis can be made using clinical features and basic lab tests. As of now there is no cure, but supportive care improved survival. However, medicines used in higher income countries are very expensive and not accessible to children with CF in LMICs. Cystic fibrosis transmembrane regulators modulators have emerged as significant advances in management. These are very expensive and beyond the reach of patients in LMICs. CF Fraternity in developed countries should work towards training of personnel and possibly making medications available in LMICs.

Integrating genomics as clinical biomarkers in pediatric pulmonology.

Respiratory diseases often result from complex interactions between an individual's genetic predisposition and their exposure to various environmental and other risk factors. Here we will briefly review how various types of "omics", particularly epigenomics and transcriptomics, hold promise for translation into clinical biomarkers in pediatric pulmonary medicine, using asthma and cystic fibrosis as examples.

Effect of Lactiplantibacillus plantarum cell-free culture on bacterial pathogens isolated from cystic fibrosis patients: in vitro and in vivo studies.

This study aimed to investigate the effects of the cell-free supernatant of Lactiplantibacillus plantarum ATCC® 10241TM on the biofilm-forming capacity of Pseudomonas aeruginosa strains isolated from cystic fibrosis (CF) patients. In addition, the study evaluated the in vivo potential of the cell-free supernatant to modulate inflammation and reduce lung damage in mice infected with P. aeruginosa strains or co-challenged with P. aeruginosa and the Streptococcus milleri group (SMG). The results showed that CF-derived P. aeruginosa strains can infect the respiratory tract of adult mice, inducing local inflammation and lung damage. The severity of these infections was exacerbated when P. aeruginosa was co-administered with SMG. Notably, nebulization with the cell-free supernatant of L. plantarum produced beneficial effects, reducing respiratory infection severity and inflammatory responses induced by P. aeruginosa, both alone or in combination with SMG. Reduced bacterial loads and lung damage were observed in supernatant-treated mice compared to controls. Although further mechanistic studies are necessary, the results show that the cell-free supernatant of L. plantarum ATCC® 10241TM is an interesting adjuvant alternative to treat P. aeruginosa respiratory infections and superinfections in CF patients.

Kidney effects of triple CFTR modulator therapy in people with cystic fibrosis.

Background: Elexacaftor/tezacaftor/ivacaftor (ETI) is a new cystic fibrosis transmembrane conductance regulator (CFTR) modulator that has transformed the respiratory prognosis of people with cystic fibrosis (pwCF). However, its impact on other organs such as the kidneys, where CFTR is expressed, remains unclear. Since pwCF are risk of both kidney disease and urolithiasis, we aimed to study the potential effects of ETI on renal function, volume status, and risk factors for urolithiasis. Methods: This prospective, observational, single-center, before-after cohort study, involved adult pwCF eligible for ETI. The changes in plasma and urinary profiles were assessed by comparing renal function (using 2021 CKD-EPIcreatinine and 2021 CKD-EPIcreatinine-cystatin C formulas), volume status (using aldosterone/renin ratio and blood pressure), and risk factors for urolithiasis, at the time of ETI introduction (M0) and 7 months after (M7). Results: Nineteen pwCF were included. No significant change in renal function was observed between M0 and M7 (2021 CKD-EPIcreatinine: 105.5 ml/min/1.73 m² at M0 vs. 103.3 ml/min/1.73 m² at M7; P = .17). There was a significant reduction in aldosterone level (370.3 pmol/l at M0 vs. 232.4 pmol/l at M7; P = .02) and aldosterone/renin ratio (33.6 at M0 vs. 21.8 at M7; P = .03). Among the risk factors for urolithiasis, a significant reduction in magnesuria level was found (4.6 mmol/d at M0 vs. 3.8 mmol/d at M7; P = .01). Conclusion: These findings suggest that ETI seem to have no short-term impact on the renal function of adult pwCF and appears to correct secondary hyperaldosteronism due to excessive sweat losses. Further investigations are needed to determine the potential impact of decreased magnesuria observed under ETI therapy on the risk of urolithiasis.

Effectiveness of hypertonic saline with or without hyaluronic acid among patients with cystic fibrosis: a systematic review and meta-analysis.

Background: The clinical effectiveness of hypertonic saline (HS) in individuals with cystic fibrosis (CF) can be compromised by adverse effects. The objective of this study was to examine the efficacy of hyaluronic acid (HA) in mitigating these negative occurrences. Methods: A comprehensive review of the literature was carried out using three electronic databases: Medline, Cochrane Central, and Embase. This systematic review and meta-analysis investigate the efficacy of hypertonic saline (HS) with and without hyaluronic acid (HA) in treating cystic fibrosis. Primary outcomes include the incidence of cough, throat irritation, unpleasant taste, and changes in FEV1. Our findings suggest that adding HA to HS significantly reduces adverse effects and enhances patient tolerability, marking a potential improvement in cystic fibrosis therapy. Risk ratios (RRs) and mean differences (MDs) with 95% CI were used to present evaluations. The quality of RCTs was evaluated using the Cochrane Risk of Bias Tool (CRBT). The quality of the observational study was evaluated using the Newcastle-Ottawa Scale. Results: From the 1960 articles retrieved from the initial search, five relevant studies (n=236 patients) were included in the final analysis. Compared with patients only on HS, patients with HS and HA were significantly less likely to experience cough (RR: 0.45; 95% CI, 0.28-0.72, P=0.001), throat irritation (RR: 0.43; 95% CI, 0.22-0.81, P=0.009), and unpleasant smell (RR: 0.43; 95% CI, 0.23-0.80, P=0.09). In addition, patients with HS with HA had significantly less forced expiratory volume (FEV1) (MD: -2.97; 95% CI, -3.79--2.15, P=0.52), compared to patients only on HS. Patients on HA + HS had significantly lower rates of cough (RR: 0.45; 95% CI, 0.28-0.72, P=0.001), throat irritation (RR: 0.43; 95% CI, 0.22-0.81, P=0.009), and bad smell (RR: 0.43; 95% CI, 0.23-0.80, P=0.09) when compared to patients on HS alone. Furthermore, compared to patients solely on HS, patients with HS plus HA exhibited a substantially lower forced expiratory volume (FEV1) (MD: -2.97; 95% CI, -3.79 to -2.15, P=0.52) as well. Conclusion: For CF patients who need ongoing HS therapy and have a history of poor therapy tolerance, adding HA is beneficial.

Survival Outcomes in US Medicare Patients with Non-Cystic Fibrosis Bronchiectasis by Rate of Baseline Exacerbations.

INTRODUCTION: There are limited real-world data on outcomes in patients with non-cystic fibrosis bronchiectasis (NCFBE). This study assessed clinical characteristics and survival in patients with NCFBE by baseline exacerbation rate. METHODS: Patients with bronchiectasis (≥ 1 inpatient or ≥ 2 outpatient claims with a bronchiectasis diagnosis code, or one outpatient claim with bronchiectasis code and a chest computed tomography scan) were from the 100% Medicare Fee-for-Service database (Jan 2014-Dec 2020). Patients had continuous enrollment ≥ 12 months pre-index (baseline) and post-index (follow-up), with index a random bronchiectasis claim preceded by ≥ 12 months bronchiectasis history. Patients with cystic fibrosis were excluded. Patients were stratified by exacerbations during baseline (0, 1, or ≥ 2). Follow-up exacerbation rate and all-cause mortality were assessed. Controls were identified using a multistep direct matching approach. Time to death from index was estimated by Kaplan-Meier analyses. RESULTS: Exacerbation analysis included 92,529 patients with NCFBE and 92,529 matched controls. Exacerbations were common (43% had ≥ 1 exacerbation), with patients with more baseline exacerbations more likely to have ≥ 2 exacerbations during follow-up (11.4%, 24.2%, and 46.8% of patients with 0, 1, and ≥ 2 baseline exacerbations, respectively). Survival analysis included 110,298 patients with NCFBE and 110,298 controls. Time to death was shorter in patients with more baseline exacerbations (P < 0.0001). Five-year survival was 55.3%, 62.6%, and 65.4% for patients with ≥ 2, 1, and 0 baseline exacerbations, respectively, compared with 64.1% for controls. CONCLUSIONS: In these patients with NCFBE, exacerbations were common. History of exacerbations was associated with future exacerbations and increased all-cause mortality.

The battle within: how Pseudomonas aeruginosa uses host-pathogen interactions to infect the human lung.

Pseudomonas aeruginosa is a versatile Gram-negative pathogen known for its ability to invade the respiratory tract, particularly in cystic fibrosis patients. This review provides a comprehensive analysis of the multifaceted strategies for colonization, virulence, and immune evasion used by P. aeruginosa to infect the host. We explore the extensive protein arsenal of P. aeruginosa, including adhesins, exotoxins, secreted proteases, and type III and VI secretion effectors, detailing their roles in the infective process. We also address the unique challenge of treating diverse lung conditions that provide a natural niche for P. aeruginosa on the airway surface, with a particular focus in cystic fibrosis. The review also discusses the current limitations in treatment options due to antibiotic resistance and highlights promising future approaches that target host-pathogen protein-protein interactions. These approaches include the development of new antimicrobials, anti-attachment therapies, and quorum-sensing inhibition molecules. In summary, this review aims to provide a holistic understanding of the pathogenesis of P. aeruginosa in the respiratory system, offering insights into the underlying molecular mechanisms and potential therapeutic interventions.

Exploiting inhalable microparticles incorporating hybrid polymer-lipid nanoparticles loaded with Iloprost manages lung hyper-inflammation.

This study focuses on developing of a novel inhalation therapy for managing lung hyper-inflammation, producing hybrid polymer-lipid nanoparticles loaded with Iloprost (Ilo). These nanoparticles showed a size of approximately 100 nm with a core-shell structure and provided prolonged drug release, reaching 28 wt% after 6 h of incubation. The phospholipid composition and quantity (64 wt% on the total sample weight) result in minimal interaction with mucin and a significant effect on the rheology of a cystic fibrosis mucus model, in terms of reducing complex viscosity. To obtain an inhalable microparticulate matrix suitable for incorporating Ilo@PEG-LPHNPs, the qualitative and quantitative composition of the feed fluid for the spray drying (SD) process was optimized. The selected composition (10 % wt/vol of mannitol and 10 % wt of ammonium bicarbonate relative to the weight of mannitol) was used to produce Nano-into Microparticles (NiM). The characterization of NiM revealed excellent aerodynamic properties, with a Mass Median Aerodynamic Diameter (MMAD) of 4.34 µm and a Fine Particle Fraction (FPF) of approximately 57 %. Biological characterization revealed that the particles are non-toxic to 16-HBE cells and can effectively evade macrophage uptake, likely due to the presence of PEG in their composition. Moreover, the delivered Iloprost significantly downregulates the production of the pro-inflammatory cytokine IL-6, showing the therapeutic potential of this drug delivery system.

Safety and tolerability of a low glycemic load dietary intervention in adults with cystic fibrosis: a pilot study.

Introduction: To achieve and maintain adequate weight, people with cystic fibrosis (CF) May often consume energy-dense, nutrient-poor foods high in added sugars and refined carbohydrates; however, little is known about the glycemic and metabolic effects of dietary composition in this patient population. The objective of this pilot study was to investigate the safety and tolerability of a low glycemic load (LGL) diet in adults with CF and abnormal glucose tolerance (AGT). Methods: Ten adults with CF and AGT completed this prospective, open-label pilot study. Mean age was 27.0 ± 2.1 years, 64% were female, and all had pancreatic insufficiency. Each participant followed his/her typical diet for 2 weeks, then transitioned to a LGL diet via meal delivery service for 8 weeks. The primary outcome was change in weight from baseline to study completion, with safety established if no significant decline was noted. Other key safety outcomes included change in hypoglycemia measured by patient report and continuous glucose monitoring (CGM). Exploratory outcomes included changes in other CGM measures, body composition by dual energy X-ray absorptiometry (DXA), and patient reported outcomes. Results: There were no significant changes in weight or in subjectively-reported or objectively-measured hypoglycemia. Favorable non-significant changes were noted in CGM measures of hyperglycemia and glycemic variability, DXA measures of fat mass, and gastrointestinal symptom surveys. Discussion: A LGL dietary intervention was safe and well tolerated in adults with CF and AGT. These results lay the groundwork for future trials investigating the impact of low-glycemic dietary interventions on metabolic outcomes in the CF population.

The impact of a whole foods dietary intervention on gastrointestinal symptoms, inflammation, and fecal microbiota in pediatric patients with cystic fibrosis: A pilot study.

BACKGROUND: Gastrointestinal (GI) complications are a significant source of morbidity for people with cystic fibrosis (PwCF). Historically, dietary recommendations in CF have focused on calories, typically emphasizing a high fat diet. The changing landscape of CF highlights the need to update this nutritional strategy. There is little research into how the quality of calories consumed by PwCF influences nutritional outcomes, GI symptoms, or likely contributors: intestinal inflammation and GI microbiology. We assessed the feasibility of a whole foods-based diet (WFD) and avoidance of ultra-processed foods, measuring safety/tolerability, adherence, and GI symptoms, as well as fecal measures of inflammation and microbiota among children with CF (CwCF) with GI symptoms. METHODS: Single center, 4-week dietary intervention involving CwCF aged 5-14 years who screened positive on GI symptom questionnaire. Assessments included weight, symptom questionnaires and adverse events (AEs). Stool was analyzed for microbiota (16S rRNA) and calprotectin. RESULTS: 108 children were pre-screened, 9 enrolled and 8 initiated and completed the study. There were no significant changes in weight and no AEs. PEDS-QL GI identified overall improvement in symptoms. Certain symptom domains (constipation, diarrhea, gas/bloating, stomach pain and hurt) demonstrated significant improvement on the WFD. Of two participants with abnormal fecal calprotectin at enrollment, both exhibited decreased values on WFD. There was no significant change in microbiota diversity. CONCLUSION: A WFD diet was feasible and safe in CwCF. There was improvement in GI symptom scores based on both parent and child assessments. Larger studies are needed to further investigate effects on intestinal inflammation and microbiota.

Collaboration between registered dietitians and gastroenterologists in cystic fibrosis care: Results of an international cross-sectional survey.

BACKGROUND: Collaboration between registered dietitians and gastroenterologists has not been evaluated in cystic fibrosis (CF). We surveyed registered dietitians and gastroenterologists regarding the current participation of gastroenterologists in CF centers and identified possible areas to enhance partnership between the two disciplines. METHODS: An anonymous online survey was distributed targeting registered dietitians and gastroenterologists involved in CF care through three international listservs (CF Nutrition, CF DIGEST, and PEDGI) over a 6-week period. SurveyMonkey was used, and informed consent was obtained. RESULTS: A total of 131 respondents participated in this survey, including 80 registered dietitians and 51 gastroenterologists (41 pediatric and 10 adult gastroenterologists). Most respondents (82%) were from the United States, and two-thirds had ≥5 years of experience in CF. A significant number of registered dietitians reported the nonavailability of gastroenterologists for collaboration and there was greater availability of gastroenterologists in pediatric centers. Barriers to interdisciplinary collaboration included lack of CF expertise and dedicated time among the gastroenterologists and difficulties in coordinating the gastroenterology clinics. More gastroenterologists than registered dietitians perceived that they worked collaboratively with the other discipline in various domains (clinical care, quality improvement, research, presentations, and publications). Both disciplines had mutual respect and interest to further the collaboration. CONCLUSION: There is an increased need for gastroenterologist participation and collaboration (particularly in adult centers) in CF alongside registered dietitians to enhance comprehensive patient care. Future efforts should focus on training more gastroenterologists in CF and facilitating easier access to gastroenterologists for the CF population.

CCR2+ monocytes are dispensable to resolve acute pulmonary Pseudomonas aeruginosa infections in WT and Cystic Fibrosis mice.

Extravasation of CCR2-positive monocytes into tissue and to the site of injury is a fundamental immunological response to infections. Nevertheless, exuberant recruitment and/or activity of these monocytes and monocyte-derived macrophages can propagate tissue damage, especially in chronic inflammatory disease conditions. We have previously shown that inhibiting the recruitment of CCR2-positive monocytes ameliorates lung tissue damage caused by chronic neutrophilic inflammation in cystic fibrosis (CF) mouse models. A potential concern with targeting monocyte recruitment for therapeutic benefit in CF, however, is whether they are essential for eradicating infections such as Pseudomonas aeruginosa (PA), a pathogen that commonly colonizes and damages the lungs of patients with CF. In this study, we investigated the role of CCR2-positive monocytes in the immune response to acute pulmonary PA infection. Our data show that the altered host immune response caused by the lack of monocyte recruitment to the lungs does not impact PA lung colonization, clearance, and the severity of the infection. These results also hold up in a CF mouse background, which have a hyper-inflammatory immune response, yet exhibit reduced bactericidal activity. Thus, we lay the groundwork for future studies to investigate the use of CCR2 inhibitors as a potential therapy to ameliorate lung tissue damage in CF. This could be given alone or as an adjunct therapy with CFTR modulators that significantly improve clinical outcomes for eligible patients, but do not completely resolve the persistent infection and inflammation that drive lung tissue damage.

Microbiome and metabolome patterns after lung transplantation reflect underlying disease and chronic lung allograft dysfunction.

BACKGROUND: Progression of chronic lung disease may lead to the requirement for lung transplant (LTx). Despite improvements in short-term survival after LTx, chronic lung allograft dysfunction (CLAD) remains a critical challenge for long-term survival. This study investigates the molecular and microbial relationships between underlying lung disease and the development of CLAD in bronchoalveolar lavage fluid (BALF) from subjects post-LTx, which is crucial for tailoring treatment strategies specific to allograft dysfunctions. METHODS: Paired 16S rRNA gene amplicon sequencing and untargeted LC-MS/MS metabolomics were performed on 856 BALF samples collected over 10 years from LTx recipients (n = 195) with alpha-1-antitrypsin disease (AATD, n = 23), cystic fibrosis (CF, n = 47), chronic obstructive pulmonary disease (COPD, n = 78), or pulmonary fibrosis (PF, n = 47). Data were analyzed using random forest (RF) machine learning and multivariate statistics for associations with underlying disease and CLAD development. RESULTS: The BALF microbiome and metabolome after LTx differed significantly according to the underlying disease state (PERMANOVA, p = 0.001), with CF and AATD demonstrating distinct microbiome and metabolome profiles, respectively. Uniqueness in CF was mainly driven by Pseudomonas abundance and its metabolites, whereas AATD had elevated levels of phenylalanine and a lack of shared metabolites with the other underlying diseases. BALF microbiome and metabolome composition were also distinct between those who did or did not develop CLAD during the sample collection period (PERMANOVA, p = 0.001). An increase in the average abundance of Veillonella (AATD, COPD) and Streptococcus (CF, PF) was associated with CLAD development, and decreases in the abundance of phenylalanine-derivative alkaloids (CF, COPD) and glycerophosphorylcholines (CF, COPD, PF) were signatures of the CLAD metabolome. Although the relative abundance of Pseudomonas was not associated with CLAD, the abundance of its virulence metabolites, including siderophores, quorum-sensing quinolones, and phenazines, were elevated in those with CF who developed CLAD. There was a positive correlation between the abundance of these molecules and the abundance of Pseudomonas in the microbiome, but there was no correlation between their abundance and the time in which BALF samples were collected post-LTx. CONCLUSIONS: The BALF microbiome and metabolome after LTx are particularly distinct in those with underlying CF and AATD. These data reflect those who developed CLAD, with increased virulence metabolite production from Pseudomonas, an aspect of CF CLAD cases. These findings shed light on disease-specific microbial and metabolic signatures in LTx recipients, offering valuable insights into the underlying causes of allograft rejection. Video Abstract.

Modeling respiratory tract diseases for clinical translation employing conditionally reprogrammed cells.

Preclinical models serve as indispensable tools in translational medicine. Specifically, patient-derived models such as patient-derived xenografts (PDX), induced pluripotent stem cells (iPSC), organoids, and recently developed technique of conditional reprogramming (CR) have been employed to reflect the host characteristics of diseases. CR technology involves co-culturing epithelial cells with irradiated Swiss-3T3-J2 mouse fibroblasts (feeder cells) in the presence of a Rho kinase (ROCK) inhibitor, Y-27632. CR technique facilitates the rapid conversion of both normal and malignant cells into a "reprogrammed stem-like" state, marked by robust in vitro proliferation. This is achieved without reliance on exogenous gene expression or viral transfection, while maintaining the genetic profile of the parental cells. So far, CR technology has been used to study biology of diseases, targeted therapies (precision medicine), regenerative medicine, and noninvasive diagnosis and surveillance. Respiratory diseases, ranking as the third leading cause of global mortality, pose a significant burden to healthcare systems worldwide. Given the substantial mortality and morbidity rates of respiratory diseases, efficient and rapid preclinical models are imperative to accurately recapitulate the diverse spectrum of respiratory conditions. In this article, we discuss the applications and future potential of CR technology in modeling various respiratory tract diseases, including lung cancer, respiratory viral infections (such as influenza and Covid-19 and etc.), asthma, cystic fibrosis, respiratory papillomatosis, and upper aerodigestive track tumors. Furthermore, we discuss the potential utility of CR in personalized medicine, regenerative medicine, and clinical translation.

Longitudinal Changes in Bone Mineral Density in Adults with Cystic Fibrosis.

BACKGROUND: Improved survival in people with cystic fibrosis (pwCF) presents new complexities of care, including CF-related bone disease, a common complication in older pwCF. The trajectory of bone loss with age in this population remains unclear. The objective of this study was to estimate the average rate of change in bone mineral density (BMD) in adults with CF. METHODS: This retrospective study included adults with CF, aged 25-48 years, followed between January 2000 and December 2021. Subjects with at least one dual-energy X-ray absorptiometry (DXA) scan were included. Scans obtained post-transplantation, after the initiation of bisphosphonates or cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapy were excluded. The primary outcome was BMD (g/cm2) at the lumbar spine (LS) and femoral neck (FN). A linear mixed-effects model with both random intercept and random slope terms was used to estimate the average annual change in BMD. RESULTS: A total of 1502 DXA scans in 500 adults (average age 28.4y) were included. There was a statistically significant annual decline in BMD of -0.008 gm/cm2/year (95% CI -0.009, -0.007) at the FN and -0.006 gm/cm2/year (95% CI -0.007, -0.004) at the LS. Relative to BMD at age 25, there was a -18.8% decline at the FN by age 48 years and a -11% decline at the LS. Pancreatic insufficient (PI) subjects had a faster rate of decline in BMD compared to pancreatic sufficient (PS) subjects. After adjusting for markers of disease severity, the annual rate of decline remained significant. CONCLUSIONS: Individuals with CF experience bone loss at an age when it is not anticipated, thereby entering early adulthood, where further bone loss is inevitable especially with the decrease in estrogen during menopause, with suboptimal BMD. As the CF population ages, it will become very important to consider interventions to maximize bone health.

Improved survival in people with cystic fibrosis (pwCF) presents new complexities of care, including CF-related bone disease, a common complication in older pwCF. The objective of this study was to estimate how bone mineral density (BMD) changes over time in adults with CF. The study included 500 adults with CF, aged 25-48 years, followed between January 2000 and December 2021 who underwent a scan to assess BMD. On average, BMD decreased over time both at the spine and the hip. People who have pancreatic insufficiency had a faster rate of decline in BMD than people with pancreatic sufficiency. Individuals with CF experience bone loss at an age when bone density is expected to be stable. As the CF population ages, interventions to maximize bone health should be emphasized to prevent fractures in the future.

Lung ultrasound in children with primary ciliary dyskinesia or cystic fibrosis.

INTRODUCTION: Primary ciliary dyskinesia (PCD) and cystic fibrosis (CF) are respiratory conditions requiring regular chest radiography (CXR) surveillance to monitor pulmonary disease. However, CXR is insensitive for lung disease in CF and PCD. Lung ultrasound (LU) is a radiation-free alternative showing good correlation with severity of lung disease in CF but has not been studied in PCD. METHOD: Standardized, six-zone LU studies and CXR were performed on a convenience sample of children with PCD or CF during a single visit when well. LU studies were graded using the LU scoring system, while CXR studies received a modified Chrispin-Norman score. Scores were correlated with clinical outcomes. RESULT: Data from 30 patients with PCD and 30 with CF (median age PCD 11.5 years, CF 9.1 years) with overall mild pulmonary disease (PCD median FEV1 90% predicted, CF FEV1 100%) were analyzed. LU abnormalities appear in 11/30 (36%) patients with PCD and 9/30 (30%) with CF. Sensitivity, specificity, positive predictive, and negative predictive values for abnormal LU compared to the gold standard of CXR are 42%, 61%, 42%, and 61% in PCD, and 44%, 81%, 50%, and 77% in CF, respectively. Correlation between LU and CXR scores are poor for both diseases (PCD r = -0.1288, p = 0.4977; CF r = 0.0343, p = 0.8571), and LU score does not correlate with clinical outcomes in PCD. CONCLUSION: The correlation of LU findings with CXR surveillance studies is poor in patients with mild disease burdens from PCD or CF, and LU scores do not correlate with clinical outcomes in PCD.

Assessment of patients' baseline cystic fibrosis knowledge levels following translation and adaptation of the CF R.I.S.E translation program into Turkish.

BACKGROUND: Cystic fibrosis (CF) patients have a limited life expectancy, but significant medical advances now highlight the need for successful transition programs from pediatric to adult care. The goal of this project was to introduce the transition program CF R.I.S.E (Responsibility. Independence. Self-care. Education.) to a CF center with limited resources at Marmara University (MU). METHODS: The program was adapted and translated into Turkish with the CF Foundation's permission. A team of experts collaborated to develop educational materials for patients and families. After translation and implementation of the CF S.O.B.E program, 11 Knowledge Assessment Questionnaire (KQA) tests were administered online to the patients aged between 16 and 25 years to assess the lack of patient knowledge. RESULTS: The CF R.I.S.E program was successfully implemented within 6 months. A pilot study showed positive feedback from randomly selected patients, indicating the program's effectiveness and understandability. The mean age of the patients was 19.4 ± 2.9 years, and 42 (52%) were female. The mean forced expiratory volume (FEV1pp) was 76.3 ± 23.2. Fourteen (17.3%) and 4 (4.9%) of the patients colonized with Pseudomonas aeruginosa and Methicillin-resistant Staphylococcus aureus (MRSA), respectively. Fifteen (18.5%) were on modulator therapy. Eleven Knowledge Assessment Questionnaires (KAQ) surveys were administered to 81 patients. The percentage of correct responses to the KAQs ranged from 47.9% to 68.3%. CONCLUSION: MU CF Center in Turkey implemented the CF S.O.B.E (Responsibility, Self-care, Independence, and Education in Turkish) program. The center aims to make the program a regular practice and expand collaboration with adult clinics. Future studies will assess its long-term impact and applicability in different health settings. The final goal is to disseminate the program's resources and promote structured transition practices across the country.

IL-6 and TIMP-1 Correlated to Airway Pathogen Colonization and Predict Disease Severity in Patients with Non-Cystic Fibrosis Bronchiectasis.

Background: Non-cystic fibrosis bronchiectasis is associated with airway pathogen colonization. We planned to investigate the inflammatory markers in patients with different airway pathogens and their correlation with disease severity. Methods: We enrolled patients aged between 20 and 75 from October 2021 to August 2022. All patients had sputum evaluation for bacterial and fungal cultures before enrollment, and were classified into four groups according to the culture results. Results: Forty-four patients with non-CF bronchiectasis and six controls were enrolled and categorized as follows: Group 1, no pathogens identified in sputum cultures (n = 14); Group 2, positive fungal culture results (n = 18); Group 3, positive P. aeruginosa culture results (n = 7); and Group 4, positive culture results for both fungi and P. aeruginosa (n = 5). Group 4 had significantly higher serum defensin α1, IL-6 and tissue inhibitors of MMP (TIMP)-1 levels than group 1 patients. The serum levels of IL-6 and TIMP-1 were positively correlated with the FACED score and negatively correlated with distance-saturation product. Conclusion: Significantly higher levels of serum IL-6 and TIMP-1 were found in the patients who had concomitant fungal and P. aeruginosa colonization, and were closely related to clinical severity and may have important roles in disease monitoring.

Evaluating the correspondence between the EQ-5D-5L and disease severity and quality of life in adults and adolescents with cystic fibrosis.

BACKGROUND: The EQ-5D is the recommended measure to capture health-related quality of life (HRQoL), recognised for use in health technology appraisal bodies. In order to assess whether it is appropriate to use the EQ-5D for making decisions about the cost-utility of treatments in cystic fibrosis (CF), this study assesses the performance of the EQ-5D-5L in adults and adolescents with CF. METHOD: This was a cross-sectional observational survey study of patients with CF attending a single large CF centre. Participants were asked to complete a survey that included two HRQoL measures; the EQ-5D-5L and CF Quality of Life (CFQoL) questionnaires. RESULTS: Among 213 participants, the median EQ-5D-5L index score was 0.76 (IQR 0.66 - 0.84) and the visual analogue (EQ-VAS) was 70 (60 - 80). Both the EQ-5D index and EQ-VAS discriminated between disease severity based on lung function (p = 0.01 and p < 0.01, respectively) and pulmonary exacerbation (p = 0.02 and p < 0.01, respectively); however, EQ-VAS differentiated between more lung function severity groups compared to EQ-5D index. The EQ-5D-5L demonstrated convergent validity as its dimensions, index score, and EQ-VAS had significant correlations with most CFQoL domains. Though, EQ-VAS significantly predicted more domains of CFQoL (4 domains) compared to EQ-5D index (only 1 domain). CONCLUSION: The generic EQ-5D-5L performed adequately in discriminating between CF disease severity, and its index score and EQ-VAS had moderate correlations with CFQoL. However, using a complementary condition-specific measure alongside the EQ-5D-5L can provide better insight of HRQoL in CF and benefit the process of cost-utility analysis.