Microbiol Spectr. 2025 Jul 30:e0227524. doi: 10.1128/spectrum.02275-24. Online ahead of print.

ABSTRACT

Fungal infection, especially allergic bronchopulmonary aspergillosis, is a leading cause of infection-associated morbidity and death in patients with cystic fibrosis. We have previously discovered that the new leading treatment in cystic fibrosis, CFTR modulators Elexacaftor/Tezacaftor/Ivacaftor (ETI, Trikafta), drastically reduces the colonization and infection by Aspergillus fumigatus. However, the reasons for this decrease in patients are not known so far. In this study, we have shown, using A. fumigatus reference strains and strains isolated from patients with cystic fibrosis, that CFTR modulators have no discernible impact on initial conidia growth in vitro. However, in a condition-dependent manner, we demonstrated a decrease in the minimal effective concentration (MEC) of caspofungin when administered with ETI on conidia. By contrast, during macrophage infection, we observed that high concentrations of ETI treatment promoted fungal growth but inhibited inflammasome activation.IMPORTANCEThe advent of ETI therapy represents a pivotal moment, signaling the onset of major changes in the medical field of cystic fibrosis and its related infectious diseases. However, the impact of ETI treatment on the patient's microbiota and pathogens has to be further studied as proof arises of changes in patient colonization.

PMID:40736245 | DOI:10.1128/spectrum.02275-24

Front Immunol. 2025 Jul 15;16:1592597. doi: 10.3389/fimmu.2025.1592597. eCollection 2025.

ABSTRACT

BACKGROUND: Pseudomonas aeruginosa (PA) causes severe respiratory infections utilizing multiple virulence functions. Previous findings on the PA secreted quorum sensing (QS)-regulated small molecule, 2'-aminoacetophenone (2-AA), revealed its impact on immune and metabolic functions, favouring a long-term presence of PA in the host. However, the 2-AA's specific effects on bronchial-airway epithelium and pulmonary endothelium remain elusive. To evaluate the spatiotemporal changes in 2AA within the human airway, considering endothelial cells as the primary point of contact when the route of lung infection is hematogenic, we utilized the airway-on-achip platform. This dynamic culture system recapitulates critical elements of the human airway microphysiological environment.

METHODS: We utilized the microfluidic airway-on-chip platform, lined by polarized primary human pulmonary microvascular endothelial cells (HPMEC) and adjacent primary normal human bronchial epithelial cells (NHBE) obtained from healthy female donors. Cells exposed to 2-AA (20 μm) through continuous flow for 12 hours were used for whole-genome RNA sequencing and analyzed for their responses and potential cross-talk. Transcriptome findings were validated through in vivo studies in mice and additional cell culture experiments.

RESULTS: Analyses revealed that 2-AA differentially regulates specific signaling and biosynthesis pathways in epithelial cells, including HIF-1 and pyrimidine signaling, glycosaminoglycan and glycosphingolipid biosynthesis. In endothelial cells, fatty acid metabolism, phosphatidylinositol, and estrogen receptor signaling, as well as proinflammatory signaling pathways, were identified. Significant overlap was found in both cell types in response to 2-AA in genes implicated in immune response and cellular functions. In contrast, we found that genes related to barrier permeability, cholesterol metabolism, and oxidative phosphorylation were differentially regulated in response to 2-AA exposure in the studied cell types. Murine in vivo and additional in vitro cell culture studies confirmed the accumulation of cholesterol in epithelial cells. Results also revealed that specific biomarkers associated with cystic fibrosis and idiopathic pulmonary fibrosis were modulated by 2-AA in both cell types, with the expression of cystic fibrosis transmembrane regulator being affected only in endothelial cells.

PMID:40735328 | PMC:PMC12305196 | DOI:10.3389/fimmu.2025.1592597

GE Port J Gastroenterol. 2025 Jun 10. doi: 10.1159/000546859. Online ahead of print.

ABSTRACT

INTRODUCTION: Giant condyloma acuminatum, known as Buschke-Löwenstein tumor, is a rare benign tumor. Several risk factors are described, including immunosuppression, diabetes, tobacco use, and multiple sexual partners. About 90% of cases are associated with human papillomavirus infection. Given the rarity of this lesion, there are still no established guidelines for the assessment and treatment of this tumor. The most reported and consensus approach described in the literature is surgical intervention.

CASE PRESENTATION: We report a case of a 32-year-old man who was immunosuppressed following a lung transplant due to cystic fibrosis. He also had stage IV chronic kidney disease and chronic pancreatitis. The patient was evaluated in a proctology consultation due to complaints of itching, perianal pain, and constipation with a 4-month history. Clinical examination showed a cauliflower-like, papillomatous tumor measuring 9 cm along the perianal area with other surrounding smaller lesions. The evaluation of immunodeficiency virus, hepatitis C virus, hepatitis B virus and syphilis was negative. The patient denied engaging in receptive anal sex and other risky sexual behaviors. A macro biopsy of the lesion was performed, and the histopathological examination revealed an anal condyloma acuminatum, with no signs of malignancy. Therapy with imiquimod was initiated for several weeks, with no significant reduction in lesion size. In a multidisciplinary discussion, it was decided to start neoadjuvant chemoradiotherapy with capecitabine and mitomycin. After 5 months of treatment, a significant reduction in lesion size was observed with significant clinical improvement. Currently, the patient has no proctological symptoms and no need for analgesia.

PMID:40734682 | PMC:PMC12303575 | DOI:10.1159/000546859

Viruses. 2025 Jun 30;17(7):938. doi: 10.3390/v17070938.

ABSTRACT

Pseudomonas aeruginosa is a major opportunistic pathogen with high levels of antibiotic resistance. Phage therapy represents a promising alternative for the treatment of difficult infections both alone and in combination with antibiotics. Here, we isolated and characterized three novel lytic myoviruses, Cisa, Nello, and Moonstruck. Genomic analysis revealed that Cisa and Nello belong to the Pbunavirus genus, while Moonstruck is a novel Pakpunavirus species. All lacked lysogeny, virulence, or resistance-associated genes, supporting their therapeutic suitability. Phage Nello and Moonstruck were active against P. aeruginosa Pa3GrPv, isolated from a patient with lung infection candidate for phage therapy. Moonstruck exhibited superior lytic activity with ciprofloxacin sub-MIC value (0.125 µg/mL), achieving bacterial suppression for 48 h. However, to improve the lytic efficacy of the phages on the clinical isolate, phage adaptation via serial passage was investigated. The killing efficacy of Nello was enhanced, whereas Moonstruck showed a less consistent improvement, suggesting phage-specific differences in evolutionary dynamics. Sequencing of the evolved phages revealed point mutations in tail-associated genes, potentially linked to a better phage-host interaction. These results support the use of phage-antibiotic combinations and directed evolution as strategies to enhance phage efficacy against drug-resistant infections. Overall, these findings support the therapeutic potential of the newly isolated phages in treating P. aeruginosa lung infections.

PMID:40733556 | DOI:10.3390/v17070938

Viruses. 2025 Jun 27;17(7):919. doi: 10.3390/v17070919.

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of the 2019 coronavirus disease pandemic. The virus primarily spreads through person-to-person contact via aerosols and droplets, contributing to high case numbers and related morbidities. SARS-CoV-2 targets the respiratory tract, causing acute respiratory distress syndrome, particularly in immunocompromised individuals such as those with cystic fibrosis (CF). CF is a life-threatening genetic disorder caused by mutations in the CF transmembrane conductance regulator (CFTR) gene, leading to impaired respiratory function and recurrent severe respiratory symptoms. Despite their potential vulnerability, CF patients have shown a lower incidence of severe COVID-19, suggesting protective factors against SARS-CoV-2. Differential expression of the ACE2 receptor, crucial for viral entry, and other host factors, such as TMPRSS2, may play a role in this resistance to SARS-CoV-2. Analyzing the genomics and transcriptomics profiles of CF patients could provide insights into potential resistance mechanisms. The potential resistance mechanisms include blood and extracellular ATP levels, a deleted/dysfunctional CFTR gene, ACE and ACE2 regulation and expression, ACE and ACE2 polymorphism effects, host proteins and SARS-CoV-2 interactions, and SMN1 and ACE/ACE2 interactions. This review discusses the underlying factors and potential resistance mechanisms contributing to CF patients' responses to SARS-CoV-2 infection. The review provides an opportunity to further investigate future therapy and research through understanding the underlying potential resistance mechanisms exhibited by CF patients against SARS-CoV-2, including ACE and ACE2 polymorphisms.

PMID:40733537 | DOI:10.3390/v17070919

Pharmaceuticals (Basel). 2025 Jul 10;18(7):1028. doi: 10.3390/ph18071028.

ABSTRACT

Background: "CFTR modulators" (also named "caftor") have been developed and introduced into clinical practice to improve the functionality of defective CFTR protein. Therapeutic drug monitoring (TDM) is not currently used for CFTR modulators in routine clinical practice and there is still much to learn about the pharmacokinetic/pharmacodynamic (PK/PD) and the safety profiles of these drugs in a real-world setting. Moreover, therapeutic ranges are not yet available for both pediatric and adult cystic fibrosis (CF) patients. Methods: A new and sensitive liquid chromatography tandem mass spectrometry (LC-MS/MS) method for contemporary quantification of ivacaftor (IVA), tezacaftor (TEZ) and elexacaftor (ELX) in plasma samples has been developed and validated. The clinical performance of our method has been tested on samples collected during the routine clinical practice from n = 25 pediatric patients (aged between 7 and 17 years) affected by cystic fibrosis. This LC-MS/MS method has been validated according to ICH (International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use) guidelines for the validation of bioanalytical methods. Results: Our method fulfilled ICH guidelines in terms of accuracy, precision, selectivity, specificity and carry-over. Intra- and inter-day accuracy and precision were ≤15%. The 9-day autosampler stability was 90-100% for TEZ and ELX; meanwhile, it fell to 76% for IVA. An injection volume of 1 µL and a wider quantification range (0.1-20 µg/mL) represent a novelty of our method in terms of sensitivity and fields of application. Finally, the evaluation of PK exposure parameters for IVA revealed strong agreement with previously published reports and with results from the summary of product characteristics (SmPCs). Conclusions: This method could be adopted to contemporarily measure ELX/TEZ/IVA plasma levels for both PK studies and monitor therapy compliance, especially in case of poor or partial responses to treatment, or to evaluate drug-drug interactions when multiple concomitant medications are required. Considering also the high cost burden of these medications to the health system, a TDM-based approach could facilitate more cost-effective patient management.

PMID:40732316 | DOI:10.3390/ph18071028

Microorganisms. 2025 Jun 30;13(7):1527. doi: 10.3390/microorganisms13071527.

ABSTRACT

Cystic fibrosis (CF) is a life-limiting autosomal recessive disorder affecting a large number of individuals in Europe. The disease arises from mutations in the CFTR gene encoding the cystic fibrosis transmembrane conductance regulator, a chloride ion channel crucial for maintaining epithelial ion and fluid homeostasis. Dysfunctional CFTR disrupts mucociliary clearance, particularly in the respiratory tract, resulting in persistent bacterial colonization, chronic inflammation, and progressive pulmonary damage-ultimately leading to respiratory failure, the principal cause of mortality in CF patients. Early diagnosis and advances in therapy have substantially improved both survival and quality of life. A hallmark of CF pathology is the establishment of polymicrobial infections within the thickened airway mucus. Pseudomonas aeruginosa is the dominant pathogen in chronic CF lung infections and demonstrates a remarkable capacity for adaptation via biofilm formation, metabolic reprogramming, and immune evasion. Biofilms confer increased tolerance to antimicrobial agents and facilitate long-term persistence in hypoxic, nutrient-limited microenvironments. P. aeruginosa exhibits a wide range of virulence factors, including exotoxins (e.g., ExoU, ExoS), pigments (pyoverdine, pyochelin), and motility structures (flagella and pili), which contribute to tissue invasion, immune modulation, and host damage. During chronic colonization, P. aeruginosa undergoes significant genotypic and phenotypic changes, such as mucoid conversion, downregulation of acute virulence pathways, and emergence of hypermutator phenotypes that facilitate rapid adaptation. Persistent cells, a specialized subpopulation characterized by metabolic dormancy and antibiotic tolerance, further complicate eradication efforts. The dynamic interplay between host environment and microbial evolution underlies the heterogeneity of CF lung infections and presents significant challenges for treatment. Elucidating the molecular mechanisms driving persistence, hypermutability, and biofilm resilience is critical for the development of effective therapeutic strategies targeting chronic P. aeruginosa infections in CF.

PMID:40732035 | DOI:10.3390/microorganisms13071527

Sci Rep. 2025 Jul 29;15(1):27582. doi: 10.1038/s41598-025-13172-3.

ABSTRACT

Pseudomonas aeruginosa is a primary driver of morbidity and mortality in cystic fibrosis (CF) patients. Throughout the course of infection, P. aeruginosa undergoes significant evolution and adaptation to the dynamic environment of the CF respiratory tract, leading to the emergence of diverse phenotypes. Among the variants that arise during this process are mutations in the regulatory gene lasR. While clinical significance of LasR deficiency is well recognized, current evidence does not fully elucidate the metabolic changes associated with the absence of this master regulator. To address this, we conducted untargeted metabolic profiling of cell supernatants (exometabolomes) to compare twenty-four P. aeruginosa strains, collected over 3-8 years from ten CF patients classified either as LasR functional (LasR+) or LasR non-functional (LasR-). We found a highly significant relationship between the LasR phenotype and the global exometabolic profile of the clinical strains. Furthermore, our analysis identified several metabolites whose production appears to be linked to LasR expression. These findings were validated using a loss of function/gain of function approach. This connection between lasR genetic expression, the chronic adaptation of P.aeruginosa to the CF lung environment and the generation of traceable metabolic markers highlights a potential avenue for diagnosing and monitoring respiratory infections caused by this pathogen.

PMID:40731143 | DOI:10.1038/s41598-025-13172-3

Pediatr Pulmonol. 2025 Jul;60(7):e71197. doi: 10.1002/ppul.71197.

ABSTRACT

BACKGROUND: Dupilumab improved clinical outcomes in children (aged 6-11 years) with moderate-to-severe asthma and type 2 inflammation (baseline blood eosinophil count ≥ 150 cells/μL or fractional exhaled nitric oxide [FeNO] ≥ 20 ppb) in the phase 3 VOYAGE study (NCT02948959). We evaluated dupilumab plus medium-dose ICS versus placebo plus continued high-dose ICS in children in VOYAGE.

METHODS: Children were randomized to dupilumab 100/200 mg by body weight or placebo every 2 weeks for 52 weeks. Annualized severe exacerbation rates, change from baseline in pre-bronchodilator percent predicted forced expiratory volume in 1 s (ppFEV1), morning peak expiratory flow (PEF), 7-item Asthma Control Questionnaire-Investigator Administered (ACQ-7-IA) score, FeNO, blood eosinophil count, and total IgE at Week 52 were assessed.

RESULTS: Data from 184 children were analyzed (dupilumab plus medium-dose ICS, n = 134; placebo plus high-dose ICS, n = 50). At Week 52, dupilumab plus medium-dose ICS versus placebo plus high-dose ICS significantly reduced exacerbations by 74.3%, and significantly improved ppFEV1, morning PEF, ACQ-7-IA score, FeNO, and total IgE. There was no significant difference in blood eosinophil counts between the two groups.

CONCLUSION: In children with moderate-to-severe asthma and type 2 inflammation, treatment with dupilumab plus medium-dose ICS reduced exacerbations and improved lung function and asthma control compared with placebo plus continued high-dose ICS.

PMID:40728026 | PMC:PMC12305753 | DOI:10.1002/ppul.71197

BMC Med Ethics. 2025 Jul 29;26(1):109. doi: 10.1186/s12910-025-01269-3.

ABSTRACT

Advancing organoid technology requires human tissue donations and collaboration between researchers and commercial parties. However, many potential donors have reservations about commercial involvement in organoid research. To better understand these reservations, we conducted four focus groups with potential donors. Two focus groups were held with individuals with cystic fibrosis (n = 10). One focus group included individuals with neurodegenerative diseases (Parkinson's or Huntington's disease) (n = 4) and the other consisted of individuals with neurological disease (epilepsy) (n = 5). Four themes were identified: (1) benefits and concerns regarding commercial involvement, (2) trust in involved parties in research, (3) control over commercial parties and (4) appreciation of donors. To address these themes, we recommend that researchers and commercial parties communicate transparently and effectively, actively engage and appreciate donors, implement robust oversight mechanisms and (re)establish trust and trustworthiness through responsible practices. These considerations can help researchers and commercial parties work toward responsible and sustainable organoid research.

PMID:40730998 | DOI:10.1186/s12910-025-01269-3

Sci Rep. 2025 Jul 29;15(1):27571. doi: 10.1038/s41598-025-12333-8.

ABSTRACT

The elexacaftor/tezacaftor/ivacaftor (ETI) combination for cystic fibrosis transmembrane regulator modulators is a safe and effective treatment in both adults and children who are homozygous or compound heterozygous for the F508del variant. However, few cases involving a significant reduction in blood platelets and an increase in the alanine aminotransferase/platelet ratio have been described in adult and pediatric patients receiving ETI therapy. In the present study, we describe 272 people with cystic fibrosis (pwCF) (166 adult and 106 pediatric pwCF) who were independently followed at two centers; moreover, these individuals were homozygous or compound heterozygous for the F508del variant, were treated with ETI for at least one year, and exhibited monitored platelet and leukocyte counts (together with liver and inflammatory biochemical indices). As controls, 272 healthy subjects (HCs) matched for sex and age were evaluated. At baseline, both adult and pediatric pwCF demonstrated significantly (p < 0.01) greater blood platelet and leukocyte counts compared with HCs. One year of treatment significantly reduced blood platelet counts (adults: 248*103/mmc vs. 288*103/mmc, p < 0.01; children: 283*103/mmc vs. 320*103/mmc, p < 0.01) and leukocyte counts (adults: 6.5*103/mmc vs. 7.6*103/mmc, p < 0.01; children: 6.8*103/mmc vs. 7.9*103/mmc, p < 0.01). In addition, the serum C-reactive protein (CRP) level was significantly (p < 0.01) decreased after therapy, whereas the alanine aminotransferase (ALT) level and the ALT/platelet ratio were significantly increased (p < 0.01). After the second year of therapy, the laboratory parameters were not further altered in approximately half of the patients. The reduction in platelets was significantly correlated with a decrease in leukocytes (rs: 0.352, p < 0.001), serum CRP levels (rs: 0.392, p < 0.001) and exacerbations (oral antibiotic cycles, rs: 0.241, p = 0.002; intravenous antibiotic cycles, rs: 0.153, p = 0.049). These findings suggest that the normalization of platelets may be dependent on the reduction in systemic inflammation induced by ETI therapy.

PMID:40730841 | DOI:10.1038/s41598-025-12333-8

Biosens Bioelectron. 2025 Jul 24;288:117805. doi: 10.1016/j.bios.2025.117805. Online ahead of print.

ABSTRACT

Monitoring chloride ions (Cl-) in sweat is critical for assessing hydration, diagnosing cystic fibrosis (CF), and evaluating other health conditions. Existing wearable sweat chloride sensors either exhibit low sensitivity based on potentiometric sensing or irreversible readings based on colorimetric sensing. To address these challenges, we report the design of a hydrogel-based wearable sweat sensor that allows for monitoring of Cl- based on an electrolyte concentration gradient. This reported sensor features a coplanar design with a cation-selective hydrogel (CH), a high-salinity hydrogel (HH), and a sweat chamber. The gradient between the HH and the sweat chamber drives ion diffusion through the CH, generating an open-circuit voltage (VOC) that corresponds to the Cl- concentration in the sweat chamber. A stable device performance is achieved by further integrating a superhydrophilic poly(vinylidene fluoride-co-hexafluoropropylene) (PVDF-HFP) thin film that prevents ion exchange and hydrogel swelling. The resulting sensor exhibits an ultrahigh sensitivity of 1.7 mV/mM and a fast response time of 7.1 s, with excellent linearity and reversibility in the range from 10 to 100 mM. Integrating the sensor with a microfluidic module along with temperature calibration provides continuous and calibrated, accurate measurements during physical activities. The design concepts for real-time sweat Cl- detection can also be applied to monitor the other biomarkers for personalized diagnostics and health monitoring.

PMID:40730067 | DOI:10.1016/j.bios.2025.117805

Microbiol Spectr. 2025 Jul 29:e0045625. doi: 10.1128/spectrum.00456-25. Online ahead of print.

ABSTRACT

Pseudomonas aeruginosa is an opportunistic pathogen responsible for 10% of nosocomial urinary tract infections (UTIs). Its large genome and adaptability enable it to cause a wide variety of infections, from respiratory disorders in cystic fibrosis patients to recurrent UTIs. While genomic and phenotypic adaptations of P. aeruginosa have been well-studied in respiratory infections, few studies have investigated pathoadaptation in recurrent UTIs. Here, we investigated the impact of genomic alterations of sequential urinary isolates collected from three patients on phenotypic responses to environmental stresses, virulence, and motility. In addition, to gain insight on adaptive mechanisms of P. aeruginosa in urine, proteomic analyses were conducted using pooled human urine compared to a standard Trypticase Soy (TS) medium. Late isolates showed significantly impaired growth and reduced responses to acid and osmotic stresses compared to early isolates, although responses to oxidative stress remained unchanged. Furthermore, the late isolates were significantly less virulent in the Galleria mellonella infection model. Finally, proteomic analyses revealed the accumulation of proteins associated with flagellum and chemotaxis only in early isolates of two out of three patients, regardless of the culture medium. Motility assays confirmed these results, with late isolates being less motile than early ones. Moreover, siderophore-related proteins were significantly less abundant in late isolates when cultured in human urine, a result not observed in TS medium, suggesting a convergent adaptation trajectory in urine. Our results provide an initial insight into the adaptive mechanisms of P. aeruginosa in the urinary tract.IMPORTANCEP. aeruginosa is the third most common pathogen causing healthcare-associated UTIs. Its ability to form biofilms and develop antibiotic resistance often leads to relapses. Here, we investigated the phenotypic characteristics of longitudinal urinary isolates under specific stress conditions and used an in vivo model to evaluate the virulence of these isolates. Integrating proteomic analysis into this approach allowed us to identify the metabolic and regulatory pathways involved in bacterial adaptation and to establish innovative correlations between genomic, phenotypic, and proteomic data. Altogether, these data enabled us to map the adaptation mechanisms of P. aeruginosa in the urinary environment. These findings provide putative new therapeutic targets and contribute to our understanding of recurrent UTIs caused by this pathogen.

PMID:40728320 | DOI:10.1128/spectrum.00456-25

ERJ Open Res. 2025 Jul 26;11(4):00799-2024. doi: 10.1183/23120541.00799-2024. eCollection 2025 Jul.

ABSTRACT

BACKGROUND: Cystic fibrosis is characterised by defective mucociliary clearance, chronic lung infection and exaggerated neutrophilic inflammation. Airway epithelium damage and remodelling affect lung defence functions and are therefore important components of lung pathology progression in cystic fibrosis. Identifying compounds that favour mucociliary clearance by improving airway epithelial structure and regeneration is therefore crucial for patients with cystic fibrosis.

MATERIALS AND METHODS: Using air-liquid interface culture of human airway epithelial cells obtained from patients with cystic fibrosis, we examined the influence of low-molecular-weight hyaluronic acid (LMW-HA) (∼40 kDa) on the regeneration and remodelling of cystic fibrosis human airway epithelial cells.

RESULTS: Our results show that LMW-HA normalises cystic fibrosis epithelial regeneration, even in an inflamed environment, by preventing remodelling in terms of epithelial height and basal cell hyperplasia, by avoiding inflammation-related goblet cell hyperplasia and by stimulating multiciliated cell differentiation. Because remodelling is mainly due to either intrinsic inflammation of cystic fibrosis human airway epithelial cells or an extrinsic inflammatory environment, we examined the impact of LMW‑HA on epithelial interleukin 8 pro-inflammatory chemokine and found that it exerts an anti-inflammatory effect, evidenced by reduced epithelial interleukin 8 expression and secretion.

CONCLUSION: We report here that LMW-HA prevents cystic fibrosis human airway epithelial cell remodelling and normalises its cell structure, probably through the epithelial cell inflammatory phenotype modulation, and improves multiciliated cell differentiation by a mechanism that is independent of its anti-inflammatory effect. These results demonstrate that LMW-HA should be considered as a therapeutic candidate for the treatment of cystic fibrosis lung disease.

PMID:40726511 | PMC:PMC12301892 | DOI:10.1183/23120541.00799-2024

J Clin Med. 2025 Jul 9;14(14):4856. doi: 10.3390/jcm14144856.

ABSTRACT

Background: An increase in hemoglobin (Hb) has been reported in subjects with CF treated with the CFTR modulator Ivacaftor and with the combination Lumacaftor/Ivacaftor (LI), while the literature about the impact of Elexacaftor/Tezacaftor/Ivacaftor (ETI) on Hb levels in the pediatric population is lacking. Materials and Methods: We retrospectively evaluated Hb levels in 35 subjects with CF (18 males, median age: 8 years; interquartile range (IQR): 6-13 years) treated with LI and 60 (24 males, median age: 10 years; IQR: 6-14 years) treated with ETI. For each subject we considered the values of Hb, serum potassium, total bilirubin (TB), and conjugated bilirubin (CB) at baseline, after 3 days, and 1, 3, 6, 9, and 12 months from the start of treatment. Results: In subjects with CF treated with LI, we observed a significant increase in Hb values 3 days after the introduction of the drug, which remained constant throughout the year of treatment. In subjects treated with ETI, a significant decrease in Hb was observed 3 days after the first dose up to 1 month. At 6 months, Hb returned to pre-treatment values remaining stable for up to 12 months. At 3 days of treatment, we also observed a significant increase in serum potassium, which returned to normal at one month, while both TB and CB values significantly increased at 3 days of treatment and remained significantly higher for the whole one-year period of ETI therapy. Conclusions: We confirmed an increase in Hb values over time in subjects treated with LI. While the Hb response in those treated with ETI showed a transient reduction that lasted for one month, this may have depended on hemolysis, and returned to pre-treatment levels. Further studies will clarify the mechanisms that govern changes in Hb in subjects with CF treated with ETI.

PMID:40725549 | DOI:10.3390/jcm14144856

Int J Mol Sci. 2025 Jul 16;26(14):6804. doi: 10.3390/ijms26146804.

ABSTRACT

Exophiala dermatitidis is an emerging black yeast recognized in both superficial and life-threatening infections, including those in immunocompetent hosts. This narrative review focuses on recent developments (mostly between 2019 and 2025) in two major areas. First, we examined the clinical and epidemiological background of E. dermatitidis, with particular focus on its involvement in cystic fibrosis and CARD9 deficiency, as well as central nervous system, ocular, and systemic infections. Second, we address the molecular basis of its pathogenicity, with particular attention to melanin production, capsule formation, and metabolic adaptation. We also discuss diagnostic challenges and antifungal susceptibility, highlighting gaps between laboratory studies and clinical outcomes.

PMID:40725051 | DOI:10.3390/ijms26146804

Int J Mol Sci. 2025 Jul 13;26(14):6708. doi: 10.3390/ijms26146708.

ABSTRACT

Cystic fibrosis (CF) is the most common life-limiting autosomal recessive disorder among Caucasian populations, with an incidence of 1 in 2500-3500 live births across Europe [...].

PMID:40724963 | DOI:10.3390/ijms26146708

Int J Mol Sci. 2025 Jul 10;26(14):6625. doi: 10.3390/ijms26146625.

ABSTRACT

Mutations in the CFTR gene, which cause the autosomal recessive disease cystic fibrosis, can also affect male fertility. The aim of this study was to investigate the spectrum and carrier frequency of common pathogenic CFTR variants among men from the general population, analyze ethnic differences, and assess associations with male fertility indicators. Male volunteers (n = 1895) from six cities in Russia and Belarus were analyzed for the carrier frequencies of 17 pathogenic CFTR variants and two polymorphisms, as well as semen quality and reproductive hormone levels. Heterozygous carriers of six pathogenic CFTR mutations, F508del, G542X, N1303K, 3849+10kbC>T, CFTRdele2,3, and R117C, and two polymorphisms, IVS9-5T and 5T-(12-13) TG, were identified, with cumulative frequencies of 2.06% and 6.65%, respectively. Significant ethnic differences were revealed in the spectrum and carrier frequencies of pathogenic CFTR variants among Slavs, Buryats, and Yakuts. Slavs exhibited a high proportion of heterozygous carriers of CFTR mutations (2.70%), whereas none were detected among Buryats and Yakuts. The highest carrier frequency for the CFTR polymorphism was observed among Slavs (8.35%), followed by Buryats (5.83%) and Yakuts (1.36%). No association was found between the carriers of identified CFTR variants and male fertility indicators. Thus, the spectrum and carrier frequency of genetic CFTR variants are determined by the ethnic composition of the population, providing a basis for ethnicity-specific screening of pathogenic CFTR variants.

PMID:40724872 | DOI:10.3390/ijms26146625

Int J Mol Sci. 2025 Jul 10;26(14):6614. doi: 10.3390/ijms26146614.

ABSTRACT

Cystic fibrosis (CF) is the most common severe autosomal recessive disease among Caucasians. Modulators of cystic fibrosis transmembrane conductance regulator (CFTR) mutated protein significantly improved the outcome of subjects with CF. In the present study, we studied epigenetic age, applying the Horvath clock model, in 52 adult subjects with CF, all treated with elexacaftor/tezacaftor/ivacaftor (ETI). At baseline (T0), we found that half of the subjects have a significantly accelerated epigenetic age and a worse lung function, evaluated by forced expiratory volume in one second (FEV1). One year of ETI therapy (T1) impacted both the parameters, indicating that therapy with modulators must be started early, particularly in CF subjects with impaired lung function. The second group of CF subjects had an epigenetic age lower than the chronological one at T0 and lung function was better maintained. In these subjects, ETI therapy further improved lung function and tended to increase the epigenetic age, possibly improving metabolic functions and the general state of well-being. This also translates into an increase in the physical activities of a group of subjects who, before the therapy, had grown up under a glass bell. The analysis of epigenetic age may represent a potential biomarker to assess the individual outcome of the therapy in subjects with CF, although long-term studies need to evaluate it.

PMID:40724864 | DOI:10.3390/ijms26146614

Children (Basel). 2025 Jul 3;12(7):878. doi: 10.3390/children12070878.

ABSTRACT

Objective: The objective of this study was to analyze respiratory muscle function in children and adolescents with cystic fibrosis (CF) treated with Elexacaftor/Tezacaftor/Ivacaftor (ETI) compared to healthy individuals, based on the hypothesis that CFTR modulators may improve respiratory muscle strength. Methods: A descriptive, observational, cross-sectional study was conducted with patients with CF treated with ETI aged 6-18 years. Lung function, maximal expiratory and inspiratory pressures (MIP and MEP), diet quality (KIDMED), and physical activity levels (PAQ) were assessed. The student's t-test or the Mann-Whitney U-test was used to compare differences between groups. The effect size was calculated with Cohen's d. Significance level was set as a p-value < 0.05. Results: A total of 48 children and adolescents (60.4% male) were analyzed in this study (24 healthy and 24 with CF). The participants with CF had mild pulmonary involvement. No significant differences were found in respiratory muscle strength between groups (MEPmaxp = 0.440, MIPmaxp = 0.206). Patients with CF showed lower KIDMED (p = 0.022) and PAQ (p = 0.010) scores. However, the MIP and MEP values observed in CF participants were higher than those reported in previous studies conducted before the introduction of ETI modulators. Conclusions: Children and adolescents with CF treated with ETI showed respiratory muscle strength comparable to that of healthy controls. Despite differences in lifestyle factors, these findings may reflect a positive impact of CFTR modulators on respiratory muscle function, although further longitudinal and controlled studies are needed.

PMID:40723074 | DOI:10.3390/children12070878