Am J Respir Cell Mol Biol. 2025 Apr 16. doi: 10.1165/rcmb.2024-0225OC. Online ahead of print.

ABSTRACT

The respiratory tract possesses a highly regulated innate defence system which includes cilia-mediated mucociliary clearance (MCC). Efficient MCC relies on appropriate hydration of airway surfaces, which is controlled by a blend of transepithelial sodium and liquid absorption, and anion and liquid secretion The latter is primarily mediated by the cystic fibrosis transmembrane conductance regulator (CFTR) anion channel. Succinate is derived from parasites, microorganisms and inflammatory cells, and its concentration increases in the airway surface liquid (ASL) during infections, activating the G-protein coupled succinate receptor (SUCNR1), which acts as a succinate sensor. Since MCC is tightly regulated by second messengers we tested the hypothesis that succinate signalling was linked to CFTR activity. We observed that SUCNR1 activation stimulated anion secretion, increased mucus transport, and induced tracheal constriction in mouse airways. In the CftrΔF508/ΔF508 mouse, increased mucus transport and tracheal constriction were observed, while succinate-induced electrogenic anion secretion remained unaffected. Stimulation of normal human bronchial epithelial cells (HBECs) with succinate activated CFTR-dependent anion secretion and increased ASL height. Moreover, when HBECs derived from ΔF508-CF individuals lacked succinate-induced anion secretion, unless incubated with elexacaftor-tezacaftor-ivacaftor (ETI), which restored succinate-induced anion secretion, confirming the tight relationship between SUCNR1 signalling and CFTR function. We have identified a novel mechanism for regulating CFTR/MCC activation which is defective in CF airways. We propose that succinate acts as a danger molecule that alerts the airways to the presence of pathogens leading to a flushing out of the airways.

PMID:40239014 | DOI:10.1165/rcmb.2024-0225OC

Pediatr Allergy Immunol. 2025 Apr;36(4):e70090. doi: 10.1111/pai.70090.

ABSTRACT

BACKGROUND: Allergic bronchopulmonary aspergillosis (ABPA) is a hypersensitivity response to the allergens of Aspergillus fumigatus, which is the most frequently isolated fungus from the sputum of cystic fibrosis (CF) patients. Because a low number of Th17 lymphocytes is associated with the risk of fungal infections, we investigated inflammatory markers, Th17 cells, and T-cell polarization in CF patients with ABPA.

METHODS: We analyzed the levels of inflammatory markers, blood counts, chemokines, cytokines, and T cell subsets in blood and sputum of CF subjects to elucidate the immunological factors associated with CF patients with Aspergillus fumigatus (AF) positive sputum (AFS+) or with ABPA.

RESULTS: We observed that AFS+ patients have higher sputum and blood IL-6 levels than AF-negative sputum (AFS-) patients. Analysis of blood memory T-helper subsets associated with Th1, Th2, and Th17 polarization among circulating CD45RA-/CD4+ memory T-cell subsets showed higher numbers of CCR4+/CCR6+/CXCR3- and CCR4+/CCR6+/CXCR3+ memory CD4 cells in AFS+ compared to AFS- subjects. Further analysis of Th17-related subsets and IL-17 secreting T cells in subjects with AFS+ showed that those with ABPA have statistically significantly lower levels of Th17 cells as compared to those without ABPA.

CONCLUSION: In CF, AF airway colonization is associated with increased blood counts of Th17-related subsets. However, CF patients with ABPA exhibit lower numbers of CCR4+/CCR6+/CXCR3+ memory CD4 cells and IL-17-secreting CD4 cells compared to control subjects and CF patients without AF sensitization.

PMID:40238087 | DOI:10.1111/pai.70090

Virulence. 2025 Apr 16:2493221. doi: 10.1080/21505594.2025.2493221. Online ahead of print.

ABSTRACT

The incidence of infection by nontuberculous mycobacteria, mainly Mycobacterium abscessus, is increasing in patients with cystic fibrosis and other chronic pulmonary diseases, leading to an accelerated lung function decline. In most cases, M. abscessus coinfects Pseudomonas aeruginosa, the most common pathogen in these conditions. However, how these two bacterial species interact during infection remains poorly understood. This study explored their behaviour in three relevant pathogenic settings: dual-species biofilm development using a recently developed method to monitor individual species in dual-species biofilms, coinfection in bronchial epithelial cells, and in vivo coinfection in the Galleria mellonella model. The results demonstrated that both species form stable mixed biofilms and reciprocally inhibit single-biofilm progression. Coinfections in bronchial epithelial cells significantly decreased cell viability, whereas in G. mellonella, coinfections induced lower survival rates than individual infections. Analysis of the immune response triggered by each bacterium in bronchial epithelial cell assays and G. mellonella larvae revealed that P. aeruginosa induces the overexpression of proinflammatory and melanization cascade responses, respectively. In contrast, M. abscessus and P. aeruginosa coinfection significantly inhibited the immune response in both models, resulting in worse consequences for the host than those generated by a single P. aeruginosa infection. Overall, this study highlights the novel role of M. abscessus in suppressing immune responses during coinfection with P. aeruginosa, emphasizing the clinical implications for the management of cystic fibrosis and other pulmonary diseases. Understanding these interactions could inform the development of new therapeutic strategies to mitigate the severity of coinfections in vulnerable patients.

PMID:40237819 | DOI:10.1080/21505594.2025.2493221

bioRxiv [Preprint]. 2025 Mar 31:2025.03.31.646406. doi: 10.1101/2025.03.31.646406.

ABSTRACT

Pseudomonas aeruginosa causes acute and chronic infections such as those that occur in the lungs of people with cystic fibrosis (CF). In infection environments, oxygen (O 2 ) concentrations are often low. The transcription factor Anr responds to low O 2 by upregulating genes necessary for P. aeruginosa fitness in microoxic and anoxic conditions. Anr regulates dnr , a gene encoding a transcriptional regulator that promotes the expression of genes required for using nitrate as an alternative electron acceptor during denitrification. In CF sputum, transcripts involved in denitrification are highly expressed. While Dnr is necessary for the anoxic growth of P. aeruginosa in CF sputum and artificial sputum media (ASMi), the contribution of denitrification to P. aeruginosa fitness in oxic conditions has not been well described. Here we show that P. aeruginosa requires dnr for fitness in ASMi and the requirement for dnr is abolished when nitrate is excluded from the media. Additionally, we show that P. aeruginosa consumes nitrate in lysogeny broth (LB) under microoxic conditions. Furthermore, strains without a functioning quorum sensing regulator LasR, which leads to elevated Anr activity, consume nitrate in LB even in normoxia. There was no growth advantage for P. aeruginosa when nitrate was present at concentrations from 100 µM to 1600 µM. However, P. aeruginosa consumption of nitrate in oxic conditions created a requirement for Dnr and Dnr-regulated NorCB likely due to the need to detoxify nitric oxide. These studies suggest that Anr- and Dnr-regulated processes may impact P. aeruginosa physiology in many common culture conditions.

IMPORTANCE: Pseudomonas aeruginosa is an opportunistic pathogen commonly isolated from low-oxygen environments such as the lungs of people with cystic fibrosis. While the importance of P. aeruginosa energy generation by denitrification is clear in anoxic environments, the effects of denitrification in oxic cultures is not clear. Here, we show that nitrate is consumed even in oxic environments and while it does not appear to stimulate growth, it does impact fitness. Further, we report that two regulators that are best known for their roles in anoxic conditions also contribute to P. aeruginosa fitness in commonly- used laboratory media in presence of oxygen.

PMID:40236165 | PMC:PMC11996506 | DOI:10.1101/2025.03.31.646406

bioRxiv [Preprint]. 2025 Apr 2:2025.04.01.646652. doi: 10.1101/2025.04.01.646652.

ABSTRACT

Many bacteria carry phage genome(s) in their chromosome (i.e., prophage), and this intertwines the fitness of the bacterium and the phage. Most Pseudomonas aeruginosa strains carry filamentous phages called Pf that establish chronic infections and do not require host lysis to spread. However, spontaneous mutations in the Pf repressor gene ( pf5r ) can allow extreme phage production that slows bacterial growth and increases cell death, violating an apparent détente between bacterium and phage. We observed this paradoxical outcome in an evolution experiment with P. aeruginosa in media simulating nutrients from the cystic fibrosis airway. Bacteria containing pf5r mutant phage grow to a lower density but directly outcompete their ancestor and convert them into pf5r mutants via phage superinfection. Reduced fitness therefore spreads throughout the bacterial population, driven by weaponized Pf. Yet high intracellular phage replication facilitates another evolutionary conflict: "cheater miniphages" lacking capsid genes invade populations of full-length phages within cells. Although bacteria containing both full-length phages and miniphages are most immune to superinfection by limiting the Pf receptor, this hybrid vigor is extremely unstable, as a classic Tragedy of the Commons scenario ensues that results in complete prophage loss. The entire cycle - from phage hyperactivation to miniphage invasion to prophage loss - can occur within 24h, showcasing rapid coevolution between bacteria and their filamentous phages. This study demonstrates that P. aeruginosa , and potentially many other bacterial species that carry filamentous prophages, risk being exploited by these phages in a runaway process that reduces fitness of both host and virus.

PMID:40236058 | PMC:PMC11996451 | DOI:10.1101/2025.04.01.646652

bioRxiv [Preprint]. 2025 Mar 31:2025.03.30.646208. doi: 10.1101/2025.03.30.646208.

ABSTRACT

The World Health Organization and the U.S. Centers for Disease Control and Prevention have reported that antibiotic resistant infections with Pseudomonas aeruginosa present a significant health risk world-wide. In the genetic disease Cystic Fibrosis (CF), chronic antibiotic resistant Pseudomonas lung infections and persistent inflammation remain the leading causes of morbidity and mortality. While highly effective modulator therapy (HEMT) dramatically improves lung function in CF, they fail to eradicate chronic infections or eliminate the associated hyperinflammatory state. Thus, there is an urgent need for innovative therapies that can simultaneously eliminate antibiotic resistant P. aeruginosa lung infection and the attendant hyperinflammatory lung environment. Mesenchymal stromal cell-derived extracellular vesicles (MSC EVs) represent a promising solution, offering potent anti-inflammatory, immunomodulatory, and antimicrobial properties while being safe and non-toxic. This study demonstrates using a CF mouse model of infection that MSC EVs reduce acute P. aeruginosa lung infection and inflammation. MSC EVs reduced Pseudomonas burden, immune cell infiltration, and pro-inflammatory cytokine levels. As the first investigation of MSC EVs in CF, this research underscores the dual effects of MSC EVs; mitigating inflammation and reducing bacterial burden. These findings mark an important advancement in antimicrobial therapy, addressing the unmet need for reducing antibiotic resistant infections and hyperinflammation for people with CF as well as the multitude of others with chronic, antibiotic resistant P. aeruginosa lung infections.

NEW AND NOTEWORTHY: This is the first study demonstrating the ability of Mesenchymal Stromal Cell Extracellular Vesicles (MSC EVs) to reduce Pseudomonas aeruginosa burden and inflammation in a CF mouse model of infection.

PMID:40236005 | PMC:PMC11996391 | DOI:10.1101/2025.03.30.646208

J Clin Transl Endocrinol. 2025 Mar 27;40:100388. doi: 10.1016/j.jcte.2025.100388. eCollection 2025 Jun.

ABSTRACT

BACKGROUND: Modern cystic fibrosis (CF) treatments, particularly CFTR modulators, have allowed males with CF (MwCF) to live longer, healthier lives and pursue parenthood. Approximately 98% of MwCF have congenital bilateral absence of the vas deferens (CBAVD). While research shows MwCF experience spermatogenic dysfunction alongside obstructive azoospermia, understanding male reproductive health in MwCF remains limited. This study retrospectively examines testicular function and intracytoplasmic sperm injection outcomes of the partners of males with CBAVD, stratified by CF mutation status (CF, CF carriers, no known mutation).

SUBJECTS AND METHODS: This multicenter, retrospective study assessed sperm retrieval outcomes and testicular function in males with CBAVD. Participants were categorized into three groups: MwCF (Group 1), CFTR gene mutation carriers (CFTR carriers, Group 2), and CBAVD males without CFTR mutations (Group 3). We collected data on genetic testing, testicular hormone levels (FSH, LH, total testosterone), sperm retrieval methods, and reproductive outcomes. Statistical analysis was used to assess intergroup differences.

RESULTS: Thirty subjects were included (Group 1: 14, Group 2: 11, Group 3: 5). No significant differences in demographic, anthropometric, or reproductive characteristics were found across groups. Hormone levels (LH, FSH, and testosterone) were similar among groups. In Group 1, 42 % had elevated FSH levels. The prevalence of hypogonadism was 16.7 % in Group 1. Group 3 had a significantly lower fertilization rate (p < 0.01), but no differences were found in blastocyst formation, pregnancy, miscarriage, or live birth rates.

CONCLUSIONS: Our data support the presence of primary spermatogenic dysfunction in some MwCF. However, reproductive outcomes were similar across all groups.

PMID:40235519 | PMC:PMC11997341 | DOI:10.1016/j.jcte.2025.100388

NMR Biomed. 2025 Jun;38(6):e70033. doi: 10.1002/nbm.70033.

ABSTRACT

MRI can provide localized assessment of lung function for monitoring people with lung disease. Hyperpolarized 129Xe MRI directly images pulmonary gas distribution but requires specialized hardware. Conventional 1H MRI acquisitions can also provide functional maps using free-breathing approaches. The purpose of this study is to evaluate regional ventilation derived from 3D ultrashort echo-time (UTE) 1H MRI using Motion-Compensated Low-Rank constrained reconstruction (MoCoLoR), by comparing against 129Xe MRI and pulmonary function testing as reference-standard. The study is retrospective in design. The study included 57 participants (25.4 ± 15.8 years, 35 males and 22 females): 12 healthy volunteers, 20 pediatric, and 25 adult people with cystic fibrosis (CF) scanned between January 2022 and February 2023. Field strength/sequence: 3T; 129Xe: 2D multislice spoiled gradient-recalled sequence; UTE 1H: variable-density 3D radial sequence. K-means-based 129Xe ventilation defect percent (VDP), forced expiratory volume in 1 s (FEV1), and lung clearance index (LCI) were evaluated against UTE 1H VDP from a modified k-means method. The correspondence of ventilation defect maps from 129Xe and UTE 1H was also evaluated. Statistical tests included the Pearson correlation coefficient (r) and t tests, with p < 0.05 considered significant. 129Xe and UTE 1H VDP were significantly correlated (r = 0.64, p = 9.1 × 10 - 8 $$ 9.1\times {10}^{-8} $$ ). Bland-Altman analysis showed a bias of -0.05 (p = 7.2 × 10 - 5 $$ 7.2\times {10}^{-5} $$ ) and limits of agreement of (0.07, -0.17). The Dice spatial accuracy of the UTE-based ventilation defect regions using 129Xe as reference was 0.64 ± 0.05. UTE 1H VDP was significantly correlated with FEV1 (r = -0.54, p = 2.9 × 10 - 4 $$ 2.9\times {10}^{-4} $$ ) and LCI (r = 0.48, p = 5.9 × 10 - 3 $$ 5.9\times {10}^{-3} $$ ) and was significantly different between healthy and CF participants (p = 0.017), although the correlations and differences were stronger for 129Xe VDP. UTE 1H VDP correlated with 129Xe VDP, FEV1, and LCI, and demonstrated high, consistent Dice spatial accuracy against 129Xe VDP. UTE 1H VDP captured variations in lung ventilation and has the advantage that it can be widely implemented on any MR system for evaluation and monitoring of patients with lung disease.

PMID:40235063 | DOI:10.1002/nbm.70033

BMJ Open Qual. 2025 Apr 15;14(2):e002847. doi: 10.1136/bmjoq-2024-002847.

ABSTRACT

Aminoglycoside antibiotics cause ototoxicity for which baseline audiometric testing is recommended but often not done. Barriers to successful implementation include limited availability of sound-booths and audiologists. An ototoxicity monitoring programme (OMP) was implemented using tablet-based audiometry (TBA) by non-audiologists.A quality improvement project conducted over 1 year (19 April 2021 to 18 April 2022), using Plan Do Study Act (PDSA) cycles, monitored the adherence to the OMP using Shoebox Standard Edition application on iPads. Barriers to adoption were identified to determine potential solutions for improved adherence. Adult respiratory patients (cystic fibrosis (CF), bronchiectasis, non-tuberculosis mycobacteria (NTM) infection) aged 17-82 years receiving >1 day of intravenous aminoglycosides (IVAGs) at a single tertiary-referral hospital were included. Other reported outcomes were patient characteristics, risk factors associated with abnormal hearing and ototoxic shift.73 patients were tested in the OMP (46 received ≥2 hearing tests) giving an overall adherence rate of 69% after 12 months. Patient identification using referral and reporting systems initially improved adherence from 36% to 88% (p=0.03) during PDSA 1. Barriers to successful adherence were staff availability and COVID-19 infection outbreaks (p=0.057). Older age (p<0.001), higher Body Mass Index (p=0.041), non-CF bronchiectasis (p=0.01), non-CF NTM (p=0.028) and higher Hearing Handicap Inventory for Adults scores (p=0.002) were significantly associated with abnormal baseline hearing. 78% with hearing loss were asymptomatic. Ototoxic shift was associated with gentamicin use compared to amikacin/tobramycin (p=0.027). TBA was associated with high usability in patients ≤50 years old.TBA by non-audiologists was feasible and demonstrated good patient usability, permitting screening of patients within 72 hours of starting IVAG and earlier referrals for formal audiometry. Hearing loss and ototoxicity were detected at earlier stages, enabling more rapid decision-making and treatment modification.

PMID:40233985 | DOI:10.1136/bmjoq-2024-002847

Curr Opin Allergy Clin Immunol. 2025 Apr 11. doi: 10.1097/ACI.0000000000001077. Online ahead of print.

ABSTRACT

PURPOSE OF REVIEW: Allergen immunotherapy (AIT) is increasingly popular as a treatment strategy for food allergy. Unfortunately, there is significant heterogeneity in reported outcomes, specifically in the dose-thresholds selected for evaluation and the symptoms used to define a "tolerated dose". These considerations are often investigator-driven and do not consider patient perspectives.

RECENT FINDINGS: A systematic review by the EAACI CO-FAITH taskforce recently flagged the need to better standardize and harmonize outcomes used in clinical trials of food-AIT. Using less objective symptoms to define dose-limiting symptoms can underestimate the reaction threshold determined at baseline food challenge. As a consequence, this can overestimate the efficacy of food-AIT by 15%. In this review, we perform an individual patient data (IPD) meta-analysis using data from three randomized-controlled trials and one real-world registry, to evaluate how the definition of dose "tolerance" impacts upon reported desensitization rates.

SUMMARY: This analysis provides insight into how clinical efficacy rates for food-AIT are impacted by using different dose thresholds and definitions for when a dose might be consider tolerated. Using more patient-centric outcomes may be a more useful metric to harmonize reporting of outcomes and inform clinical practice, paving the way towards reaching a consensus on outcome reporting in trials of food-AIT.

PMID:40233247 | DOI:10.1097/ACI.0000000000001077

Mycoses. 2025 Apr;68(4):e70058. doi: 10.1111/myc.70058.

ABSTRACT

BACKGROUND: Pulmonary aspergillosis is a major global health concern, yet its diagnosis remains challenging. Aspergillus-specific IgG measurement is essential for identifying chronic and allergic forms.

OBJECTIVE: This study aimed to evaluate a quantitative method, the ImmunoCAP assay IgG m3 (ICAP) (Phadia-ThermoFisher Scientific, Waltham, USA), a qualitative method, the Aspergillus IgG Western blot kit (Asp-WB) (LDBio Diagnostics, Lyon, France) and a combination of both methods for the diagnosis of Aspergillus lung disease.

METHODS: A retrospective study was conducted at the University Hospital of Marseille, France, during 1 year. Patients undergoing Aspergillus serology were divided into three groups: Group 1 (G1) with ICAP ≥ 40 mgA/L and positive Asp-WB, Group 2 (G2) with ICAP ≥ 40 mgA/L and negative Asp-WB and Group 3 (G3) with ICAP < 40 mgA/L and positive Asp-WB. Data were collected on demographics, underlying diseases, imaging and biological outcomes. Patients were classified according to their Aspergillus lung disease, whether acute pulmonary aspergillosis, chronic pulmonary aspergillosis (CPA), allergic broncho-pulmonary aspergillosis (ABPA), colonisation or Aspergillus sensitisation.

RESULTS: A total of 536 patients were studied: 173 in G1, 204 in G2 and 200 in G3, with 38 patients found in several groups. The primary underlying disease was cystic fibrosis in 44.6% of patients. Twenty-two patients were diagnosed with ABPA. The number of diagnosed ABPA cases in G1 (20; 11.6%) combining positive ICAP and Asp-WB was significantly higher than that found in the groups with a single positive test result (p < 0.001). Fifteen patients were diagnosed with CPA. Isolated positive Western blot (G3) identified five cases of aspergilloma. Significantly fewer Aspergillus lung diseases were diagnosed in isolated positive ICAP G2 (8.8%) than in G1 (53.8%) and G3 (42.5%) (p < 0.001).

CONCLUSIONS: This study highlights the benefits of combining Asp-WB and ICAP for the diagnosis of Aspergillus lung disease and the relatively high false-positive rate in patients with isolated positive ICAP results.

PMID:40231710 | DOI:10.1111/myc.70058

Curr Mol Pharmacol. 2025 Apr 11. doi: 10.2174/0118761429368288250401054301. Online ahead of print.

ABSTRACT

BACKGROUND: Airway mucus hypersecretion is a prominent pathophysiological characteristic observed in chronic obstructive pulmonary disease (COPD), cystic fibrosis, and asthma. It is a significant risk factor for lung dysfunction and impaired quality of life. Therefore, it is crucial to investigate changes in the major genes expressed in the lungs during airway mucus hypersecretion. Such investigations can help to identify genetic targets for the development of effective treatments to manage airway mucus hypersecretion and improve clinical outcomes for those affected by these respiratory disorders.

OBJECTIVE: Our study aims to identify changes in the expression of key genes in the lungs during airway mucus hypersecretion in mice.

METHODS: Thirty male C57BL/6 mice were randomly allocated into two groups. The Pyocyanin (PCN) group was intranasally infected with 25 μl of pyocyanin solution (1 μg/μl), while the phosphate-buffered saline (PBS) group received 25 μl of PBS intranasally once daily. The lung tissue of mice was extracted after 21 days for the purpose of identifying causal genes through a combination of transcriptomic and proteomic analysis. Finally, we validated the differentially expressed proteins using qRT-PCR and western blot.

RESULTS: Our findings revealed significant alterations in 35,268 genes and 7,004 proteins within the lung tissue of mice treated with PCN. Pathway enrichment analysis, utilizing the Kyoto Encyclopedia of Genes and Genomes (KEGG) database, showed that the differentially expressed proteins were mainly associated with apoptosis, galactose metabolism, and asthma, among the overlapping genes and proteins. To validate the results of the transcriptomic and proteomic analyses, we used qRT-PCR to examine the expression levels of fourteen differentially expressed proteins (DEPs), namely Fpr1, Ear1, Lama3, Col19a1, Spag16, Ropn1l, Dnali1, Cfap70, Ear2, Drc1, Ifit3, Lrrc23, Slpi, and Fam166b. Subsequently, we confirmed the expression of Spag16, Dnali1, and Ropn1l by western blotting.

CONCLUSIONS: Our study identified three DEPs, namely Spag16, Dnali1, and Ropn1l, which are closely associated with the movement and organization of cilia. This study provides novel insights for the development of therapeutic interventions targeting airway mucus hypersecretion.

PMID:40231527 | DOI:10.2174/0118761429368288250401054301

ERJ Open Res. 2025 Apr 14;11(2):01262-2024. doi: 10.1183/23120541.01262-2024. eCollection 2025 Mar.

ABSTRACT

This highlights article shares key updates in the field of respiratory infections from the 2024 #ERSCongress, focusing on new research and the need for fair access to care to help tackle global challenges in respiratory infections and improve patient care https://bit.ly/40gDmrj.

PMID:40230434 | PMC:PMC11995276 | DOI:10.1183/23120541.01262-2024

J Cyst Fibros. 2025 Apr 13:S1569-1993(25)00767-2. doi: 10.1016/j.jcf.2025.04.001. Online ahead of print.

NO ABSTRACT

PMID:40229182 | DOI:10.1016/j.jcf.2025.04.001

Crit Rev Eukaryot Gene Expr. 2025;35(4):55-64. doi: 10.1615/CritRevEukaryotGeneExpr.2025057731.

ABSTRACT

BACKGROUND: Cystic fibrosis (CF) is common genetic disorder in Europe and North America but rarer in Asian populations.

OBJECTIVE: To explore the clinical manifestations and gene mutations of cystic fibrosis.

METHODS: This case series study enrolled children with CF diagnosed in the pediatric respiratory department of Shandong Provincial Hospital affiliated to Shandong First Medical University between June 2016 and August 2022.

RESULTS: Seven children, including 6 girls and 1 boy, were enrolled. All 7 patients had recurrent wet cough and (chronic) pneumonia. Six patients suffered from chronic sinusitis, 4 patients had recurrent wheezing; 2 patients had chronic diarrhea, malnutrition and growth lag; 2 patients were complicated by allergic bronchopulmonary aspergillosis; and 1 patient had pancreatic insufficiency. Bronchiectasis, thickening of bronchial wall and mucous impaction, were seen in the chest CT of 7 children. Six patients showed a large amount of viscous sputum adhered to the bronchial wall by bronchoscopy. Infection of Pseudomonas aeruginosa was found in 6 cases, Staphylococcus aureus in 2 cases, and Aspergillus fumigatus in 2 cases by bronchoalveolar lavage fluid or sputum culture. Sweat sodium chloride test was performed in 3 cases, and the result showed that Cl-> 60 mmol/L. CFTR gene mutations were found in 7 cases, which were rare mutations of Caucasians, including 2 cases with new mutation sites (c.325T>G and 326A>G).

CONCLUSIONS: The major clinical presentations of CF could be chronic and recurrent upper and lower respiratory tract infections, malnutrition, and digestive tract diseases. The rare and even new mutations of Caucasians on CFTR gene may occur in Chinese children.

PMID:40228226 | DOI:10.1615/CritRevEukaryotGeneExpr.2025057731

Antioxidants (Basel). 2025 Mar 4;14(3):310. doi: 10.3390/antiox14030310.

ABSTRACT

A critical challenge in the age of advanced modulator therapies is to understand and determine how effectively chronic oxidative stress and oxidative stress-induced inflammation can be reversed and physiological balance restored when CFTR function is pharmacologically improved. The triple therapy with elexacaftor-tezacaftor-ivacaftor (ETI) suggests that CFTR activity in individuals with at least one F508del mutation can be partially restored to about 50% of normal levels. Although incomplete, the partial recovery of CFTR function has been shown to drastically lower sputum pathogen content, enhance microbiome diversity, and lower inflammation markers within the first year of treatment in adolescents and adults with cystic fibrosis. However, despite these advancements, residual airway infection, oxidative stress and inflammation persist, with levels similar to other chronic lung conditions, like non-CF bronchiectasis. This persistence highlights the necessity for innovative antioxidant and anti-inflammatory treatments, in particular for individuals with advanced lung disease. To address this issue, emerging multi-omics technologies offer valuable tools to investigate the impact of modulator therapies on various molecular pathways. By analyzing changes in gene expression, epigenetic modifications, protein profiles and metabolic processes in airway-derived samples, it could be possible to uncover the mechanisms driving persistent oxidative stress and inflammation. These insights could pave the way for identifying new therapeutic targets to fully restore airway health and overall physiological balance.

PMID:40227282 | DOI:10.3390/antiox14030310

Pediatr Pulmonol. 2025 Apr;60(4):e71084. doi: 10.1002/ppul.71084.

ABSTRACT

OBJECTIVE: The primary objective of this study was to examine the performance of the Asthma Clinical Score (ACS) relative to the Pediatric Respiratory Assessment Measure (PRAM). Our secondary objectives were to determine interrater reliability, discriminative validity, responsiveness, and predictive validity of the ACS and PRAM.

METHODS: This was a single-site prospective observational study of children ages 2 to < 18 years presenting to the emergency department (ED) for asthma exacerbations. Clinicians completed paired assessments using ACS and PRAM at three time points of each patients ED stay. Construct validity correlating the performance of the ACS to PRAM, and interrater reliability were analyzed using Spearmen's rank correlation coefficients and Cohen's kappa coefficient, respectively. Cohen's d was calculated to compare the scores of patients who received certain treatments to patients who did not. Reliable change index (RCI) was used to determine the responsiveness of each score. Predictive validity for hospitalization was analyzed using Area Under the Receiver Operating Characteristic curve (AUROCc) and Akaike Information Criterion (AIC).

RESULTS: 399 children were enrolled with 338 paired clinician observations. The ACS and PRAM scores were strongly correlated at all time points (n = 1383, ρ $\rho $ = 0.874). Both the ACS and PRAM showed moderate interrater reliability at all time points (n = 338, κw = 0.77 and κw = 0.69, respectively). Patients receiving albuterol nebulization or adjunctive medications had higher average ACS and PRAM scores. ACS showed a better ability to detect responsiveness than the PRAM (31% vs 15% respectively). The pretreatment ACS showed comparable predictive validity to the PRAM.

CONCLUSION: The ACS was highly correlated with PRAM and is a reliable score in this cohort. The ACS showed good discriminative validity, predictive validity and responsiveness. This study supports the ACS as a useful tool in ED assessment of asthma exacerbation severity in children.

PMID:40226890 | DOI:10.1002/ppul.71084

Cell Biomater. 2025 Mar 25;1(2):100013. doi: 10.1016/j.celbio.2025.100013. Epub 2025 Mar 3.

ABSTRACT

Mucociliary clearance (MCC) is critical in maintaining lung health and preventing respiratory infections. MCC is impaired in people with cystic fibrosis, due to accumulation of thick, sticky mucus resulting from defective cystic fibrosis transmembrane conductance regulator channel function. In this study, we developed a unique 3D lung submucosal gland ductal airway model utilizing primary human submucosal gland epithelial cells, which enables the formation of physiologically relevant architecture of the ductal epithelium including ciliary cells within a 3D bioprinted scaffold. Our observation demonstrates that this model not only enables the fabrication of human lung submucosal gland ductal airway-like structure mimicking in vivo physiology, also facilitates quantitative measurement of patient-specific MCC and determines pharmacological effects. Our results suggest that this model could be a valuable tool for understanding mechanisms underlying impaired MCC and testing the efficacy of novel therapeutic strategies for the treatment of respiratory diseases such as cystic fibrosis.

PMID:40226365 | PMC:PMC11984632 | DOI:10.1016/j.celbio.2025.100013

Hum Mutat. 2024 Oct 16;2024:6165547. doi: 10.1155/2024/6165547. eCollection 2024.

ABSTRACT

Cystic fibrosis (CF) is a complex monogenic disorder with a large variability in disease severity. Growing evidence suggests that the variation observed depends not only on variations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene but also on modifier genes. Utilizing five databases (including CINAHL, PubMed, Science Direct, Scopus, and Web of Science), a systematic review was conducted to examine the current literature on the known impacts of genomic variations in modifier genes on the CF disease progression, severity, and therapeutic response. A total of 70 full-text articles describing over 80 gene modifiers associated with CF were selected. The modifier genes included genes associated with the CFTR interactome, the inflammatory response, microbial profiles, and other genes affecting the critical physiological pathways of multiple organ systems, such as the respiratory and gastrointestinal systems. Limitations of the existing literature embrace the lack of clinical studies investigating pharmacogenetic impacts and the significance of gene modifiers on the CF clinical picture, including a limited number of replication and validation studies. Further investigations into other potential gene modifiers using genome-wide association studies are needed to critically explore new therapeutic targets and provide a better understanding of the CF disease phenotype under specific drug treatments.

PMID:40225935 | PMC:PMC11919198 | DOI:10.1155/2024/6165547

J Thorac Dis. 2025 Mar 31;17(3):1424-1443. doi: 10.21037/jtd-24-1525. Epub 2025 Mar 27.

ABSTRACT

BACKGROUND: An expanding array of inhaled antibiotic therapies can be effective for the treatment of chronic Pseudomonas aeruginosa (P. aeruginosa) infection in patients with cystic fibrosis (CF) and non-CF bronchiectasis (NCFB). Nonetheless, there is a paucity of direct studies comparing the curative effects of these regimens. This network meta-analysis (NMA) aimed to assess the efficacy and safety of different inhaled antibiotic therapies for the relative short-term (4 weeks) and long-term (≥4 months) management of chronic P. aeruginosa infection in patients with CF and NCFB, respectively.

METHODS: We searched PubMed, Web of Science, Embase, and Cochrane Library database as at 25th February, 2024. Randomized controlled trials (RCTs) involving inhaled antibiotic therapies for treatment of CF or NCFB were thoroughly screened. We conducted this NMA within a Bayesian framework. The surface under the cumulative ranking curve (SUCRA) was calculated to estimate relative effects of interventions per outcome.

RESULTS: A total of 39 RCTs were included, involving 18 inhaled antibiotic treatment regimens and 7,486 participants. The primary outcomes assessed were microbiological efficacy and tolerability. According to SUCRA results, for patients with CF, tobramycin inhalation powder (TIP) had the best profile regarding microbiological efficacy at both short-term and long-term follow-up (SUCRA, 94.5%; 90.5%). Colistin for inhalation (SUCRA, 84.0%) and tobramycin inhalation solution (TIS; SUCRA, 75.7%) had the best tolerability profile at short-term and long-term follow-up, respectively. For patients with NCFB, TIP (SUCRA, 84.2%) and gentamicin injectable solution (GM) for inhalation (SUCRA, 92.2%) had the best profile regarding microbiological efficacy at short-term and long-term follow-up, respectively. Ciprofloxacin inhalation powder had the best tolerability profile at both short-term and long-term follow-up (SUCRA, 66.4%; 85.6%).

CONCLUSIONS: The present study suggests that inhalation of TIS and GM are deemed exhibiting favorable profile across various outcomes for treating chronic P. aeruginosa infection in patients with CF and NCFB, respectively. Further large-scale and higher-quality studies are needed to support the conclusion.

PMID:40223951 | PMC:PMC11986750 | DOI:10.21037/jtd-24-1525