Pediatr Pulmonol. 2025 Jun;60(6):e71162. doi: 10.1002/ppul.71162.

ABSTRACT

BACKGROUND: Inhaled tobramycin solution is recommended for eradication treatment of Pseudomonas aeruginosa (PA) infections in people with cystic fibrosis (PwCF). However, there is limited information on the safety of inhaled tobramycin in PwCF less than 1 year old and no studies primarily analyzing the safety of the 300 mg inhaled solution. The objective of this study was to compare the incidence of adverse drug events (ADE) of inhaled tobramycin in PwCF less than 1 year old to PwCF ages 1 year to 18 years old.

METHODS: This retrospective analysis evaluated the incidence of inhaled tobramycin ADEs in PwCF ages 14 days to 18 years with CF between January 01, 2008 to January 01, 2022. PwCF less than 1 year of age (infant group) were matched based on genotype in a 1:3 ratio with a PwCF at least a year old to 18 year-old (children group).

RESULTS: Forty-eight patients were included (infant group: 12, children group: 36). Median (IQR) age was 0.48 years (0.2-0.7) and 4.7 years (2.3-10) in infant group and children group respectively (p < 0.05). There were 5 (41.7%) ADE in the infant group and 3 (8.3%) in the children group (p = 0.016). When cough was removed there was no significant difference between the two groups [2 (16.7%) vs. 1 (2.7%), p = 0.15]. There was no difference in treatment failure [3 (25%) vs. 7 (19.4%), p = 0.68].

CONCLUSIONS: This study found a higher incidence of inhaled tobramycin ADE in infants compared to children. These results show a low risk of ADE outside of cough, indicating that inhaled tobramycin may be safely used in this age group.

PMID:40525716 | DOI:10.1002/ppul.71162

Genet Epidemiol. 2025 Jul;49(5):e70013. doi: 10.1002/gepi.70013.

ABSTRACT

For complex traits such as lung disease in Cystic Fibrosis (CF), Gene x Gene or Gene x Environment interactions can impact disease severity but these remain largely unknown. Unaccounted-for genetic interactions introduce a distributional shift in the quantitative trait across the genotypic groups. Joint location and scale tests, or full distributional differences across genotype groups can account for unknown genetic interactions and increase power for gene identification compared with the conventional association test. Here we propose a new joint location and scale test (JLS), a quantile regression-basd JLS (qJLS), that addresses previous limitations. Specifically, qJLS is free of distributional assumptions, thus applies to non-Gaussian traits; is as powerful as the existing JLS tests under Gaussian traits; and is computationally efficient for genome-wide association studies (GWAS). Our simulation studies, which model unknown genetic interactions, demonstrate that qJLS is robust to skewed and heavy-tailed error distributions and is as powerful as other JLS tests in the literature under normality. Without any unknown genetic interaction, qJLS shows a large increase in power with non-Gaussian traits over conventional association tests and is slightly less powerful under normality. We apply the qJLS method to the Canadian CF Gene Modifier Study (n = 1,997) and identified a genome-wide significant variant, rs9513900 on chromosome 13, that had not previously been reported to contribute to CF lung disease. qJLS provides a powerful alternative to conventional genetic association tests, where interactions may contribute to a quantitative trait.

PMID:40525595 | DOI:10.1002/gepi.70013

Pharmacol Res Perspect. 2025 Aug;13(4):e70138. doi: 10.1002/prp2.70138.

NO ABSTRACT

PMID:40525539 | DOI:10.1002/prp2.70138

ERJ Open Res. 2025 Jun 16;11(3):00247-2024. doi: 10.1183/23120541.00247-2024. eCollection 2025 May.

ABSTRACT

The microbiome in bronchiectasis shows day to day variability in sputum samples from people with bronchiectasis and cystic fibrosis. This should be taken into account in studies of the airway microbiome in chronic airway disease. https://bit.ly/3URkv42.

PMID:40524921 | PMC:PMC12168179 | DOI:10.1183/23120541.00247-2024

ACG Case Rep J. 2025 Jun 16;12(6):e01736. doi: 10.14309/crj.0000000000001736. eCollection 2025 Jun.

NO ABSTRACT

PMID:40524808 | PMC:PMC12169966 | DOI:10.14309/crj.0000000000001736

Folia Med (Plovdiv). 2025 May 16;67(3). doi: 10.3897/folmed.67.e150928.

ABSTRACT

Cystic fibrosis is a multi-organ genetic disorder with over 1,300 known mutations in the CFTR gene. The diversity of genetic variations leads to a wide range of clinical manifestations and disease severity.

PMID:40524579 | DOI:10.3897/folmed.67.e150928

Ther Adv Respir Dis. 2025 Jan-Dec;19:17534666251323487. doi: 10.1177/17534666251323487. Epub 2025 Mar 13.

ABSTRACT

BACKGROUND: The 2018 guidelines on the diagnosis of idiopathic pulmonary fibrosis (IPF) conditionally recommend multidisciplinary discussion (MDD) for diagnostic decision-making. However, limited data concerning the diagnostic impact of MDD on interstitial lung diseases (ILDs) are available.

OBJECTIVES: The objective of this prospective study was to assess the impact of MDD at a tertiary referral ILD center on diagnostic trajectories, prognosis, and identification of potential treatable traits in ILD management.

DESIGN: This prospective study enrolled all consecutive adult ILD patients referred for MDD to a tertiary academic center in San Antonio, TX, USA from January 2017 to May 2020. The subjects were followed during a 3-year follow-up period after the MDD.

METHODS: Patients were stratified into three groups according to the pre-MDD diagnosis: unspecified ILD, IPF, and not IPF, and compared to the re-stratification post-MDD diagnosis into: unclassifiable ILD, IPF, and not IPF. The primary outcome was the percentage change in diagnostic trajectories after the MDD discussion.

RESULTS: A total of 201 ILD patients (61.7% male; mean (DS) age: 67.2 (10.4) years) were included in the study. The total diagnostic trajectory change occurred in 122 (60.7%) patients. The diagnostic trajectories changed in 40 (46.5%) patients in the IPF group and 8 (19.5%) in the non-IPF group (p-value = 0.0003). Patients with pre-MDD unspecified-ILD were classified as not-IPF in 32.4% (n = 24), IPF in 23% (n = 17), and unclassifiable-ILD in 44.6% (n = 33) post-MDD. Considering the post-MDD diagnosis, differences in mortality were detected among the three groups (p = 0.037).

CONCLUSION: Our results suggest that MDD has a significant impact not only on the diagnostic trajectories (DT) but also on the prognosis of patients with ILDs.

PMID:40524316 | DOI:10.1177/17534666251323487

Life Sci Alliance. 2025 Jun 16;8(9):e202402720. doi: 10.26508/lsa.202402720. Print 2025 Sep.

ABSTRACT

RNA-protein interactions play a key role in the aberrant splicing of CFTR exon 9. Exon 9 skipping leads to the production of a nonfunctional chloride channel associated with severe forms of cystic fibrosis. The missplicing depends on TDP-43 binding to an extended UG-rich binding site upstream of CFTR exon 9 3' splicing site (3'ss) and is associated with concomitant hnRNP A1 recruitment. Although TDP-43 is the dominant inhibitor of exon 9 inclusion, the role of hnRNP A1, a protein with two RNA recognition motifs, remained unclear. In this work, we have studied the interaction between hnRNP A1 and the CFTR pre-mRNA using NMR spectroscopy and Isothermal Titration Calorimetry. The affinities are submicromolar, and Isothermal Titration Calorimetry data suggest complexes with a 1:1 stoichiometry. NMR titrations reveal that hnRNP A1 interacts with model CTFR 3'ss sequences in a fast exchange regime at the NMR timescale. Splicing assays finally show that this hnRNP A1 binding site represents a previously unknown exonic splicing silencer element. Together, our results shed light on the mechanism of aberrant CFTR exon 9 splicing.

PMID:40523798 | DOI:10.26508/lsa.202402720

CMAJ. 2025 Jun 15;197(23):E646-E652. doi: 10.1503/cmaj.250057.

NO ABSTRACT

PMID:40523683 | DOI:10.1503/cmaj.250057

JAMA Intern Med. 2025 Jun 16. doi: 10.1001/jamainternmed.2025.1853. Online ahead of print.

ABSTRACT

IMPORTANCE: Cystic fibrosis is one of the most commonly diagnosed autosomal recessive disorders in the US. It is estimated that more than 10 million individuals are heterozygous for a pathogenic CFTR gene variant in the US (heterozygotes). The phenotypic risk of these heterozygotes is not well defined, particularly among populations of predominantly non-European genetic ancestry. Understanding disease risk across each population can improve management strategies for all.

OBJECTIVE: To examine associations of diseases across the phenome with CFTR heterozygotes.

DESIGN, SETTING, AND PARTICIPANTS: The All of Us Research Program is a US-based ongoing longitudinal cohort study whose enrollment started nationally in 2018. In this genetic association study, whole-genome sequencing data were linked to electronic health records (EHRs) and surveys. Participants were 18 years and older. Similarity to genetic ancestral groups was genetically inferred using All of Us data and 2 large reference datasets, the 1000 Genomes Project and Human Genome Diversity Project. This analysis was conducted between February and April 2025.

EXPOSURES: A single pathogenic CFTR variant.

MAIN OUTCOMES AND MEASURES: The main variables included clinical diagnoses documented in EHRs. Multivariable-adjusted phenome-wide association studies were performed. The main measures were odds ratios (ORs), indicating risk for a particular disease or condition.

RESULTS: Overall, 363 pathogenic variants were identified in the cohort. Among 317 964 adult participants (55.7% female; mean [SD] last age in EHR, 56.1 [16.9] years), 7957 heterozygotes and 280 995 noncarriers were identified. Participants were followed up through EHRs with a mean (SD) follow-up of 12.4 (9.0) years. The genetically inferred ancestral distribution of the cohort was 18.0% African, 16.2% American or Admixed American, 2.1% East Asian, 53.4% European, 0.3% South Asian, and 0.4% West Asian. Frequencies of heterozygotes varied by groups of genetic similarity to reference populations: 3.62% in participants most genetically similar to a European reference population (n = 169 812), 1.35% in participants most genetically similar to an African reference population (n = 57 297), and 1.86% in participants most genetically similar to an Admixed American reference population (n = 51 483). A total of 2909 phenotypes were analyzed. No statistically significant associations were identified in heterozygotes of all populations combined or within each genetic ancestral group. Among 52 cystic fibrosis-associated diseases, although an elevated risk of respiratory diseases and infections was observed in some heterozygotes (allergic bronchopulmonary aspergillosis [OR, 2.50; 95% CI, 1.27-4.95]; bronchiectasis [OR, 1.21; 95% CI, 1.00-1.47]; pneumonia due to Streptococcus pneumoniae [OR, 1.54; 95% CI, 1.05-2.26]; chronic obstructive pulmonary disease [OR, 1.14; 95% CI, 1.05-1.24]; asthma [OR, 1.08; 95% CI, 1.01-1.15]; and Pseudomonas infection [OR, 1.34; 95% CI, 1.03-1.74]), effect sizes of these associations were several orders of magnitude lower than those found in homozygotes or predicted compound heterozygotes.

CONCLUSIONS AND RELEVANCE: In this genetic association study, most heterozygotes did not appear to have a substantially higher risk of cystic fibrosis-associated diseases during their adulthood compared to noncarriers. Additional studies are needed to investigate the underlying factors for the elevated risk of respiratory and infectious diseases in some heterozygotes.

PMID:40522671 | DOI:10.1001/jamainternmed.2025.1853

Biofilm. 2025 May 27;9:100293. doi: 10.1016/j.bioflm.2025.100293. eCollection 2025 Jun.

ABSTRACT

Pseudomonas aeruginosa is an opportunistic pathogen that causes both acute and chronic infections, including pneumonia, bloodstream infections, urinary tract infections, and surgical site infections. It poses a significant threat to individuals with chronic lung conditions, particularly those with cystic fibrosis. Squalamine and claramine A1 have emerged as promising antibacterial compounds, exhibiting activity against a broad range of both Gram-positive and Gram-negative bacteria. Beyond their potent antibacterial properties, our findings reveal that sub-inhibitory concentrations of claramine A1 and squalamine can disperse pre-formed P. aeruginosa biofilm without impacting bacterial growth. While claramine A1, but not squalamine, enhances membrane fluidity, the structural difference between these compounds lies primarily in their spermine and spermidine moieties. Notably, we found that spermine, unlike spermidine, was able to both disperse biofilm and increase membrane fluidity. Together, our results suggest that while both compounds are effective at disrupting P. aeruginosa biofilm, they likely act through distinct mechanisms.

PMID:40519941 | PMC:PMC12166708 | DOI:10.1016/j.bioflm.2025.100293

Cureus. 2025 May 14;17(5):e84110. doi: 10.7759/cureus.84110. eCollection 2025 May.

ABSTRACT

Cystic fibrosis (CF) is an autosomal recessive genetic disorder characterized by the dysfunction of the cystic fibrosis transmembrane conductance regulator (CFTR) gene on the long (q) arm of chromosome number 7. It is characterized by the buildup of thick, sticky mucus that can damage various body organs. The most commonly affected organs are the pancreas, liver, intestines, and lungs. Diabetes mellitus is a complex multi-system metabolic disorder. It is characterized by the relative or absolute insufficiency of insulin secretion with or without concomitant insulin resistance, leading to high blood sugar levels. One of the feared complications of CF is cystic fibrosis-related diabetes (CFRD). In this narrative review, we examine various treatment options, their mechanisms of action, their side effects, and their impact on the lives of patients with CFRD. In conclusion, insulin remains the cornerstone of treatment in the management of CFRD. However, oral medications for diabetes can also be considered safe and effective, in selected patients, with stable liver function and preserved lung capacity.

PMID:40519490 | PMC:PMC12166097 | DOI:10.7759/cureus.84110

Am J Med Sci. 2025 Jun 13:S0002-9629(25)01074-2. doi: 10.1016/j.amjms.2025.06.008. Online ahead of print.

ABSTRACT

BACKGROUND: Bronchiectasis is a chronic airway disease caused by abnormal and permanent dilation of the airways. This study aimed to evaluate the effects of inhaler therapy use on respiratory functions and clinical outcomes in patients with non-cystic fibrosis bronchiectasis.

METHODS: One hundred forty-six patients with non-cystic fibrosis bronchiectasis aged over 18 years, diagnosed using high-resolution computed tomography, were included in the study. Age, sex, body mass index, smoking status, additional diseases, known etiologic factors, and vaccination status of the patients included in the retrospectively designed study were recorded as sociodemographic data. Respiratory functions, disease severity, and clinical outcomes of patients with bronchiectasis who did and did not receive inhaled anticholinergic and steroid treatments were compared.

RESULTS: Ninety (61.6%) of the 146 patients included in the study were women. The mean age was 56.14±16.22 years. The etiology of bronchiectasis was unknown in 78 (53.4%) patients. The most prevalent comorbidity was asthma. According to modified Reiff scoring, 91 (62.3%) patients were classified as having mild bronchiectasis. Twenty-six (17.8%) patients had airway obstruction. There were 93 (63.7%) patients using inhaled corticosteroids and 32 (21.9%) using inhaled anticholinergics.

CONCLUSION: It was determined that patients using inhaler anticholinergics or inhaled steroids were in the more severe group. However, inhaler anticholinergic and inhaler steroid treatments had no effect on hospital admissions and exacerbation frequency in patients with bronchiectasis. Hospitalizations were more frequent among patients with bronchiectasis using inhaled steroids.

PMID:40518077 | DOI:10.1016/j.amjms.2025.06.008

Soc Sci Med. 2025 Jun 10;381:118293. doi: 10.1016/j.socscimed.2025.118293. Online ahead of print.

ABSTRACT

In all societies, demand for healthcare exceeds available resources. When resources for healthcare are limited, clinicians inevitably engage in distributive decisions that affect the care of individual patients: so-called bedside rationing. Clinical practice guidelines intend to steer bedside rationing through transparent eligibility criteria. Still, the distributive challenge is exacerbated by increasingly available high-cost treatments for rare diseases, treatments entrenched in a great deal of uncertainty due to limited evidence of therapeutic effect. In this qualitative study, we investigated the real-life implementation of a clinical practice guideline for a costly cystic fibrosis treatment, elexacaftor/tezacaftor/ivacaftor (Kaftrio), reimbursed in Norway since 2022. Thereby, we provide empirical and theoretical contributions to the health economics literature on priority setting by drawing on policy enactment theory and the clinical decision-making literature. Using data from 18 in-depth interviews analysed by reflexive thematic analysis, we found that clinicians perceived Kaftrio to be exceptionally effective, making it very difficult to withdraw treatment in cases of uncertain or inadequate effect as suggested by the start-stop criteria intended to steer initiation and discontinuation of treatment. Clinicians enacted the guideline to deliver, not withhold treatment in cases of uncertain eligibility by shaping the guideline's meaning. Building on the empirical findings, we propose a model that theorises how clinicians negotiated the treatment's therapeutic effect across various axes of medical knowledge from observed to justified effects. In the era of high-cost genetic therapeutics, our study provides an important contribution to the understanding of tools and mechanisms to ensure fair and open priority setting.

PMID:40517648 | DOI:10.1016/j.socscimed.2025.118293

Arch Pediatr. 2025 Jun 13:S0929-693X(25)00096-X. doi: 10.1016/j.arcped.2025.03.005. Online ahead of print.

ABSTRACT

The number of pregnancies in women with cystic fibrosis (CF) has significantly increased in recent years, leading to a corresponding rise in the number of healthy infants exposed to cystic fibrosis transmembrane conductance regulator modulator (CFTRm) such as elexacaftor-tezacaftor-ivacaftor (ETI) or Kaftrio/Kalydeco® (K/K) triple therapy. Currently, data on the immediate outcomes for these children is reassuring; however, some cases of abnormal liver tests and cataracts have been reported in a few newborns indirectly exposed to ETI in utero or postnatally. Long-term neurodevelopment remains a concern that requires further investigation. A working group from the Société Française de la Mucoviscidose has developed recommendations for monitoring these children during the first two years and beyond. Given the increasing number of infants born to mothers taking CFTR modulators, as well as questions regarding their immediate care during the maternity stay and the feasibility of breastfeeding, it is crucial for pediatricians to be aware of these recommendations, which are based on a comprehensive review of the literature.

PMID:40517123 | DOI:10.1016/j.arcped.2025.03.005

Clin Med (Lond). 2025 Jun 12:100340. doi: 10.1016/j.clinme.2025.100340. Online ahead of print.

ABSTRACT

Women with cystic fibrosis (wwCF) are increasingly undertaking pregnancy. This study assessed the current state of relationships, fertility, pregnancy and parenthood in a total cohort of 217 wwCF. Overall, 64% of wwCF were in long-term heterosexual relationships, 32% were single and 4% were in same-sex relationships; 64 wwCF had 111 children; 97 (87.4%) were conceived naturally and 10 (9%) by assisted reproduction. One woman had two children by surrogacy, one couple adopted a child and 6 had a role as a step-parent. Of the 217 wwCF 31 (14%) died at a mean age of 41.4 years; they had 18 children and 8 (44%) were less than 18 years old when the mother died. There was a marked increase in pregnancies associated with the introduction of CF modulator medications, from 3 in 2020 to 16 in 2023. There were 50 pregnancies between 2020 and 2024;17 (34%) were not planned (5 were terminated); and 15 (30%) partners did not have CF genetic tests pre-conception. There were 8 miscarriages. Exacerbations of lung disease occurred in 11 (31%) completed pregnancies, gestational diabetes in 12 (34%), one gastrointestinal bleeding, and one pre-eclampsia. Delivery was by caesarean section in 14 (40%) and 4 (11%) births were pre-mature (<37 weeks gestation). Although outcomes are generally good, pre-conception planning is suboptimal, pregnancy is associated with increased complications and parenthood raises complex issues regarding prognosis. CF teams should have close links with maternal medicine services to meet the specific needs of wwCF.

PMID:40516789 | DOI:10.1016/j.clinme.2025.100340

ISME J. 2025 Jun 14:wraf125. doi: 10.1093/ismejo/wraf125. Online ahead of print.

ABSTRACT

People with cystic fibrosis (pwCF) have reduced mucociliary clearance in their airways, leading to the build-up of thick, sticky mucus susceptible to opportunistic infection. A new treatment, comprised of three small molecule drugs called Elexacaftor/Tezacaftor/Ivacaftor (ETI), has improved mucociliary clearance and lung function in pwCF, but how this therapy alters lung infections is poorly understood. This study experimentally modeled the biochemical changes in airway mucus caused by ETI to determine its effect on the CF lung microbiome structure and function. We prepared Artificial Sputum Medium (ASM) with reduced primary carbon sources (amino acids, deoxyribonucleic acid DNA, and mucin) to mimic the effects of ETI on mucus biochemistry due to improved mucociliary clearance and reduced pulmonary inflammation. The control and modified ASM were inoculated with pure CF pathogens or mixed-species communities and then grown in oxic and anoxic conditions, followed by multi-omics data analysis. Although oxygen strongly altered the community structure, the nutrient depletions in ASM had little effect. Instead, the reduced carbon sources altered the physiology of the collective community and its individual pathogens. This included modified growth kinetics in addition to altered nitrogen and nucleotide metabolism. Under reduced amino acid concentrations, a known effect of ETI on the sputum metabolome, the production of both Pseudomonas aeruginosa's quinolones and rhamnolipids was significantly reduced. This indirect effect of ETI translates to reduced killing of competing pathogens and reduced toxicity to epithelial cells isolated from the airways of explanted human lung tissues. These findings indicate that ETI may provide further benefit to pwCF by reducing the competition and virulence of its principal pathogen and highlight how microenvironmental effects can have powerful impacts on polymicrobial infections.

PMID:40515620 | DOI:10.1093/ismejo/wraf125

Br Dent J. 2025 Jun;238(11):864. doi: 10.1038/s41415-025-8844-7.

NO ABSTRACT

PMID:40514492 | DOI:10.1038/s41415-025-8844-7

Respir Med. 2025 Jun 11:108198. doi: 10.1016/j.rmed.2025.108198. Online ahead of print.

ABSTRACT

BACKGROUND: Inhaled steroids dose reduction is a relevant goal in severe asthma management.

RESEARCH QUESTION: We aimed to investigate ICS use trajectories and their clinical impact in severe asthma patients on benralizumab over 36 months.

STUDY DESIGN AND METHODS: We conducted a retrospective real-life observational study including clinical and inflammatory parameters. Patients were stratified according to ICS dose trends over time: "stable" (same dose at ≥80% of visits), "decreasing" (≥50% of visits with lower ICS dose vs baseline), and "increasing" (≥50% of visits with higher ICS dose vs baseline).

RESULTS: 92 patients were included. Post-bronchodilation FEV1 significantly increased over 36 months, while pre-bronchodilation FEV1 remained stable. An overall statistically significant improvement was observed also for ACT, ACQ, AQLQ and annual exacerbation rate. The probability of decreasing ICS dose was 19.0% at 12 months and 37.4% at 36 months. In the decreasing group (30% of the cohort), baseline blood eosinophil count (BEC) was higher than in the stable group, and BEC suppression over time was greater. The decreasing group was also less frequently treated with OCS at baseline. At 24 months, the stable group showed a greater reduction in OCS use compared to the decreasing group. Across all groups, OCS use dropped from 89.8% to 4.9% at 36 months.

INTERPRETATION: The findings suggest that ICS tapering is feasible and safe in selected patients under benralizumab therapy.

CONCLUSIONS: To the best of our knowledge, this is the first real-life study specifically supporting the ICS-sparing effect of benralizumab over a 36-month period.

PMID:40513966 | DOI:10.1016/j.rmed.2025.108198

Microb Genom. 2025 Jun;11(6). doi: 10.1099/mgen.0.001411.

ABSTRACT

Data on the genomics of Porphyromonas species other than Porphyromonas gingivalis (POTG), particularly within pulmonary environments, are scarce. In this study, we conducted whole-genome sequencing on pulmonary isolates of POTG, specifically Porphyromonas catoniae (n=3), Porphyromonas pasteri (n=1) and Porphyromonas uenonis (n=2), from people with cystic fibrosis. These genomic analyses were complemented with antimicrobial susceptibility tests for these strains. We compared the genomic sequences of these pulmonary isolates with those of previously characterized Porphyromonas species. Our study revealed a distinct clade differentiation between non-pigmented and pigmented Porphyromonas species. Unlike P. gingivalis, the pulmonary POTG strains lacked known virulence genes, with the exception of a putative haemolysin gene. Regarding antibiotic resistance, notable resistances were limited to vancomycin in P. catoniae and clindamycin in P. uenonis. These findings support the hypothesis that POTG species may predominantly behave as commensals in the lung environment rather than as pathogens.

PMID:40512666 | DOI:10.1099/mgen.0.001411