Infect Immun. 2025 Jun 13:e0023025. doi: 10.1128/iai.00230-25. Online ahead of print.

ABSTRACT

Mouse models of cystic fibrosis (CF) have been used to study chronic lung infections; however, these models have lacked the airway mucus that defines human CF pathophysiology and required the use of mucoid Pseudomonas aeruginosa. Alternative models have used either transgenic Scnn1b-Tg mice overexpressing a lung epithelial sodium channel to mimic the mucus-rich CF lung environment, synthetic CF sputum medium (SCFM2) to induce bacterial phenotypes consistent with human CF, or agar beads to promote chronic infections by non-mucoid P. aeruginosa. Here, we combined these alternative models and established a chronic P. aeruginosa lung infection model using SCFM2 agar beads and Scnn1b-Tg mice (SCFM2-Scnn1b-Tg) to recapitulate nutrient and mucus characteristics of the human CF lung environment and test the effects of chronic infections on bacterial burden, lung function, and the immune response. Using wild-type SCFM2-C57BL/6 mice as controls, SCFM2-Scnn1b-Tg mice failed to clear bacterial infections, and lung function measurements showed that infected SCFM2-Scnn1b-Tg mice had decreased inspiratory capacity and compliance, elevated airway resistance, and significantly reduced forced expiratory volumes. Flow cytometry and cytokine arrays showed that, like people with CF, SCFM2-Scnn1b-Tg mice developed inflammation characterized by neutrophil and eosinophil infiltration and Th2 lymphocytic cytokine responses. Chronically infected SCFM2-Scnn1b-Tg mice developed an exacerbated mix of innate and Th1, Th2, and Th17-mediated inflammation, causing higher lung cellular damage and elevated numbers of unusual Siglec F+ neutrophils. SCFM2-Scnn1b-Tg mice will be useful for investigating bacterial pathogenesis by non-mucoid P. aeruginosa, including treatments and the roles of Siglec F+ neutrophils in CF inflammation.

PMID:40512037 | DOI:10.1128/iai.00230-25

Br J Clin Pharmacol. 2025 Jun 13. doi: 10.1002/bcp.70131. Online ahead of print.

ABSTRACT

AIMS: The clinical effectiveness of tezacaftor-ivacaftor in children with cystic fibrosis (cwCF) varies; some patients respond while others do not or have adverse effects. The pharmacokinetics (PK) of tezacaftor-ivacaftor are inadequately published, especially in children. Knowledge of the PK in this cohort in relation to clinical outcomes may give further insight into the drug's exposure-response relationship and its associated interindividual variability. The aim of this study was to assess the real-world PK of tezacaftor-ivacaftor in cwCF.

METHODS: A prospective, observational PK study was performed in cwCF using tezacaftor-ivacaftor. PK samples were obtained by dried blood spots at home and during routine outpatient hospital visits. Population PK (popPK) models were created using nonlinear mixed-effects modelling. Due to data scarcity, prior information from adolescent/adult PK models was required.

RESULTS: The study involved 21 children (age 6-17 years, weight 24-70 kg). Novel popPK models were created for tezacaftor-ivacaftor and its main metabolites. Variability in PK was explained by variation in body weight. The area under the curve of tezacaftor-ivacaftor varied significantly within and across age groups, which corresponded to the reported area under the curve in the product information. Maximum concentration and elimination half-lives closely matched adult reported values.

CONCLUSIONS: This is the first study to investigate the popPK of tezacaftor-ivacaftor in cwCF. The established models can be used for more personalized dosing in children experiencing suboptimal efficacy, adverse effects, drug-drug interactions, or where adherence is a concern.

PMID:40511640 | DOI:10.1002/bcp.70131

J Pharm Bioallied Sci. 2025 May;17(Suppl 1):S1008-S1010. doi: 10.4103/jpbs.jpbs_469_25. Epub 2025 Apr 9.

ABSTRACT

The F508del CFTR gene mutation primarily leads to cystic fibrosis development yet produces infertility complications in males. The presented case concerns a 32-year-old man who has azoospermia but does not display cystic fibrosis symptoms. Testing showed the presence of the F508del CFTR mutation, which resulted in identifying obstructive azoospermia with congenital absence of the vas deferens (CAVD). The woman suffered from inadequate ovarian function. Fertility solutions for couples can be obtained through assisted reproductive methods which include testicular sperm extraction (TESE) along with percutaneous epididymal sperm aspiration (PESA) that utilizes intracytoplasmic sperm injection techniques (ICSI). Genetic counseling remains essential for risk assessment because it tells family members if they carry this genetic defect. The assessment matters more when women also have the genetic defect. The research confirms how CFTR mutations affect infertility while demonstrating the need for early genetic screening to properly manage male infertility with unknown causes.

PMID:40511152 | PMC:PMC12156486 | DOI:10.4103/jpbs.jpbs_469_25

Int J Mol Sci. 2025 Jun 4;26(11):5400. doi: 10.3390/ijms26115400.

ABSTRACT

Major mutations of SERPINA1, the gene encoding alpha1-antitrypsin (A1AT), are known to cause severe emphysema. Our study aimed to investigate the role of major mutations modulating A1AT levels in several lung pathologies and control groups. Blood samples were collected from healthy non-smokers (N0 = 85), healthy smokers (N0 = 291), healthy ex-smokers (N0 = 127), smokers with chronic obstructive lung disease (COPD, N0 = 187), ex-smokers with COPD (N0 = 64), and patients with asthma (N0 = 194), interstitial lung disease (ILD) (N0 = 93), sarcoidosis (N0 = 30) and cystic fibrosis (N0 = 26). Clinical and respiratory parameters, A1AT levels, the extent of emphysema and comorbidities on low-dose CT scans were evaluated, and patients answered a smoking history and comorbidity questionnaire. A1AT single-nucleotide polymorphisms were determined for the S, Z, M2/M4, 0 and eQTL locations by SNP probes using real-time PCR. A1AT levels showed significant differences between cigarette smoke-induced and other lung diseases. Compared to controls, A1AT levels were found to be lower in sarcoidosis and increasingly higher in smokers and patients with COPD, ILD and CF, respectively. The presence and pattern of emphysema were found to influence A1AT levels: lower values were observed in COPD patients without emphysema, while higher values were observed in patients with central and panlobular emphysema. Antitrypsin levels increased with COPD GOLD stages and asthma GINA stages. Variable A1AT levels were also found in ILD subgroups. The distribution of variants at the S, Z, M2/M4 and 0 polymorphic sites and the eQTL location showed no significant differences between patient groups with impaired lung function, except for Z heterozygotes, which were prevalent in patients with severe asthma. The eQTL TT genotypes had higher A1AT levels and the occurrence of emphysema and/or bronchitis was increased. A1AT levels correlated with several clinical and respiratory parameters in pulmonary patients, while FEV1/FVC inversely correlated with levels of A1AT. Molar antielastase activity was increased in smokers and patients with lung diseases; however, in COPD, antielastase activity decreased. The most reduced antielastase activity could be found in CF. Certain genotypes were characterized by increased cardiovascular comorbidity scores and antitrypsin levels. Our data suggest that in addition to emphysema, A1AT may play an important role in the development of a wide variety of lung diseases and cardiovascular comorbidities. Further research is needed to clarify the role of A1AT and its regulation in lung pathologies.

PMID:40508213 | DOI:10.3390/ijms26115400

Int J Mol Sci. 2025 May 31;26(11):5306. doi: 10.3390/ijms26115306.

ABSTRACT

Cystic Fibrosis (CF) is a common genetic disease in the United States, resulting from mutations in the Cystic Fibrosis transmembrane conductance regulator (cftr) gene. CFTR modulators, particularly Elexacaftor/Tezacaftor/Ivacaftor (ETI), have significantly improved clinical outcomes for patients with CF. However, many CFTR mutations are not eligible for CFTR modulator therapy due to their rarity. In this study, we report that a patient carrying rare complex CFTR mutations, c.1680-877G>T and c.3067_3072delATAGTG, showed positive clinical outcomes after ETI treatment. We demonstrate that ETI was able to increase the expression of CFTR harboring c.3067_3072delATAGTG in a heterologous system. Importantly, patient-derived nasal epithelial cells in an air-liquid interface (ALI) culture showed improved CFTR function following ETI treatment. These findings supported the initiation of ETI with the patient. Retrospective studies have suggested that the patient has shown small but steady improvement over the past two years in several clinical metrics, including lung function, body mass index (BMI), and sweat chloride levels. Our studies suggest that ETI could be beneficial for patients carrying c.3067_3072delATAGTG.

PMID:40508114 | DOI:10.3390/ijms26115306

J Clin Med. 2025 Jun 5;14(11):3978. doi: 10.3390/jcm14113978.

ABSTRACT

Fibrosis transmembrane conductance regulator (CFTR) modulators (CFTRms) have significantly improved outcomes in people with cystic fibrosis (CF). Real-world evidence, particularly from national and international CF registries, is essential to assess their long-term effectiveness and safety. We reviewed published studies using registry data to evaluate the impact of CFTRms on clinical outcomes in individuals with CF. A narrative review of studies published between 2015 and 2025 was conducted, focusing on registry-based evaluations of ivacaftor, lumacaftor/ivacaftor, tezacaftor/ivacaftor, and elexacaftor/tezacaftor/ivacaftor. Primary outcomes included lung function, pulmonary exacerbations, nutritional status, and survival. Fifty-seven registry-based studies confirmed the benefits of CFTRms across diverse CF populations. Ivacaftor has demonstrated sustained improvements in forced expiratory volume in one second (FEV1), reduced exacerbations, and improved nutritional outcomes. Lumacaftor/ivacaftor and tezacaftor/ivacaftor have shown modest benefits, especially in homozygous F508del patients. The introduction of elexacaftor/tezacaftor/ivacaftor has led to unprecedented improvements in lung function and quality of life, along with a reduced need for lung transplantation. Methodological heterogeneity and incomplete data remain challenges. Registry data provide essential, complementary evidence to clinical trials and support the effectiveness of CFTRms in routine care. Continued efforts are needed to harmonize registry methodologies and outcome measures.

PMID:40507740 | DOI:10.3390/jcm14113978

Nutrients. 2025 May 31;17(11):1890. doi: 10.3390/nu17111890.

ABSTRACT

Background/Objectives: Cystic fibrosis (CF) is a multisystem disease caused by CFTR gene variants, with a high prevalence of vitamin D (VitD) deficiency despite the supplementation and schedules specifically developed for this population. Lower VitD levels have been associated with an increased risk of respiratory infections and pulmonary exacerbations in CF, with some pilot studies indicating the potential benefits of supplementation during acute episodes. This study aimed to describe the occurrence of VitD deficiency according to the supplemented dose in pediatric patients with CF. Methods: A cross-sectional analytical study was conducted to assess serum VitD levels in a pediatric population with cystic fibrosis. Clinical and biochemical data were collected, along with information on VitD intake and pancreatic enzyme dosage at the time of evaluation. Results: A total of 48 patients were included in the study. Normal VitD levels were observed in 41.7% of the patients, insufficiency in 31.3%, and deficiency in 27%. The median VitD intake was 2050 IU. A statistically significant difference was observed in patients with a daily intake exceeding 2000 IU. Only 10% of patients achieved levels above 30 ng/mL with a lower dose. No statistically significant association was identified between the pancreatic enzyme dosage and vitamin D levels. Conclusions: Vitamin D deficiency/insufficiency is a persistent problem in the pediatric CF population; the interventions targeting factors associated with this condition are required to refine supplementation schedules. These findings underscore the need for personalized strategies to optimize vitamin D status in PwCF. Ideally, these strategies should consider all associated factors, including genetic variants; however, with limited resources, our results suggest that a daily dose of 2000 IU of vitamin D may represent a reasonable and effective starting point for supplementation.

PMID:40507160 | DOI:10.3390/nu17111890

Transplantation. 2025 Jun 13. doi: 10.1097/TP.0000000000005470. Online ahead of print.

NO ABSTRACT

PMID:40506820 | DOI:10.1097/TP.0000000000005470

JAMA Netw Open. 2025 Jun 2;8(6):e2515094. doi: 10.1001/jamanetworkopen.2025.15094.

ABSTRACT

IMPORTANCE: Atopic dermatitis (AD) is the most common inflammatory disease in childhood, and children with AD are more likely to develop other allergic diseases, including food allergy, allergic rhinitis, and asthma.

OBJECTIVE: To determine the phenotypes of AD expression across 12 US birth cohorts and identify factors associated with phenotype and development of allergic diseases.

DESIGN, SETTING, AND PARTICIPANTS: This cohort study compiled longitudinal data from 12 observational US birth cohorts across decades (children born from April 1980 to June 2019) in the Environmental Influences on Child Health Outcomes (ECHO) Children's Respiratory and Environmental Workgroup with follow-up to September 2022. Participants were enrolled prenatally; children with 3 or more AD assessments across the first 84 months of life were included in analyses. Data were analyzed from December 2020 to April 2024.

EXPOSURES: Exposures included decade of birth, cohort type (population-based or high-risk), family history of asthma (mother, father, or sibling), birth order, gestational age at birth, delivery mode, breastfeeding, pet exposure, antibiotic use, environmental tobacco smoke exposure, allergic sensitization, peripheral blood eosinophil count, and total IgE.

MAIN OUTCOMES AND MEASURES: Primary outcomes were AD phenotype, food allergy, allergic rhinitis, asthma, and wheeze. Longitudinal latent class analysis was used to identify underlying longitudinal patterns of AD expression, and associations of AD phenotype with allergic outcomes were examined using logistic regression, multinomial logistic regression, and linear regression.

RESULTS: In 5314 children from 9 cohorts (1896 born in the 2000s [35.7%]; 2585 female [48.6%]; 1083 Black or African American [20.4%]; 3344 White [62.9%]; 350 other reported race [6.6%; including 8 American Indian or Alaska Native (0.2%); 58 Asian (1.1%); 4 Native Hawaiian or Pacific Islander (0.1%) and 280 multiracial or with any race not otherwise specified (5.3%)]), 3382 (63.6%) were from a population-based cohort, while 1932 (36.4%) were from a high-risk cohort. AD prevalence ranged from 24.1% (540 children) to 28.4% (1156 children) at each time point, and 5 phenotypes of AD were identified: transient early AD, early AD with potential reoccurrence, late-onset AD, persistent AD, and minimal or no AD. Compared with White children, Black children were at higher risk for AD (transient early AD: aOR, 3.26; 95% CI, 2.06-5.18; early AD with potential reoccurrence: aOR, 3.72; 95% CI, 2.35-5.90; persistent AD: aOR, 2.01; 95% CI, 1.54-2.63), as were children with other reported race (transient early AD: aOR, 2.31; 95% CI, 1.13-4.70; early AD with potential reoccurrence: aOR, 3.27; 95% CI, 1.73-6.18). Female children were significantly less likely to have early AD with potential reoccurrence (aOR, 0.45; 95% CI, 0.27-0.74) and persistent AD (aOR, 0.60; 95% CI, 0.49-0.74) than male children. Compared with miniml or no AD, phenotypes with early AD expression were associated with food allergy (transient early AD: adjusted odds ratio [aOR], 2.15; 95% CI, 1.48-3.08; early AD with potential reoccurrence: aOR, 2.43; 95% CI, 1.66-3.50; persistent AD: aOR, 2.26; 95% CI, 1.84-2.78), later AD expression was associated with allergic rhinitis (late-onset AD: aOR, 1.84; 95% CI, 1.38-2.43; persistent AD: aOR, 2.02; 95% CI, 1.64-2.48), and any AD disease was associated with asthma.

CONCLUSIONS AND RELEVANCE: In this birth cohort study of 5314 children, timing of AD expression was associated with increased risk for atopic march pathways. Identifying risk factors for AD phenotypes may inform targeted therapeutic prevention strategies.

PMID:40504529 | PMC:PMC12163678 | DOI:10.1001/jamanetworkopen.2025.15094

Orphanet J Rare Dis. 2025 Jun 12;20(1):303. doi: 10.1186/s13023-025-03818-w.

ABSTRACT

BACKGROUND: People with a rare disease find it difficult to obtain a diagnosis and access appropriate services. Evidence suggests that this can lead to health inequity amongst the rare disease community, i.e. systemic, unfair and avoidable differences in health opportunities and outcomes. This scoping review aims to identify and describe evidence on health inequities experienced by the rare disease community with regards to receipt of a diagnosis and access to health and social care services.

METHODS: We searched ASSIA, CINAHL, Embase, HMIC, MEDLINE and Social Policy and Practice for relevant studies. Studies were double screened at title and abstract and full-text using pre-specified inclusion criteria. As this research was commissioned by the UK National Institute for Health and Care Research Policy Research Programme, primary studies were limited to UK settings. These were supplemented with international systematic reviews. We also applied a 2010 date limit. Relevant data were extracted and presented narratively and tabulated.

RESULTS: One hundred thirty-six studies met the inclusion criteria, including 96 primary studies and 40 systematic reviews. The most frequently occurring rare diseases were motor neurone disease, cystic fibrosis and sickle cell disease. Seventeen types of inequity were identified: delayed diagnosis, lack of knowledge amongst clinicians, lack of information provision, limited services provision (across six different services), limited services for undiagnosed conditions, lack of care co-ordination; in addition, inequity was identified relating to place of residence, race/ethnicity, gender, socioeconomic status, age and disability.

CONCLUSION: This review has drawn attention to experiences of the rare disease community with respect to receipt of a diagnosis and access to services which are different to experiences in the general population, and within the rare disease community itself. Some of these experiences are clearly attributable to factors which are unfair, avoidable and systemic, particularly those which relate to specific groups in the rare disease community. Experiences relating to delayed diagnosis, lack of knowledge, information, care co-ordination and access to various services, also appeared to indicate inequity. These issues are less likely to be encountered with respect to more common diseases experienced in the general population.

PMID:40506782 | DOI:10.1186/s13023-025-03818-w

J Cyst Fibros. 2025 Jun 11:S1569-1993(25)01471-7. doi: 10.1016/j.jcf.2025.05.002. Online ahead of print.

ABSTRACT

BACKGROUND: Tobacco smoke exposure (TSE) is associated with diminished benefit of ivacaftor and tezacaftor/ivacaftor in people with CF (PwCF). This study assessed the association of TSE with clinical benefit from elexacaftor/tezacaftor/ivacaftor (E/T/I), focusing on lung function (ppFEV1) and pulmonary exacerbations (PEx).

METHODS: We conducted a retrospective longitudinal analysis of data from the Cystic Fibrosis Foundation Patient Registry (2019-2021) on PwCF aged ≥ 12 years with documented prescription of E/T/I. TSE was defined by self-report of daily or weekly exposure, including living with a smoker or active smoking. Outcome measures were change in ppFEV1 and PEx after E/T/I initiation. Mixed effects modeling adjusted for sociodemographic and clinical characteristics quantified the interaction between TSE and E/T/I response.

RESULTS: In 15,005 PwCF (mean age 27.7 years, 51.9 % F508del homozygous), TSE was associated with a 2.7 % lower ppFEV1 (69.1 % vs 71.8 %, p < 0.001) before E/T/I therapy. After E/T/I initiation, ppFEV1 increased in both groups, with a similar peak ΔppFEV1 of 8.5 % at 6 months. However, after 6 months on E/T/I therapy, TSE was associated with an additional 0.03 % monthly decrease in ppFEV1, resulting in a 3.4 % lower ppFEV1 (76.3 % vs 79.7 %, p < 0.001) at the end of 2021. Smoke-exposed PwCF on E/T/I had twice the odds of a PEx compared to unexposed counterparts (OR 2.2, p < 0.001).

CONCLUSION: E/T/I increases ppFEV1 and decreases PEx in all PwCF, but this benefit is not sustained past 6 months of E/T/I therapy among those with TSE, thus widening long-term disparities in pulmonary outcomes.

PMID:40506287 | DOI:10.1016/j.jcf.2025.05.002

Eur Respir J. 2025 Jun 12:2402443. doi: 10.1183/13993003.02443-2024. Online ahead of print.

ABSTRACT

BACKGROUND: This study explores the effectiveness and safety of microbiome-directed-antimicrobial-therapy versus usual-antimicrobial-therapy in adult cystic fibrosis pulmonary exacerbations.

METHODS: A multi-centre two-arm parallel randomised control trial conducted across Europe/North-America enrolled 223 participants (January 2015 - August 2017). All participants were chronically colonised with Pseudomonas aeruginosa and were randomised 1:1 into two study-arms. The "usual-therapy group" received 2-weeks of IV ceftazidime 3g thrice-daily (for allergies: aztreonam 2g thrice-daily) and tobramycin 5-10mg·kg-1 once-daily. The "microbiome-directed group" received the same usual-therapy plus an additional antibiotic with greatest presumed activity against the 2nd, 3rd and 4th most abundant genera present in the sputum microbiome, selected by a Consensus Expert Treatment Panel. The primary outcome was change in percentage of predicted FEV1 (ppFEV1) at 14 days post initiation of antibiotics. Secondary outcomes examined ppFEV1 at 7 days, 28 days, and 3 months; time-to-next exacerbation; symptom burden at 7 days; Health Related Quality of Life (HRQoL) at 28 days; and number of exacerbations and IV antibiotic days at 12 months.

RESULTS: 149 participants had an eligible exacerbation (usual-therapy n=83, microbiome-directed therapy n=66). There was no difference between the groups for ppFEV1 at day 14 (-1.1%, 95%CI -3.9 to 1.7; p=0.46), or ppFEV1 measured at other time-points, or for time-to-next exacerbation (microbiome-directed versus usual-therapy Hazard Ratio 0.91 [95%CI 0.60 to 1.38; p=0.66]). The microbiome-directed group trended to have more IV days (median 42 versus 28; p=0.08) and more subsequent exacerbations (median 3 versus 2; p=0.044) the following year. There were no appreciable differences in symptom burden; however, HRQoL sub-scores were consistently worse in the microbiome-directed group (-4.3 points versus usual therapy (95%CI -8.3 to -0.3, p=0.033).

CONCLUSION: The addition of a third antibiotic based on sputum microbiome sequencing analysis did not result in improved clinical outcomes.

PMID:40506211 | DOI:10.1183/13993003.02443-2024

Eur J Pediatr. 2025 Jun 12;184(7):416. doi: 10.1007/s00431-025-06220-7.

ABSTRACT

The sweat test (ST) is the gold standard for the diagnosis of cystic fibrosis. There are several reports in the literature regarding conditions that are known to be associated with a false positive result. The aim of this article is to describe a previously unreported cause of a false positive ST. An observational, cross-sectional single-center study was performed. We recruited three patients with a neurosensory deafness caused by a deletion in both alleles of connexin 30. The first-degree relatives of these three patients with hearing impairment due to other mutations were also included. A ST was performed in all the selected cases. Among the three patients with a deletion in both connexin 30 alleles, two had a positive ST, whereas the third patient had a close-to-positivity borderline result (57 mmol/L). Moreover, there were no positive sweat tests in individuals with other mutation patterns.

CONCLUSION: Patients with affection of both alleles of connexin 30 were the only ones to show a positive ST, which may translate to a higher risk of hyponatremic dehydration. The reason for the ST positivity remains unclear and may be related to the fact that connexin 30 plays a role in modulating other molecules in both the inner ear and sweat glands.

WHAT IS KNOWN: • The sweat test is the gold standard for the diagnosis of cystic fibrosis. However, the causes of false positives in the test are increasingly recognized.

WHAT IS NEW: • This study describes a previously unreported cause of a false positive sweat test. Three patients with homozygous mutations in the connexin 30 gene are described. All of them had an abnormal sweat test, and two of them presented with severe hyponatremic dehydration.

PMID:40504319 | DOI:10.1007/s00431-025-06220-7

Pediatr Pulmonol. 2025 Jun;60(6):e71155. doi: 10.1002/ppul.71155.

ABSTRACT

BACKGROUND: Modulators have revolutionized cystic fibrosis (CF) management, but their effects on respiratory pathogens remain unclear. This study evaluated changes in lower respiratory tract pathogen detection after modulator therapy in children with CF, registered in the Cystic Fibrosis Registry of Turkey.

METHOD: This retrospective, multicenter cohort study included children receiving modulator therapy between 2020 and 2022. Chronic respiratory tract colonization rates before and after therapy were compared, along with inhaler treatments, oral steroid, azithromycin use, pulmonary function tests, and hospitalizations for pulmonary exacerbations. The cohort was stratified by age, modulator type, and lung disease severity. Changes in microbiologic data over a 1-year period were also analyzed for children not receiving modulator therapy.

RESULTS: A total of 101 children (mean age 9.95 ± 4.44 years) were included. Following modulator therapy, respiratory cultures of 57 (56.4%) were negative. Among 32 children with chronic Pseudomonas aeruginosa (P. aeruginosa) colonization, 14 (44%) showed negative respiratory cultures after receiving modulator therapy (p = 0.039). Conversion to culture-negative status was significant for methicillin-sensitive Staphylococcus aureus (MSSA) (p = 0.022) and methicillin-resistant Staphylococcus aureus (MRSA) (p = 0.034), with ETI therapy yielding the highest conversion rates. Inhaled antibiotic use for chronic respiratory pathogens decreased significantly (p = 0.039), and spirometry parameters improved (p < 0.001). Among 1232 children not receiving modulators, 180 (14.6%) had negative respiratory cultures when examined at 1-year interval. In the same group, intermittent/chronic P. aeruginosa colonization was negative in 58 cases, while 85 developed new growth, following modulator therapy, with positivity rates rising from 16.3% to 18.5% (p = 0.030). No significant changes in other pathogen detection were observed.

CONCLUSION: Modulators, particularly ETI, reduced respiratory pathogen detection and improved lung function in children with CF.

PMID:40504038 | DOI:10.1002/ppul.71155

Clin Exp Immunol. 2025 Jun 12:uxaf038. doi: 10.1093/cei/uxaf038. Online ahead of print.

ABSTRACT

BACKGROUND: Growing evidence links immune dysfunction, notably impaired IFNγ production, to chronic pulmonary aspergillosis (CPA), but understanding of the immune phenotype in CPA patients remains limited.

METHODS: To investigate this, we recruited 25 CPA patients and 25 controls with bronchiectasis, isolating immune cells from peripheral blood for detailed flow cytometric phenotyping at resting state and after ex vivo stimulation with the TLR2/Dectin-1 agonist Zymosan.

RESULTS: CPA patients exhibited pronounced neutrophilia and a reduced frequency of conventional dendritic cell (DC) subsets at baseline compared to bronchiectasis controls. Post-stimulation, DC and monocyte subsets in CPA patients showed significantly lower expression of activation markers. Notably, cDC1s displayed reduced IL-12p40, TNFα, and CD86 expression. CPA patients with a history of tuberculosis (TB) had significantly higher frequencies of activated cDC1s. Machine learning analysis validated these immunological parameters as predictive of CPA status.

CONCLUSION: Our findings suggest that immune dysfunction in CPA involves DC and monocyte impairments, potentially contributing to IFNγ deficiency through reduced IL-12 production and co-stimulatory capacity in cDC1s. These results also hint at the presence of innate immune memory in CPA patients with prior TB. Our study advances understanding of the immune dysfunction underlying CPA.

PMID:40503945 | DOI:10.1093/cei/uxaf038

Microbiol Spectr. 2025 Jun 12:e0318324. doi: 10.1128/spectrum.03183-24. Online ahead of print.

ABSTRACT

Bacteria are often found in polymicrobial communities where competition for limited space and resources drives antagonistic interactions. Therefore, bacteria have evolved various antibacterial weapons to outcompete their neighbors. These antagonistic interactions can have profound effects on the structure, dynamics, and composition of bacterial communities. To study interactions between two bacterial species, co-culture assays are often employed. The most common approach utilizes selection plates for each bacterial species to quantify recovery after co-incubation. Although this method is relatively accurate and inexpensive, there are some limitations. These assays can be time-consuming, low-throughput, and may present difficulties if the bacteria of interest show similar resistance patterns to one another or if the tolerance to selective agents is unknown. Here, we have developed and validated a method that uses fluorescence as a proxy to screen antibacterial interactions between two species. We utilized two fluorescently tagged bacteria, Staphylococcus aureus JE2 and Escherichia coli DH5⍺, both expressing a red fluorescent protein (RFP), and competed them against non-fluorescent bacteria: two strains of Pseudomonas aeruginosa or one strain of Stenotrophomonas maltophilia. We observed that RFP production correlates with growth in the reporter strains and that a reduction in relative fluorescent units from the reporter strains corresponds with a reduction in colony-forming units. This method is fast, semi-quantitative, semi-high-throughput, and can be used to rapidly screen for antagonistic activity during bacterial co-cultures. We propose that our protocol can be a useful tool to detect antibacterial activity using fluorescently labeled target bacteria.IMPORTANCEIn nature, bacteria often reside in communities where limited space and resources drive competition. Bacterial antagonistic interactions can profoundly affect microbial communities. A common approach to study these interactions is to measure the recovery of each bacterium after competition by using selective media. While relatively accurate and inexpensive, this approach has a few limitations: the assay can be labor-intensive and time-consuming, is low throughput, and can present issues when the bacterial strains of interest have similar antimicrobial resistance or if their resistance profile is unknown. We developed and validated a fast and semi-high-throughput protocol that gauges antagonistic bacterial interactions using fluorescence as a proxy. As proof of principle, this screening protocol was tested with known antagonistic bacteria, using a fluorescently labeled target bacterium.

PMID:40503833 | DOI:10.1128/spectrum.03183-24

Expert Rev Respir Med. 2025 Jun 12. doi: 10.1080/17476348.2025.2517898. Online ahead of print.

ABSTRACT

INTRODUCTION: For many years the major cause of morbidity and mortality in people with cystic fibrosis (PWCF) was lung disease, characterized by progressive airway inflammation, bacterial colonization and premature death. With the advent of highly effective modulator therapies (HEMT) many of the parameters predicting premature death have been beneficially altered with resultant predicted improvement in survival. It is unknown how much residual airway inflammation will persist in PWCF on HEMT, whether bacterial colonization will be eradicated and whether the beneficial effects decrease over times. In addition, a significant number of PWCF cannot avail of HEMT.

AREAS COVERED: We discuss pathogenesis of airways disease in CF, airway inflammation and bacterial colonization in PWCF on and off HEMT, and whether new anti-inflammatory strategies are required to decrease residual inflammation and improve bacterial eradication. We discuss the potential therapeutic options for those PWCF for whom HEMT are not an option.

EXPERT OPINION: PWCF on HEMT may expect prolonged survival but in many, particularly those in whom HEMT therapy was instituted after the onset of structural lung disease there will be persistent inflammation requiring further therapy.

PMID:40503676 | DOI:10.1080/17476348.2025.2517898

Can J Hosp Pharm. 2025 Jun 11;78(2):e3700. doi: 10.4212/cjhp.3700. eCollection 2025.

NO ABSTRACT

PMID:40503554 | PMC:PMC12119097 | DOI:10.4212/cjhp.3700

Eur J Case Rep Intern Med. 2025 May 13;12(6):005373. doi: 10.12890/2025_005373. eCollection 2025.

ABSTRACT

INTRODUCTION: Cystic fibrosis, an autosomal recessive disorder (1 in 3,000-6,000 births), causes thick mucus and recurrent lung infections. Improved survival has revealed rare complications such as constrictive pericarditis and cardiac tamponade.

CASE DESCRIPTION: A 24-year-old female with cystic fibrosis, diagnosed at nine months, presented with two weeks of dyspnoea. Examination revealed bilateral rhonchi, facial oedema and non-pitting thigh oedema. Laboratory results showed a white blood cell count of 11.3 ×109/l, erythrocyte sedimentation rate of 99 mm/hr and C-reactive protein level of 45.3 mg/dl. Initially admitted for cystic fibrosis exacerbation, she was found to have pericardial effusion. Despite facial and lower extremity swelling, she denied cardiac symptoms. During hospitalisation, she developed haemodynamic instability requiring pericardiocentesis, with echocardiography confirming constrictive pericarditis. Chest computed tomography angiography showed pericardial calcifications; autoimmune workup was negative. She was discharged on colchicine with close follow-up.

CONCLUSION: Clinicians should have a high index of suspicion for underlying cardiac complications in patients presenting with exacerbations of cystic fibrosis.

LEARNING POINTS: Pericardial disease - including constrictive pericarditis and tamponade - though rare, can complicate cystic fibrosis in adults and may mimic pulmonary exacerbations. Early cardiac imaging is crucial for timely diagnosis.This case highlights the need for a high index of suspicion in cystic fibrosis patients with unexplained dyspnoea, oedema or haemodynamic instability, especially in the setting of pericardial calcifications.Medical management with colchicine and diuretics can be effective in selected cystic fibrosis patients with constrictive physiology, potentially avoiding the need for invasive pericardiectomy.

PMID:40502958 | PMC:PMC12151577 | DOI:10.12890/2025_005373

bioRxiv [Preprint]. 2025 May 28:2025.05.25.656006. doi: 10.1101/2025.05.25.656006.

ABSTRACT

Pancreatitis is a potentially fatal and difficult to control exocrine-tissue defect with no FDA approved therapies to date. Variants of a chloride/bicarbonate transporter cystic fibrosis transmembrane conductance regulator (CFTR), increase the risk of pancreatitis by two- to three-fold in up to 40% of the patients. However, the relationship between the duct-restricted CFTR-function and total exocrine tissue defect during pancreatitis remains less known and animal models do not clearly translate to human disease. To overcome this challenge, we developed a robust iPSC-derived model system of pancreatic ductal tissues from an idiopathic pancreatitis patient with a common CFTR variant to understand CFTR-associated ductal tissue pancreatitis leading to the complete exocrine defect. In the patient line termed PANx, we found deficient CFTR function as well as a distinct gene expression signature for ductal tissue pancreatitis marked by aberrant mucin production, inflammatory cytokines and pancreatic neoplasms. By applying clinically used CFTR-modulator drug ivacaftor, we observed a remarkable restoration of deficient CFTR-mediated fluid secretion as well as upto 40% reversal of the differential gene signature for PANx including the reduction in mucinous neoplasms and cytokines such as IL-11, CCL20 and CXCL8 that drive immune cell infilteration during pancreatitis. We further employed a microsystem device that modeled pancreatitis-associated hyperamylasemia, a diagnostic feature of acute pancreatitis attack, due to a ductal reaction affecting acinar cell-released amylase and viability. The key mucinous signature was validated in primary pancreatitis ductal tissues with a CFTR variant. Overall, we unraveled new layers of CFTR-related pathology in pancreatitis to help us better understand the course of this debilitating condition. Additionally, the test methods and model systems discovered in this study will significantly expedite the discovery of diagnostic and therapeutic tools for treating idiopathic pancreatitis. For the first time, we provided molecular and physiologic evidence supporting the benefit of CFTR modulator drug ivacaftor in human CFTR-related pancreatitis.

PMID:40502040 | PMC:PMC12154907 | DOI:10.1101/2025.05.25.656006