Respir Med Res. 2025 Jun 16;88:101186. doi: 10.1016/j.resmer.2025.101186. Online ahead of print.

ABSTRACT

BACKGROUND: Cystic fibrosis (CF) patients often undergo treatment with CFTR modulators, which have demonstrated high efficacy but also potential involvement in drug interactions. Inquiries regarding the risks of drug interactions with complementary and alternative medicine products (CAMp) and self-medication drugs have become frequent among patients and prescribers at Toulouse University Hospital. Currently, there is lack of literature on these practices within CF patients, particularly in France, and more so since the advent of CFTR modulators.

METHODS: This observational monocentric study (MUCAUTOMED) aimed to characterize and quantify the prevalence of CAMp utilization among CF patients under our hospital's care. A secondary objective was to assess and describe the prevalence of self-medication practices. Surveys were administered to outpatients during visits from January 10 to June 6, 2022.

RESULTS: Out of 171 included patients, responses from 64 adults and 69 children were analyzed (response rate 133/171 = 77.8 %). CAMp usage was reported by 56.3 % of adults and 46.4 % of children. Most patients use CAMp for enhancing wellness, addressing digestive concerns, and managing respiratory issues. Remarkably, 71.4 % of participants were unaware of potential drug interactions with CAMp, and 48.9 % initiated such use without consulting healthcare professionals. Notably, a significant correlation between CAMp utilization and self-medication was identified within the pediatric population.

CONCLUSION: Our investigation underscores a notably high prevalence of CAMp use among the CF population. Given these findings, it is imperative to routinely discuss CAMp utilization and self-medication practices when initiating CFTR modulator therapy. A multidisciplinary approach is recommended to address potential interactions that may impact overdosing and underdosing, ensuring patients and families are informed of associated risks. Registration number 2021-A02593-38.

PMID:40768781 | DOI:10.1016/j.resmer.2025.101186

Proc Natl Acad Sci U S A. 2025 Aug 12;122(32):e2506821122. doi: 10.1073/pnas.2506821122. Epub 2025 Aug 6.

ABSTRACT

The emergence of immune-evasive SARS-CoV-2 Omicron subvariants highlights the need to develop a mucosal SARS-CoV-2 vaccine that can provide broad protection against virus infection and transmission. Here, we developed an intranasal monovalent SARS-CoV-2 vaccine expressing the six-proline-stabilized prefusion spike proteins (preS-6P) of Omicron XBB.1.5 based on the attenuated mumps virus (MuV) Jeryl Lynn (JL1) vaccine strain. We also developed an intranasal trivalent vaccine expressing the preS-6P of ancestral SARS-CoV-2 WA1 and two Omicron subvariants, BA.1 and XBB.1.5, using the attenuated measles virus (MeV) and MuV-JL1 and JL2 vaccine strains, respectively. Intranasal immunization of hamsters with the monovalent rMuV-JL1-XBB.1.5 or the trivalent vaccine induced high levels of neutralizing antibodies (NAbs) that efficiently neutralized Omicron subvariants XBB.1.5, EG.5, and JN.1, providing complete protection against these Omicron subvariants. Similar levels of Omicron XBB.1.5 NAbs were detected in monovalent rMuV-JL1-XBB.1.5 and trivalent vaccine groups even when hamsters had been preimmunized with the rMuV-JL2-WA1 vaccine, suggesting that both intranasal vaccines are effective in the presence of immune imprinting induced by the spike of SARS-CoV-2 WA1. Intranasal, but not subcutaneous, immunization generated high levels of S-specific mucosal IgA antibodies as well as lung-resident memory T cells in IFNAR1-/- mice. Finally, intranasal immunization with the trivalent vaccine efficiently blocked transmission of SARS-CoV-2 WA1 and Omicron XBB.1.5 among hamsters in a direct contact transmission setting. In summary, we have developed intranasal MeV and MuV-based trivalent vaccines that induce broad NAbs, robust mucosal immunity, and strong protection against both virus challenge and virus transmission.

PMID:40768351 | DOI:10.1073/pnas.2506821122

Phytother Res. 2025 Aug 6. doi: 10.1002/ptr.8367. Online ahead of print.

ABSTRACT

The increasing prevalence of inflammatory diseases in the respiratory tract worldwide has raised concerns, and due to its high prevalence and poor prognosis, it remains a clinical focus and research hotspot. These inflammatory diseases include airway inflammation, asthma, bacterial antigens-induced tonsil epithelial inflammation, chronic obstructive pulmonary disease (COPD), cystic fibrosis (CF), COVID-19, acute lung injury, and lung cancer. This review summarizes the relevant molecular mechanisms of inflammatory diseases in the respiratory tract and the progress of natural bioactive components in inflammatory diseases in the respiratory tract. The natural bioactive components have good therapeutic or intervention effects on inflammatory airway diseases in vitro, in vivo, and in clinical trials. The information on inflammatory diseases in the respiratory tract and natural bioactive ingredients in anti-inflammatory diseases were collected from famous literature databases such as Web of Science, PubMed, and Google Scholar, with keywords including bioactive components, inflammatory diseases, respiratory tract, and so forth. The bioactive phytochemicals, such as curcumin, ginsenoside, safranal, melatonin, could improve inflammatory diseases through the regulation of PI3K/Akt, NF-κB, NRF2/HO-1, MAPK, cAMP-PKA, and MEK/ERK Signaling pathways. Further high-quality studies are still needed to firmly establish the clinical efficacy of bioactive ingredients. This review provides new insight for future research on functional food or drug-lead compound development on natural products improving inflammatory diseases in the respiratory tract.

PMID:40767628 | DOI:10.1002/ptr.8367

J Asthma. 2025 Aug 6:1-12. doi: 10.1080/02770903.2025.2494233. Online ahead of print.

ABSTRACT

OBJECTIVE: Age of asthma onset is critical for determining heterogeneous asthma phenotypes. How onset and duration affect therapeutic response is not well understood. Phase 3 QUEST (NCT02414854) and open-label extension TRAVERSE (NCT02134028) studies demonstrated dupilumab's efficacy up to three years in patients ≥12 years with uncontrolled, moderate-to-severe asthma. We assessed how age of asthma onset and asthma duration affect clinical efficacy of dupilumab in patients with moderate-to-severe type 2 inflammatory asthma.

METHODS: This post hoc analysis included patients with type 2 asthma from QUEST who enrolled in TRAVERSE. Annualized severe exacerbation rates (AER), change from parent study baseline (PSBL) in pre-bronchodilator forced expiratory volume in 1 s (FEV1), and five-item Asthma Control Questionnaire (ACQ-5) score were assessed according to asthma age of onset (<18 years, 18-40 years, >40 years) and duration (<20 years, ≥20 years).

RESULTS: In all subgroups, treatment with dupilumab through QUEST and TRAVERSE progressively reduced AER (TRAVERSE Week 48-96 range, 0.160-0.333), increased pre-bronchodilator FEV1 (TRAVERSE Week 96 change from PSBL range, 0.20-0.44 L), and reduced ACQ-5 scores (TRAVERSE Week 48 change from PSBL range, -1.63 to -1.84). In patients who received placebo during QUEST, treatment with dupilumab in TRAVERSE improved AER, FEV1, and ACQ-5 in all subgroups.

CONCLUSIONS: In patients with uncontrolled, moderate-to-severe type 2 asthma, treatment with dupilumab provides sustained, long-term exacerbation rate reductions and improvements in lung function and asthma control, across all subgroups, with higher reductions in AER and improvements in pre-bronchodilator FEV1 seen in patients with later onset or longer duration.

PMID:40767333 | DOI:10.1080/02770903.2025.2494233

Health Sci Rep. 2025 Aug 5;8(8):e71142. doi: 10.1002/hsr2.71142. eCollection 2025 Aug.

ABSTRACT

BACKGROUND AND AIMS: People with cystic fibrosis (pwCF) often have vitamin D deficiency and require vitamin D supplementation. The primary objective of this study was to evaluate the impact of ultrahigh dose cholecalciferol ("stoss dosing") in pwCF with variable adherence to maintenance cholecalciferol.

METHODS: Retrospective cohort study of pwCF who received initial stoss dose per protocol between January 2017 and November 2021 at University of Iowa Health Care adult and pediatric CF centers. Serum 25(OH)D concentrations were extracted from the EMR. The increase in serum 25(OH)D concentration associated with receiving stoss doses was evaluated using a longitudinal linear mixed effects regression model.

RESULTS: Fifty-eight patients were included in the final analysis. The mean baseline 25(OH)D concentration before stoss therapy was 20.1 ng/mL (standard deviation [SD] = 5.9). The mean serum 25(OH)D concentration following stoss therapy increased to 27.9 ng/mL (SD = 7.5) and was measured on average 116 days after stoss administration. For patients with self-reported non-adherence to vitamin regimens, 16 out of 20 (80%) achieved a serum 25(OH)D concentration of at least 30 ng/mL after stoss therapy.

CONCLUSIONS: Our findings suggest that stoss dosing was associated with increased serum 25(OH)D concentrations. This benefit also existed for individuals with self-reported non-adherence to maintenance cholecalciferol regimens with most patients reaching concentration goals.

PMID:40766771 | PMC:PMC12322582 | DOI:10.1002/hsr2.71142

Respirol Case Rep. 2025 Aug 4;13(8):e70308. doi: 10.1002/rcr2.70308. eCollection 2025 Aug.

ABSTRACT

People with cystic fibrosis (CF) typically experience chronic respiratory infections, but neurological sequelae are rare. Guillain-Barre Syndrome (GBS) is classically precipitated by a respiratory or gastrointestinal infection, although other rarer aetiologies exist. This case series outlines four adults with CF who developed GBS. The association with acute and chronic respiratory infections in people with CF is explored, as well as other potential precipitants. An autoimmune phenomenon in the context of chronic systemic inflammation or a possible contributory role of dysfunctional CFTR protein is also considered.

PMID:40766167 | PMC:PMC12322314 | DOI:10.1002/rcr2.70308

Respir Med Case Rep. 2025 Jul 22;57:102267. doi: 10.1016/j.rmcr.2025.102267. eCollection 2025.

ABSTRACT

Prompt eradication of Pseudomonas aeruginosa following isolation in sputum samples is a fundamental part of therapy in people with cystic fibrosis in order to prevent chronic infection. Whilst multiple eradication regimens exist, none have been proven to be more efficacious than any other. Eradication treatment is effective but not always successful. Ciprofloxacin has been the preferred choice of oral antimicrobial in these eradication regimens due to its superior in-vitro activity against Pseudomonas aeruginosa compared to other fluoroquinolones. Delafloxacin, a fourth-generation fluoroquinolone, has been shown to have superior activity against Pseudomonas aeruginosa compared to ciprofloxacin in-vitro. We show herein, what we believe is the first documented successful eradication of Pseudomonas aeruginosa in a person with CF following a new isolation of the pathogen using oral delafloxacin in combination with nebulised tobramycin, instead of ciprofloxacin after the failure of first line treatment and the emergence of ciprofloxacin-resistance on antimicrobial sensitivity testing.

PMID:40761664 | PMC:PMC12320081 | DOI:10.1016/j.rmcr.2025.102267

ERJ Open Res. 2025 Aug 4;11(4):01248-2024. doi: 10.1183/23120541.01248-2024. eCollection 2025 Jul.

ABSTRACT

BACKGROUND: Elexacaftor/tezacaftor/ivacaftor (ETI) has improved outcomes for people with cystic fibrosis (pwCF). This study evaluated changes in airway microbiological infection status after initiating ETI.

METHODS: Using the European Cystic Fibrosis Society registry, pwCF who started ETI between 2019 and 2021 were identified. The changes in microbiological status from 1 year before to 1 year after ETI initiation, were compared with the changes seen from 3 to 1 years before starting ETI. Mixed-effect regression models were used to analyse changes. Data from 2 years after initiation were examined for those starting ETI in 2019-2020.

RESULTS: Included were 15 739 pwCF from 30 countries. In the year before ETI, 38.4% were positive for Pseudomonas aeruginosa (PsA) and 36.4% for methicillin-sensitive Staphylococcus aureus (MSSA). After ETI, 38.7% of PsA-positive and 47.2% of MSSA-positive patients transitioned to negative status, compared with 14.8% and 29.1%, respectively, in the previous years. The adjusted difference in transitioning to negative was 14.6% (PsA) and 17.1% (MSSA), both p<0.001. Similar improvements were seen for Burkholderia cepacia complex and Stenotrophomonas maltophilia. For those starting ETI in 2019-2020, PsA positivity remained low over 2 years, decreasing from 46.8% pre-ETI to 30.4% and 27.7% at 1 and 2 years after ETI treatment.

CONCLUSION: One year after starting ETI, many pwCF who were initially positive for various CF-related pathogens, shifted to a negative status, a change less common before ETI. These findings suggest that ETI reduces airway infections, with benefits extending into the second year of treatment, although some pwCF continue to carry these pathogens despite treatment.

PMID:40761658 | PMC:PMC12320108 | DOI:10.1183/23120541.01248-2024

ERJ Open Res. 2025 Aug 4;11(4):00211-2025. doi: 10.1183/23120541.00211-2025. eCollection 2025 Jul.

ABSTRACT

ETI reduces pathogen detection rates in respiratory samples, yet a significant proportion of pwCF continue to harbour hallmark pathogens putting them at risk of more rapid decline in lung function https://bit.ly/3DAcKKH.

PMID:40761647 | PMC:PMC12320102 | DOI:10.1183/23120541.00211-2025

APMIS. 2025 Aug;133(8):e70058. doi: 10.1111/apm.70058.

ABSTRACT

Cystic fibrosis (CF) is commonly associated with musculoskeletal issues including inflammatory arthritis, CF arthritis. We present a retrospective cohort study which aims to describe the clinical characteristics, prevalence, and demographic associations of CF arthritis using both a clinical and literature cohort. We identified adult CF patients (≥ 18 years) with arthritis from the rheumatology clinic at Rigshospitalet (2020-2022). The clinical cohort (CC) was reviewed through electronic medical records. Literature cases were identified by searching online databases for relevant studies, case reports, and reviews on CF arthritis. Eleven CF patients with arthritis were identified (CC) from our clinic and 54 cases from the literature (literature cohort, LC). Both cohorts showed equal gender distribution. In the LC, arthritis onset had a median age of 11 years (range 2-28), while in the CC it was 26 years (range 13-43). Clinical features were similar in both cohorts: the majority had episodic relapsing arthritis, with two-thirds having mono-/oligoarthritis and one-third polyarthritis. Large joints were most commonly affected. No clear link to pulmonary disease or serologic markers was found. Immunosuppressive treatment was safe. CF arthritis is a heterogeneous condition, presenting as non-erosive, episodic oligo- or polyarthritis affecting both large and small joints.

PMID:40761185 | DOI:10.1111/apm.70058

J Biol Chem. 2025 Aug 2:110559. doi: 10.1016/j.jbc.2025.110559. Online ahead of print.

ABSTRACT

Guanylate cyclase 2C (GCC) upon binding to the bacterial heat-stable enterotoxin ST, generates excessive cGMP, driving intestinal chloride and fluid secretion that manifests as diarrhea. We investigated the regulatory mechanism of GCC through its interactions with Scaffolding proteins sodium-hydrogen exchanger regulatory factor (NHERF)1-4. PSD95, Dlg1, ZO-1 (PDZ) domain in NHERF4 inhibited GCC catalytic activity while NHERF1-3 binary binding had no impact. NHERF4-mediated inhibition was mimicked by two synergistically acting peptides, (N4-110 [NH2-LERPRFCLL-COOH] and N4-195 [NH2-RHAHDVARAQLG-COOH]), localized in close proximity within the PDZ1 domain. These peptides, which show high sequence homology to the GCC catalytic domain, were mapped via 3-D structural modeling to the GCC dimer interface. Fluorescence resonance energy transfer (FRET) analysis confirmed that NHERF4-PDZ1 domain binding interfered with GCC oligomerization. In mouse and human enteroid models, NHERF4 peptides dose-dependently reduced GCC-mediated fluid secretion. Additionally, NHERF4-GCC interaction was enhanced upon ST stimulation, suggesting NHERF4 functions as a negative regulator of aberrant GCC activity during enterotoxin-induced diarrhea. Furthermore, we described macromolecular complex of GCC with multi-drug resistance protein 4 (MRP4), a cAMP/cGMP efflux transporter, in the regulation of fluid secretion through NHERF3 mediated assembly. Overall, our findings reveal novel regulatory mechanisms for GCC, offering insights into targeted therapies for enterotoxin-triggered diarrheas.

PMID:40759370 | DOI:10.1016/j.jbc.2025.110559

Am J Respir Crit Care Med. 2025 Aug 4. doi: 10.1164/rccm.202501-0186OC. Online ahead of print.

ABSTRACT

RATIONALE: Primary ciliary dyskinesia (PCD) is a rare respiratory disorder of motile cilia caused by pathogenic variants in >50 known genes. Genetic testing routinely examines the coding regions of these genes and bi-allelic pathogenic variants are reported in up to 70% of patients. Many patients remain with an incomplete or no genetic diagnosis.

OBJECTIVES: To retrospectively analyse the diagnostic yield in 497 patients referred for genetic testing and the increase in yield by investigating pathogenic DNA variants in the non-coding regions of PCD genes, in 42 patients with an incomplete genetic diagnosis.

METHODS: End-to-end next-generation gene sequencing including coding and non-coding regions of 17 PCD genes was performed, following routine genetic diagnosis of a panel of 46+ genes. Intronic variants were prioritised for pathogenicity using in silico tools to predict splice effects, that were subsequently confirmed in RNA extracted from nasal epithelium.

MAIN RESULTS: 232 of 496 patients (46.8%) had a complete genetic diagnosis of PCD after stringent variant assessment during routine genetic testing. Eighty-six patients (17.3%) had an incomplete genetic diagnosis, 42 of whom had end-to-end gene sequencing. Novel, potentially pathogenic, non-coding variants were identified in 16 of 42 patients (38.1%). Three recurrent deep-intronic variants were found.

CONCLUSION: Diagnostic yield for PCD is increased by end-to-end gene sequencing. Non-coding variants that affect splicing are recurrent and are an important source of pathogenic genomic variation in patients with PCD. This work illustrates the potential clinical utility of end-to-end geneor genome sequencing for PCD.

PMID:40758541 | DOI:10.1164/rccm.202501-0186OC

Lancet Respir Med. 2025 Aug;13(8):698-708. doi: 10.1016/S2213-2600(25)00089-X. Epub 2025 Jun 16.

ABSTRACT

BACKGROUND: Despite increasing recognition of bronchiectasis worldwide, there are no multicountry data characterising bronchiectasis in children. We aimed to describe clinical features, comparing inter-country and regional variations, and describe indices of overall quality-of-care standards assessed against international consensus statements for children and young people with bronchiectasis.

METHODS: Child-BEAR-Net is an international collaborative paediatric bronchiectasis network across several continents. Using our International Paediatric Bronchiectasis Registry data from secondary and tertiary hospitals across eight countries, we conducted a multicentre, cross-sectional cohort study of all patients in the registry younger than 18 years diagnosed with bronchiectasis. Data were grouped into four geographical regions: Australia, South Africa, Greece-Italy-Spain, and Albania-Türkiye-Ukraine. Patients with cystic fibrosis or a history of heart or lung transplantation were excluded. We assessed baseline clinical characteristics, causes, treatments, and quality-of-care indicators, and compared findings across regions. Data were analysed using descriptive statistics and non-parametric tests for between-group comparisons.

FINDINGS: Between June 1, 2020, and Feb 9, 2024, 408 patients were enrolled (median age at diagnosis 6·0 years [IQR 3·2-9·0]; 229 (56%) male and 179 (44%) female patients). The most common underlying causes were post-infection (127 [31%]), primary and secondary immunodeficiencies (79 [19%]), and known genetic disorders (55 [13%]). Common comorbidities included asthma (70 [17%]), otorhinolaryngeal disorders (58 [14%]), and congenital major airway malformation (51 [13%]). In the previous 12 months, 106 (38%) had at least three exacerbations and 89 (49%) required hospitalisation at least once. 107 (27%) of 400 reported daily sputum. Lung function was normal in 133 (59%) of 227 patients but with considerable between-group differences (median forced vital capacity Z score ranged from -0·12 [-0·95 to 0·65] in Australia to -1·54 [-3·39 to -0·04] in South Africa). We found marked inter-group differences in lower airway bacteria (Haemophilus influenzae in 56 [70%] of 80 patients in Australia to three [16%] of 19 in Albania-Türkiye-Ukraine; Pseudomonas aeruginosa in eight [24%] of 34 in South Africa to one [5%] in Albania-Türkiye-Ukraine), treatment (long-term azithromycin for 47 [50%] of 94 in Greece-Italy-Spain to 15 [19%] of 79 in Albania-Türkiye-Ukraine; and inhaled corticosteroids for 48 [61%] in Albania-Türkiye-Ukraine to 28 [22%] of 126 in Australia), and radiographic markers (cystic bronchiectasis in 49 [45%] of 109 in South Africa to three [2%] of 126 in Australia [p<0·0001]). In quality-of-care standard markers, the recommended panel of investigations was done in 66-95% of patients; only 78 (47%) of 167 saw a paediatric physiotherapist in the previous 12 months.

INTERPRETATION: Our study presents the first internationally derived paediatric registry data highlighting geographical variations in cause, lung function, bacteriology, and treatment in children and young people with bronchiectasis, as well as the need to improve quality care.

FUNDING: None.

PMID:40757932 | DOI:10.1016/S2213-2600(25)00089-X

J Community Hosp Intern Med Perspect. 2025 Jul 3;15(4):66-68. doi: 10.55729/2000-9666.1497. eCollection 2025.

ABSTRACT

Familial hypocalciuric hypercalcemia (FHH) is a rare autosomal dominant condition caused by mutations in the calcium-sensing receptor gene (CASR), leading to asymptomatic hypercalcemia. Here, we report a case of hypercalcemia in a patient with acute pancreatitis, subsequently diagnosed with FHH. A 41-year-old male presented with abdominal pain and elevated pancreatic enzymes. Imaging revealed changes consistent with acute pancreatitis. Surprisingly, serum calcium was elevated, which is uncommon in acute pancreatitis. Further work-up demonstrated normal parathyroid hormone (PTH), PTH-related peptide (PTHrp), and vitamin D levels. A 24-h urinary calcium excretion of 24 mg/24 h and a calcium to creatinine clearance ratio (CCCR) of 0.002 confirmed the diagnosis of FHH. This condition is typically asymptomatic, with few complications, and is managed conservatively with patient education and genetic counselling.

PMID:40757212 | PMC:PMC12315876 | DOI:10.55729/2000-9666.1497

Respir Med Case Rep. 2025 Jul 24;57:102264. doi: 10.1016/j.rmcr.2025.102264. eCollection 2025.

ABSTRACT

BACKGROUND: The missense CFTR variant I1234V (c.3700A > G) produces class II protein-folding defects and is prevalent in the Middle East, yet clinical evidence for elexacaftor/tezacaftor/ivacaftor (ETI) in homozygous carriers is sparse. We prospectively evaluated ETI efficacy and safety in two paediatric siblings with homozygous I1234V cystic fibrosis (CF).

METHODS: A single-centre, prospective case series was undertaken at King Fahad Medical City. Baseline assessments included spirometry, body-mass index (BMI), sputum microbiology, liver biochemistry and high-resolution chest CT. ETI was initiated according to weight-based dosing and patients were reviewed at 6 and 8 months. Primary outcomes were change in percent-predicted forced expiratory volume in 1 second (ppFEV1) and BMI; secondary outcomes were Pseudomonas aeruginosa status, radiological changes and adverse events.

RESULTS: After eight months of ETI, ppFEV1 increased from 36 % to 46 % in the 11-year-old girl and from 57 % to 73 % in the 9-year-old boy. Corresponding BMI rose from 11.71 kg/m2 (z = -4.37) to 15.48 kg/m2 (z = -1.22) and from 12.69 kg/m2 (z = -3.12) to 15.74 kg/m2 (z = -0.55), respectively. Chronic P. aeruginosa was eradicated in both patients. Chest CT demonstrated reduced mucus plugging and peribronchial wall thickening with partial regression of cystic bronchiectasis.

CONCLUSIONS: ETI produced clinically meaningful improvements in lung function, nutritional status, microbiological clearance and radiological appearance in two children homozygous for the rare I1234V mutation. These real-world findings support extending ETI access to patients with rare class II CFTR variants and justify larger multicentre studies to confirm efficacy and long-term safety.

PMID:40755839 | PMC:PMC12318305 | DOI:10.1016/j.rmcr.2025.102264

Cureus. 2025 Jul 4;17(7):e87264. doi: 10.7759/cureus.87264. eCollection 2025 Jul.

ABSTRACT

Hypereosinophilic syndrome (HES) is a rare condition characterized by persistent eosinophilia (eosinophil count ≥1.5 × 109/L) and end-organ damage in the absence of an identifiable cause. Cardiac involvement is common and may lead to life-threatening complications. Cystic fibrosis (CF) is a chronic multisystem disease predominantly associated with neutrophilic inflammation, and eosinophilic disorders are less often reported in this population. A 32-year-old woman with CF, complicated by CF-related diabetes and pancreatic insufficiency, presented with chest pain and peripheral eosinophilia (3.2 × 10⁹/L); infectious, autoimmune, and allergic evaluations were negative. Imaging revealed perimyocarditis, and systemic corticosteroids were initially effective but discontinued due to cushingoid side effects and anasarca. She subsequently experienced a recurrence of chest pain accompanied by eosinophilia (1.7 × 10⁹/L), and a diagnosis of idiopathic HES was made based on persistent eosinophilia, cardiac involvement, and exclusion of secondary causes. She responded favorably to monthly subcutaneous mepolizumab, a monoclonal antibody that prevents interleukin-5 (IL-5) from binding to its receptor, thereby inhibiting the recruitment and activation of eosinophils, with resolution of eosinophilia and improvement in symptoms. This case underscores the importance of considering HES in CF patients presenting with unexplained eosinophilia and extrapulmonary symptoms. It also illustrates the efficacy of targeted biologic therapy in managing idiopathic HES when corticosteroids are poorly tolerated.

PMID:40755600 | PMC:PMC12318349 | DOI:10.7759/cureus.87264

J Cyst Fibros. 2025 Aug 2:S1569-1993(25)01538-3. doi: 10.1016/j.jcf.2025.07.015. Online ahead of print.

ABSTRACT

BACKGROUND: Data from cystic fibrosis (CF) animal models and case studies suggests that in utero administration of CF transmembrane conductance regulator (CFTR) modulators (variant specific therapies, VST) can rescue CFTR-related pathophysiology in the fetus. Use of VST during pregnancy to prevent disease in infants has not been systematically studied. Through stakeholder engagement, we sought to determine if formal research evaluation is warranted.

METHODS: We surveyed CF care center directors to assess their awareness of the potential off-label use of VST for in utero treatment of a fetus with CF. We then conducted a one-day, international multidisciplinary workshop to review available pre-clinical and clinical data, embryology principles and federal drug regulation considerations, identify knowledge gaps, and consider future clinical study designs.

RESULTS: Sixty-two unique individuals responded to the survey; 92% were aware of use of VST to treat pregnant females who are CF carriers for the prevention of CF complications in the fetus. Expert workshop presentations suggested that use of VST in pregnant females carrying a fetus with CF to mitigate complications of CF is relatively safe and effective in animal models and human case series to date. Further research is needed to understand the optimal timing of VST initiation during pregnancy to improve clinical outcomes, to understand VST pharmacokinetics, and optimize dosing of VST during pregnancy and lactation, and to evaluate the long-term infant safety among those exposed to VST in utero.

CONCLUSIONS: Based on available data and knowledge gaps, stakeholders agreed that formal evaluation of in utero and early life VST therapy in a prospective trial is warranted.

PMID:40754574 | DOI:10.1016/j.jcf.2025.07.015

Clin Pharmacokinet. 2025 Aug 3. doi: 10.1007/s40262-025-01550-z. Online ahead of print.

ABSTRACT

BACKGROUND AND OBJECTIVES: Brensocatib, an oral, competitive, and reversible inhibitor of dipeptidyl peptidase 1 (DPP1), reduces exacerbations and lung function decline in non-cystic fibrosis bronchiectasis (NCFBE). This study aimed to evaluate the pharmacokinetics (PK), pharmacodynamics (PD), safety, and tolerability of brensocatib in adults with cystic fibrosis (CF), comparing these findings with data from previous trials in healthy adults and in those with NCFBE to inform dose selection for future clinical trials.

METHODS: A phase IIa, single-blind, randomized, placebo-controlled trial was conducted to assess the PK, PD, safety, and tolerability of brensocatib in adults with CF. Participants were randomly assigned to receive once-daily brensocatib (10 mg, 25 mg, or 40 mg) or placebo for 28 days. The study planned enrollment of up to 34 adults, stratified on the basis of their CF transmembrane conductance regulator (CFTR) modulator use, to evaluate the PK profile of brensocatib and its safety compared with placebo. Primary PK parameters, including maximum plasma concentration (Cmax), time to maximum concentration (Tmax), area under the concentration-time curve from 0 to 24 h (AUC0-24), and half-life (t1/2), were determined on day 1 and day 28. Dose-dependency of brensocatib exposure was analyzed, and safety and tolerability were assessed through treatment-emergent adverse events. Data from participants were compared with previous data from healthy adults and from those with NCFBE.

RESULTS: A total of 29 participants were randomized to treatment, with 21 stratified to the CFTR modulator group. Baseline characteristics were similar among cohorts. Mean age was 37.9 (standard deviation (SD) 14.6) years, and most participants exhibited mild-to-moderate lung disease. PK analysis showed dose-dependent and predictable brensocatib exposure, with comparable profiles between participants with and without use of CFTR modulators. In addition, PK profiles in participants were comparable to those of healthy adults and of those with NCFBE. Pharmacodynamic analysis revealed dose-dependent reduction in neutrophil serine protease (NSP) activity, reaching saturation around the 25-mg dose, particularly in blood. Brensocatib at all doses was well tolerated with no new identified safety signals.

CONCLUSIONS: Brensocatib demonstrated consistent PK profiles independent of CFTR therapy and comparable to those of healthy and NCFBE adults. Brensocatib reduced blood and sputum NSP levels. The safety profile was comparable to previous studies, with no new safety concerns identified, supporting the use of similar dosing for adults with CF as for other populations. These findings advocate for further investigation of brensocatib in CF.

CLINICAL TRIAL REGISTRATION: NCT05090904.

PMID:40753522 | DOI:10.1007/s40262-025-01550-z

J Cyst Fibros. 2025 Aug 1:S1569-1993(25)01537-1. doi: 10.1016/j.jcf.2025.07.016. Online ahead of print.

ABSTRACT

Multiple breath washout (MBW) testing and its derived measurements (e.g., lung clearance index (LCI)) are useful for measuring ventilation heterogeneity in patients with cystic fibrosis, monitoring disease progression, and assessing the response to treatments. However, the use of MBW in routine clinical practice is limited by the long washout time and total test duration, especially in patients with more advanced disease. Recommendations are to complete three MBW repeats. In this analysis, we examine whether two acceptable repeats would provide an accurate assessment of the LCI and could therefore avoid the need for a third measurement, thus reducing total test time.

PMID:40753053 | DOI:10.1016/j.jcf.2025.07.016

Acta Biomater. 2025 Jul 31:S1742-7061(25)00577-X. doi: 10.1016/j.actbio.2025.07.068. Online ahead of print.

ABSTRACT

Inhalable nucleic acid drug delivery systems have garnered increasing attention as a promising strategy for the treatment of chronic pulmonary diseases, such as asthma, chronic obstructive pulmonary disease (COPD), cystic fibrosis (CF), and idiopathic pulmonary fibrosis (IPF). These diseases are often characterized by chronic inflammation, airway remodeling, and progressive lung dysfunction, posing significant clinical challenges. Nucleic acid therapeutics, including plasmid DNA, messenger RNA (mRNA), microRNA (miRNA), small interfering RNAs (siRNAs), and antisense oligonucleotides (ASOs), offer the potential to correct genetic defects, modulate aberrant gene expression, or suppress pathogenic signaling pathways. The inhalation route enables direct, non-invasive access to the lungs, offering localized delivery, rapid onset of action, and reduced systemic side effects. However, the lung presents multiple biological barriers that limit the delivery and activity of nucleic acids, including mucus clearance, enzymatic degradation, alveolar macrophage uptake, and cellular membrane penetration. To address these challenges, various delivery vectors-ranging from viral vectors to non-viral systems such as lipid nanoparticles, polymeric carriers, and hybrid nanomaterials-have been engineered to enhance stability, targeting, and transfection efficiency. This review highlights recent advances in inhalable nucleic acid delivery platforms, discusses the critical physiological and pathological barriers in the pulmonary microenvironment, and outlines current clinical progress. Finally, we explore future directions and challenges toward clinical translation of these innovative therapies. STATEMENT OF SIGNIFICANCE: Chronic pulmonary diseases, including COPD, asthma, IPF, and CF, remain among the leading causes of morbidity and mortality worldwide, with limited treatment options that target disease pathogenesis at the molecular level. Nucleic acid therapeutics offer transformative potential to precisely regulate gene expression, correct mutations, and modulate inflammatory or fibrotic pathways. However, effective delivery to the lungs remains a critical barrier to clinical translation. This review highlights the emerging field of inhalable nucleic acid delivery systems, integrating recent advances in nanocarrier design, pulmonary targeting strategies, and the navigation of biological barriers. By bridging nucleic acid pharmacology with pulmonary drug delivery science, this review provides a comprehensive framework for the rational design and clinical development of next-generation genetic therapies for respiratory diseases. It also offers forward-looking perspectives on overcoming current translational hurdles, thereby accelerating the realization of precision gene therapy for chronic lung disorders.

PMID:40752856 | DOI:10.1016/j.actbio.2025.07.068