Curr Opin Pulm Med. 2025 Apr 28. doi: 10.1097/MCP.0000000000001176. Online ahead of print.

ABSTRACT

PURPOSE OF REVIEW: Over the past decade, increased knowledge has contributed to improved medical and technical treatments across the spectrum of respiratory diseases. As a result, timing for transplant evaluation might be more challenging. In this review, the focus is on timing of lung transplant evaluation of patients from the main respiratory diseases referred. Disease-specific predictors of survival in relation to timing of transplant evaluation and alternative treatments will be reviewed.

RECENT FINDINGS: Treatment options have evolved for respiratory diseases like chronic obstructive pulmonary disease, pulmonary fibrosis, cystic fibrosis and pulmonary arterial hypertension. These treatments have led to improved quality of life, exercise tolerance, lung function and outcome. However, the effect of these alternative treatments on transplant candidacy and knowledge on timing of lung transplant evaluation are lacking.

SUMMARY: This article reviews the current best evidence to guide clinicians regarding the optimum timing for transplant referral and highlights considerations to optimize transplant candidacy and outcomes.

PMID:40276963 | DOI:10.1097/MCP.0000000000001176

Cureus. 2025 Mar 25;17(3):e81151. doi: 10.7759/cureus.81151. eCollection 2025 Mar.

ABSTRACT

This clinical overview reflects on a case of a nine-month-old boy presenting with mild bronchiolitis and persistently elevated transaminases. A total creatine kinase (CK) was requested to assess for dystrophinopathies, which was significantly elevated at 3000 U/L on repeat samples. Molecular testing confirmed the diagnosis of Becker's muscle dystrophy (BMD). During molecular testing, two cystic fibrosis (CF) mutations were incidentally detected, a p.Phe312del mutation and the classic CF-causing mutation p.Phe508del. Sweat chloride testing was repeatedly elevated in keeping with the diagnosis of CF. Despite the significantly elevated sweat chloride and molecular genetic profile showing heterozygosity for p.Phe508del and p.Phe312del mutations, the patient did not show any clinical manifestation of CF. During the newborn screening, immunoreactive trypsinogen (IRT) was 26 ng/mL, below the upper limit value used for screening (54 ng/mL) at that time. This case illustrates two important points: firstly, patients heterozygous for p.Phe312del and p.Phe508del mutations may not be detected during newborn screening and may not have clinical manifestations of cystic fibrosis despite having unequivocally elevated sweat chloride. Secondly, an unexplained elevation of transaminases should trigger creatine kinase testing to check for dystrophinopathies.

PMID:40276426 | PMC:PMC12020654 | DOI:10.7759/cureus.81151

JHLT Open. 2025 Mar 18;8:100252. doi: 10.1016/j.jhlto.2025.100252. eCollection 2025 May.

ABSTRACT

Non-White patients with interstitial lung disease (ILD) experience racial disparities in lung transplant waitlist mortality. Race-specific equations for spirometry may contribute by underestimating restriction severity in non-White candidates. We analyzed US lung transplant candidates to assess for disparities in forced vital capacity (FVC) at listing, comparing absolute and adjusted values using race-specific and race-neutral equations. We identified 17,457 adults with ILD listed May 4, 2005 to September 31, 2023. At listing, mean absolute FVC was higher for White patients (2.03 ± 0.80 liters) than Black patients (1.61 ± 0.67 liters) and Asian patients (1.49 ± 0.86 liters). Differences were attenuated after applying race-specific equations (White patients 50.0 ± 17.5%, Black patients 47.7 ± 17.9%, Asian patients 46.2 ± 24.2%). Compared with race-neutral equations, race-specific equations had higher odds of classifying FVC as severe (≤40%) requiring listing in White patients (OR 1.37, 95% CI 1.28-1.40) but lower odds in Black patients (OR 0.82, 95% CI 0.74-0.90). Using race-neutral equations might help improve racial disparities for lung transplant candidates with ILD.

PMID:40276319 | PMC:PMC12019416 | DOI:10.1016/j.jhlto.2025.100252

J Res Pharm Pract. 2025 Mar 11;13(3):72-77. doi: 10.4103/jrpp.jrpp_54_24. eCollection 2024 Jul-Sep.

ABSTRACT

OBJECTIVE: This study investigated the efficacy of adding the oral N-acetyl cysteine (NAC) supplement to the cystic fibrosis (CF) treatment regimen compared to adding a placebo. It also studied the quality of life and respiratory indicators of patients aged 6-18 with mild-to-moderate pulmonary involvement.

METHODS: This clinical trial was a randomized, quasi-experimental pilot and add-on therapy controlled with a placebo for 3 months. The case group received 200 mg of oral NAC three times a day. In contrast, the control group had a placebo in the same way. From the 2021 fall to the summer of 2022, 38 CF patients referred to Imam Hossein Children's Hospital Clinic were finally examined. They were clinically stable with a forced expiratory volume in the first second (FEV1) level of more than 50% and no history of underlying cardiovascular and renal diseases.

FINDINGS: The differences between the groups were not significant. In the placebo group, key measures remained unchanged, whereas the NAC group had an improvement in the CF Questionnaire-Revised score but no notable changes in other indices. Overall, comparisons of forced vital capacity (FVC) between the groups showed no variation.

CONCLUSION: The indicators of FEV1, FVC, FEV1/FVC, forced expiratory flow between 25% and 75% of vital capacity, and the quality of life of the case group were not significantly different from those of the placebo group, and no significant differences were observed between this medicine and placebo.

PMID:40275972 | PMC:PMC12017402 | DOI:10.4103/jrpp.jrpp_54_24

J Clin Transl Endocrinol. 2025 Apr 7;40:100392. doi: 10.1016/j.jcte.2025.100392. eCollection 2025 Jun.

ABSTRACT

CONTEXT: Diabetes and bone disease are common in cystic fibrosis (CF) and primarily occur alongside exocrine pancreatic insufficiency (PI). "Incretins," glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1), augment insulin secretion and regulate bone metabolism. In CF, PI dampens the incretin response. Loss of the insulinotropic effect of GIP in CF was recently identified, but effects on bone are unknown.

OBJECTIVE: Determine effects of incretins on bone resorption markers in adults with PI-CF.

DESIGN: Secondary analysis of a mechanistic double-blinded randomized placebo-controlled crossover trial including adults ages 18-40 years with PI-CF (n = 25).

INTERVENTION: Adults with PI-CF received either GIP (4 pmol/kg/min) or GLP-1 (1.5 pmol/kg/min) infusion, followed by double-blind randomization to either incretin or placebo infusion. Non-CF healthy controls received double-blind GIP (4 pmol/kg/min) or placebo. Serum C-terminal telopeptide (CTX), a bone resorption marker, was assessed during the infusion over 80 (GIP) or 60 (GLP-1) minutes.

MAIN OUTCOME MEASURES: CTX (mg/dL) concentrations.

RESULTS: In PI-CF, CTX decreased during GIP infusion, but not during placebo (time-by-treatment interaction P < 0.01). GLP-1 did not affect CTX. In non-CF healthy controls, time-by-treatment interaction was not significant (P = 0.23), but CTX decreased during GIP (P = 0.02) but not placebo (P = 0.47).

CONCLUSIONS: GIP evokes a bone anti-resorptive effect in people with PI-CF. Since the incretin response is perturbed in PI-CF, and an infusion of GIP lowers bone resorption, the "gut-bone axis" in CF-related bone disease requires attention.

PMID:40275940 | PMC:PMC12019020 | DOI:10.1016/j.jcte.2025.100392

Drugs Aging. 2025 Apr 24. doi: 10.1007/s40266-025-01207-3. Online ahead of print.

ABSTRACT

Cystic fibrosis (CF) is an inherited condition that leads to multiorgan dysfunction, especially in the respiratory, gastrointestinal, and reproductive tracts, with associated conditions including persistent pulmonary infection, liver disease, pancreatic insufficiency, and infertility. Historically, people with CF (pwCF) suffered a shortened lifespan due to complications of the condition, namely respiratory. The emphasis on center-based, multidisciplinary care and the widespread introduction of cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapy has resulted in pwCF living longer and healthier lives. Now they may encounter some of the health and social issues associated with growing older, which previously were not a typical experience for this population. In this article, we review relevant health issues for the aging CF population, including complications that arise from the condition itself, issues encountered due to treatment, and general conditions associated with aging that may manifest earlier or differently in pwCF. We discuss the recommendations for screening and treatment of relevant conditions, and considerations for the integration of healthcare professionals across disciplines into the care of this population.

PMID:40274760 | DOI:10.1007/s40266-025-01207-3

Best Pract Res Clin Haematol. 2025 Mar;38(1):101602. doi: 10.1016/j.beha.2025.101602. Epub 2025 Mar 7.

ABSTRACT

Innovation in cystic fibrosis (CF) supportive care, including implementing new antimicrobial agents, improved physiotherapy, and highly effective modulators therapy, has advanced patient survival into the 4th and 5th decades of life. However, even with these remarkable improvements in therapy, CF patients continue to suffer from pulmonary infection and other visceral organ complications associated with long-term deficient cystic fibrosis transmembrane conductance regulator (CFTR) expression. Human mesenchymal stem cells (MSCs) have been utilized in tissue engineering based upon their capacity to provide structural components of mesenchymal tissues. An alternative role of MSCs, however is their versatile utilization as cell-based infusion powerhouses due to the unique capacity to deliver milieu specific soluble biologic factors, promoting immune supportive antimicrobial and anti-inflammatory potency. MSCs derived from umbilical cord blood, bone marrow, adipose and other tissues can be expanded in ex vivo using good manufacturing procedure facilities for a safe, unique therapeutic to reduce and limit CF infection and facilitate the resolution of multi-organ inflammation. In our efforts, we conducted extensive preclinical development and validation of an allogeneic derived bone marrow derived MSC product in preparation for a clinical trial in CF. In this process, potency models were developed to ensure the functional capacity of the MSC product to provide clinical benefit. In vitro, murine in vivo and patient tissue ex vivo potency models were utilized to follow MSC anti-infective and anti-inflammatory potency associated with the CFTR deficient environment. We showed in our "First in CF" clinical trial that the allogeneic MSCs obtained from healthy volunteer bone marrow samples were safe. The advent of improved CF care measures and exciting new small molecules has changed the survival and morbidity phenotype of patients with CF, however, there are CF patients who cannot tolerate or have genotypes that are non-responsive to modulators. Additionally, even with the small molecule therapy, CF patients are living longer, but without genetic correction, with the CF disease manifestation aggravated by the continuance of pre-existing CFTR-associated clinical issues such as ongoing inflammation. MSCs secrete bio-active factors that enhance and protect tissue function and can promote "self-immune" regulation. These properties can provide therapeutic support for the traditional and changing face of CF disease clinical complications. Further, MSC-derived bio-active factors can directly mitigate colonizing pathogens' survival by producing antimicrobial peptides (AMPs) which change the pathogen surface and increase host recognition, elimination, and sensitivity to antibiotics. Herein, we review the potential of MSC therapeutics for treating many facets of CF, emphasizing the potential for providing great additive therapeutics for managing morbidity and quality of life.

PMID:40274338 | DOI:10.1016/j.beha.2025.101602

Respir Med. 2025 Apr 22:108109. doi: 10.1016/j.rmed.2025.108109. Online ahead of print.

ABSTRACT

BACKGROUND: Methicillin-resistant Staphylococcus aureus (MRSA) commonly occur in cystic fibrosis (CF) individuals with advanced disease, but their role in younger CF children is unknown. This study aimed to investigate clinical, functional, and radiological outcomes of CF children with early MRSA colonization.

METHODS: This retrospective cohort study compared CF individuals with MRSA isolation in cultures from respiratory secretions during the first 5 years of life (MRSA group) to age-matched controls. Data from the Brazilian CF Patient Registry and electronic medical records were used. Nutritional outcomes, lung function results between 6 and 7 years, and the first chest CT scan results were comparatively analysed. A linear regression model verified associations between MRSA identification before age 5 and potential confounders with lung function results.

RESULTS: The MRSA group (n=32) had greater oral antibiotic exposure but similar hospital admission rates compared to controls (n=49). The proportion of cultures with methicillin-sensitive S. aureus was greater in the control group (48% vs 29.4%, p=0.009). The MRSA group had lower FEV1 (80.02% vs 92.51%, p=0.023) and higher bronchiectasis scores on chest CT scans (1.9 vs 0.38, p= 0.031). MRSA identification before age 5 was significantly associated with an average 10.1% (95%CI -19.518 - -0.586, p= 0.038) decrease of FEV1.

CONCLUSIONS: Early MRSA identification was associated with increased exposure to antibiotics, higher bronchiectasis scores and lower FEV1 values at age 6. While these findings cannot define a relationship of causality, they provide insight into the associations between early MRSA infection and CF lung disease.

PMID:40273997 | DOI:10.1016/j.rmed.2025.108109

Diabetes. 2025 Apr 24:db250039. doi: 10.2337/db25-0039. Online ahead of print.

ABSTRACT

This year marks the 75th anniversary of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) of the National Institutes of Health. NIDDK's long history of research and innovation includes support of four types of collaborative research centers focused on diabetes, endocrinology, and metabolic diseases. The Diabetes Research Centers promote basic and clinical diabetes research, while the Centers for Diabetes Translation Research conduct diabetes research across the translation science spectrum. The Mouse Metabolic Phenotyping Center (MMPC)-Live program provides the research community with standardized phenotyping services for mouse models of diabetes and obesity, and the Cystic Fibrosis Research and Translation Centers advance basic, preclinical, and clinical research for cystic fibrosis. These centers have evolved over time in response to new scientific opportunities and to expand their reach to be an asset to the larger scientific community. Looking to the future, NIDDK will continue to ensure that these centers enhance the research community, foster novel and synergistic scientific collaborations, and promote career development of scientists in the early stages of their careers. We will also ensure that our centers align with NIDDK's goal of improving health outcomes for all people with and at risk for diseases, within our mission.

ARTICLE HIGHLIGHTS: NIDDK's research centers focused on diabetes, endocrinology, and metabolism serve broad communities of investigators and address existing research gaps to propel scientific progress. The Diabetes Research Centers support basic and clinical research, and the Centers for Diabetes Translation Research support research across the translation science spectrum. The MMPC-Live program provides phenotyping services for mouse models of diabetes and obesity, and the Cystic Fibrosis Research and Translation Centers advance basic, preclinical, and clinical research for cystic fibrosis. Future goals for the centers include fostering novel and synergistic scientific collaborations, as well as continuing to promote career development.

PMID:40272256 | DOI:10.2337/db25-0039

Elife. 2025 Apr 24;13:RP98851. doi: 10.7554/eLife.98851.

ABSTRACT

Pseudomonas aeruginosa (PA) is an opportunistic, frequently multidrug-resistant pathogen that can cause severe infections in hospitalized patients. Antibodies against the PA virulence factor, PcrV, protect from death and disease in a variety of animal models. However, clinical trials of PcrV-binding antibody-based products have thus far failed to demonstrate benefit. Prior candidates were derivations of antibodies identified using protein-immunized animal systems and required extensive engineering to optimize binding and/or reduce immunogenicity. Of note, PA infections are common in people with cystic fibrosis (pwCF), who are generally believed to mount normal adaptive immune responses. Here, we utilized a tetramer reagent to detect and isolate PcrV-specific B cells in pwCF and, via single-cell sorting and paired-chain sequencing, identified the B cell receptor (BCR) variable region sequences that confer PcrV-specificity. We derived multiple high affinity anti-PcrV monoclonal antibodies (mAbs) from PcrV-specific B cells across three donors, including mAbs that exhibit potent anti-PA activity in a murine pneumonia model. This robust strategy for mAb discovery expands what is known about PA-specific B cells in pwCF and yields novel mAbs with potential for future clinical use.

PMID:40272253 | DOI:10.7554/eLife.98851

Virulence. 2025 Dec;16(1):2494039. doi: 10.1080/21505594.2025.2494039. Epub 2025 Apr 24.

ABSTRACT

Multispecies biofilms are communities composed of different microorganisms embedded in an auto-synthesized polymeric matrix. Pseudomonas aeruginosa and Burkholderia cenocepacia are two multidrug-resistant and biofilm-forming opportunistic pathogens often found in the lungs of people living with cystic fibrosis. In this context, planktonic, static, and dynamic biofilms and in vivo models of both species were optimized in this work to understand their population dynamics, disposition, virulence, and antibiotic susceptibility. From the coculture models optimized in this work, we determined that B. cenocepacia grows in a clustered, aggregative manner at the bottom layers of biofilms, in close contact with P. aeruginosa, that tends to occupy the top layers. Their coexistence increases virulence-related gene expression in both species at early stages of coinfection and in in vivo models, while there was a general downregulation of virulence-related genes after longer coexistence periods as they eventually reach a non-competitive stage during chronic infections. When evaluating antimicrobial susceptibility, a decrease of antimicrobial tolerance was observed in both species when co-cultured. These findings shed light on the differential behavior of P. aeruginosa and B. cenocepacia in dual-species systems, stressing the relevance of multispecies studies in the clinical context.

PMID:40272017 | DOI:10.1080/21505594.2025.2494039

J Chem Inf Model. 2025 Apr 24. doi: 10.1021/acs.jcim.4c01932. Online ahead of print.

ABSTRACT

Cystic fibrosis (CF) is an autosomal recessive genetic disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel. The first nucleotide-binding domain (NBD1) of the CFTR is considered to be a hotspot for CF-causing mutations, and some of these mutations compromise the domain's thermal stability as well as its interactions with other domains. The mechanisms by which such mutations exert their deleterious effects are important in the basic research of this complex disease as well as for the development of mutation-specific therapies. With this in mind, we studied two class-II, severe, CF-causing mutations, L467P and A559T, known to destabilize the domain by 19.3 and 10.7 °C, respectively, and to lead to a misfolded, nonfunctioning CFTR, by conducting microsecond-long molecular dynamics (MD) simulations at an elevated temperature of 410 K on L467P-NBD1 and A559T-NBD1 constructs. For comparison, similar simulations were also performed on the wild-type (WT) construct and on the 6SS-NBD1 and 2PT/M470V-NBD1 constructs, both bearing sets of stabilizing mutations that stabilize the domain by 17.5 and 8.2 °C, respectively. The resulting trajectories were analyzed using multiple metrics, leading to a good correlation between the experimental ΔTm values and the results of the simulations, as well as multiple experimental observations and results of previous modeling efforts. Specifically, our analyses point to specific regions within NBD1 that are substantially affected by the L467P and A559T mutations and, therefore, may play some role in their pathogenesis. Many of these regions are also known to be important for the proper folding and function of the full-length CFTR. Using time-dependent assignment of DSSP elements, we also found that the two mutants follow different disintegration pathways, that of L467P-NBD1 starting in region 464-471 which resides within the F1-like ATP-binding core subdomain and continues in regions 550-562 and 514-523 within the ABCα subdomain whereas that of A559T-NBD1 simultaneously starting at the 550-562 and 514-523 regions. We propose that the analyses presented in this work may pave the way toward the development of L467P and A559T-specific CF therapies and by extension to other mutation-specific therapies for CF and for other diseases involving mutations in NBDs of other proteins.

PMID:40271665 | DOI:10.1021/acs.jcim.4c01932

Commun Biol. 2025 Apr 23;8(1):653. doi: 10.1038/s42003-025-07877-4.

ABSTRACT

Cystic fibrosis (CF) is a genetic disease caused by dysfunction in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) chloride channel. Patients with CF are hypersusceptible to Mycobacterium abscessus infection, a fast-growing mycobacterium and harmful opportunistic pathogen. Although CFTR dysfunction is known as a host susceptibility factor for M. abscessus infection, the functional impact of the trimeric Epithelial sodium Channel (ENaC), whose activity is negatively regulated by CFTR, towards M. abscessus infection has not been explored yet. To address this issue, we took advantage of miR-263a deficient Drosophila presenting a CF-like phenotype due to ENaC hyperactivity (ENaC+ ). We observed that the ENaC+ flies were as hypersusceptible to M. abscessus infection as the Cftr-deficient flies. The hypersensitivity of ENaC+ flies to M. abscessus infection was fully rescued by blocking ENaC hyperactivity, both chemically and genetically. Furthermore, we observed that ENaC hyperactivity per se was detrimental to ENaC+ Drosophila, as they were unable to mount an efficient humoral immune response. Upon infection, ENaC+ flies failed to upregulate 20-hydroxyecdysone production, which subsequently altered the production of protective antimicrobial peptides against M. abscessus. Overall, our results show that ENaC plays a key role in host susceptibility to M. abscessus infection and, correlatively to other CF pathogens.

PMID:40269088 | DOI:10.1038/s42003-025-07877-4

Paediatr Respir Rev. 2025 Apr 5:S1526-0542(25)00033-8. doi: 10.1016/j.prrv.2025.04.002. Online ahead of print.

ABSTRACT

It is a challenge to select the "best" recent publications in a field. This is especially so when faced with a feast of outstanding manuscripts across a broad range of topics. I therefore reached out to a Who's Who of friends and colleagues in pediatric pulmonary and sleep medicine for suggestions, and I was delighted and overwhelmed by the response - please see the Acknowledgements for those who contributed ideas. Overwhelmed, by having to read 77 publications suggested by one or more colleagues and having to winnow the list down to a somewhat reasonable number. I chose to include all papers mentioned by two or more of my colleagues and I then selected the remainder to cover the broad range of our field, based upon my belief that a manuscript represented an important contribution to our understanding and clinical care. What follows are the chosen papers organized by topic area. Given the number of papers that made the final cut, I have briefly summarized each of these manuscripts. I hope that you will find something new and exciting in these publications and that you will have as much fun in reading them as I did.

PMID:40268602 | DOI:10.1016/j.prrv.2025.04.002

Eur Respir J. 2025 Apr 23:2402490. doi: 10.1183/13993003.02490-2024. Online ahead of print.

NO ABSTRACT

PMID:40268505 | DOI:10.1183/13993003.02490-2024

Chest. 2025 Apr 22:S0012-3692(25)00518-5. doi: 10.1016/j.chest.2025.04.017. Online ahead of print.

ABSTRACT

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is characterized by persistent inflammation that is responsible for remodeling the bronchovascular bundles, which may lead to poor quality of life. Quantitative computed tomography (QCT) textures of the lung can capture local disease patterns of inflammation and related respiratory morbidity.

RESEARCH QUESTION: Are bronchovascular bundle textures, obtained from the adaptive multiple feature method (AMFM), associated with systemic inflammation, morbidity, and mortality in COPD?

STUDY DESIGN AND METHODS: We analyzed data from the SPIROMICS (n = 2,981) and COPDGene (n = 10,305) studies. The predictors included two QCT biomarkers, the bronchovascular bundles (BVB) and CT density gradient (CTDG) textures, age, sex, BMI, race, smoking status, smoking pack-years, CT emphysema, and Pi10 (airway wall thickness). Outcomes included plasma biomarker concentrations from Meso Scale Discovery proteomics assays and complete blood counts, both as markers of inflammation, along with FEV1, FEV1/FVC ratio, SGRQ, 6MWD, and mMRC dyspnea scale. Associations of these QCT textures with FEV1 decline and all-cause mortality were also investigated.

RESULTS: Increased BVB texture was significantly associated with elevated neutrophil and monocyte counts, and the neutrophil-to-lymphocyte ratio (NLR), independent of clinical covariates, CT emphysema, and Pi10. Elevated CTDG was associated with increased neutrophil count, NLR, and tumor necrosis factor (TNF)-α. Increased CTDG and BVB textures were also associated with a lower FEV1 and six-minute walk distance. CTDG at baseline was also associated with decline in FEV1 at five-year follow-up in COPDGene. We observed a significant association of both BVB (HRSPIROMICS=1.084, 95% CI: 1.035, 1.135, P<0.001; HRCOPDGene=1.106, 95% CI: 1.080, 1.131, P<0.001) and CTDG (HRSPIROMICS=1.033, 95% CI: 1.003, 1.064, P=0.03; HRCOPDGene=1.079, 95% CI: 1.061, 1.096, P<0.001) textures with all-cause mortality independent of CT emphysema and Pi10.

INTERPRETATION: QCT textures may provide imaging evidence of the spatial heterogeneity of lung inflammation and overall disease burden in COPD.

PMID:40268239 | DOI:10.1016/j.chest.2025.04.017

N Engl J Med. 2025 Apr 24;392(16):1569-1581. doi: 10.1056/NEJMoa2411664.

ABSTRACT

BACKGROUND: In bronchiectasis, neutrophilic inflammation is associated with an increased risk of exacerbations and disease progression. Brensocatib, an oral, reversible inhibitor of dipeptidyl peptidase 1 (DPP-1), targets neutrophil serine proteases, key mediators of neutrophilic inflammation.

METHODS: In a phase 3, double-blind trial, we randomly assigned patients with bronchiectasis (in a 1:1:1 ratio for adults and a 2:2:1 ratio for adolescents) to receive brensocatib (10 mg or 25 mg once per day) or placebo. The primary end point was the annualized rate of adjudicated pulmonary exacerbations over a 52-week period. The secondary end points, listed in hierarchical testing order, were the time to the first exacerbation during the 52-week period; the percentage of patients remaining exacerbation-free at week 52; the change in forced expiratory volume in 1 second (FEV1); the annualized rate of severe exacerbations; and change in quality of life.

RESULTS: A total of 1721 patients (1680 adults and 41 adolescents) underwent randomization and received brensocatib or placebo. The annualized rate of pulmonary exacerbations was 1.02 in the 10-mg brensocatib group, 1.04 in the 25-mg brensocatib group, and 1.29 in the placebo group (rate ratio, brensocatib vs. placebo, 0.79 [95% confidence interval {CI}, 0.68 to 0.92; adjusted P = 0.004] with the 10-mg dose and 0.81 [95% CI, 0.69 to 0.94; adjusted P = 0.005] with the 25-mg dose). The hazard ratio for the time to the first exacerbation was 0.81 (95% CI, 0.70 to 0.95; adjusted P = 0.02) with the 10-mg dose and 0.83 (95% CI, 0.70 to 0.97; adjusted P = 0.04) with the 25-mg dose. In each brensocatib group, 48.5% of patients remained exacerbation-free at week 52, as compared with 40.3% in the placebo group (rate ratio, 1.20 [95% CI, 1.06 to 1.37; adjusted P = 0.02] with the 10-mg dose and 1.18 [95% CI, 1.04 to 1.34; adjusted P = 0.04] with the 25-mg dose). At week 52, FEV1 had declined by 50 ml with the 10-mg dose, 24 ml with the 25-mg dose, and 62 ml with placebo (least-squares mean difference vs. placebo, 11 ml [95% CI, -14 to 37; adjusted P = 0.38] with the 10-mg dose and 38 ml [95% CI, 11 to 65; adjusted P = 0.04] with the 25-mg dose). The incidence of adverse events was similar across groups, except for a higher incidence of hyperkeratosis with brensocatib.

CONCLUSIONS: Among patients with bronchiectasis, once-daily treatment with brensocatib (10 mg or 25 mg) led to a lower annualized rate of pulmonary exacerbations than placebo, and the decline in FEV1 was less with the 25-mg dose of brensocatib than with placebo. (Funded by Insmed; ASPEN ClinicalTrials.gov number, NCT04594369; EudraCT number, 2020-003688-25.).

PMID:40267423 | DOI:10.1056/NEJMoa2411664

Pediatr Pulmonol. 2025 Apr;60(4):e71097. doi: 10.1002/ppul.71097.

ABSTRACT

BACKGROUND: New 2023 CF liver disease (CFLD) guidelines advocate for additional screening in people with cystic fibrosis (PwCF), including biennial abdominal ultrasound. As a first step towards effective and equitable guidelines implementation, we examined our current practice of CFLD screening and hepatobiliary involvement (HBI) evaluation. We identified characteristics of PwCF at-risk for incomplete screening and factors affecting evaluation.

METHODS: We retrospectively reviewed medical records of PwCF aged 0-21 years, with native liver and ≥ 2 outpatient CF clinic visits 2017-2023. Logistic regression was used to identify characteristics associated with incomplete screening and with HBI.

RESULTS: Amongst 112 PwCF at our center: 37% (n = 42) self-reported as mixed race, 27% (n = 30) as Hispanic; 53% (n = 59) had public insurance. Incomplete lab screening was identified in 19% of our cohort. GGT was the most frequently missed component (14%, n = 16). Hispanics and publicly insured people were more likely to have incomplete screening. Of the 112, 45 met criteria for HBI. Demographics did not predict HBI. Five with CF and HBI had the full hepatitis workup recommended by the new guidelines. Those with HBI documented (42%, n = 19) were more likely to receive additional workup. PwCF who were seen by a gastroenterologist were more likely to have additional diagnostic work-up for HBI.

CONCLUSION: One in five PwCF at our center were incompletely screened for CFLD, with Hispanics and publicly insured at higher risk. Accurate diagnosis and adequate documentation are the first steps to identifying HBI in PwCF. A dedicated CF gastroenterologist is key to completing CFLD screening and liver diagnosis.

PMID:40265529 | DOI:10.1002/ppul.71097

Int J Neonatal Screen. 2025 Apr 17;11(2):27. doi: 10.3390/ijns11020027.

ABSTRACT

Because a delayed diagnosis of cystic fibrosis (CF) is detrimental and may be fatal, screening at birth has become routine in the Western world and has proven beneficial for many reasons, in addition to enabling prompt specialized care. Newborn screening (NBS) programs have elucidated the true incidence of CF in a variety of populations and enabled rapid genotype identification through the analysis of the cystic fibrosis transmembrane regulator (CFTR) gene. NBS studies also have revealed regional and population differences in CFTR variants and refuted the dogma that CF is a "white person's disease". But some regions have not yet implemented CF NBS, particularly in Asia where the disease prevalence has been uncertain. While the needs of a few low-and-middle-income countries are being addressed sequentially, one of the regions of greatest current interest is the Indian subcontinent because of recent data suggesting a higher incidence than that previously assumed, and clinical observations indicating tragic outcomes due to delayed diagnoses or failure to diagnose the disorder in young children. Thus, we conclude that the opportunities for research combined with service in the Indian subcontinent are urgent and potentially very impactful. Consequently, India is the last and best frontier for CF NBS, as we argue herein.

PMID:40265448 | DOI:10.3390/ijns11020027

Int J Neonatal Screen. 2025 Apr 2;11(2):24. doi: 10.3390/ijns11020024.

ABSTRACT

Newborn screening for cystic fibrosis (CF) has been universal in the US since 2010; however, there is significant variation among newborn screening algorithms. Systematic reviews were used to develop seven recommendations for newborn screening program practices to improve timeliness, sensitivity, and equity in diagnosing infants with CF: (1) The CF Foundation recommends the use of a floating immunoreactive trypsinogen (IRT) cutoff over a fixed IRT cutoff; (2) The CF Foundation recommends using a very high IRT referral strategy in CF newborn screening programs whose variant panel does not include all CF-causing variants in CFTR2 or does not have a variant panel that achieves at least 95% sensitivity in all ancestral groups within the state; (3) The CF Foundation recommends that CF newborn screening algorithms should not limit CFTR variant detection to the F508del variant or variants included in the American College of Medical Genetics-23 panel; (4) The CF Foundation recommends that CF newborn screening programs screen for all CF-causing CFTR variants in CFTR2; (5) The CF Foundation recommends conducting CFTR variant screening twice weekly or more frequently as resources allow; (6) The CF Foundation recommends the inclusion of a CFTR sequencing tier following IRT and CFTR variant panel testing to improve the specificity and positive predictive value of CF newborn screening; (7) The CF Foundation recommends that both the primary care provider and the CF specialist be notified of abnormal newborn screening results. Through implementation, it is anticipated that these recommendations will result in improved sensitivity, equity, and timeliness of CF newborn screening, leading to improved health outcomes for all individuals diagnosed with CF following newborn screening and a decreased burden on families.

PMID:40265445 | DOI:10.3390/ijns11020024