Am J Respir Crit Care Med. 2025 Mar 25. doi: 10.1164/rccm.202503-0579ED. Online ahead of print.

NO ABSTRACT

PMID:40132170 | DOI:10.1164/rccm.202503-0579ED

JCI Insight. 2025 Mar 25:e191098. doi: 10.1172/jci.insight.191098. Online ahead of print.

ABSTRACT

Type 2 inflammatory diseases are common in cystic fibrosis (CF) including asthma, sinusitis, and allergic bronchopulmonary aspergillosis. CD4+ T helper 2 (Th2) cells promote these diseases through secretion of IL-4, IL-5, and IL-13. Whether the cystic fibrosis transmembrane conductance regulator (CFTR), the mutated protein in CF, has a direct effect on Th2 development is unknown. Using murine models of CFTR deficiency and human CD4+ T cells, we show CD4+ T cells expressed Cftr transcript and CFTR protein following activation. Loss of T cell CFTR expression increased Th2 cytokine production compared to control cells. Mice with CFTR-deficient T cells developed increased allergic airway disease to Alternaria alternata extract compared to control mice. Culture of CFTR-deficient Th2 cells demonstrated increased IL-4Rα expression and increased sensitivity to IL-4 with greater induction of GATA3 and IL-13 compared to control Th2 cell cultures. The CFTR potentiator ivacaftor reduced allergic inflammation and type 2 cytokine secretion in bronchoalveolar lavage of "humanized" CFTR mice following Alternaria alternata extract challenge and decreased Th2 development in human T cell culture. Together, these data support a direct role of CFTR in regulating T cell sensitivity to IL-4 and demonstrate a potential CFTR-specific therapeutic strategy for Th2 cell-mediated allergic disease.

PMID:40131363 | DOI:10.1172/jci.insight.191098

Curr Res Microb Sci. 2025 Feb 28;8:100367. doi: 10.1016/j.crmicr.2025.100367. eCollection 2025.

ABSTRACT

Antimicrobial peptides (AMPs) offer a promising alternative to control airway infections with multi-resistant bacteria, such as methicillin-resistant Staphylococcus aureus (MRSA), which commonly infects patients with cystic fibrosis (CF). However, the behavior of AMPs in the CF context has yet to be fully elucidated. CF airways produce large amounts of proteases and viscous mucus (sputum), which may affect the efficacy of AMPs. The present work aimed to determine whether CF conditions affect the bactericidal efficacy of CAMA, a promising AMP known to kill clinical MRSA strains efficiently. Using a killing assay, we quantified CAMA bactericidal activity on a CF clinical MRSA strain in the presence of several compounds of CF airways, including sputum and bronchial epithelial cells (BECs). Our results indicate that CF sputum impairs the bactericidal efficacy of CAMA. Similar results were observed when CAMA was incubated with an artificial sputum medium (ASM). When used separately, sputum components (DNA, lipids, and mucins) reproduced the inhibitory effects of ASM. Additionally, the bactericidal efficacy of CAMA was also slightly altered when planktonic S. aureus strains were co-cultured with CF BECs. However, CAMA was not active against S. aureus cultured on BEC in biofilm mode, characteristic of chronic infections in CF patients. These findings suggest that although CAMA represents a promising tool to treat MRSA strains, the CF environment may impair the efficacy of this AMP. Identifying strategies to protect AMPs from the deleterious effects of CF sputum is a key priority.

PMID:40129463 | PMC:PMC11931299 | DOI:10.1016/j.crmicr.2025.100367

United European Gastroenterol J. 2025 Mar 25. doi: 10.1002/ueg2.70012. Online ahead of print.

ABSTRACT

Malabsorption is a complex and multifaceted condition characterised by the defective passage of nutrients into the blood and lymphatic streams. Several congenital or acquired disorders may cause either selective or global malabsorption in both children and adults, such as cystic fibrosis, exocrine pancreatic insufficiency (EPI), coeliac disease (CD) and other enteropathies, lactase deficiency, small intestinal bacterial overgrowth (SIBO), autoimmune atrophic gastritis, Crohn's disease, and gastric or small bowel resections. Early recognition of malabsorption is key for tailoring a proper diagnostic work-up for identifying the cause of malabsorption. A patient's medical and pharmacological history is essential for identifying risk factors. Several examinations such as endoscopy with small intestinal biopsies, non-invasive functional tests and radiological imaging are useful in diagnosing malabsorption. Because of its high prevalence, CD should always be looked for in cases of malabsorption with no other obvious explanations and in high-risk individuals. Nutritional support is key in the management of patients with malabsorption; different options are available, including oral supplements, enteral or parenteral nutrition. In patients with short bowel syndrome, teduglutide proved effective in reducing the need for parenteral nutrition, thus improving the quality of life of these patients. Primary care physicians play a central role in the early detection of malabsorption and should be involved in multidisciplinary teams for improving the overall management of these patients. In this European consensus, involving ten scientific societies and several experts, we have dissected all the issues around malabsorption, including the definitions and diagnostic testing (Part 1), high-risk categories and special populations, nutritional assessment and management, and primary care perspective (Part 2).

PMID:40129317 | DOI:10.1002/ueg2.70012

Orphanet J Rare Dis. 2025 Mar 24;20(1):142. doi: 10.1186/s13023-025-03661-z.

ABSTRACT

BACKGROUND: Hereditary bronchiectasis refers to a subset of bronchiectasis related to genetic mutations, presenting with common clinical features. Historically, diagnosing this condition has been difficult due to the inaccessibility of diagnostic services coupled with a lack of awareness of the syndrome. We hypothesize that whole exome sequencing (WES) in patients with supporting clinical features, combined with non-genetic testing methods, will enhance the diagnosis of hereditary bronchiectasis.

RESULTS: In total, 87 patients with clinical features suggestive of hereditary bronchiectasis, such as diffuse bronchiectasis (≥ 2 lobes) combined with early onset symptoms, recurrent otitis media, rhinosinusitis, infertility, organ laterality defects or a family history of bronchiectasis, were included in this study. Among them, 49.4% (43/87) were diagnosed with hereditary bronchiectasis, including 15 patients with cystic fibrosis, 27 patients with primary ciliary dyskinesia, and 1 patient with immunodeficiency-21. The combined use of WES and non-genetic testing methods significantly improved the diagnostic rate of hereditary bronchiectasis compared to non-genetic testing alone (47.1% vs. 25.3%, P = 0.005). Re-analysis of negative commercial genetic tests led to two additional diagnoses, though this increase was not statistically significant (47.1% vs. 49.4%, P = 0.879).

CONCLUSIONS: We have described the supporting clinical features of patients with hereditary bronchiectasis. Clinicians should recommend WES for patients exhibiting these characteristics, in combination with accessible non-genetic testing methods, to maximize diagnostic accuracy. For patients with negative initial genetic test results, re-analysis of WES data may facilitate obtaining a new diagnosis.

PMID:40128832 | DOI:10.1186/s13023-025-03661-z

Function (Oxf). 2025 Mar 24:zqaf016. doi: 10.1093/function/zqaf016. Online ahead of print.

ABSTRACT

Extracellular ATP is a signaling molecule that acts as a paracrine and autocrine modulator of cell function. Here we characterized the role of luminal ATP in the regulation of epithelial principal cells (PCs) in the epididymis, an understudied organ that plays crucial roles in male reproduction. We previously showed that ATP secretion by PCs is part of a complex communication system that ensures the establishment of an optimal luminal acidic environment in the epididymis. However, the molecular mechanisms regulating ATP release and the role of ATP-mediated signaling in PCs acidifying functions are not fully understood. In other cell types, Pannexin 1 (PANX-1) has been associated with ATP-induced ATP release through interaction with the purinergic P2 × 7 receptor. Here, we show that PANX-1 and P2 × 7 are located in the apical membrane of PCs in the mouse epididymis. Functional analysis using the immortalized epididymal PCs cell line (DC2) and the mouse epididymis perfused in vivo showed that: 1) PANX-1 and P2 × 7 participate in ATP release by DC2 cells, together with Cystic Fibrosis Transmembrane Conductance Regulator (CFTR); 2) Several ATP-activated P2Y and P2X purinergic receptors are expressed in DC2 cells; 3) The non-hydrolysable ATP analogue ATPγS induces a dose-dependent increase in intracellular Ca2+ concentration in DC2 cells, a process that is mainly mediated by P2 × 7; and 4) Perfusion of the epididymal lumen in vivo with ATPγS induces the internalization of apical sodium-hydrogen exchanger 3 (NHE3) in PCs. Altogether, this study shows that luminal ATP, regulated by CFTR, PANX-1 and P2 × 7, modulates sodium-proton exchange in PCs in an autocrine-manner through activation of purinergic receptor-mediated intracellular calcium signaling.

PMID:40128095 | DOI:10.1093/function/zqaf016

J Clin Endocrinol Metab. 2025 Mar 24:dgaf165. doi: 10.1210/clinem/dgaf165. Online ahead of print.

NO ABSTRACT

PMID:40126533 | DOI:10.1210/clinem/dgaf165

Am J Respir Crit Care Med. 2025 Mar 24. doi: 10.1164/rccm.202502-0338ED. Online ahead of print.

NO ABSTRACT

PMID:40126387 | DOI:10.1164/rccm.202502-0338ED

Physiol Rev. 2025 Mar 24. doi: 10.1152/physrev.00032.2024. Online ahead of print.

ABSTRACT

Nanosized extracellular vesicles (EVs) are released by all cells to convey cell-to-cell communication. EVs, including exosomes and microvesicles, carry an array of bioactive molecules, such as proteins and RNAs, encapsulated by a membrane lipid bilayer. Epithelial cells, endothelial cells, and various immune cells in the lung contribute to the pool of EVs in the lung microenvironment and carry molecules reflecting their cellular origin. EVs can maintain lung health by regulating immune responses, inducing tissue repair, and maintaining lung homeostasis. They can be detected in lung tissues and biofluids such as bronchoalveolar lavage fluid and blood, offering information about disease processes and can function as disease biomarkers. Here, we discuss the role of EVs in lung homeostasis and pulmonary diseases such as asthma, chronic obstructive pulmonary disease, cystic fibrosis, idiopathic pulmonary fibrosis, and lung injury. The mechanistic involvement of EVs in pathogenesis and their potential as disease biomarkers are discussed. Lastly, the pulmonary field benefits from EVs as clinical therapeutics in severe pulmonary inflammatory disease, as EVs from mesenchymal stem cells attenuate severe respiratory inflammation in multiple clinical trials. Further, EVs can be engineered to carry therapeutic molecules for enhanced and broadened therapeutic opportunities, such as the anti-inflammatory molecule CD24. Finally, we discuss the emerging opportunity of using different types of EVs for treating severe respiratory conditions.

PMID:40125970 | DOI:10.1152/physrev.00032.2024

F1000Res. 2025 Mar 6;11:1513. doi: 10.12688/f1000research.128260.2. eCollection 2022.

ABSTRACT

BACKGROUND: Vancomycin is an effective first-line therapy primarily in methicillin-resistant Staphylococcus aureus (MRSA) infection and Clostridium difficile, however, it has been shown that its effectiveness and the reduction of nephrotoxicity depend on maintaining adequate therapeutic levels. Population pharmacokinetic (PopPk) models attempt to parameterize the behavior of plasma concentrations in different target populations and scenarios such as renal replacement therapy, to successful therapeutic outcome and avoid these side effects.

METHODS: A scoping review was conducted following the guidelines of Preferred Reporting Items for Systematic reviews and Meta-Analyses Extension for Scoping Reviews (PRISMA-ScR), through a search in PubMed, LILACS, OVID Medline, Scopus, Web of Science, SAGE Journals, Google Scholar and previous known registers of PopPk models in non-critically ill adult patients, published between 1998 and 2024.

RESULTS: A total of 190 papers were fully screened, of which were included 36 studies conducted in different populations; 12 in general population, 23 in special populations (surgical, with impaired renal function, obese, elderly, with cancer and cystic fibrosis), and 1 in mixed population (general and with cancer). The main parameters in the models were renal clearance and volume of distribution. The principal covariables that affected the models were creatinine clearance and weight. All studies used internal evaluation and 4 of them used an external group.

DISCUSSION: The technology for the development and implementation of PopPk models requires experts in clinical pharmacology and is limited to university and research centers. The software is mostly expensive and, in most cases, the pharmacokinetic models and the heterogeneity in the parameters and evaluation methods depend on which compartmental model, parameters, covariates and software have been used.

CONCLUSIONS: These models require validation in the clinical context and conducting experiments to adapt them for precision dosing in different subpopulations.

PMID:40124851 | PMC:PMC11928783 | DOI:10.12688/f1000research.128260.2

Front Immunol. 2025 Mar 7;16:1508584. doi: 10.3389/fimmu.2025.1508584. eCollection 2025.

ABSTRACT

INTRODUCTION: Mycobacterium abscessus is a pathogen recently associated with patients with chronic lung conditions such as bronchiectasis and cystic fibrosis. M. abscessus is an environmental bacterium but recent evidence suggests that the pathogen is also transmitted from host-to-host. Because M. abscessus is known to form biofilms on the respiratory mucosa the release of bacteria from the biofilm becomes an important aspect on the transmission of the infection.

METHODS: A biofilm releasing system was established. A transposon library of M. abscessus was then screened to identify genes associated with the release from biofilms.

RESULTS: Several enzymes and genes of unidentified function were linked with the ability to detach from the biofilm. It was also shown that detached bacteria were increased capable of establish a new biofilm, attach to epithelial cells, and infect macrophages. To determine the surface molecules linked with the ability to infect new hosts, a surface proteomic was performed, showing that detaching bacteria express many proteins do not present in biofilm bacteria.

DISCUSSION: Detached M. abscessus, one of the possible infectious phenotypes, contains specific proteins and lipids in the surface that facilitate the infection of new hosts. In addition, we identified many small proteins that have the likelihood to be associated with the release of the biofilm bacteria.

PMID:40124375 | PMC:PMC11925935 | DOI:10.3389/fimmu.2025.1508584

Thorax. 2025 Mar 23:thorax-2024-221825. doi: 10.1136/thorax-2024-221825. Online ahead of print.

ABSTRACT

INTRODUCTION: Current bronchiectasis guidelines advise against the use of inhaled corticosteroids (ICS) except in patients with associated asthma, allergic bronchopulmonary aspergillosis (ABPA) and/or chronic obstructive pulmonary disease (COPD). This study aimed to describe the use of ICS in patients with bronchiectasis across Europe.

METHODS: Patients with bronchiectasis were enrolled into the European Bronchiectasis Registry from 2015 to 2022. Patients were grouped into ICS users and non-users at baseline and clinical characteristics associated with ICS use were investigated. Patients were followed up for clinical outcomes of exacerbation, hospitalisation and mortality for up to 5 years. We evaluated if elevated blood eosinophil counts (above the laboratory upper limit of normal) modified the effect of ICS on exacerbations.

RESULTS: 19 324 patients were included for analysis and 10 109 (52.3%) were recorded as being prescribed ICS at baseline. After exclusion of patients with a history of asthma, COPD and/or ABPA, 3174/9715 (32.7%) patients with bronchiectasis were prescribed ICS. Frequency of ICS use varied across countries, ranging from 17% to 85% of included patients. ICS users had more severe disease, with significantly worse lung function, higher Bronchiectasis Severity Index scores and more frequent exacerbations at baseline (p<0.0001). Overall, ICS users did not have a reduced risk of exacerbation or hospitalisation during follow-up, but a significant reduction in exacerbation frequency was observed in the subgroup of ICS users with elevated blood eosinophil counts (relative risk 0.70, 95% CI 0.59 to 0.84, p<0.001).

CONCLUSION: ICS use is common in bronchiectasis, including in those not currently recommended ICS according to bronchiectasis guidelines. ICS use may be associated with reduced exacerbation frequency in patients with elevated blood eosinophils.

PMID:40122611 | DOI:10.1136/thorax-2024-221825

Respir Med. 2025 Mar 21:108047. doi: 10.1016/j.rmed.2025.108047. Online ahead of print.

ABSTRACT

INTRODUCTION: Newborn screening (NBS) for cystic fibrosis (CF) facilitates early diagnosis and has been shown to significantly improve long-term clinical outcomes. In this study, we aimed to evaluate the 7-year results of the immunoreactive trypsinogen (IRT)/IRT NBS of Turkey.

METHODS: The study included all CF patients who were born after NBS implementation, and who were enrolled in the CF Registry of Turkey (CFRT) in 2022. Patients were divided into three groups according to NBS results: Group 1 with positive NBS, Group 2 with negative NBS, and Group 3 with no screening or unknown screening results. All clinical and demographic data were compared between the three groups.

RESULTS: A total of 853 patients were included in the study, 668 (78.3%) patients were in Group 1, 90 (10.5%) in Group 2, and 95 (11.2%) in Group 3. The age at diagnosis was 0.17 (0.08-0.33) years in Group 1, 0.50 (0.25-1.0) in Group 2, and 0.33 (0.17-0.75) in Group 3 (p<0.001). The first and second sweat test results and frequency of pancreatic insufficiency were lowest in Group 2 (p<0.05). Median FEV1 (%) was 88 (77-103) in Group 1, 90 (71.5-104) in Group 2, 89.5 (81.75-97.5) in Group 3 (p>0.05). 49% of the patients had a severe genotype and it was detected most frequently in Group 1 (p=0.021).

CONCLUSIONS: Patients with pancreatic sufficiency may be missed by IRT/IRT NBS and lower and negative sweat test results may contribute to delays in CF diagnosis. Approximately 22% of patients are not diagnosed through this screening method.

PMID:40122405 | DOI:10.1016/j.rmed.2025.108047

Fertil Steril. 2025 Mar 21:S0015-0282(25)00162-1. doi: 10.1016/j.fertnstert.2025.03.014. Online ahead of print.

ABSTRACT

Male-factor infertility is a multifactorial, complex, and increasingly common condition, of which genetic factors have more frequently been implicated in. Not only are the causal relationships between genetic variation and male infertility phenotypes understudied, but also the differences in frequency of disease-causing genetic alterations within different geographic and ethnic groups. Guidelines remain inconsistent as to recommended genomic testing during the male infertility workup. Our current fund of knowledge limits our diagnostic capability where the etiology of male infertility remains idiopathic in about 40% of patients, despite advances in genomic sequencing and testing.

PMID:40122225 | DOI:10.1016/j.fertnstert.2025.03.014

Eur J Clin Nutr. 2025 Mar 22. doi: 10.1038/s41430-025-01589-y. Online ahead of print.

ABSTRACT

Elexacaftor/Tezacaftor/Ivacaftor (ETI) has led to improved lung function, life expectancy, and body mass index for people with Cystic Fibrosis (CF). The aim of this systematic review was to evaluate the impact that ETI has had on body composition in people with CF. A systematic review was performed using MEDLINE, EMBASE, CINAHL, and the Cochrane Central Register of Controlled Trials. Quality assessment using the Joanna Briggs Institute critical appraisal tools were performed. Results were summarised narratively. Five observational cohort studies involving a total of 185 participants were reviewed. Three studies showed an increase in fat mass (7.0-8.6 kg, 13.2-14.3 kg, and 13.4-15.5 kg). Two studies reported an increase in fat-free mass (49.4-50.1 kg, 52.5-55 kg), while one reported a decrease (50.5-48.9 kg). Two studies found an increase in fat mass index (4.1-6.3 kgm/2 and 4.7-5.4 kg/m2) and fat-free mass index (17.4-17.7 kg/m2 and 18.1-18.8 kg/m2). Two studies observed an increase in percentage body fat mass (12.1-15.4% and 23.1-27.6%). Four studies were classified as low quality, while one was considered medium quality. This review suggest that commencing ETI results in changes in body composition. Firm conclusions about the type and distribution of change in body composition cannot be made due to limited studies, high heterogeneity, and methodical weaknesses. It highlights the necessity for higher quality and longer-term studies to explore the impact that ETI is having on body composition.

PMID:40121317 | DOI:10.1038/s41430-025-01589-y

J Cyst Fibros. 2025 Mar 21:S1569-1993(25)00078-5. doi: 10.1016/j.jcf.2025.03.010. Online ahead of print.

ABSTRACT

BACKGROUND: CFTR modulators in post-transplant people with cystic fibrosis (pwCF) are less frequently used due to uncertainty regarding effectiveness and interactions with immunosuppressive agents. Elexacaftor/tezacaftor/ivacaftor (ETI) is a triple combination cystic fibrosis (CF) therapeutic with benefits in multiple organ systems where complications can impact lung transplant (LTx) outcomes, including malnutrition, diabetes, and sinus disease. ETI use in LTx recipients is variable.

METHODS: We conducted a pharmacokinetics (PK) study of concentrations of ETI parent compounds and the four major metabolites (M23-ELX, M1-TEZ, M1-IVA, M6-IVA) in a prospective non-randomized observational study, with all transplant participants concomitantly taking tacrolimus for LTx immunosuppression and excluded if taking any other medication with known interactions (e.g., azole antifungals) and compared to a non-transplant group of pwCF. We completed non-compartmental analysis (NCA) for both groups and compared the transplant to non-transplant PK parameters, as well as to published data from the manufacturer for non-transplant pwCF. Area under the curve (AUC), average concentrations (Cavg), minimum and maximum concentrations, clearance, and other parameters were determined.

RESULTS: Twelve transplant and fourteen non-transplant participants with CF completed the study. There were no significant differences between the mean values for any PK parameters for the transplant and non-transplant groups and no substantial differences in frequency of concentrations outside the therapeutic ranges in the two groups.

CONCLUSIONS: Our data suggest there are not significant differences in concentrations of ELX, TEZ, IVA, or their major human metabolites in LTx recipients compared to non-transplant pwCF.

PMID:40121139 | DOI:10.1016/j.jcf.2025.03.010

Trends Mol Med. 2025 Mar 21:S1471-4914(25)00034-6. doi: 10.1016/j.molmed.2025.02.001. Online ahead of print.

NO ABSTRACT

PMID:40121136 | DOI:10.1016/j.molmed.2025.02.001

Tissue Cell. 2025 Mar 19;95:102865. doi: 10.1016/j.tice.2025.102865. Online ahead of print.

ABSTRACT

The lungs are constantly subjected to enormous amounts of air and potentially transmitted agents, leading to a high incidence of severe and complex ailments urging the demand for defensive actions to maintain their regular function. Numerous studies have demonstrated how certain probiotics have many advantages including hindering pulmonary exacerbations in individuals with cystic fibrosis, which encourages the idea of combining them with approved antibiotics as a therapeutic choice for treatment patients with lung fibrosis who also have bacterial infections. This investigation aimed to test the possibility of a combination of Torulaspora delbrueckii as a probiotic with ciprofloxacin in an animal model having pulmonary fibrosis with a moderate load of Klebsiella pneumonia. Ninety adult male rats were split into six groups (15 rats/each): GI (control), GII (lung fibrosis), GIII (lung fibrosis infected by K. pneumonia), GIV (lung fibrosis infected by K. pneumonia then treated with ciprofloxacin), GV (lung fibrosis infected by K. pneumonia and fed with T. delbrueckii) and GVI (lung fibrosis infected by K. pneumonia then treated with combined therapy of ciprofloxacin and T. delbrueckii) for 28 days. Survival rate and bacterial load were determined in various experimental animal groups. Histological variations were examined as well as scanning electron microscopy. Gene expression, various levels of cytokines, redox enzymes, and oxidative stress markers were assessed and compared in different tested groups. The treatment using a combination of T. delbrueckii and ciprofloxacin is suggested as a new method to treat induced lung fibrosis in animals and infected with K. pneumonia as a possible option in complicated infection.

PMID:40120428 | DOI:10.1016/j.tice.2025.102865

Biochem Biophys Res Commun. 2025 Mar 14;758:151645. doi: 10.1016/j.bbrc.2025.151645. Online ahead of print.

ABSTRACT

Mycobacterium abscessus (M. abscessus) is an emerging, rapidly growing mycobacterium that causes chronic lung infection, particularly in patients with cystic fibrosis, as well as skin and soft tissue infections. Adipose tissue is recognized as an important niche that supports M. tuberculosis persistence. However, the dormancy, latency, and persistence mechanisms of M. abscessus in the host remain poorly understood. This study investigated how adipose tissue serves as a niche for M. abscessus using both a human adipose tissue ex vivo infection model and a murine adipose tissue in vivo infection model. M. abscessus infected not only the cytosol of adipocytes but also entered host lipid droplets, where it formed intracytoplasmic lipid inclusions in the bacterial cell. To our knowledge, this unique localization has never been reported for M. abscessus or any other mycobacterium. Within host lipid droplets, M. abscessus lost acid-fastness and gained Nile Red positivity. These results suggest that M. abscessus acquires a dormancy-like phenotype within host lipid droplets of adipocytes, potentially contributing to its persistence, virulence, and resistance to treatment. These findings provide valuable insights into mycobacterial persistence mechanisms and could offer a promising foundation for developing novel therapeutic approaches.

PMID:40120350 | DOI:10.1016/j.bbrc.2025.151645

J Cyst Fibros. 2025 Mar 20:S1569-1993(25)00074-8. doi: 10.1016/j.jcf.2025.03.006. Online ahead of print.

ABSTRACT

We present a case of a carrier mother treated with elexacaftor/tezacaftor/ivacaftor (ETI) for in-utero management of meconium ileus in a fetus diagnosed with cystic fibrosis (CF), homozygous for the F508del variant. Following multidisciplinary discussion and shared decision-making involving the parents, ETI was initiated at 27 weeks of gestation. At 38+4 weeks, the infant was delivered. Despite the treatment, the newborn developed meconium ileus, necessitating emergency surgery after birth. We explore potential factors contributing to the lack of success in our case compared to previously reported successful cases in USA and Spain. Drug levels measured in neonatal blood and in maternal breast milk indicated minimal drug exposure, raising questions about whether variability in placental transfer and excretion in breast milk or suboptimal ETI dosing in the overweight mother impacted the outcome. Additionally, the natural variability in meconium ileus outcome, which can range from spontaneous resolution to severe complications must be considered. In our case, ETI may have mitigated the severity of the condition, preventing serious complications like bowel perforation or peritonitis. However, given that about 20 % of all fetal bowel dilation resolves spontaneously, it remains uncertain whether the positive outcomes in prior cases were attributable to ETI or the natural course of the disease. We emphasize the need for more evidence on in utero ETI exposure by advocating for the collection of cases involving ETI treatment for fetal meconium ileus, regardless of outcomes. Developing guidelines will be essential to optimize benefits for both mother and fetus while minimizing risks.

PMID:40118755 | DOI:10.1016/j.jcf.2025.03.006