Hum Mutat. 2024 Oct 16;2024:6165547. doi: 10.1155/2024/6165547. eCollection 2024.

ABSTRACT

Cystic fibrosis (CF) is a complex monogenic disorder with a large variability in disease severity. Growing evidence suggests that the variation observed depends not only on variations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene but also on modifier genes. Utilizing five databases (including CINAHL, PubMed, Science Direct, Scopus, and Web of Science), a systematic review was conducted to examine the current literature on the known impacts of genomic variations in modifier genes on the CF disease progression, severity, and therapeutic response. A total of 70 full-text articles describing over 80 gene modifiers associated with CF were selected. The modifier genes included genes associated with the CFTR interactome, the inflammatory response, microbial profiles, and other genes affecting the critical physiological pathways of multiple organ systems, such as the respiratory and gastrointestinal systems. Limitations of the existing literature embrace the lack of clinical studies investigating pharmacogenetic impacts and the significance of gene modifiers on the CF clinical picture, including a limited number of replication and validation studies. Further investigations into other potential gene modifiers using genome-wide association studies are needed to critically explore new therapeutic targets and provide a better understanding of the CF disease phenotype under specific drug treatments.

PMID:40225935 | PMC:PMC11919198 | DOI:10.1155/2024/6165547

J Thorac Dis. 2025 Mar 31;17(3):1424-1443. doi: 10.21037/jtd-24-1525. Epub 2025 Mar 27.

ABSTRACT

BACKGROUND: An expanding array of inhaled antibiotic therapies can be effective for the treatment of chronic Pseudomonas aeruginosa (P. aeruginosa) infection in patients with cystic fibrosis (CF) and non-CF bronchiectasis (NCFB). Nonetheless, there is a paucity of direct studies comparing the curative effects of these regimens. This network meta-analysis (NMA) aimed to assess the efficacy and safety of different inhaled antibiotic therapies for the relative short-term (4 weeks) and long-term (≥4 months) management of chronic P. aeruginosa infection in patients with CF and NCFB, respectively.

METHODS: We searched PubMed, Web of Science, Embase, and Cochrane Library database as at 25th February, 2024. Randomized controlled trials (RCTs) involving inhaled antibiotic therapies for treatment of CF or NCFB were thoroughly screened. We conducted this NMA within a Bayesian framework. The surface under the cumulative ranking curve (SUCRA) was calculated to estimate relative effects of interventions per outcome.

RESULTS: A total of 39 RCTs were included, involving 18 inhaled antibiotic treatment regimens and 7,486 participants. The primary outcomes assessed were microbiological efficacy and tolerability. According to SUCRA results, for patients with CF, tobramycin inhalation powder (TIP) had the best profile regarding microbiological efficacy at both short-term and long-term follow-up (SUCRA, 94.5%; 90.5%). Colistin for inhalation (SUCRA, 84.0%) and tobramycin inhalation solution (TIS; SUCRA, 75.7%) had the best tolerability profile at short-term and long-term follow-up, respectively. For patients with NCFB, TIP (SUCRA, 84.2%) and gentamicin injectable solution (GM) for inhalation (SUCRA, 92.2%) had the best profile regarding microbiological efficacy at short-term and long-term follow-up, respectively. Ciprofloxacin inhalation powder had the best tolerability profile at both short-term and long-term follow-up (SUCRA, 66.4%; 85.6%).

CONCLUSIONS: The present study suggests that inhalation of TIS and GM are deemed exhibiting favorable profile across various outcomes for treating chronic P. aeruginosa infection in patients with CF and NCFB, respectively. Further large-scale and higher-quality studies are needed to support the conclusion.

PMID:40223951 | PMC:PMC11986750 | DOI:10.21037/jtd-24-1525

Exp Clin Transplant. 2025 Mar;23(3):220-226. doi: 10.6002/ect.2024.0243.

ABSTRACT

OBJECTIVES: Lung transplant recipients are vulnerable to respiratory infections because of their compromised immune response. Limited research has been published on mental health as a result of the COVID-19 pandemic on lung transplant recipients, and uncertainty remains whether the COVID-19 vaccine affected mental health in lung transplant recipients.

MATERIALS AND METHODS: In this longitudinal, retrospective study, we assessed the psychosocial wellbeing of lung transplant recipients during the COVID-19 pandemic at 2 different time points (before and after COVID-19 vaccination). We measured wellbeing with the Hospital Anxiety and Depression Scale (cutoff of 11 points indicated anxiety and depression) and the Symptom Checklist consisting of 9 questions.

RESULTS: Our study included 83 patients (mean age 52.4 ± 14.5 years, 55.4% male). Among the patients, 3.8% and 4.8% of patients with cystic fibrosis had abnormal values for anxiety before and after the vaccine, respectively; abnormal values for depression were shown in 0% and 2.4% of patients with cystic fibrosis before and after the vaccine, respectively. Sex, age, level of education, time since transplant, and chronic allograft dysfunction were not significantly associated with psychosocial wellbeing. Vaccination against COVID-19 was not associated with a change in psychosocial wellbeing.

CONCLUSIONS: We found no evidence that the COVID-19 vaccine affected the psychosocial wellbeing of lung transplant recipients. However, it may be important to monitor wellbeing closely during a pandemic, especially in patients with cystic fibrosis.

PMID:40223386 | DOI:10.6002/ect.2024.0243

Dig Liver Dis. 2025 Apr 12:S1590-8658(25)00299-3. doi: 10.1016/j.dld.2025.03.021. Online ahead of print.

ABSTRACT

BACKGROUND & AIMS: The SCOPE (Sclerosing Cholangitis Outcomes in Pediatrics) index was developed to provide the first pediatric prognostic score for primary sclerosing cholangitis (PSC), but its efficacy has yet to be confirmed. We aimed to assess its ability to predict liver transplantation (LT) over a 5-year follow-up.

METHODS: We retrospectively included PSC-diagnosed patients under 18 years of age from two European tertiary-care centers. The SCOPE index was calculated at diagnosis and at 1, 3, and 5 years post-diagnosis. The ability of the SCOPE index to predict LT was assessed using multivariate Cox regression and ROC curve analysis.

RESULTS: Sixty patients were included. In transplanted patients, the mean SCOPE index at diagnosis was similar to non-transplanted patients, but significantly higher at 1, 3, and 5 years post-diagnosis (p < 0.001, p = 0.009, p = 0.006, respectively). Patients with overlapping autoimmune hepatitis (AIH) had higher SCOPE at diagnosis (p = 0.005), but this difference diminished over time. The SCOPE index was a significant predictor of LT at various time points (HRs: 1.32 to 3.44) and showed good-to-excellent discriminative power (AUC 0.87 at diagnosis; 0.97 at 1 year).

CONCLUSIONS: The SCOPE index effectively predicts LT in pediatric PSC, with strong reliability over time. Coexisting AIH may affect score accuracy at diagnosis due to inflammation.

PMID:40222859 | DOI:10.1016/j.dld.2025.03.021

J Cyst Fibros. 2025 Apr 12:S1569-1993(25)00765-9. doi: 10.1016/j.jcf.2025.03.669. Online ahead of print.

ABSTRACT

Bacteriophages (phages) are viruses that selectively infect bacteria and have been utilized to treat Mycobacterium abscessus (Mab) with varying success. The POSTSTAMP study is an ongoing, multi-site phage therapy protocol for treatment-refractory pulmonary Mab disease in people with cystic fibrosis (pwCF). Participants (n = 10) are prospectively assessed while utilizing FDA investigational new drug (IND) approval for compassionate use. Participants are >6 years old, able to produce sputum, have been treated with guideline-based antibiotic therapy (GBT) for >12 months without culture conversion, and are currently receiving GBT with at least 3 and ≥ 80 % positive Mab cultures in the prior year. At enrollment, an isolate is assessed for the availability of lytic phage(s). Open-label phage therapy consists of 1 or 2 phages administered intravenously twice daily for 52 weeks. Participants without a phage match will be followed on GBT as a comparison group. Follow-up visits will occur monthly, with one follow-up visit at completion and intermittent visits for a year after phage therapy. Efficacy will be assessed by culture, standard clinical measures and a patient-reported quality-of-life instrument. Frequency of Mab detection 12 months prior to treatment will be compared with the 12-month period beginning 6 months after treatment initiation. Individual-level tests of difference in percent positive cultures within subjects will be used to identify "responders". Collectively and including all persons, a mixed-effect model will be used to test for a difference in frequency of Mab detection following treatment or without treatment. The trial will also test for markers of treatment failure and pathogen adaptation in participants who did not achieve microbiological response, and will monitor for safety and tolerance.

PMID:40222858 | DOI:10.1016/j.jcf.2025.03.669

Orphanet J Rare Dis. 2025 Apr 12;20(1):176. doi: 10.1186/s13023-025-03676-6.

ABSTRACT

BACKGROUND: Treatment satisfaction can be described as the patient's experience in patients with cystic fibrosis (CF). It can be influenced using modulators and clinical characteristics. The aims of this study were to evaluate and compare adult CF patients with and without modulators regarding treatment satisfaction, related factors and to manage their drug related problems (DRPs).

METHODS: A single-center prospective cohort study was conducted between June 2023 and January 2024. Treatment Satisfaction Questionnaire for Medication (TSQM 1.4), including effectiveness, side effects, convenience, global satisfaction domains, CF Questionnaire-Revised (CFQ-R), and Medication Adherence Report Scale were applied and assessed with and without modulator therapy groups. The relationship between clinical characteristics and TSQM was analyzed by correlations and regression analysis. Recommendations on DRPs identified by clinical pharmacists were made to the physicians and patients and classified according to Pharmaceutical Care Network Europe (PCNE v9.1).

RESULTS: A total of 110 patients with 51 modulator therapy and 59 without modulator therapy were included. The mean global satisfaction score of modulator users was found to be 19.733 (p < 0.001) points higher than non-users. When the CFQ-R treatment burden score improved by 1point, global satisfaction score increased by 0.233 points (p < 0.001). When the number of hospitalizations increased by 1 day, the global satisfaction score decreased by 4.751 points (p < 0.001). A total of 84 DRPs were identified, and 69 (82.1%) of them were resolved.

CONCLUSIONS: Treatment satisfaction in adult CF patients is influenced by modulators, treatment burden, and clinical factors, so access to modulators is important. This is the first study to classify DRPs according to PCNE in CF. Clinical pharmacists contribute to the management of CF.

PMID:40221761 | DOI:10.1186/s13023-025-03676-6

NPJ Antimicrob Resist. 2025 Apr 12;3(1):27. doi: 10.1038/s44259-025-00093-4.

ABSTRACT

Two of the three most commonly used classes of antifungal drugs target the fungal membrane through perturbation of sterol biosynthesis or function. In addition to these triazole and polyene antifungals, recent research is identifying new antifungal molecules that perturb lipid biosynthesis and function. Here, we review fungal lipid biosynthesis pathways and their potential as targets for antifungal drug development. An emerging goal is discovering new molecules that potentiate contemporary antifungal drugs in part through perturbation of lipid form and function.

PMID:40221522 | DOI:10.1038/s44259-025-00093-4

Clin Pediatr (Phila). 2025 Apr 12:99228251330121. doi: 10.1177/00099228251330121. Online ahead of print.

ABSTRACT

In 2020, Kaftrio, a combination of Elexacaftor, Tezacaftor, and Ivacaftor, gained approval for treating cystic fibrosis (CF) in patients from the age of 12 years. This study aims to analyze 1 year of treatment with Kaftrio in pediatric patients, comparing their clinical characteristics with pre-treatment data. This is an observational, descriptive, and longitudinal study in patients with CF older than 12 years with at least 1 F508del mutation treated with Kaftrio for 1 year. Forced expiratory volume in 1 second (FEV1) z-score increased by +1.1 (95% confidence interval [CI] = 0.55 to 1.64), forced vital capacity (FVC) by +0.56 (95% CI = 0.10 to 1.04), and maximal mid-expiratory flow (MMEF) 25/75 improved by +1.53 (95% CI = 0.59 to 2.47). In addition, a reduction of 25.50 points (95% CI = -37.95 to -13.06) in sweat chloride levels was observed. Body mass index (BMI)-for-age z-score (WHO 2006/2007) increased +0.39 (95% CI = 0.02 to 0.77). A transient increase in cough and secretions was noted in 61.53% after starting treatment. Kaftrio improves lung function and BMI and also reduces respiratory exacerbations and sweat chloride levels.

PMID:40219783 | DOI:10.1177/00099228251330121

Nutrients. 2025 Apr 2;17(7):1239. doi: 10.3390/nu17071239.

ABSTRACT

Background/Objective: Cystic Fibrosis (CF) is a common, life-threatening genetic disorder that leads to progressive lung function decline, respiratory failure, and premature death. Musculoskeletal complications, affecting both peripheral and respiratory muscles, are major concerns in CF patients. Inflammatory cytokines seem to be responsible for the activation of the molecular pathways involved in the imbalance between protein synthesis and catabolism, with consequent loss of muscle mass and function. This study aims to assess the effects of amino acid supplements on functional status, muscle mass and strength, inflammation, and quality of life in adult CF patients. Methods: We conducted a randomized, double-blind, placebo-controlled pilot trial with 60 adult CF patients, aged 18 or older. Participants were randomly assigned to receive either amino acid supplementation or a placebo for 4 weeks. Physical function tests and self-assessment questionnaires on quality of life, global health, and sleep status, as well as blood samples to measure pro-inflammatory cytokines, were performed at baseline and after the treatment period. Results: The amino acid supplementation group showed a significant improvement in self-perceived physical performance and health status. Interleukin-6 serum levels were significantly reduced in this group compared to those who received the placebo (p = 0.042). Conclusions: Amino acid supplementation in adult CF patients improves self-perception of health status and may reduce systemic inflammation, significantly decreasing serum levels of Interleukin-6. This suggests potential benefits for the overall well-being of CF patients and a reduction in their inflammatory status.

PMID:40218996 | DOI:10.3390/nu17071239

J Clin Med. 2025 Apr 3;14(7):2437. doi: 10.3390/jcm14072437.

ABSTRACT

Background/Objectives: The prevalence of Achromobacter xylosoxidans is increasing in people with Cystic Fibrosis (pwCF), yet its clinical pathogenicity remains controversial. The objective of this study was to chart the longitudinal prevalence and examine clinical associations before and after infection. Methods: This observational, retrospective study was conducted at a single CF center over a 14-year period. Data were collated from patient charts and clinic databases. Patients with Achromobacter sputum cultures were compared to those without the bacterium and analyzed according to whether they had single, intermittent, or chronic infections. Results: During the study period, an annual average of 124 pwCF were followed up at our clinic, with a median age of 13.6 years (IQR = 7.6-27.7). The Achromobacter detection rate increased from 0 to 6.1%. Twenty-three percent (29/124) of patients had at least one positive culture. The median age at acquisition was 17 years (IQR = 14.5-33). At the time of acquisition, the median FEV1 was 81% (IQR = 46-94), compared to 90% (IQR = 72-99) for patients without Achromobacter, p < 0.001. Patients with Achromobacter tended to demonstrate more chronic Pseudomonas (55% vs. 27%, p = 0.06) and pancreatic insufficiency (66% vs. 47%, p = 0.07). At two years post-acquisition, the median FEV1 for patients with intermittent and chronically infected decreased by 11.5% (IQR = -3.75-7.5), compared to 1.5% (IQR = -2.5-12.5) for those with a single positive culture, p = 0.03. Similarly, pulmonary exacerbations per year became more frequent post-acquisition in intermittent and chronically infected patients: Median (range) 2.5 (0-8) pre-, versus 3.0 (0-9) post-acquisition, p = 0.036. Conclusions: Chronic and intermittent infection with Achromobacter were associated with accelerated lung function decline and increased exacerbation frequency. Larger prospective studies are needed to confirm these findings and examine the effect of eradication on the clinical course.

PMID:40217889 | DOI:10.3390/jcm14072437

J Clin Med. 2025 Mar 28;14(7):2320. doi: 10.3390/jcm14072320.

ABSTRACT

Background/Objectives: Cystic Fibrosis (CF) is an autosomal recessive genetic disorder caused by variants in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR) protein. Recently, a targeted therapy for CF has been developed, represented by the CFTR modulators that enhance or restore the function of the CFTR protein. The most recent is the combination of three modulators, Elexacaftor, Tezacaftor, and Ivacaftor (ETI). This study describes the presentation, management, and follow-up of tracheal diverticulum (TD) in pwCF receiving ETI therapy. Methods: This retrospective study included people with CF (pwCF) on ETI treatment and followed up in two CF Italian centers who developed an asymptomatic TD, diagnosed incidentally at chest CT scan. Results: Among 268 pwCF receiving ETI, three (1.19%) were diagnosed with TD identified after chest CT and were included in this study. Endoscopic confirmation was obtained in one patient. All patients were on inhaled colistimethate, two of them for chronic Pseudomonas aeruginosa colonization, and one undergoing eradication therapy. Conclusions: TD may be identified in chest CT obtained in pwCF in treatment with ETI. Further studies and a longer follow up are needed to confirm these findings.

PMID:40217771 | DOI:10.3390/jcm14072320

J Clin Med. 2025 Mar 25;14(7):2241. doi: 10.3390/jcm14072241.

ABSTRACT

Objectives: Chronic kidney disease (CKD) among lung transplant (LTx) recipients has increased in recent decades. However, there is insufficient evidence regarding clinical outcomes, and current guidelines lack specific recommendations for its management. Methods: This single-center retrospective study included all patients who underwent LTx and were subsequently referred to a dedicated nephrology outpatient clinic. Major adverse renal events were defined as a composite event. Results: Eighty LTx recipients with underlying lung disease etiology such as cystic fibrosis, chronic obstructive pulmonary disease, or interstitial lung disease were included. The mean time from LTx to first nephrologist evaluation was 4.7 years with an eGFR of 31.7 mL/min/1.73 m2. LTx recipients experienced a 48% reduction in eGFR within the first few months after LTx. Rapid progressors require renal replacement therapy earlier than the slow progressors. Patients requiring dialysis had higher all-cause mortality compared to those who did not require dialysis. Conclusions: Early post-LTx functional impairment appears to be the most significant predictor for CKD progression and the eventual need for RRT. Although CNI toxicity is the most common cause of CKD, early nephrology evaluation can uncover other causes and promote early renoprotective measures. For this patient population, specific guidelines addressing CKD after LTx and a multidisciplinary approach are essential.

PMID:40217693 | DOI:10.3390/jcm14072241

J Investig Med High Impact Case Rep. 2025 Jan-Dec;13:23247096251334248. doi: 10.1177/23247096251334248. Epub 2025 Apr 11.

ABSTRACT

Cystic fibrosis (CF) is a genetic disorder typically diagnosed in early childhood, caused by mutations in the cystic fibrosis transmembrane conductance regulator gene, leading to thick mucus accumulation in the lungs, pancreas, and other organs. While most diagnoses occur in childhood, a growing number of cases are being identified in adulthood, presenting unique challenges for recognition and management. This case highlights a 37-year-old patient diagnosed with CF after presenting with chronic respiratory symptoms, and weight loss. Late diagnosis of CF remains rare but can delay appropriate treatment, potentially impacting long-term outcomes.

PMID:40215399 | DOI:10.1177/23247096251334248

Rhinology. 2025 Apr 11. doi: 10.4193/Rhin24.545. Online ahead of print.

ABSTRACT

BACKGROUND: Chronic rhinosinusitis (CRS) is a highly prevalent upper airway disease. Its pathogenesis remains poorly understood, especially non-eosinophilic CRS. Currently, no validated mouse model exists to study disease mechanisms, indicating an important research gap. We aimed at establishing a reproducible mouse model of non-eosinophilic CRS to allow further research on its pathophysiology.

METHODOLOGY: Mice were infected with relevant bacteria for sinus disease via surgical insertion of a nasal tampon in their nasal cavity. Inflammatory features in sinus mucosa were evaluated after 4, 8 and 12 weeks on decalcified skulls by histology and immunohistochemistry and by cytospins and enzyme-linked immunoassay on nasal lavage.

RESULTS: S. aureus-inoculated mice showed better survival than S. pneumoniae- and P. aeruginosa- inoculated mice. S. aureus and, to lesser extent, P. aeruginosa were still detectable in the nasal lavage up to 12 weeks. Mice with S. aureus and P. aeruginosa-induced CRS showed significant hypertrophia of the epithelium, neutrophilic infiltration and fibrosis in the sinus mucosa, with increased non-Type 2 cytokines in the nasal lavage.

CONCLUSIONS: S. aureus and P. aeruginosa are more potent inducers of neutrophilic inflammation than S. pneumoniae in mice. This model allows us to further study non-eosinophilic chronic rhinosinusitis pathophysiology in vivo.

PMID:40215396 | DOI:10.4193/Rhin24.545

Ann Med Surg (Lond). 2025 Mar 27;87(4):2398-2401. doi: 10.1097/MS9.0000000000003087. eCollection 2025 Apr.

ABSTRACT

INTRODUCTION: Allergic bronchopulmonary mycoses, primarily from Aspergillus fumigatus, complicate asthma and cystic fibrosis, presenting diagnostic challenges due to overlapping respiratory symptoms.

CASE PRESENTATION: A 48-year-old male with asthma and a history of Guillain-Barré syndrome presented with cough, chest pain, dyspnea, and weight loss. He was diagnosed with allergic bronchopulmonary aspergillosis after a series of investigations, including CT scans and bronchoscopy.

CLINICAL DISCUSSION: Allergic bronchopulmonary aspergillosis (ABPA) is a rare lung disease caused by an immune reaction to Aspergillus fungi in individuals with pre-existing respiratory conditions like asthma or cystic fibrosis. The primary treatment for ABPA involves systemic corticosteroids, often combined with antifungal agents, to reduce the need for long-term high-dose steroid therapy.

CONCLUSION: This case highlights the need for accurate and early diagnosis of ABPA, especially in patients with asthma or other respiratory diseases, which helps prevent potential complications. Additionally, the case provides valuable insights into how to manage patients with ABPA, contributing to the improvement of protocols and medical care in the future.

PMID:40212161 | PMC:PMC11981463 | DOI:10.1097/MS9.0000000000003087

Med Mycol. 2025 Apr 10:myaf030. doi: 10.1093/mmy/myaf030. Online ahead of print.

ABSTRACT

Allergic bronchopulmonary aspergillosis (ABPA) is a significant complication in people with cystic fibrosis (pwCF), driven by hypersensitivity to Aspergillus fumigatus. This study aimed to identify factors associated with the development of ABPA in pwCF, using data from the French CF Registry (FCFR). We conducted a multicenter case-control study utilizing anonymized data from the FCFR, spanning the period from 2016 to 2021. A total of 312 ABPA cases were matched to 936 controls. Various clinical factors, including CFTR variants, nutritional status, glucose disorders, respiratory function, chronic bacterial colonization, and treatments such as antibiotics, corticosteroids, and antifungals, were analyzed. Multivariate analyses and logistic regression models were used to identify associations with ABPA. PwCF who received more frequent intravenous antibiotics (OR = 2.47, P = 0.013), long-term inhaled corticosteroids (OR = 1.82, P < 0.001), or antifungals (OR = 5.83, P < 0.0001) exhibited a higher likelihood of developing ABPA. Additionally, glucose disorders were significantly associated with ABPA (OR = 1.41, P = 0.03). In contrast, a higher BMI (> 25 kg/m²) appeared to be a protective factor (OR = 0.47, P = 0.03). No significant associations were observed with lung function, CFTR variants, or chronic P. aeruginosa colonization. These findings suggest that certain clinical factors and treatments, particularly glucose disorders, frequent antibiotic use, and corticosteroid therapy, are associated with the development of ABPA in pwCF. Notably, a higher BMI may have a protective effect. Further research is needed to explore the underlying mechanisms of these associations and optimize treatment strategies for ABPA in CF, especially as CF therapies continue to evolve.

PMID:40210589 | DOI:10.1093/mmy/myaf030

Arch Bronconeumol. 2025 Mar 28:S0300-2896(25)00111-5. doi: 10.1016/j.arbres.2025.03.014. Online ahead of print.

NO ABSTRACT

PMID:40210501 | DOI:10.1016/j.arbres.2025.03.014

Eur Respir J. 2025 Apr 10:2402435. doi: 10.1183/13993003.02435-2024. Online ahead of print.

ABSTRACT

AIMS: Elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) was efficacious and safe in children aged 6-11 years with cystic fibrosis (CF) heterozygous for F508del and a minimal function CFTR variant (F/MF genotypes) in a 24-week, placebo-controlled trial. We conducted a 96-week open-label extension study for children who completed the 24-week parent study.

METHODS: In this phase 3b extension study, dosing was based on weight and age with children weighing <30 kg and aged <12 years receiving ELX 100 mg once daily (qd), TEZ 50 mg qd, and IVA 75 mg every 12 h (q12) and children ≥30 kg or ≥12 years receiving ELX 200 mg qd, TEZ 100 mg qd, and IVA 150 mg q12. Primary endpoint was safety and tolerability. Secondary and other efficacy endpoints included absolute changes from parent study baseline in sweat chloride concentration, LCI2.5, ppFEV1, and CFQ-R respiratory domain score.

RESULTS: A total of 120 children were enrolled and dosed. One hundred and eighteen children (98.3%) had adverse events (AEs), which for most were mild (43.3%) or moderate (48.3%) in severity. The most common AEs (≥20% of children) were COVID-19 (58.3%), cough (51.7%), nasopharyngitis (45.0%), pyrexia (40.0%), headache (37.5%), upper respiratory tract infection (30.8%), oropharyngeal pain (26.7%), rhinitis (24.2%), abdominal pain (22.5%), and vomiting (20.0%). Children who transitioned from the placebo and ELX/TEZ/IVA groups of the parent study had improvements from parent study baseline at Week 96 in mean sweat chloride concentration (-57.3 [95% CI: -61.6, -52.9] and -57.5 [95% CI: -62.0, -53.0] mmol·L-1), LCI2..5 (-1.74 [95% CI: -2.09, -1.38] and -2.35 [95% CI: -2.72, -1.97] units), ppFEV1 (6.1 [95% CI: 2.6, 9.7] and 6.9 [95% CI: 3.2, 10.5] percentage points), and CFQ-R respiratory domain score (6.6 [95% CI: 2.5, 10.8] and 2.6 [95% CI: -1.6, 6.8] points).

CONCLUSIONS: ELX/TEZ/IVA treatment was generally safe and well-tolerated, with a safety profile consistent with parent study and older age groups. After starting ELX/TEZ/IVA, children had robust improvements in sweat chloride concentration and lung function that were maintained through 96 weeks. These results demonstrate the safety and durable efficacy of ELX/TEZ/IVA in this pediatric population. (Clinical Trials.gov, NCT04545515; EudraCT, 2020-001404-42).

PMID:40210412 | DOI:10.1183/13993003.02435-2024

Eur Respir J. 2025 Apr 10:2401855. doi: 10.1183/13993003.01855-2024. Online ahead of print.

ABSTRACT

BACKGROUND: In people with cystic fibrosis (pwCF), human nasal epithelial cultures (HNECs) can be used to assess response to CFTR modulators. However, thresholds of in vitro responses that predict clinical benefit remain poorly understood. In this study we describe the concordance between in vitro response in HNECs and clinical outcomes in pwCF harbouring the F508del variant, treated with either Lumacaftor/Ivacaftor, Tezacaftor/Ivacaftor or Elexacaftor/Tezacaftor/Ivacaftor.

METHODS: Response of HNECs to CFTR modulators was assessed by CFTR-mediated chloride current stimulated by forskolin or inhibited by CFTRInh-172 in both pwCF and healthy controls. Clinical response was defined as the change in Forced Expiratory Volume in 1 s (FEV1), Lung Clearance Index (LCI), sweat chloride or the cystic fibrosis questionnaire respiratory domain (CFQr) between baseline and within 3 months after the start of modulator treatment.

RESULTS: In 58 unique in vitro:clinical pairs, in vitro measures of functional rescue correlated with changes in FEV1, LCI and sweat chloride, but not CFQr. The concordance between in vitro response and clinical outcomes was highest when a composite outcome was used. For example, an in vitro response of 10% of healthy controls had positive and negative predictive values of 90.5 and 100%, respectively, for a clinical response in either FEV1, LCI or sweat chloride.

CONCLUSIONS: We identified thresholds of nasal epithelial cell theratype response in pwCF to predict clinical benefit from CFTR modulator therapy. The utility of this therapy testing platform to predict a clinical response improves when multiple clinical outcome measures are combined.

PMID:40210411 | DOI:10.1183/13993003.01855-2024

J Adv Res. 2025 Apr 8:S2090-1232(25)00228-0. doi: 10.1016/j.jare.2025.04.009. Online ahead of print.

ABSTRACT

INTRODUCTION: Radiation enteritis is one of the most frequent clinical complications of radiotherapy (RT), yet few effective strategies currently exist to protect against that. Anoctamin 1 (ANO1) functions both as a chloride channel and a signal transduction protein, influencing numerous pathophysiological processes.

OBJECTIVES: This study aimed to investigate whether targeting ANO1 could mitigate radiation-induced enteritis while enhancing tumor radiosensitivity.

METHODS: Quantitative PCR (qPCR) and Western blot (WB) were used to assess ANO1 expression and its changes after irradiation. Survival rates were recorded to evaluate the effects of ANO1 agonist and inhibitors. A cystic fibrosis transmembrane conductance regulator (CFTR) inhibitor was administered to irradiated mice to investigate the role of chloride channel in radiation protection. qPCR and WB were executed to analyze the expression of relevant ion channels in intestinal epithelium. Functional validation was conducted using inhibitors in mice and 3D organoids. Fluorescent probe kits detected intracellular ion levels and membrane potential, and WB was performed to elucidate the underlying mechanisms. Finally, the radiosensitizing effect of CaCCinh-A01 was assessed in colorectal cancer (CRC) cells and validated in in vivo models.

RESULTS: Blocking the calcium-activated chloride channel (CaCC) protein ANO1, which is highly expressed in the colon, protects the intestine from radiation-induced damage. The ANO1 inhibitor CaCCinh-A01, suppresses CaCC currents, downregulates ANO1 protein expression, alleviates radiation-induced intestine injury, and enhances the radiosensitivity of CRC. Mechanistically, CaCCinh-A01 upregulates Na-K-Cl Cotransporter 1 (NKCC1) protein expression, leading to an increase in intracellular Cl- concentration and the inhibition of membrane depolarization in MODE-K cells. This subsequently inhibits p53-mediate DNA damage signaling, ultimately alleviating ionizing radiation-induced intestinal injury.

CONCLUSION: These findings suggest that targeting ANO1 not only alleviates radiation-induced intestinal injury in mice but also enhances CRC radiosensitivity. Thus, ANO1 represents a promising therapeutic target for mitigating the side effects of RT in CRC patients.

PMID:40210148 | DOI:10.1016/j.jare.2025.04.009