Biomarkers associated with clinical response to cystic fibrosis pulmonary exacerbation treatment and adjuvant prednisone therapy.

Background: Cystic fibrosis (CF) pulmonary exacerbations are characterized by increased inflammation. The objectives of this study were to identify inflammatory biomarkers associated with 1) early clinical response to IV antibiotics (by day 7); and 2) response to the delayed use of prednisone (from day 7 to 14).

Methods: This was a secondary analysis of a clinical trial evaluating the adjunctive use of prednisone in pwCF.

Multi-center Study of Hyperpolarized Xenon MRI in Children with Cystic Fibrosis Following Initiation of CFTR Modulator Therapy (HyPOINT).

Rationale: Elexacaftor/tezacaftor/ivacaftor (ETI) has significantly improved lung function in people with cystic fibrosis (CF), prompting the need for outcome measures that can detect mild disease. In this new era of CFTR modulator therapy, more sensitive endpoints are required to evaluate the progression of early lung disease and to determine the efficacy of new CF therapies. Prior to the availability of highly effective therapies 129Xenon magnetic resonance imaging (Xe MRI) was shown to be more sensitive to regional ventilation changes compared to spirometry.

Repeatability of Multiple Breath Washout in Pediatric Primary Ciliary Dyskinesia.

Background: Primary ciliary dyskinesia (PCD) is a motile ciliopathy characterized by abnormal mucociliary clearance and progressive lung disease. Spirometry is commonly used to monitor lung health and response to treatment, but it is known to be insensitive to early subclinical lung disease in PCD. Multiple breath washout is more sensitive than spirometry, but its repeatability in PCD has not been assessed.

Feasibility and Utility of Multiple Breath Washout Measured Scond and Sacin in Preschool Children With Cystic Fibrosis.

Background: The lung clearance index (LCI) is a sensitive measure of global ventilation inhomogeneity but does not describe the gas mixing mechanisms that lead to inhomogeneity. Multiple breath washout normalized phase III slope (SnIII) metrics may complement LCI when assessing lung disease; Scond describes convection-dependent inhomogeneity and Sacin reflects diffusion convection-interaction-dependent inhomogeneity respectively. We aim to determine the feasibility and utility of Scond and Sacin in preschool children with CF.

Clinical Effectiveness of Elexacaftor/Tezacaftor/Ivacaftor in 6 to 11-Year-Olds with Cystic Fibrosis.

: Elexacaftor/tezacaftor/ivacaftor (ETI) provided substantial health benefits to children with cystic fibrosis (CF) in clinical trials; there is less information about its effectiveness in a "real world" setting. The pediatric PROMISE substudy enrolled CF children 6 to <12 years of age starting ETI. Outcomes measured at baseline (pre-ETI), 1, 3, 6 and 12 months after ETI initiation included the lung clearance index (LCI), % predicted forced expiratory volume in 1 second (ppFEV), the CFQ-R respiratory domain symptom score (CFQ-R RD), height, weight, oropharyngeal (OP) cultures, culture and DNA-based analysis of sputum microbiology (when sputum available).

Long-Term Safety and Efficacy of Elexacaftor/Tezacaftor/Ivacaftor in Children ≥6 Years with Cystic Fibrosis and at Least One Allele: A 192-Week, Phase 3, Open-Label Extension Study.

Rationale: Elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) was shown to be safe and efficacious in children 6 through 11 years of age with cystic fibrosis (CF) and at least one allele in a 24-week phase 3 study. Children completing this study could enroll into a 192-week extension study.

Objectives: Evaluate long-term safety and efficacy of ELX/TEZ/IVA in children ≥6 years.

Relationship between theratyping in nasal epithelial cells and clinical outcomes in people with cystic fibrosis.

Background: In people with cystic fibrosis (pwCF), human nasal epithelial cell (HNEC) cultures can be used to assess response to CF transmembrane conductance regulator (CFTR) modulators. However, thresholds of responses that predict clinical benefit remain poorly understood. In this study we describe the concordance between response in HNECs and clinical outcomes in pwCF harbouring the F508del variant, treated with either lumacaftor/ivacaftor, tezacaftor/ivacaftor or elexacaftor/tezacaftor/ivacaftor.

Antibiotic treatment for non-tuberculous mycobacteria lung infection in people with cystic fibrosis.

Rationale: Cystic fibrosis (CF) is a common genetic condition in which progressive lung disease leads to morbidity and mortality. Non-tuberculous mycobacteria (NTM) are mycobacteria, other than those in the Mycobacterium tuberculosis complex, and are commonly found in the environment. NTM pulmonary infections affect a significant proportion of people with CF worldwide, which may be associated with a more rapid decline in lung function and even death in certain circumstances.

Application of the defect distribution index to functional lung MRI of pediatric cystic fibrosis lung disease and controls.

Introduction: Functional magnetic resonance imaging (MRI) of the lung usually assesses lung impairment as ventilation defect percentage (VDP). However, VDP only reflects the overall burden of disease and does not characterize the regional distribution (i.e.

Does using the Lung Clearance Index (LCI) inform clinical decisions in children with cystic fibrosis?

Introduction: The Lung Clearance Index (LCI) is an established research test, but its role in clinical decision-making is not well defined. This study estimated the proportion of treatment decisions that are changed or supported by the added information provided by LCI.

Methods: A mixed methods prospective observational study was conducted in North America.

An update on multiple breath washout in children with cystic fibrosis.

Introduction: Cystic fibrosis (CF) is an autosomal recessive disorder caused by mutations in the CF transmembrane regulator (CFTR) gene, leading to progressive lung disease and systemic complications. Lung disease remains the primary cause of morbidity and mortality, making early detection of lung function decline crucial. The Lung Clearance Index (LCI), derived from the multiple breath washout (MBW) test, has emerged as a sensitive measure for identifying early airway disease.

Lung Function Recovery from Pulmonary Exacerbations Treated with Oral Antibiotics in Primary Ciliary Dyskinesia.

Patients with primary ciliary dyskinesia (PCD) experience acute pulmonary exacerbations (PExs). In patients with cystic fibrosis (CF), PExs that were treated with oral antibiotics (oPExs) were found to be related to short- and long-term lung function deficits; however, the impact of oPExs on lung function in patients with PCD has not yet been assessed. We sought to assess the impact of oPExs on lung function recovery in PCD and determine the factors associated with poorer response.

Extracellular vesicles in sputum of children with cystic fibrosis pulmonary exacerbations.

Background: The aim of this study was to quantify mediators of neutrophilic inflammation within airway extracellular vesicles (EVs) of children treated for a cystic fibrosis (CF) pulmonary exacerbation (PEx).

Methods: EVs were isolated from stored sputum samples collected before and after antibiotic therapy for PEx between 2011 and 2013, and characterised by nanoparticle tracking analysis (NTA) and transmission electron microscopy (TEM). Western blot analysis of EV protein extracts was used for EV canonical protein markers CD63, CD9 and flotillin-1 (FLOT1), as well as neutrophil elastase (NE), myeloperoxidase (MPO) and interleukin-8.

Brain and lung arteriovenous malformation rescreening practices for children and adults with hereditary hemorrhagic telangiectasia.

Background: Patients with hereditary hemorrhagic telangiectasia (HHT) are at risk for organ vascular malformations including arteriovenous malformations (AVMs) in the brain and lungs. North American HHT Centers of Excellence (CoEs) routinely screen for brain and lung AVMs, with the primary goal of detecting AVMs which can be treated before complications arise. Current international HHT guidelines provide recommendations for initial screening for brain and lung AVMs among children and adults with the disease, but rescreening recommendations are not comprehensively addressed and have not been reported.

The future of cystic fibrosis: A global perspective.

The severity of lung disease as well as other disease manifestations have dramatically improved in those patients with cystic fibrosis (CF) that both have mutations responsive to small molecule- based therapies with CF transmembrane regulator (CFTR) modulators and do have access to these drugs. Unfortunately, these medications are not available to many patients with CF across the globe with access largely limited to high income countries. For those eligible to CFTR modulators new questions have arisen regarding the ongoing need for other medications addressing CF lung disease as well current care models with tight monitoring.

Same-Day Repeatability and 28-Day Reproducibility of Xenon MRI Ventilation in Children With Cystic Fibrosis in a Multi-Site Trial.

Background: MRI with xenon-129 gas (Xe MRI) can assess airflow obstruction and heterogeneity in lung diseases. Specifically, Xe MRI may represent a sensitive modality for future therapeutic trials of cystic fibrosis (CF) therapies. The reproducibility of Xe MRI has not yet been assessed in the context of a multi-site study.

De Novo Brain Vascular Malformations in Hereditary Hemorrhagic Telangiectasia.

Background: Approximately 10% of people with hereditary hemorrhagic telangiectasia (HHT) have brain vascular malformations (VMs). Few reports describe de novo brain VM formation. International HHT Guidelines recommend initial brain VM screening upon HHT diagnosis in children but do not address rescreening.