scholarly journals Airway Inflammation and Host Responses in the Era of CFTR Modulators

2020 ◽  
Vol 21 (17) ◽  
pp. 6379
Author(s):  
Karen Keown ◽  
Ryan Brown ◽  
Declan F. Doherty ◽  
Claire Houston ◽  
Michael C. McKelvey ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Lung Function ◽  
Lung Disease ◽  
Airway Inflammation ◽  
Host Responses ◽  
Current Evidence ◽  
Future Research ◽  
Clinical Endpoints ◽  
New Class ◽  
Cftr Modulators

The arrival of cystic fibrosis transmembrane conductance regulator (CFTR) modulators as a new class of treatment for cystic fibrosis (CF) in 2012 represented a pivotal advance in disease management, as these small molecules directly target the upstream underlying protein defect. Further advancements in the development and scope of these genotype-specific therapies have been transformative for an increasing number of people with CF (PWCF). Despite clear improvements in CFTR function and clinical endpoints such as lung function, body mass index (BMI), and frequency of pulmonary exacerbations, current evidence suggests that CFTR modulators do not prevent continued decline in lung function, halt disease progression, or ameliorate pathogenic organisms in those with established lung disease. Furthermore, it remains unknown whether their restorative effects extend to dysfunctional CFTR expressed in phagocytes and other immune cells, which could modulate airway inflammation. In this review, we explore the effects of CFTR modulators on airway inflammation, infection, and their influence on the impaired pulmonary host defences associated with CF lung disease. We also consider the role of inflammation-directed therapies in light of the widespread clinical use of CFTR modulators and identify key areas for future research.

scholarly journals From Ivacaftor to Triple Combination: A Systematic Review of Efficacy and Safety of CFTR Modulators in People with Cystic Fibrosis

2020 ◽  
Vol 21 (16) ◽  
pp. 5882 ◽  
Author(s):  
Andrea Gramegna ◽  
Martina Contarini ◽  
Stefano Aliberti ◽  
Rosaria Casciaro ◽  
Francesco Blasi ◽  
...  
Keyword(s):  
Systematic Review ◽  
Cystic Fibrosis ◽  
Lung Function ◽  
Real Life ◽  
Scientific Data ◽  
Current Evidence ◽  
Symptom Improvement ◽  
Efficacy And Safety ◽  
Beneficial Effects ◽  
Cftr Modulators

Over the last years CFTR (cystic fibrosis transmembrane conductance regulator) modulators have shown the ability to improve relevant clinical outcomes in patients with cystic fibrosis (CF). This review aims at a systematic research of the current evidence on efficacy and tolerability of CFTR modulators for different genetic subsets of patients with CF. Two investigators independently performed the search on PubMed and included phase 2 and 3 clinical trials published in the study period 1 January 2005–31 January 2020. A final pool of 23 papers was included in the systematic review for a total of 4219 patients. For each paper data of interest were extracted and reported in table. In terms of lung function, patients who had the most beneficial effects from CFTR modulation were those patients with one gating mutation receiving IVA (ivacaftor) and patients with p.Phe508del mutation, both homozygous and heterozygous, receiving ELX/TEZ/IVA (elexacaftor/tezacaftor/ivacaftor) had the most relevant beneficial effects in term of lung function, pulmonary exacerbation decrease, and symptom improvement. CFTR modulators showed an overall favorable safety profile. Next steps should aim to systematize our comprehension of scientific data of efficacy and safety coming from real life observational studies.

scholarly journals Early Detection of Lung Disease in Children with Cystic Fibrosis Using Lung Function

2008 ◽  
Vol 9 (3) ◽  
pp. 160-167 ◽  
Author(s):  
Sarath Ranganathan ◽  
Barry Linnane ◽  
Gary Nolan ◽  
Catherine Gangell ◽  
Graham Hall
Keyword(s):  
Cystic Fibrosis ◽  
Lung Function ◽  
Early Detection ◽  
Lung Disease

scholarly journals Impact of Airway Inflammation on the Efficacy of CFTR Modulators

Cells ◽  
2021 ◽  
Vol 10 (11) ◽  
pp. 3260
Author(s):  
Carla M. P. Ribeiro ◽  
Martina Gentzsch
Keyword(s):  
Cystic Fibrosis ◽  
Airway Inflammation ◽  
Primary Cultures ◽  
Lavage Fluid ◽  
Improved Outcomes ◽  
Inflammatory Stimuli ◽  
Infection And Inflammation ◽  
The Impact ◽  
Cftr Modulators

Defective CFTR biogenesis and activity in cystic fibrosis airways leads to airway dehydration and impaired mucociliary clearance, resulting in chronic airway infection and inflammation. Most cystic fibrosis patients have at least one copy of the F508del CFTR mutation, which results in a protein retained in the endoplasmic reticulum and degraded by the proteosomal pathway. CFTR modulators, e.g., correctors, promote the transfer of F508del to the apical membrane, while potentiators increase CFTR activity. Corrector and potentiator double therapies modestly improve lung function, whereas triple therapies with two correctors and one potentiator indicate improved outcomes. Enhanced F508del rescue by CFTR modulators is achieved by exposing F508del/F508del primary cultures of human bronchial epithelia to relevant inflammatory stimuli, i.e., supernatant from mucopurulent material or bronchoalveolar lavage fluid from human cystic fibrosis airways. Inflammation enhances the biochemical and functional rescue of F508del by double or triple CFTR modulator therapy and overcomes abrogation of CFTR correction by chronic VX-770 treatment in vitro. Furthermore, the impact of inflammation on clinical outcomes linked to CFTR rescue has been recently suggested. This review discusses these data and possible mechanisms for airway inflammation-enhanced F508del rescue. Expanding the understanding of how airway inflammation improves CFTR rescue may benefit CF patients.

scholarly journals Forced Oscillation Technique for Monitoring the Respiratory Status of Children with Cystic Fibrosis: A Systematic Review

Children ◽  
2021 ◽  
Vol 8 (10) ◽  
pp. 857
Author(s):  
Ioanna Loukou ◽  
Maria Moustaki ◽  
Agni Deligianni ◽  
Olympia Sardeli ◽  
Konstantinos Douros
Keyword(s):  
Cystic Fibrosis ◽  
Lung Function ◽  
Children And Adolescents ◽  
Forced Oscillation ◽  
Clinical Symptoms ◽  
Current Evidence ◽  
Forced Oscillation Technique ◽  
Gold Standard Method ◽  
Respiratory Status ◽  
Alternative Modality

Spirometry is considered the gold standard method for monitoring lung function of patients with cystic fibrosis (CF) but it requires patients’ cooperation and therefore it is not useful for the majority of preschool-aged children. Oscillometry is an alternative modality for lung function monitoring that requires minimal cooperation and can be applied in children as young as 3 years of age. Furthermore, it generates lesser aerosol compared to spirometry, an issue that is of considerable importance in the COVID-19 era. The aim of this review was to present the existing clinical data regarding the application of oscillometry in children and adolescents with CF. The method seems to have acceptable feasibility and repeatability. However, there is conflicting data regarding the correlation of oscillometry values with the clinical symptoms of CF patients either in clinically stable or in exacerbation periods. Furthermore, it is not clear to what extent oscillometry measurements correlate with the spirometry indices. Based on current evidence, spirometry cannot be substituted by oscillometry in the monitoring of the respiratory status of children and adolescents with CF.

Neutrophils in cystic fibrosis

2016 ◽  
Vol 397 (6) ◽  
pp. 485-496 ◽  
Author(s):  
Julie Laval ◽  
Anjali Ralhan ◽  
Dominik Hartl
Keyword(s):  
Cystic Fibrosis ◽  
Lung Disease ◽  
Structural Damage ◽  
Fungal Pathogens ◽  
Therapeutic Potential ◽  
Inflammatory Cells ◽  
Current Evidence ◽  
Infection And Inflammation ◽  
Shed Light

Abstract Cystic fibrosis (CF) lung disease is characterized by chronic infection and inflammation. Among inflammatory cells, neutrophils represent the major cell population accumulating in the airways of CF patients. While neutrophils provide the first defensive cellular shield against bacterial and fungal pathogens, in chronic disease conditions such as CF these short-lived immune cells release their toxic granule contents that cause tissue remodeling and irreversible structural damage to the host. A variety of human and murine studies have analyzed neutrophils and their products in the context of CF, yet their precise functional role and therapeutic potential remain controversial and incompletely understood. Here, we summarize the current evidence in this field to shed light on the complex and multi-faceted role of neutrophils in CF lung disease.

scholarly journals Cystic Fibrosis Lung Disease in the Aging Population

2021 ◽  
Vol 12 ◽  
Author(s):  
Lisa Künzi ◽  
Molly Easter ◽  
Meghan June Hirsch ◽  
Stefanie Krick
Keyword(s):  
Cystic Fibrosis ◽  
Lung Disease ◽  
Airway Inflammation ◽  
Chronic Inflammation ◽  
Accelerated Aging ◽  
Aging Population ◽  
Chronic Obstructive ◽  
Obstructive Pulmonary Disease ◽  
Repair Mechanisms ◽  
Inflammatory State

The demographics of the population with cystic fibrosis (CF) is continuously changing, with nowadays adults outnumbering children and a median predicted survival of over 40 years. This leads to the challenge of treating an aging CF population, while previous research has largely focused on pediatric and adolescent patients. Chronic inflammation is not only a hallmark of CF lung disease, but also of the aging process. However, very little is known about the effects of an accelerated aging pathology in CF lungs. Several chronic lung disease pathologies show signs of chronic inflammation with accelerated aging, also termed “inflammaging”; the most notable being chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF). In these disease entities, accelerated aging has been implicated in the pathogenesis via interference with tissue repair mechanisms, alterations of the immune system leading to impaired defense against pulmonary infections and induction of a chronic pro-inflammatory state. In addition, CF lungs have been shown to exhibit increased expression of senescence markers. Sustained airway inflammation also leads to the degradation and increased turnover of cystic fibrosis transmembrane regulator (CFTR). This further reduces CFTR function and may prevent the novel CFTR modulator therapies from developing their full efficacy. Therefore, novel therapies targeting aging processes in CF lungs could be promising. This review summarizes the current research on CF in an aging population focusing on accelerated aging in the context of chronic airway inflammation and therapy implications.

scholarly journals An 8 week open-label interventional multicenter study to evaluate the lung clearance index as endpoint for clinical trials in cystic fibrosis patients ≥8 years of age, chronically infected with Pseudomonas aeruginosa

2020 ◽  
Author(s):  
Sivagurunathan Sutharsan ◽  
Susanne Naehrig ◽  
Uwe Mellies ◽  
Christian Sieder ◽  
joerg Zeigler
Keyword(s):  
Cystic Fibrosis ◽  
Pseudomonas Aeruginosa ◽  
Lung Function ◽  
Lung Disease ◽  
Small Airways ◽  
Open Label ◽  
Lung Clearance ◽  
Efficacy Trials ◽  
Inhaled Antibiotics ◽  
Lung Clearance Index

Abstract Background Forced expiratory volume in 1 second (FEV 1 ) is the only parameter currently recognized as a surrogate endpoint in cystic fibrosis (CF) trials. However, FEV 1 is relatively insensitive to changes in the small airways of patients with milder lung disease. This pilot study aimed to evaluate the lung clearance index (LCI) as a marker for use in efficacy trials with inhaled antibiotics in CF. Methods This open-label, single-arm study enrolled CF patients with Pseudomonas aeruginosa infection, who were treated with tobramycin (28-day on/off regime). FEV 1 , LCI and bacterial load in sputum (CFU) were assessed at baseline, after 1, 4 and 8 weeks of treatment. Results All patients (n=17) showed elevated LCI of >11 despite 3 patients having normal FEV 1 (>90% predicted) at baseline. Overall, LCI improved in 8 (47%) patients and FEV 1 in 9 (53%) patients. At week 4, LCI improved by 0.88, FEV 1 increased by 0.52%, and P. aeruginosa reduced by 30481.3 CFU/mL. These changes were however statistically non-significant. Six adverse events occurred in 5/17 (29.4%) patients, most of which were mild-to-moderate in severity. Conclusions Due to the low evaluable sample size, no specific trend was observed related to the changes between LCI, FEV1 and CFU. Based on the individual data from this study and from recently published literature, LCI has been shown to be a more sensitive parameter than FEV1 for lung function. LCI can hypothesized to be an appropriate endpoint for efficacy trials in CF patients if the heterogeneity in lung function is limited by enrolling younger patients or patients with more milder lung disease and thus, limiting the ventilation inhomogeneities. Trial registration : The study is registered with ClinicalTrials.gov, identifier: NCT02248922

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