scholarly journals CF Fungal Disease in the Age of CFTR Modulators

2021 ◽  
Author(s):  
Amelia Bercusson ◽  
George Jarvis ◽  
Anand Shah
Keyword(s):  
Cystic Fibrosis ◽  
Innate Immunity ◽  
Drug Interactions ◽  
Aspergillus Fumigatus ◽  
Lung Disease ◽  
Disease Progression ◽  
Fungal Disease ◽  
Concurrent Use ◽  
The Impact ◽  
Cftr Modulators

AbstractFungi are increasingly recognised to have a significant role in the progression of lung disease in Cystic fibrosis with Aspergillus fumigatus the most common fungus isolated during respiratory sampling. The emergence of novel CFTR modulators has, however, significantly changed the outlook of disease progression in CF. In this review we discuss what impact novel CFTR modulators will have on fungal lung disease and its management in CF. We discuss how CFTR modulators affect antifungal innate immunity and consider the impact of Ivacaftor on fungal disease in individuals with gating mutations. We further review the increasing complication of drug–drug interactions with concurrent use of azole antifungal medication and highlight key unknowns that require addressing to fully understand the impact of CFTR modulators on fungal disease.

scholarly journals Coinfection with Pseudomonas aeruginosa and Aspergillus fumigatus in cystic fibrosis

2020 ◽  
Vol 29 (158) ◽  
pp. 200011
Author(s):  
Karen Keown ◽  
Alastair Reid ◽  
John E. Moore ◽  
Clifford C. Taggart ◽  
Damian G. Downey
Keyword(s):  
Cystic Fibrosis ◽  
Pseudomonas Aeruginosa ◽  
Aspergillus Fumigatus ◽  
Lung Disease ◽  
Disease Progression ◽  
Expert Knowledge ◽  
Fungal Species ◽  
Interspecies Interactions ◽  
Cross Sectional ◽  
Infection And Inflammation

ObjectivesCystic fibrosis (CF) lung disease is characterised by mucus stasis, chronic infection and inflammation, causing progressive structural lung disease and eventual respiratory failure. CF airways are inhabited by an ecologically diverse polymicrobial environment with vast potential for interspecies interactions, which may be a contributing factor to disease progression. Pseudomonas aeruginosa and Aspergillus fumigatus are the most common bacterial and fungal species present in CF airways respectively and coinfection results in a worse disease phenotype.MethodsIn this review we examine existing expert knowledge of chronic co-infection with P. aeruginosa and A. fumigatus in CF patients. We summarise the mechanisms of interaction and evaluate the clinical and inflammatory impacts of this co-infection.ResultsP. aeruginosa inhibits A. fumigatus through multiple mechanisms: phenazine secretion, iron competition, quorum sensing and through diffusible small molecules. A. fumigatus reciprocates inhibition through gliotoxin release and phenotypic adaptations enabling evasion of P. aeruginosa inhibition. Volatile organic compounds secreted by P. aeruginosa stimulate A. fumigatus growth, while A. fumigatus stimulates P. aeruginosa production of cytotoxic elastase.ConclusionA complex bi-directional relationship exists between P. aeruginosa and A. fumigatus, exhibiting both mutually antagonistic and cooperative facets. Cross-sectional data indicate a worsened disease state in coinfected patients; however, robust longitudinal studies are required to derive causality and to determine whether interspecies interaction contributes to disease progression.

scholarly journals Impact of CFTR modulator use on outcomes in people with severe cystic fibrosis lung disease

2020 ◽  
Vol 29 (155) ◽  
pp. 190112 ◽  
Author(s):  
Michal Shteinberg ◽  
Jennifer L. Taylor-Cousar
Keyword(s):  
Cystic Fibrosis ◽  
Lung Disease ◽  
Case Series ◽  
Lung Damage ◽  
Cystic Fibrosis Lung Disease ◽  
Drug Compounds ◽  
The Impact ◽  
Cftr Modulators ◽  
Severe Lung Disease

Drug compounds that augment the production and activity of the cystic fibrosis (CF) transmembrane regulator (CFTR) have revolutionised CF care. Many adults and some children with CF suffer advanced and severe lung disease or await lung transplantation. While the hope is that these drug compounds will prevent lung damage when started early in life, there is an ongoing need to care for people with advanced lung disease. The focus of this review is the accumulating data from clinical trials and case series regarding the benefits of CFTR modulator therapy in people with advanced pulmonary disease. We address the impact of treatment with ivacaftor, lumacaftor/ivacaftor, tezacaftor/ivacaftor and elexacaftor/tezacaftor/ivacaftor on lung function, pulmonary exacerbations, nutrition and quality of life. Adverse events of the different CFTR modulators, as well as the potential for drug–drug interactions, are discussed.

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 Risk factors for respiratory Aspergillus fumigatus in German Cystic Fibrosis patients and impact on lung function

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Uta Düesberg ◽  
Julia Wosniok ◽  
Lutz Naehrlich ◽  
Patience Eschenhagen ◽  
Carsten Schwarz
Keyword(s):  
Risk Factors ◽  
Cystic Fibrosis ◽  
Lung Function ◽  
Aspergillus Fumigatus ◽  
Age Groups ◽  
Antibiotic Use ◽  
Lower Lung ◽  
Lung Infections ◽  
The Impact

Abstract Airway inflammation and chronic lung infections in cystic fibrosis (CF) patients are mostly caused by bacteria, e.g. Pseudomonas aeruginosa (PA). The role of fungi in the CF lung is still not well elucidated, but evidence for a harmful and complex role is getting stronger. The most common filamentous fungus in CF is Aspergillus fumigatus (AF). Age and continuous antibiotic treatment have been discussed as risk factors for AF colonisation but did not differentiate between transient and persistent AF colonisation. Also, the impact of co-colonisation of PA and AF on lung function is still under investigation. Data from patients with CF registered in the German Cystic Fibrosis Registry database in 2016 and 2017 were retrospectively analysed, involving descriptive and multivariate analysis to assess risk factors for transient or persistent AF colonisation. Age represented an independent risk factor for persistent AF colonisation. Prevalence was low in children less than ten years, highest in the middle age and getting lower in higher age (≥ 50 years). Continuous antibiotic lung treatment was significantly associated with AF prevalence in all age groups. CF patients with chronic PA infection had a lower lung function (FEV1%predicted), which was not influenced by an additional AF colonisation. AF colonisation without chronic PA infection, however, was significantly associated with a lower function, too. Older age up to 49 years and continuous antibiotic use were found to be the main risk factors for AF permanent colonisation. AF might be associated with decrease of lung function if not disguised by chronic PA infection.

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 Upper Airway Findings and Markers of Lung Disease Progression in Patients with Cystic Fibrosis

2020 ◽  
Vol 24 (04) ◽  
pp. e434-e437
Author(s):  
Luciane Mazzini Steffen ◽  
Luise Sgarabotto Pezzin ◽  
Natassia Sulis ◽  
Nedio Steffen ◽  
Leonardo Araujo Pinto
Keyword(s):  
Cystic Fibrosis ◽  
Lung Disease ◽  
Disease Progression ◽  
Nasal Polyps ◽  
Nasal Swab ◽  
Statistical Significance ◽  
Upper Airway ◽  
Forced Expiratory Volume ◽  
Upper Respiratory Tract ◽  
Upper Airways

Abstract Introduction Cystic fibrosis (CF) is a genetic disease that limits the quality of life mainly due to respiratory symptoms. The relationship between findings of the upper airways and CF lung disease is not yet completely understood. Objective The aim of the present study is to describe the most frequent nasal findings and pathogens in patients with CF and investigate the association between the findings of the upper respiratory tract and markers of lung disease progression. Methods Retrospective study in patients with CF from the Pediatric Pulmonology Department who underwent otorhinolaryngological evaluation between 2015 and 2017. Nasal endoscopy and nasal swab collection were part of the evaluation. The severity markers used were: percentage of predicted forced expiratory volume in the first second (FEV1%), body mass index (BMI) and the Shwachman-Kulczycki (SK) clinical score. Results A total of 48 patients with CF were included. The mean of the predicted percentage of FEV1% was 83.36 ± 30.04. The average 14 and SK score 89.11 ± 10.50. The bacteriology of the nasal swab was positive in 27 (54.1%) patients. Staphylococcus aureus was positive in 18 patients, Pseudomonas aeruginosa in 5, Pseudomonas cepacea in 3 and Stenotrophomonas maltophila in 1 patient. Nasal polyps were found in nine participants. Nasal polyps were found in nine participants and were associated with lower SK score. Conclusion The pathogens found in the upper airway were, in order: S. aureus, P. aeruginosa, P. cepacea e S. maltophila. The presence of polyps in the nasal cavity showed statistical significance and appears to have association with the prognostic factor measured by the SK score.

scholarly journals Early-Life Pseudomonas aeruginosa Infection in Cystic Fibrosis and Lung Disease Progression

2017 ◽  
Vol 4 ◽  
pp. 2333794X1773846
Author(s):  
Argyri Petrocheilou ◽  
Maria Papagrigoriou-Theodoridou ◽  
Athanasios Michos ◽  
Stavros-Eleftherios Doudounakis ◽  
Ioanna Loukou ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Pseudomonas Aeruginosa ◽  
Lung Disease ◽  
Disease Progression ◽  
Early Life ◽  
Pseudomonas Aeruginosa Infection
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