Cystic Fibrosis Airway Infections Research Articles

Dpr-mediated H2O2 resistance contributes to streptococcus survival in a cystic fibrosis airway model system.

Streptococcus spp. are recognized as a highly prevalent pathogen in cystic fibrosis (CF) airway infections. However, the role of this microbe in clinical outcomes for persons with CF is poorly understood. Here, we leverage a polymicrobial community system previously developed by our group to model CF airway infections as a tool to investigate a Pseudomonas-Streptococcus interaction involving reactive oxygen species (ROS). We show that protection against ROS is required for Streptococcus sanguinis survival in a clinically relevant polymicrobial system. Using this model system to study interspecies interactions contributes to our broader understanding of the complex role of Streptococcus spp. in the CF lung.

Creation of a CF-specific antibiotic spectrum index (ASI) as an antimicrobial stewardship initiative

Antibiotics are frequently utilized for cystic fibrosis (CF)-related pulmonary exacerbation treatment. The antibiotic spectrum index (ASI) is an antimicrobial stewardship tool developed to compare the relative breadth of individual antibiotics. This study aimed to create two expanded CF-specific ASI scoring indices for use in antimicrobial stewardship research and clinical care. The first scoring index expanded the original ASI to include bacterial microorganisms common to CF airway infections (CF-ASI). The second scoring system only included scores for bacterial microorganisms classically identified in CF airway infections (CF-sASI). Sixty-two antibiotics were evaluated and included in the updated ASIs. When multiple antibiotics are prescribed, we proposed using an additive ASI approach whereby the sum of the individual prescribed antibiotic scores represents the total ASI score. The application of CF-focused ASIs into CF research and stewardship programs can help to optimize antibiotic benefits, minimize harms and allow for increased sustainability of antibiotic use in CF.

CFTR dysfunction leads to defective bacterial eradication on cystic fibrosis airways.

Dysfunction of the cystic fibrosis transmembrane conductance regulator (CFTR) anion channel by genetic mutations causes the inherited disease cystic fibrosis (CF). CF lung disease that involves multiple disorders of epithelial function likely results from loss of CFTR function as an anion channel conducting chloride and bicarbonate ions and its function as a cellular regulator modulating the activity of membrane and cytosol proteins. In the absence of CFTR activity, abundant mucus accumulation, bacterial infection and inflammation characterize CF airways, in which inflammation-associated tissue remodeling and damage gradually destroys the lung. Deciphering the link between CFTR dysfunction and bacterial infection in CF airways may reveal the pathogenesis of CF lung disease and guide the development of new treatments. Research efforts towards this goal, including high salt, low volume, airway surface liquid acidosis and abnormal mucus hypotheses are critically reviewed.

Virulence of Pseudomonas aeruginosa in Cystic Fibrosis: Relationships between Normoxia and Anoxia Lifestyle.

The airways of cystic fibrosis (CF) patients are colonized by many pathogens and the most common is Pseudomonas aeruginosa, an environmental pathogen that is able to infect immunocompromised patients thanks to its ability to develop resistance to conventional antibiotics. Over 12% of all patients colonized by P. aeruginosa harbour multi-drug resistant species. During airway infection in CF, P. aeruginosa adopts various mechanisms to survive in a hostile ecological niche characterized by low oxygen concentration, nutrient limitation and high osmotic pressure. To this end, P. aeruginosa uses a variety of virulence factors including pigment production, biofilm formation, motility and the secretion of toxins and proteases. This study represents the first report that systematically analyzes the differences in virulence features, in normoxia and anoxia, of clinical P. aeruginosa isolated from CF patients, characterized by multi- or pan-drug antibiotic resistance compared to antibiotic sensitive strains. The virulence features, such as biofilm formation, protease secretion and motility, are highly diversified in anaerobiosis, which reflects the condition of chronic CF infection. These findings may contribute to the understanding of the real-world lifestyle of pathogens isolated during disease progression in each particular patient and to assist in the design of therapeutic protocols for personalized medicine.

Integrating airway microbiome and blood proteomics data to identify multi-omic networks associated with response to pulmonary infection

Host response to airway infections can vary widely. Cystic fibrosis (CF) pulmonary exacerbations provide an opportunity to better understand the interplay between respiratory microbes and the host. This study aimed to investigate the observed heterogeneity in airway infection recovery by analyzing microbiome and host response (i.e., blood proteome) data collected during the onset of 33 pulmonary infection events. We used sparse multiple canonical correlation network (SmCCNet) analysis to integrate these two types of -omics data along with a clinical measure of recovery. Four microbe–protein SmCCNet subnetworks at infection onset were identified that strongly correlate with recovery. Our findings support existing knowledge regarding CF airway infections. Additionally, we discovered novel microbe–protein subnetworks that are associated with recovery and merit further investigation.

93 Persistent airway infections in cystic fibrosis–like mouse models correlate with phenotypic changes of clinical Pseudomonas aeruginosa isolates

93 Persistent airway infections in cystic fibrosis–like mouse models correlate with phenotypic changes of clinical Pseudomonas aeruginosa isolates

Role of Inhalational Aztreonam Lysine in Lower Airway Infections in Cystic Fibrosis: An Updated Literature Review.

Cystic fibrosis (CF) is an inherited disorder most prevalent in the Caucasian population, characterized by a functional abnormality of the transmembrane conductance regulator protein that leads to a wide array of complications, including chronic lung infections. Pseudomonas aeruginosa (PA) is a frequently acquired microbe in CF patients and is associated with deterioration in pulmonary function and increased mortality. Inhaled anti-infective agents are an established curative therapy for CF airway infections, especially with chronic PA lung disease. Amongst them, aztreonam lysine for inhalation (AZLI) is an aerosolized monobactam antibiotic aztreonam, approved for use in CF patients nearly a decade ago. This literature review aims to explore studies based on the efficacy, safety, and tolerability of AZLI use in CF patients with pulmonary infections. We searched for all the relevant articles present in PubMed, Google Scholar, Cochrane Library, EMBASE, ClinicalTrials.gov, and Journal of Cystic Fibrosis for our data collection from 2000 to 2020. The use of AZLI has substantially improved lung function, respiratory symptoms, and remarkably reduced sputum PA density in CF patients, thereby improving the patient's overall quality of life. The adverse effects reported were compatible with CF lung disease. Hence, inhalational therapy with AZLI is highly efficacious and safe in the management of chronic airway infections. More clinical trials need to be conducted in the future to assess its long-term clinical benefits and adverse events as well as to explore the role of AZLI in the setting of acute lung infections.

Airway Infection in Cystic Fibrosis: Microbiology and Management.

Airway Infection in Cystic Fibrosis: Microbiology and Management.

The Sense and Nonsense of Antimicrobial Susceptibility Testing in Cystic Fibrosis.

Antimicrobial susceptibility testing (AST) has been used to guide therapy of airway infection in persons with cystic fibrosis (CF) for decades. However, evidence that AST adds benefit to treatment outcomes in CF is lacking. In fact, the routine use of AST has potential to exacerbate inappropriate antibiotic use. Several features of airway infection in CF contribute to the limitations of AST in predicting treatment outcomes, providing rationale for abandoning this practice altogether. Other features of CF infection suggest, however, that select use of AST can provide worthwhile guidance to antibiotic selection.

Drugs, Drugs, Drugs: Current Treatment Paradigms in Cystic Fibrosis Airway Infections.

Airway infections have remained a prominent feature in persons living with cystic fibrosis (CF) despite the dramatic improvements in survival in the past decades. Antimicrobials are a cornerstone of infection management for both acute and chronic maintenance indications. Historic clinical trials of antimicrobials in CF have led to the adoption of consensus guidelines for their use in clinical care. More recently, however, there are efforts to re-think the optimal use of antimicrobials for care with the advent of novel and highly effective CF transmembrane conductance regulator modulator therapies. Encouragingly, however, drug development has remained active concurrently in this space. Our review focuses on the evidence for and perspectives regarding antimicrobial use in both acute and maintenance settings in persons with CF. The therapeutic innovations in CF and how this may affect antimicrobial approaches are also discussed.

The Elusive Role of Airway Infection in Cystic Fibrosis Exacerbation.

Cystic fibrosis (CF) pulmonary exacerbations (PEx) are clinical events that commonly result in increased treatment burden, decreased quality of life, and accelerated lung disease progression. CF PEx have historically been approached as though dealing with acute infections, and antibiotic treatments have been associated with improved outcomes. In this review, we discuss data supporting a causal role of CF airway infection in PEx as well studies that highlight our knowledge gaps in regard to PEx definitions, pathophysiology, and optimal treatment approaches. In the era of highly effective cystic fibrosis transmembrane conductance regulator modulator therapy, and the continually increasing health and longevity of persons with CF, a better understanding of PEx and further optimization of PEx antibiotic treatment approaches are needed.

CFTR Modulator Therapies: Potential Impact on Airway Infections in Cystic Fibrosis.

Cystic Fibrosis (CF) is an autosomal recessive disease caused by mutations in the gene encoding for the Cystic Fibrosis Transmembrane conductance Regulator (CFTR) protein, expressed on the apical surface of epithelial cells. CFTR absence/dysfunction results in ion imbalance and airway surface dehydration that severely compromise the CF airway microenvironment, increasing infection susceptibility. Recently, novel therapies aimed at correcting the basic CFTR defect have become available, leading to substantial clinical improvement of CF patients. The restoration or increase of CFTR function affects the airway microenvironment, improving local defence mechanisms. CFTR modulator drugs might therefore affect the development of chronic airway infections and/or improve the status of existing infections in CF. Thus far, however, the full extent of these effects of CFTR-modulators, especially in the long-term remains still unknown. This review aims to provide an overview of current evidence on the potential impact of CFTR modulators on airway infections in CF. Their role in affecting CF microbiology, the susceptibility to infections as well as the potential efficacy of their use in preventing/decreasing the development of chronic lung infections and the recurrent acute exacerbations in CF will be critically analysed.

The Effect of CFTR Modulators on Airway Infection in Cystic Fibrosis.

The advent of Cystic fibrosis transmembrane receptor (CFTR) modulators in 2012 was a critical event in the history of cystic fibrosis (CF) treatment. Unlike traditional therapies that target downstream effects of CFTR dysfunction, CFTR modulators aim to correct the underlying defect at the protein level. These genotype-specific therapies are now available for an increasing number of CF patients, transforming the way we view the condition from a life-limiting disease to one that can be effectively managed. Several studies have demonstrated the vast improvement CFTR modulators have on normalization of sweat chloride, CFTR function, clinical endpoints, and frequency of pulmonary exacerbation. However, their impact on other aspects of the disease, such as pathogenic burden and airway infection, remain under explored. Frequent airway infections as a result of increased susceptibility and impaired innate immune response are a serious problem within CF, often leading to accelerated decline in lung function and disease progression. Current evidence suggests that CFTR modulators are unable to eradicate pathogenic organisms in those with already established lung disease. However, this may not be the case for those with relatively low levels of disease progression and conserved microbial diversity, such as young patients. Furthermore, it remains unknown whether the restorative effects exerted by CFTR modulators extend to immune cells, such as phagocytes, which have the potential to modulate the response of people with CF (pwCF) to infection. Throughout this review, we look at the potential impact of CFTR modulators on airway infection in CF and their ability to shape impaired pulmonary defences to pathogens.

Network Analysis to Identify Multi-Omic Correlations in the Lower Airways of Children With Cystic Fibrosis.

The leading cause of morbidity and mortality in cystic fibrosis (CF) is progressive lung disease secondary to chronic airway infection and inflammation; however, what drives CF airway infection and inflammation is not well understood. By providing a physiological snapshot of the airway, metabolomics can provide insight into these processes. Linking metabolomic data with microbiome data and phenotypic measures can reveal complex relationships between metabolites, lower airway bacterial communities, and disease outcomes. In this study, we characterize the airway metabolome in bronchoalveolar lavage fluid (BALF) samples from persons with CF (PWCF) and disease control (DC) subjects and use multi-omic network analysis to identify correlations with the airway microbiome. The Biocrates targeted liquid chromatography mass spectrometry (LC-MS) platform was used to measure 409 metabolomic features in BALF obtained during clinically indicated bronchoscopy. Total bacterial load (TBL) was measured using quantitative polymerase chain reaction (qPCR). The Qiagen EZ1 Advanced automated extraction platform was used to extract DNA, and bacterial profiling was performed using 16S sequencing. Differences in metabolomic features across disease groups were assessed univariately using Wilcoxon rank sum tests, and Random forest (RF) was used to identify features that discriminated across the groups. Features were compared to TBL and markers of inflammation, including white blood cell count (WBC) and percent neutrophils. Sparse supervised canonical correlation network analysis (SsCCNet) was used to assess multi-omic correlations. The CF metabolome was characterized by increased amino acids and decreased acylcarnitines. Amino acids and acylcarnitines were also among the features most strongly correlated with inflammation and bacterial burden. RF identified strong metabolomic predictors of CF status, including L-methionine-S-oxide. SsCCNet identified correlations between the metabolome and the microbiome, including correlations between a traditional CF pathogen, Staphylococcus, a group of nontraditional taxa, including Prevotella, and a subnetwork of specific metabolomic markers. In conclusion, our work identified metabolomic characteristics unique to the CF airway and uncovered multi-omic correlations that merit additional study.

N-acetylcysteine (NAC) and Its Role in Clinical Practice Management of Cystic Fibrosis (CF): A Review.

N-acetylcysteine is the acetylated form of the amino acid L-cysteine and a precursor to glutathione (GSH). It has been known for a long time as a powerful antioxidant and as an antidote for paracetamol overdose. However, other activities related to this molecule have been discovered over the years, making it a promising drug for diseases such as cystic fibrosis (CF). Its antioxidant activity plays a key role in CF airway inflammation and redox imbalance. Furthermore, this molecule appears to play an important role in the prevention and eradication of biofilms resulting from CF airway infections, in particular that of Pseudomonas aeruginosa. The aim of this review is to provide an overview of CF and the role that NAC could play in preventing and eliminating biofilms, as a modulator of inflammation and as an antioxidant, restoring the redox balance within the airways in CF patients. To do this, NAC can act alone, but it can also be used as an adjuvant molecule to known drugs (antibiotics/anti-inflammatories) to increase their activity.

507: Establishing a mutant for modeling Staphylococcus aureus small colony–variant airway infection in cystic fibrosis

507: Establishing a mutant for modeling Staphylococcus aureus small colony–variant airway infection in cystic fibrosis

427: Investigating the role of Pseudomonas aeruginosa lipid A deacylase PagL in cystic fibrosis airway infection

427: Investigating the role of Pseudomonas aeruginosa lipid A deacylase PagL in cystic fibrosis airway infection

INCREASED CYTOKINE LEVELS DEFINE THE AIRWAY OF STABLE CYSTIC FIBROSIS PATIENTS COMPARED TO HEALTHY CONTROLS

TOPIC: Genetic and Developmental Disorders TYPE: Original Investigations PURPOSE: Cystic Fibrosis (CF) is a multisystem autosomal recessive disease caused by mutations in the CFTR (CF transmembrane conductance regulator) gene. Airway inflammation and infection in CF leads to tissue injury, worsening lung function, and disease progression. Increased cytokine levels reflect the exaggerated inflammation characteristic of the CF airway environment and contribute to pathogenesis even in the absence of respiratory symptoms. We sought to define individual CF-specific cytokine variations as a means to characterize the difference between healthy and CF airways, and to identify patients at risk of clinical deterioration. METHODS: Sputum samples were obtained from Forty-four adult patients with confirmed CF diagnosis from the Yale Adult CF Program. Patients were classified as CF stable at each visit if they did not meet predefined criteria for an acute exacerbation. Ten healthy controls (HC) were recruited to undergo sputum induction. Sputum samples were assayed for twelve cytokines using a multiplexed indirect ELISA. Differences in cytokine levels between CF stable and healthy controls were analyzed using the Mann-Whitney Test with Bonferroni correction. RESULTS: Twelve inflammatory cytokine levels were measured. Six cytokines were significantly increased in the sputum of stable CF patients compared to healthy controls (median values, pg/mL). These cytokines included: IL-1beta (CF 1720; HC 39.7), IL-8 (CF 28173; HC 3468), TNF-alpha (CF 98.65; HC 10.70), and IFN-alpha (CF 38.90; HC 5.60) [p < 0.0001] as well as IFN-gamma (CF 68.45; HC 17.10) and IL-13 (20.10; 0.00) [p < 0.01]. Cytokines tested without significant difference between groups included: CXCL10, G-CSF, IFNI, IL-6, MCP1, and MIP-alpha. CONCLUSIONS: Inflammatory cytokine levels of IL-1beta, IL-8, TNF-alpha, IFN-a, IFN-gamma and IL-13 are significantly increased in the sputum of stable CF patients compared to the sputum of healthy controls. CLINICAL IMPLICATIONS: Monitoring basal sputum cytokine levels may help identify patients with worsening inflammation before symptoms develop and thus prevent irreversible lung damage and disease progression. Additionally, further understanding of inflammatory cytokine dysregulation in stable CF airways may serve as the basis for a sputum inflammation marker panel that guides future therapeutic interventions. DISCLOSURES: No relevant relationships by Clemente Britto, source=Web Response Consultant relationship with AstraZeneca Please note: >$100000 by Geoffrey Chupp, source=Web Response, value=Consulting fee Consultant relationship with Genentech Please note: $20001 - $100000 by Geoffrey Chupp, source=Web Response, value=Consulting fee Consultant relationship with Genzyme Corporation Please note: $5001 - $20000 by Geoffrey Chupp, source=Web Response, value=Consulting fee Consultant relationship with Novartis Please note: $5001 - $20000 by Geoffrey Chupp, source=Web Response, value=Consulting fee Consultant relationship with Circassia Please note: $1001 - $5000 by Geoffrey Chupp, source=Web Response, value=Consulting fee Consultant relationship with Boehringer Ingelheim Please note: $1001 - $5000 by Geoffrey Chupp, source=Web Response, value=Consulting fee Consultant relationship with GlaxoSmithKline Please note: $1-$1000 by Geoffrey Chupp, source=Web Response, value=Consulting fee Consultant relationship with Regeneron Please note: 5/2019-present Added 04/26/2021 by Lauren Cohn, source=Web Response, value=Consulting fee Speaker/Speaker's Bureau relationship with Genentech Please note: 5/2019-11/2019 Added 04/26/2021 by Lauren Cohn, source=Web Response, value=Honoraria Advisory Committee Member relationship with novartis Please note: 10/2019 Added 04/26/2021 by Lauren Cohn, source=Web Response, value=Consulting fee Advisory Committee Member relationship with glaxosmithkline Please note: 12/2019 Added 04/26/2021 by Lauren Cohn, source=Web Response, value=Consulting fee Advisory Committee Member relationship with sanofi Please note: 5/2020 Added 04/26/2021 by Lauren Cohn, source=Web Response, value=Consulting fee Advisory Committee Member relationship with Pieris Please note: 5/2019 Added 04/26/2021 by Lauren Cohn, source=Web Response, value=Consulting fee Advisory Committee Member relationship with AstraZeneca Please note: 5/2019-7/2020 Added 04/26/2021 by Lauren Cohn, source=Web Response, value=Consulting fee Consultant relationship with Biohaven Please note: 6/23/2020 Added 04/26/2021 by Lauren Cohn, source=Web Response, value=Consulting fee No relevant relationships by Sara Khanal, source=Web Response No relevant relationships by qing liu, source=Web Response No relevant relationships by Jana Zielonka, source=Web Response

An in vitro model for the cultivation of polymicrobial biofilms under continuous-flow conditions.

The airways of people with cystic fibrosis (CF) are often chronically colonised with a diverse array of bacterial and fungal species. However, little is known about the relative partitioning of species between the planktonic and biofilm modes of growth in the airways. Existing in vivo and in vitro models of CF airway infection are ill-suited for the long-term recapitulation of mixed microbial communities. Here we describe a simple, in vitro continuous-flow model for the cultivation of polymicrobial biofilms and planktonic cultures on different substrata. Our data provide evidence for inter-species antagonism and synergism in biofilm ecology. We further show that the type of substratum on which the biofilms grow has a profound influence on their species composition. This happens without any major alteration in the composition of the surrounding steady-state planktonic community. Our experimentally-tractable model enables the systematic study of planktonic and biofilm communities under conditions that are nutritionally reminiscent of the CF airway microenvironment, something not possible using any existing in vivo models of CF airway infection.

Comparative genomics of ST5 and ST30 methicillin-resistant Staphylococcus aureus sequential isolates recovered from paediatric patients with cystic fibrosis

Staphylococcus aureus chronic airway infection in patients with cystic fibrosis (CF) allows this pathogen to adapt over time in response to different selection pressures. We have previously shown that the main sequence types related to community-acquired methicillin-resistant S. aureus (MRSA) infections in Argentina – ST5 and ST30 – are also frequently isolated from the sputum of patients with CF, but in these patients they usually display multi-drug antimicrobial resistance. In this study, we sequenced the genomes of MRSA from four paediatric CF patients with the goal of identifying mutations among sequential isolates, especially those possibly related to antimicrobial resistance and virulence, which might contribute to the adaptation of the pathogen in the airways of patients with CF. Our results revealed genetic differences in sequential MRSA strains isolated from patients with CF in both their core and accessory genomes. Although the genetic adaptation of S. aureus was distinct in different hosts, we detected independent mutations in thyA, htrA, rpsJ and gyrA – which are known to have crucial roles in S. aureus virulence and antimicrobial resistance – in isolates recovered from multiple patients. Moreover, we identified allelic variants that were detected in all of the isolates recovered after a certain time point; these non-synonymous mutations were in genes associated with antimicrobial resistance, virulence, iron scavenging and oxidative stress resistance. In conclusion, our results provide evidence of genetic variability among sequential MRSA isolates that could be implicated in the adaptation of these strains during chronic CF airway infection.