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Cystic fibrosis transmembrane conductance regulator (CFTR) modulators, a new series of therapeutics that correct and potentiate some classes of mutations of the CFTR, have provided a great therapeutic advantage to people with cystic fibrosis (pwCF). The main hindrances of the present CFTR modulators are related to their limitations in reducing chronic lung bacterial infection and inflammation, the main causes of pulmonary tissue damage and progressive respiratory insufficiency, particularly in adults with CF. Here, the most debated issues of the pulmonary bacterial infection and inflammatory processes in pwCF are revisited. Special attention is given to the mechanisms favoring the bacterial infection of pwCF, the progressive adaptation of Pseudomonas aeruginosa and its interplay with Staphylococcus aureus, the cross-talk among bacteria, the bronchial epithelial cells and the phagocytes of the host immune defenses. The most recent findings of the effect of CFTR modulators on bacterial infection and the inflammatory process are also presented to provide critical hints towards the identification of relevant therapeutic targets to overcome the respiratory pathology of pwCF.

The Cystic Fibrosis (CF) Foundation developed clinical care guidelines for the prevention of Pseudomonas aeruginosa infection, the treatment of initial P. aeruginosa infection, and the use of bronchoscopy to obtain routine airway cultures in individuals with CF. A multidisciplinary committee developed questions about the prevention and treatment of initial P. aeruginosa infection and the use of bronchoscopy to obtain routine airway cultures. The outcome measure of interest was cultures without P. aeruginosa growth. Systematic reviews of PubMed, EMBASE, and the Cochrane Central Register of Controlled Trials were conducted in May 2012 and August 2013. Searches combined controlled vocabulary terms and text words for CF and terms relevant to each question. The entire committee reviewed the evidence, and final recommendation statements were graded using the U.S. Preventive Services Task Force system. Recommendation 1: The CF Foundation strongly recommends inhaled antibiotic therapy for the treatment of initial or new growth of P. aeruginosa from an airway culture (certainty of net benefit, high; estimate of net benefit, substantial; grade of recommendation, A). The favored antibiotic regimen is inhaled tobramycin (300 mg twice daily) for 28 days. Recommendation 2: The CF Foundation recommends against the use of prophylactic antipseudomonal antibiotics to prevent the acquisition P. aeruginosa (certainty of net benefit, moderate; estimate of net benefit, zero; grade of recommendation, D). Recommendation 3: The CF Foundation recommends routine oropharyngeal cultures rather than bronchoalveolar lavage cultures obtained by bronchoscopy in individuals with CF who cannot expectorate sputum to determine if they are infected with P. aeruginosa (certainty of net benefit, moderate; estimate of net benefit, moderate; grade of recommendation, B).

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.

Abstract Inhaled antibiotics have been used to treat chronic airway infections since the 1940s. The earliest experience with inhaled antibiotics involved aerosolizing antibiotics designed for parenteral administration. These formulations caused significant bronchial irritation due to added preservatives and nonphysiologic chemical composition. A major therapeutic advance took place in 1997, when tobramycin designed for inhalation was approved by the U.S. Food and Drug Administration (FDA) for use in patients with cystic fibrosis (CF) with chronic Pseudomonas aeruginosa infection. Attracted by the clinical benefits observed in CF and the availability of dry powder antibiotic formulations, there has been a growing interest in the use of inhaled antibiotics in other lower respiratory tract infections, such as non-CF bronchiectasis, ventilator-associated pneumonia, chronic obstructive pulmonary disease, mycobacterial disease, and in the post–lung transplant setting over the past decade. Antibiotics currently marketed for inhalation include nebulized and dry powder forms of tobramycin and colistin and nebulized aztreonam. Although both the U.S. Food and Drug Administration and European Medicines Agency have approved their use in CF, they have not been approved in other disease areas due to lack of supportive clinical trial evidence. Injectable formulations of gentamicin, tobramycin, amikacin, ceftazidime, and amphotericin are currently nebulized “off-label” to manage non-CF bronchiectasis, drug-resistant nontuberculous mycobacterial infections, ventilator-associated pneumonia, and post-transplant airway infections. Future inhaled antibiotic trials must focus on disease areas outside of CF with sample sizes large enough to evaluate clinically important endpoints such as exacerbations. Extrapolating from CF, the impact of eradicating organisms such as P. aeruginosa in non-CF bronchiectasis should also be evaluated.

Chronic airway inflammatory and infectious respiratory diseases are the most common medical respiratory conditions, associated with significant morbidity and mortality. Vitamin D (1,25(OH) 2 D 3 ) deficiency has been shown to be highly prevalent in patients with chronic airway inflammatory and infectious diseases, correlated with increased disease severity. It has been established that vitamin D modulates ongoing abnormal immune responses in chronic respiratory diseases and is shown to restrict bacterial and viral colonization into the lungs. On the contrary, other studies revealed controversy findings regarding vitamin D efficacy in respiratory diseases. This review aims to update the current evidence regarding the role of vitamin D in airway inflammation and in various respiratory diseases. A comprehensive search of the last five years of literature was conducted using MEDLINE and non-MEDLINE PubMed databases, Ovid MEDLINE, SCOPUS-Elsevier, and data from in vitro and in vivo experiments, including clinical studies. This review highlights the importance of understanding the full range of implications that vitamin D may have on lung inflammation, infection, and disease severity in the context of chronic respiratory diseases.

Ecological guilds are groups of organisms that utilize the same class of resources and occupy similar niches, regardless of their taxonomic identities. Here we propose the Guild Model for Cystic Fibrosis Airway Microbial Ecology, which considers the ecological function and wider role of each microbe in the ecosystem. This model consists of four functional guilds: (i) \"Brewers\" metabolize host-derived substrates (e.g., mucins) and produce fermentation products; (ii) \"Drunkards\" exploit the metabolic niche built by Brewers, consuming fermentation products and secreting exopolysaccharides to build biofilms; (iii) \"Putrifiers\" produce toxic compounds causing inflammation and tissue necrosis; and (iv) \"Nihilists\" are specialist pathogens characterized by intracellular or lytic life cycles and cytotoxin production. By focusing on microbial function and the broader community context, this model offers a refined framework for interpreting cystic fibrosis airway ecology. Although developed for CF, the Guild Model is adaptable to other diseases influenced by microbial ecology.

Regulatory mechanisms governing the ability of Haemophilus influenzae to survive within the human lungs remain poorly elucidated. Here, by coordinated exploitation of multiomic approaches, and using reference and clinical strains, we present evidence that the Dam methyltransferase mediates epigenetic regulatory mechanisms facilitating bacterial phenotypic diversity and flexibility, besides reversibility, to contribute to H. influenzae survival within the lungs of individuals where disease reduces the amount of oxygen, as encountered in COPD. We reveal a novel bacterial network where DNA methylation regulates the expression of and interplay between the Fur and FNR master transcriptional regulators, which act in a coordinated manner, controlling the expression of H. influenzae genes involved in bacterial defenses against the nitrosative stress encountered in the diseased lungs, and further highlight the importance of oxygen restriction within this hostile niche.

Cystic fibrosis (CF) is an autosomal recessive multisystem disorder caused by mutations in the cystic fibrosis conductance regulator (CFTR) anion channel. In the lungs specifically, CFTR mutations lead to changes in mucus viscosity and defective mucociliary clearance. Moreover, people with CF (pwCF) mount an insufficient immune response to invading pathogens, which predisposes individuals to chronic airway disease associated with chronic inflammation, colonization, and recurrent infections by mainly opportunistic pathogens. These chronic infections in the CF lung are typically polymicrobial and frequently harbour multidrug-resistant pathogens, making both treatment and eradication very challenging. During the last decade, the development of highly effective CFTR modulator therapy (HEMT) has led to a breakthrough in treatment options for pwCF. While the majority of pwCF now live longer and have fewer CF exacerbations, colonisation with common respiratory pathogens persists, thereby contributing to chronic inflammation and infection. Interestingly, there are limited reports examining the lung microbiome in the post-modulator era. Since ETI treatment is still quite novel and has only been used for about five years by now, this review will be one of the first discussing the current literature on the effect of ETI on CF pathogens. In addition, we will identify unanswered questions that remain from the effect of HEMT on the CF microbiome.

In a large, 10-year, population-based study of adolescents and adults with cystic fibrosis in the United States, we demonstrated that chronic Pseudomonas aeruginosa infection rates have decreased significantly, with no clear concomitant increase in other common airway pathogens. Abstract Background Chronic Pseudomonas aeruginosa lung infection is associated with significant morbidity and mortality in cystic fibrosis (CF). It is not known whether recent advances in care have affected the rates of chronic infection. We aimed to determine if the rates of developing new chronic P. aeruginosa infection among adolescents and adults with CF significantly changed over time. Methods The cohort consisted of individuals with CF followed in the Cystic Fibrosis Foundation Patient Registry aged ≥13 years without chronic P. aeruginosa at baseline. Multivariable regression models accounting for within-patient correlation were used to assess the change in rate of developing chronic P. aeruginosa infection between 2003 and 2012. Results A total of 15504 individuals were followed for a median of 5 (interquartile range, 2-9) years. The annual rates of developing new chronic P. aeruginosa decreased from 14.3% in 2003 to 6.4% in 2012. After adjusting for potential confounders, relative risk (RR) of developing chronic P. aeruginosa infection decreased significantly over time compared to 2003 (P value test of trend < .001). Compared with 2003, the RR of developing chronic P. aeruginosa infection in 2012 was 0.33 (95% confidence interval, 0.30-0.37). No significant increases in risk of chronic infections with other major CF bacterial pathogens relative to 2003 were identified. Conclusions Among individuals with CF, a significant decrease in the risk and rates of developing chronic P. aeruginosa infection between 2003 and 2012 was observed. Whether this decline results in changes in clinical outcomes warrants further exploration.

Air-liquid interface (ALI) cell culture systems have improved the study of host-pathogen interactions in respiratory infections. However, most ALI models lack immune components, limiting their ability to capture epithelial-immune crosstalk. To address this, we developed a dual-cell ALI model incorporating human peripheral blood monocyte-derived macrophages beneath differentiated airway epithelial cells. Macrophages were seeded on the basolateral side of transwell inserts using fibronectin coating. Model characterization included transepithelial electrical resistance (TEER) to assess epithelial barrier integrity, IL-8 secretion as a marker of epithelial inflammatory signaling, and confocal microscopy to evaluate cellular architecture before and after infection. Mono- and dual-cell cultures were infected with the laboratory strain PAO1. Macrophages adhered stably to the basolateral surface without compromising epithelial barrier integrity. Following infection, IL-8 secretion was elevated in epithelial monocultures compared to dual-cell cultures, suggesting early immune modulation in the presence of macrophages. While overall bacterial burden was comparable, confocal imaging revealed clustered bacterial growth in monocultures and a more dispersed spatial distribution in dual-cell cultures. This dual-cell ALI model enables investigation of early epithelial-immune interactions, inflammatory modulation, and bacterial colonization dynamics during airway infection. The system provides a versatile and human-relevant platform for studying respiratory host-pathogen interactions.