Management Of Cystic Fibrosis Lung Disease Research Articles

Assessing the Potential of N-Butyl-l-deoxynojirimycin (l-NBDNJ) in Models of Cystic Fibrosis as a Promising Antibacterial Agent.

Over the past few years, l-iminosugars have revealed attractive pharmacological properties for managing rare diseases including Cystic Fibrosis (CF). The iminosugar N-butyl-l-deoxynojirimycin (l-NBDNJ, ent-1), prepared by a carbohydrate-based route, was herein evaluated for its anti-inflammatory and anti-infective potential in models of CF lung disease infection. A significant decrease in the bacterial load in the airways was observed in the murine model of Pseudomonas aeruginosa chronic infection in the presence of l-NBDNJ, also accompanied by a modest reduction of inflammatory cells. Mechanistic insights into the observed activity revealed that l-NBDNJ interferes with the expression of proteins regulating cytoskeleton assembly and organization of the host cell, downregulates the main virulence factors of P. aeruginosa involved in the host response, and affects pathogen adhesion to human cells. These findings along with the observation of the absence of an in vitro bacteriostatic/bactericidal action of l-NBDNJ suggest the potential use of this glycomimetic as an antivirulence agent in the management of CF lung disease.

Prognosis-Based Early Intervention Strategies to Resolve Exacerbation and Progressive Lung Function Decline in Cystic Fibrosis.

Cystic fibrosis (CF) is a genetic disease caused by a mutation(s) in the CF transmembrane regulator (CFTR), where progressive decline in lung function due to recurring exacerbations is a major cause of mortality. The initiation of chronic obstructive lung disease in CF involves inflammation and exacerbations, leading to mucus obstruction and lung function decline. Even though clinical management of CF lung disease has prolonged survival, exacerbation and age-related lung function decline remain a challenge for controlling the progressive lung disease. The key to the resolution of progressive lung disease is prognosis-based early therapeutic intervention; thus, the development of novel diagnostics and prognostic biomarkers for predicting exacerbation and lung function decline will allow optimal management of the lung disease. Hence, the development of real-time lung function diagnostics such as forced oscillation technique (FOT), impulse oscillometry system (IOS), and electrical impedance tomography (EIT), and novel prognosis-based intervention strategies for controlling the progression of chronic obstructive lung disease will fulfill a significant unmet need for CF patients. Early detection of CF lung inflammation and exacerbations with the timely resolution will not only prolong survival and reduce mortality but also improve quality of life while reducing significant health care costs due to recurring hospitalizations.

Advances in Imaging Cystic Fibrosis Lung Disease.

Cystic fibrosis (CF) is a life shortening, multiorgan disease, in which morbidity and mortality are dominated by pulmonary pathologies, including mucous obstruction, chronic lung infections, progressive bronchiectasis, and declining lung function. Promising new therapies, including those that target the cystic fibrosis transmembrane conductance regulator (CFTR) protein, have shown impressive efficacy in treating CF patients with specific genotypes. While spirometry is the clinical gold standard for evaluating CF lung disease, it has known insensitivities to mild lung disease and statistical weaknesses in small cohorts. Imaging has begun to play an important role in evaluating the structural abnormalities associated with CF lung disease progression. X-ray computed tomography (CT) has been established as a modality with validated metrics to evaluate disease severity, even in young patients with mild disease. Magnetic resonance imaging (MRI), as a nonionizing alternative, has very strong potential for similar metrics and longitudinal use through the lifespan. In this brief review, recent advancements in imaging CF lung disease in pediatrics are discussed, specifically in the contexts of X-ray CT, ultra-short echo time MRI, and hyperpolarized-gas MRI, with an emphasis on how emerging techniques will likely impact the management of CF lung disease in the era of CFTR-modulator therapies, targeted at smaller subpopulations of CF with specific genotypes. In the future, techniques that provide sensitive, quantitative measurements of regional lung structure and function longitudinally will become increasingly important as outcome measures for clinical trials and for monitoring individual CF patients.

Antibiotic-resistant obligate anaerobes during exacerbations of cystic fibrosis patients

Pseudomonas aeruginosa and Staphylococcus aureus are thought to cause the majority of lung infections in patients with cystic fibrosis (CF). However, other bacterial pathogens may contribute to the pathophysiology of lung disease. Here, obligate anaerobes were identified in a cross-sectional study, and cell numbers and antibiotic susceptibilities of facultative and obligate anaerobes from 114 sputum samples from nine children and 36 adults with CF were determined. Furthermore, in 12 CF patients, we investigated whether conventional intravenous antibiotic therapy, administered during acute exacerbations, would affect the numbers of obligate anaerobes. Fifteen genera of obligate anaerobes were identified in 91% of the CF patients. Cell numbers (mean: 2.2 × 107 ± standard deviation 6.9 × 107 CFU/mL of sputum sample) were comparable to those of P. aeruginosa and S. aureus. Staphylococcus saccharolyticus and Peptostreptococcus prevotii were most prevalent. Infection with P. aeruginosa did not increase the likelihood that obligate anaerobes are present in sputum specimens. Single obligate anaerobic species persisted for up to 11 months in sputum plugs in vivo. Patients with and without obligate anaerobes in sputum specimens did not differ in lung function. Intravenous therapy directed against P. aeruginosa during acute exacerbations increased lung function, but did not reduce the numbers of obligate anaerobes. Obligate anaerobic species differed widely in their patterns of resistance against meropenem, piperacillin–tazobactam, clindamycin, metronidazole and ceftazidime. In 58% of patients with acute exacerbations, obligate anaerobes were detected that were resistant to the antibiotics used for treatment. Antibiotic therapy, optimized to target anaerobes in addition to P. aeruginosa, may improve the management of CF lung disease.

Cystic Fibrosis Lung Disease in Adult Patients

As the longevity of all patients with cystic fibrosis (CF) continues to increase (median 2005 survival = 36.8 years), more adult patients will be receiving their medical care from nonpediatric adult-care providers. Cystic fibrosis remains a fatal disease, with more than 80% of patients dying after the age of 18 years, and most deaths resulting from pulmonary disease. The changing epidemiology requires adult-care providers to become knowledgeable and competent in the clinical management of adults with CF. Physicians must understand the influence of specific genotype on phenotypic disease presentation and severity, the pathogenic factors determining lung disease onset and progression, the impact of comorbid disease factors such as CF-related diabetes and malnutrition upon lung disease severity, and the currently approved or standard accepted therapies used for chronic management of CF lung disease. This knowledge is critical to help alleviate morbidity and improve mortality for the rapidly expanding population of adults with CF.

Pathophysiology and management of pulmonary infections in cystic fibrosis.

This comprehensive State of the Art review summarizes the current published knowledge base regarding the pathophysiology and microbiology of pulmonary disease in cystic fibrosis (CF). The molecular basis of CF lung disease including the impact of defective cystic fibrosis transmembrane regulator (CFTR) protein function on airway physiology, mucociliary clearance, and establishment of Pseudomonas aeruginosa infection is described. An extensive review of the microbiology of CF lung disease with particular reference to infection with P. aeruginosa is provided. Other pathogens commonly associated with CF lung disease including Staphylococcal aureus, Burkholderia cepacia, Stenotrophomonas maltophilia, Achromobacter xylosoxidans and atypical mycobacteria are also described. Clinical presentation and assessment of CF lung disease including diagnostic microbiology and other measures of pulmonary health are reviewed. Current recommendations for management of CF lung disease are provided. An extensive review of antipseudomonal therapies in the settings of treatment for early P. aeruginosa infection, maintenance for patients with chronic P. aeruginosa infection, and treatment of exacerbation in pulmonary symptoms, as well as antibiotic therapies for other CF respiratory pathogens, are included. In addition, the article discusses infection control policies, therapies to optimize airway clearance and reduce inflammation, and potential future therapies.

Potential role of macrolide antibiotics in the management of cystic fibrosis lung disease.

Current management of cystic fibrosis (CF) lung disease includes the use of antibiotics, nutritional support, and airway clearance therapies. However, despite recent advances in pharmacologic therapies including DNase and aerosolized tobramycin, deterioration in lung function persists. Recent investigations have shed new light on the pathogenic mechanisms by which establishes itself within the airways of patients with CF and contributes to the progressive decline in lung function. In particular, the presence of biofilms and other virulence mechanisms allow evasion of local host defenses and establishment of a chronic localized inflammatory response resulting in lung damage. Macrolide antibiotics appear to have a promising role in the management of CF lung disease even though they do not exhibit intrinsic antipseudomonal activity. Recent evidence demonstrates that they can disrupt quorum sensing, a cell-to-cell signaling process linked to the formation of biofilms. In addition, they inhibit NF-kappab and AP-1, nuclear factors that control the expression of proinflammatory cytokines. Their ability to decrease sputum viscosity and increase sputum clearance may complement existing airway clearance therapies. Preliminary clinical trials have shown modest improvement in pulmonary function.