Course Of Cystic Fibrosis Lung Disease Research Articles

Lived experiences of people with cystic fibrosis that were not eligible for elexacaftor-tezacaftor-ivacaftor (ETI): A qualitative study

BackgroundElexacaftor-tezacaftor-ivacaftor (ETI) represents a significant step forward in cystic fibrosis (CF) care and could change the course of CF lung disease and quality of life for many people with CF (PwCF). However, several PwCF cannot benefit from these modulators because their rare mutations are not eligible for treatment. This study aimed to investigate the lived experiences of PwCF who are not eligible for ETI. MethodsData were collected through semi-structured interviews with 13 individuals with CF that were not eligible for ETI. Thematic analysis was used to identify the key themes of their experiences. ResultsTwo main themes and six subthemes were identified. The first main theme (being deemed ineligible for ETI) had four subthemes (disappointment, information, happiness, and concerns). The second main theme (coping with a life without ETI) had two subthemes (lack of hope and continued hope). ConclusionsPwCF who are not eligible for ETI experience intense disappointment and conflicting emotions that can influence their decision-making linked to diminishing/renewal hope. Integrated care, including mental health monitoring programs, should be provided to these patients to aid them in overcoming their disappointment and to improve their coping.

Klinisches Bild der Lungenerkrankung bei zystischer Fibrose

Although cystic fibrosis (CF) is amultiorgan disease, the extent of CF lung disease is decisive for the course and survival of patients. The optimization of symptomatic therapies has led to asignificant improvement in the life expectancy of those affected in recent decades. Regular monitoring of the course of CF lung disease with microbiological, pulmonary function, and imaging examinations is essential for early detection of problems and individualized therapy. With new, causal therapy options in the form of cystic fibrosis transmembrane conductance regulator (CFTR) modulators and early diagnosis through newborn screening, afurther normalization of life expectancy and quality of life of CF patients can be expected.

CF Lung Disease - a German S3 Guideline: Module 2: Diagnostics and Treatment in Chronic Infection with Pseudomonas aeruginosa

Cystic Fibrosis (CF) is the most common autosomal-recessive genetic disease affecting approximately 8000 people in Germany. The disease is caused by mutations in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene leading to dysfunction of CFTR, a transmembrane chloride channel. This defect causes insufficient hydration of the epithelial lining fluid which leads to chronic inflammation of the airways. Recurrent infections of the airways as well as pulmonary exacerbations aggravate chronic inflammation, lead to pulmonary fibrosis and tissue destruction up to global respiratory insufficiency, which is responsible for the mortality in over 90 % of patients. The main aim of pulmonary treatment in CF is to reduce pulmonary inflammation and chronic infection. Pseudomonas aeruginosa (Pa) is the most relevant pathogen in the course of CF lung disease. Colonization and chronic infection are leading to additional loss of pulmonary function. There are many possibilities to treat Pa-infection. This is a S3-clinical guideline which implements a definition for chronic Pa-infection and demonstrates evidence-based diagnostic methods and medical treatment for Pa-infection in order to give guidance for individual treatment options.

Microbial colonization and lung function in adolescents with cystic fibrosis

With intensified antibiotic therapy and longer survival, patients with cystic fibrosis (CF) are colonized with a more complex pattern of bacteria and fungi. However, the clinical relevance of these emerging pathogens for lung function remains poorly defined. The aim of this study was to assess the association of bacterial and fungal colonization patterns with lung function in adolescent patients with CF. Microbial colonization patterns and lung function parameters were assessed in 770 adolescent European (German/Austrian) CF patients in a retrospective study (median follow-up time: 10years). Colonization with Pseudomonas aeruginosa and MRSA were most strongly associated with loss of lung function, while mainly colonization with Haemophilus influenzae was associated with preserved lung function. Aspergillus fumigatus was the only species that was associated with an increased risk for infection with P. aeruginosa. Microbial interaction analysis revealed three distinct microbial clusters within the longitudinal course of CF lung disease. Collectively, this study identified potentially protective and harmful microbial colonization patterns in adolescent CF patients. Further studies in different patient cohorts are required to evaluate these microbial patterns and to assess their clinical relevance.

Effect of pulmonary exacerbations on long-term lung function decline in cystic fibrosis

It is unknown what proportion of long-term lung function decline in cystic fibrosis (CF) is explained by pulmonary exacerbations. The aim of this study was to determine how exacerbations requiring hospitalisation contribute to the course of CF lung disease. This was a retrospective cohort study. The primary outcome was the rate of decline of forced expiratory volume in 1 s (FEV(1)) % predicted. Out of 851 subjects, 415 (48.8%) subjects had ≥ 1 exacerbation. After adjustment for confounders, the annual rate of FEV(1) decline in those without an exacerbation was 1.2% per yr (95% CI 1.0-1.5), compared with 2.5% per yr (95% CI 2.1-2.8) in those with an exacerbation. The proportion of overall FEV(1) decline associated with ≥ 1 exacerbation was 52% (95% CI 35.0-68.9). For a given number of exacerbations, the annual rate of FEV(1) decline was greatest in subjects with ≤ 6 months between exacerbations. Half of FEV(1) decline seen in CF patients was associated with pulmonary exacerbations. Time between exacerbations, specifically ≤ 6 months between exacerbations, plays an important contribution to overall lung function decline. These findings support using time to next exacerbation as a clinical end-point for CF trials.

Impact of mannose-binding lectin insufficiency on the course of cystic fibrosis: A review and meta-analysis

Mannose-binding lectin (MBL) is an innate immune protein produced by the liver. MBL binds to glycoconjugates containing mannose, fucose or N-acetylglucosamine that are present in a wide variety of bacteria, viruses and fungi. Upon binding, MBL may active the lectin pathway of complement or directly opsonize organisms to enhance phagocytosis. MBL is primarily a serum protein but accumulates in the lung during acute inflammation. Recent evidence suggests an important role for MBL in a variety of infectious disorders. Cystic fibrosis (CF) is a multisystem disease caused by mutations in the gene encoding the CF transmembrane regulator (CFTR). The course of CF lung disease is highly variable even in patients with the same CFTR genotype, suggesting that other modulator genes are important for prognosis. MBL has been proposed as a possible modulator of clinical severity in CF. In this review and meta-analysis, we found that MBL2 genotypes associated with MBL insufficiency were associated with earlier acquisition of Pseudomonas aeruginosa (P<0.0001), reduced pulmonary function among adult patients (P<0.0001 for forced expiratory volume), and an increased rate of death or requirement for lung transplantation (odds ratio 3.69; P=0.02). The available evidence therefore suggests that MBL insufficiency is associated with the severity of CF lung disease. The possible future prophylactic or therapeutic application of MBL replacement is discussed.

Power Considerations for Studies of Lung Function in Cystic Fibrosis

Observational studies and clinical trials in cystic fibrosis (CF) have largely been concerned with improving long-term survival. Lung function tests, in particular FEV(1), have proven to be reliable and objective measures for monitoring the course of CF lung disease. Over several decades, the variability and average rates of FEV(1) decline have been remarkably stable. In the past decade, specific treatments and management of CF have resulted in a more gradual rate of decline, so that large numbers of patients are needed to demonstrate a significant subgroup or treatment difference. New measures are needed that detect changes before lung function decline, and that reflect more subtle changes over time. As new measurement tools are developed, FEV(1) provides a model to show how age, sex, duration, and frequency of measurement are related to variability, sample size, and power in cross-sectional or longitudinal studies. Chest radiographs are a standard tool for clinical assessment of an individual patient. However, their use in clinical trials has been limited by the lack of an objective way of measuring the elements that characterize the disease process. The CT scan offers more specific measurements relating directly to the process of lung disease in CF. Computerized algorithms can provide objective scores, but it will be an ongoing challenge to confirm the validity of candidate measures and their relationship to CF lung disease.

The Trp64Arg polymorphism in the β 3 ‐adrenergic receptor gene is not associated with pulmonary function in cystic fibrosis

OBJECTIVE As cystic fibrosis (CF) phenotypes are highly variable even in patients carrying the same CFTR mutations, it has been suggested that the course of CF lung disease is influenced by modifying genes other than CFTR. There is recent evidence that CFTR activity isalso regulated through β3-adrenergic receptor (β3-AR) stimulation. We therefore investigated whether polymorphisms in the β3-AR gene contribute to the course of pulmonary function in CF. METHODS The Trp64Arg β3-AR polymorphism was studied by RFLP analysis in 99 CF patients. β3-AR genotypes were related to the annual decline of FEV1, FVC and MEF50 and to age at first infection with P. aeruginosa. RESULTS Genotype distribution was Trp64Trp n=84, Trp64Arg n=14, and Arg64Arg n=1. Frequencies of the β3-AR alleles in CF patients were similar compared to healthy controls. Mean (±SD) follow-up was 14.3±7.8 years. Mean (±SEM) annual decline of pulmonary function was 1.8±0.2 for FEV1, 1.3±0.2 for FVC, and 3.4±0.3 for MEF50. The course of pulmonary function was not different between β3-AR genotypes. There was also no difference in age at first P. aeruginosa infection. Median age at first infection was 7.5 years (quartiles 3.8-15.2 years) in Trp64Trp and 5.7 years (quartiles 3.5-9.4 years) in Trp64Arg patients (p=0.2, Wilcoxon sign rank test). CONCLUSIONS The Trp64Arg β3-AR gene polymorphism was not associated with the course of pulmonary function or with P. aeruginosa airway infection in CF. Therefore, these data do not suggest that the β3-AR gene acts as a modifier of CF lung disease.

Neutrophilic Inflammation as a Major Determinant in the Progression of Cystic Fibrosis

Cystic fibrosis (CF) is the most frequent recessive disease in Caucasians. While CF affects all exocrine organs throughout the body, its lung manifestation represents the main cause of morbidity and mortality. Key studies have demonstrated that neutrophilic inflammation occurs early in the course of CF lung disease and that neutrophil-derived factors, most notably elastase, play a crucial pathological role. However, the exact mechanism of neutrophilic inflammation remains unclear. Are there distinct inflammatory phases in the multidecade-long course of CF lung disease? Are CF neutrophils intrinsically abnormal or conditioned by neighboring cells? What is the role of live versus post-apoptotic lung neutrophils? These are some of the questions that this review addresses. This review also argues that the current paradigm that views neutrophils as short-lived indiscriminate killers is seriously flawed. Thus, researchers and clinicians need to view the pathophysiological importance of neutrophils in a new light, to the ultimate benefit of patients.

The relationship between infection and inflammation in the early stages of lung disease from cystic fibrosis.

We examined the relationship of pulmonary infection and inflammation in cystic fibrosis (CF) by performing 31 bronchoalveolar lavages (BAL) in 14 young children with minimal lung disease from CF. While 10 of the 14 patients had elevated polymorphonuclear leukocyte (PMN) counts initially, only 4 had bacteria generally regarded as pathogenic in the recovered BAL fluid. Three of these 4 and 6 of the others had follow-up bronchoscopies at 6 months intervals. PMN counts remained normal for only one patient. However, pathogenic bacteria were recovered during the repeat BALs only in those patients who were colonized initially. Proinflammatory cytokines and proteinases were generally elevated, and interleukin-8 (IL-8) concentration correlated inversely with oxygen saturation (SaO2). No complications of the procedure occurred. We conclude that BAL identifies inflammation and the presence of bacteria in the lower airway at an early stage of the disease. This information may be used to guide therapy in patients too young or otherwise unable to produce sputum. These data also suggest that inflammation is present early in the course of CF lung disease before colonization and infection of the lungs with potentially pathogenic bacteria occurs. Since inflammation appears to be the earliest detectable evidence of lung disease in CF, monitoring of inflammation with BAL may serve as a useful marker of clinical benefits from new treatments in patients with minimal lung disease.