A cystic fibrosis child with lung function decline

Respiratory infections are a major threat to cystic fibrosis patients. Besides bacteria, many fungi colonize the cystic fibrosis respiratory tract where an important fungal biota has been described. We report here the case of a 7-year-old cystic fibrosis child with pulmonary exacerbation and Arthrographis kalrae isolated from bronchoalveolar lavage fluid. To the best of our knowledge, this is the first reported case of lung infection due to Arhtrographis kalrae in a cystic fibrosis pediatric patient.     

Factors in childhood associated with lung function decline to adolescence in cystic fibrosis

BackgroundDespite improvements in general health and life expectancy in people with cystic fibrosis (CF), lung function decline continues unabated during adolescence and early adult life.MethodsWe examined factors present at age 5-years that predicted lung function decline from childhood to adolescence in a longitudinal study of Australasian children with CF followed from 1999 to 2017.ResultsLung function trajectories were calculated for 119 children with CF from childhood (median 5.0 [25%-75%=5.0–5.1]) years) to early adolescence (median 12.5 [25%-75%=11.4–13.8] years). Lung function fell progressively, with mean (standard deviation) annual change -0.105 (0.049) for forced vital capacity (FVC) Z-score (p<0.001), -0.135 (0.048) for forced expiratory volume in 1-second (FEV₁) Z-score (p<0.001), -1.277 (0.221) for FEV₁/FVC% (p<0.001), and -0.136 (0.052) for forced expiratory flow between 25% and 75% of FVC Z-score (p<0.001). Factors present in childhood predicting lung function decline to adolescence, in multivariable analyses, were hospitalisation for respiratory exacerbations in the first 5-years of life (FEV₁/FVC p = 0.001, FEF_25–75 p = 0.01) and bronchoalveolar lavage neutrophil elastase activity (FEV₁/FVC% p = 0.001, FEV₁ p = 0.05, FEF_25–75 p = 0.02). No examined factor predicted a decline in the FVC Z-score.ConclusionsAction in the first 5-years of life to prevent and/or treat respiratory exacerbations and counteract neutrophilic inflammation in the lower airways may reduce lung function decline in children with CF, and these should be targets of future research.     

Chronic Mycobacterium abscessus infection and lung function decline in cystic fibrosis

BackgroundAlthough nontuberculous mycobacteria (NTM) are recognized pathogens in cystic fibrosis (CF), associations with clinical outcomes remain unclear.MethodsMicrobiological data was obtained from 1216 CF patients over 8 years (481 ± 55 patients/year). Relationships to clinical outcomes were examined in the subset (n = 271, 203 ± 23 patients/year) with longitudinal data.ResultsFive hundred thirty-six of 4862 (11%) acid-fast bacilli (AFB) cultures grew NTM, with Mycobacterium abscessus (n = 298, 55.6%) and Mycobacterium avium complex (n = 190, 35.4%) most common. Associated bacterial cultures grew Stenotrophomonas or Aspergillus species more often when NTM were isolated (18.2% vs. 8.4% and 13.9% vs. 7.2%, respectively, p < 0.01). After controlling for confounders, patients with chronic M. abscessus infection had greater rates of lung function decline than those with no NTM infection (− 2.52 vs. − 1.64% predicted FEV₁/year, p < 0.05).ConclusionsNTM infection is common in CF and associated with particular pathogens. Chronic M. abscessus infection is associated with increased lung function decline.     

Multiple antibiotic-resistant Pseudomonas aeruginosa and lung function decline in patients with cystic fibrosis

BackgroundThe goal of this study was to determine the association of multiple antibiotic-resistant Pseudomonas aeruginosa (MARPA) acquisition with lung function decline in patients with cystic fibrosis (CF).MethodsUsing data from Epidemiologic Study of Cystic Fibrosis (ESCF), we identified patients with spirometry data and MARPA, defined as PA (1) resistant to gentamicin and either tobramycin or amikacin, and (2) resistant to ≥ 1 antipseudomonal beta lactam. MARPA had to be detected in a respiratory culture after ≥ 2 years of PA-positive but MARPA-negative respiratory cultures. Multivariable piecewise linear regression was performed to model the annual rate of decline in forced expiratory volume in 1 second (FEV₁) % predicted 2 calendar years before and after the index year of MARPA detection, adjusting for patient characteristics and CF therapies.ResultsIn total, 4349 patients with chronic PA and adequate PFT data were identified; 1111 subsequently developed MARPA, while 3238 patients were PA positive but MARPA negative. Compared with patients who did not acquire MARPA, MARPA-positive patients had lower FEV₁ and received more oral (p < 0.013) and inhaled (p < 0.001) antibiotic therapy. Mean FEV₁ decline did not change significantly after MARPA detection (− 2.22% predicted/year before detection and − 2.43 after, p = 0.45). There was no relationship between persistent infection or FEV₁ quartile and FEV₁ decline.ConclusionsNewly detected MARPA was not associated with a significant change in the rate of FEV₁ decline. These results suggest that MARPA is more likely to be a marker of more severe disease and more intensive therapy, and less likely to be contributing independently to more rapid lung function decline.     

Biliary stone disease in adults with cystic fibrosis

A 27-year-old woman with cystic fibrosis had a 6-month history of fatty food intolerance and biliary colic. Ultrasonographic studies confirmed the presence of gallstones. A cholecystectomy and appendectomy were performed. An intraoperative cholangiogram showed anomalous drainage of the cystic duct into an accessory right hepatic duct. Patients with cystic fibrosis now commonly survive into adulthood and are at high risk for the development of cholelithiasis. The diagnosis may be obscured by other common gastrointestinal complications of cystic fibrosis. Optimal surgical management includes meticulous preoperative and postoperative pulmonary care. The surgeon must also have a thorough knowledge of the biliary tract anomalies that have been described in patients with cystic fibrosis.     

Average rate of lung function decline in adults with cystic fibrosis in the United Kingdom: Data from the UK CF registry

BackgroundRate of change in lung function is used as a measure of disease progression and a predictor of mortality in individuals with cystic fibrosis (CF). The aim of this study was to determine the national rate of decline in percent predicted Forced Expiratory Volume in 1 second (ppFEV₁) in adults in the UK accounting for age, sex and pancreatic status.MethodsData on ppFEV₁ for adults with CF, excluding those post lung transplantation, was extracted from the UK CF registry between 2015 and 2017. Multilevel modelling was conducted to calculate the annual rate of change in ppFEV₁ accounting for age, sex and pancreatic status.ResultsOverall annual ppFEV₁ decline was -1.52% (95% CI: -1.66 to -1.38%) and -0.55% (95% CI: -0.86 to -0.23%) in pancreatic insufficient (PI) and sufficient (PS) adults respectively. In PI individuals, females had a greater rate of decline in ppFEV₁. There were differences between age groups. The fastest rate of decline was observed in the 18–28 years group, declining -1.76% (95% CI: -2.06 to -1.46) and -1.61% (95% CI: -1.91 to -1.31) per year in PI females and males respectively. The pattern between the sexes and age categories was more inconsistent in the PS group.ConclusionsThe average annual rates of decline in lung function in adults with CF in the UK are similar to reports from other large international cohorts. Pancreatic status has a marked impact on average rate of decline. Younger adults, especially females, have a faster rate of decline and need close monitoring.     

Progression of lung disease on computed tomography and pulmonary function tests in children and adults with cystic fibrosis

BACKGROUND: A study was undertaken to compare the ability of computed tomographic (CT) scores and pulmonary function tests to detect changes in lung disease in children and adults with cystic fibrosis (CF). METHODS: CT scans and pulmonary function tests were retrospectively studied in a cohort of patients with CF aged 5-52 years for whom two or three CT scans at 3 year intervals were available, together with pulmonary function test results. All CT scans were scored by two observers. Pulmonary function results were expressed as percentage predicted and Z scores. RESULTS: Of 119 patients studied, two CT scans were available in 92 patients and three in 24. CT (composite and component) scores and lung function both deteriorated significantly (p<0.02). Peripheral bronchiectasis worsened by 1.7% per year in children (p<0.0001) and by 1.5% per year in adults (p<0.0001). Bronchiectasis worsened in 68 of 92 patients while forced expiratory volume in 1 second (FEV1) worsened in 54 of 92 patients; bronchiectasis also deteriorated in 27 patients with stable or improving FEV1. The CT score (and its components) and pulmonary function tests showed similar rates of deterioration in adults and children (p>0.09). CONCLUSION: The peripheral bronchiectasis CT score deteriorates faster and more frequently than lung function parameters in children and adults with CF, which indicates that pulmonary function tests and CT scans measure different aspects of CF lung disease. Our data support previous findings that the peripheral bronchiectasis CT score has an added value to pulmonary function tests in monitoring CF lung disease.     

Relationship between airway dysbiosis,inflammation and lung function in adults with cystic fibrosis

Airway dysbiosis has been associated with lung disease severity in patients with cystic fibrosis (CF). However, the relationship between dysbiosis, airway inflammation and lung function impairement remains poorly understood. The aim of this study was therefore to determine how the structure of the sputum microbiota, airway inflammation markers and spirometry are related in patients with CF.Sputum samples were collected from 106 CF patients between 12 and 72 years. These were analyzed by 16S rRNA gene amplicon sequencing. Moreover, levels of pro-inflammatory cytokines (IL-1β, IL-8, IL-6 and TNF-α) and Neutrophil elastase (NE) were determined. The relationship between the microbiota, inflammation markers and forced expiratory volume in one second percent predicted (FEV₁% predicted) was evaluated by multi-parameter analysis.The microbiota α-diversity correlated inverse with inflammation markers IL-1β, IL-8, TNF-α, NE and positively with FEV₁% predicted. Patients could be divided into 7 clusters based on their microbiota structure. The most diverse cluster was defined by oropharyngeal-like flora (OF) while the others were characterized by the dominance of a single pathogen. Patients with the diverse OF microbiota cluster had lower sputum inflammatory markers and higher FEV₁% predicted compared to patients with a pathogen-dominated microbiota including Pseudomonas aeruginosa.Our results suggest that the diversity of the airway microbiota is an important biomarker of the severity of airway inflammation linking dysbiosis to lung function decline in patients with CF.     

Risk factors for Pseudomonas aeruginosa airway infection and lung function decline in children with cystic fibrosis

Background Cystic fibrosis (CF) lung disease is characterised by recurrent Pseudomonas aeruginosa (Pa) infections, leading to structural lung damage and decreased survival. The epidemiology of Pa infection and its impact on lung function in people with CF (pwCF), especially in recent birth cohorts, remain uncertain.Methods We included 1,231 French pwCF under 18 years of age. Age at initial acquisition (Pa-IA), chronic colonisation (Pa-CC), and duration from Pa-IA to Pa-CC were estimated using the Kaplan–Meier method. Demographic, clinical, and genetic characteristics were analysed as risk factors for Pa infection using Cox regression models. Lung function decline was assessed by modelling percent-predicted forced expiratory volume in 1 s (ppFEV1) before Pa infection, after Pa-IA, and after Pa-CC.Results Among the 1,231 pwCF, 50% had Pa-IA by the age of 5.1 years [95% confidence interval (CI) 3.8–6.2] and 25% had Pa-CC by the age of 14.7 years (95% CI 12.1 to ∞). We observed that CF-related diabetes and liver disease were risk factors for Pa, while gender, CFTR variants, and CF centre size were not. Genetic variants of TNF, DCTN4, SLC9A3, and CAV2 were confirmed to be associated with Pa. The annual rate of ppFEV1 decline before Pa was -0.38% predicted/year (95% CI -0.59 to -0.18), which decreased significantly after Pa-IA to -0.93% predicted/year (95% CI -1.14 to -0.71) and after Pa-CC to -1.51% predicted/year (95% CI -1.86 to -1.16).Conclusions We identified and replicated several risk factors associated with Pa infection and showed its deleterious impact on lung function in young pwCF. This large-scale study confirmed that Pa airway infection is a major determinant of lung disease severity.     

TGF-beta(1) genotype and accelerated decline in lung function of patients with cystic fibrosis

BACKGROUND: Polymorphisms in transforming growth factor (TGF)-beta(1) associated with variations in cytokine levels are linked to fibrosis in a number of tissues. However, the contribution of this cytokine to organ fibrosis in patients with cystic fibrosis is presently unclear. This study was undertaken to examine the association between TGF-beta(1) gene polymorphisms and the development of pulmonary dysfunction in patients with cystic fibrosis. METHODS: Polymorphisms in the TGF-beta(1) gene defining amino acids of codons 10 and 25 were determined by ARMS-PCR using DNA stored on 171 Caucasian patients who were homozygous for the DeltaF508 mutation of the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Clinical information on the patients was obtained from medical records. RESULTS: Patients with cystic fibrosis of a TGF-beta(1) high producer genotype for codon 10 had more rapid deterioration in lung function than those with a TGF-beta(1) low producer genotype. The relative risk of accelerated decline in forced expiratory volume in one second (FEV(1)) to 50% predicted and forced vital capacity (FVC) to 70% predicted of patients with a high producer genotype was 1.74 (95% CI 1.11 to 2. 73) compared with 1.95 (95% CI 1.24 to 3.06) for those with a low producer genotype. DISCUSSION: TGF-beta(1) genotypes may have a role in mediating pulmonary dysfunction in patients with cystic fibrosis. Further work is required to determine whether inhibition of TGF-beta(1) activity in these patients may slow disease progression.     

Variation in lung function and nutritional decline in cystic fibrosis by genotype: An analysis of the Canadian cystic fibrosis registry

BackgroundThis study aimed to improve our understanding of the natural history of cystic fibrosis (CF) by comparing lung function and body mass index z-score (zBMI) between patients with different genotypes and identify a genotype with outcomes most comparable to homozygous ΔF508 patients.MethodsData was obtained from the Canadian CF Registry between January 1st 2007-January 1st 2016. Patients were categorized into one of five groups based on their genotype. A mixed-effects model was conducted with adjustments for age, sex, age of diagnosis, and baseline clinical measures.ResultsAmong 2612 patients, those with non-mild forms of CF, and particularly adult patients with the same functional allele classification were found to have a lung function trajectory comparable to individuals with the homozygous ∆F508 genotype (annual change in percent predicted forced expiratory volume in 1 s of −0.83, 95% CI: −0.93, −0.73). The rates of zBMI change over the study period were not significantly different between the genotype groups.ConclusionThis population-based study of Canadian CF patients provides adjusted rates of lung function decline and zBMI over ten years. The finding that there are different genotypes with comparable rates of lung function decline to patients of the homozygous ∆F508 group supports the use of multiple comparison groups to assess the long-term efficacy of emerging CF therapies.     

Improving rate of decline of FEV1 in young adults with cystic fibrosis

BACKGROUND: CF is characterised by a progressive decline in lung function; reductions in this decline are often used as a measure of success in clinical trials. With improvements in treatment it may be that there has been a temporal shift in the pattern of the disease. METHODS: 318 patients born in five successive cohorts and attending a specialist clinic with at least two routine measurements of lung function made between the ages of 18 and 22 were included. The declines in their lung function were estimated and compared. RESULTS: The mean (SE) slopes for percentage predicted forced expiratory volume in 1 second (FEV(1)) and forced vital capacity (FVC) were -1.53 (0.36)% and -1.27 (0.34)%, respectively (NS). The annual deterioration in FEV(1) was -2.49%, -1.99% -2.20%, -1.65%, and -0.65% from the earliest to the most recent birth cohort; a similar pattern was observed for changes in FVC. There were no differences between male and female patients. Patients infected with Pseudomonas had a greater average decline in FEV(1) (-1.6% v -1.1%). CONCLUSIONS: The rates of decline in lung function in young adults with CF have diminished with successive birth cohorts. This has important implications for the design of clinical studies in this disease.     

Year-to-year changes in lung function in individuals with cystic fibrosis

BackgroundWe examined the year-to-year change in FEV₁ for individuals and the overall cystic fibrosis population to better understand how individual trends may differ from population trends.MethodsWe calculated individual yearly changes using the largest annual FEV₁ percent predicted (FEV₁%) measurement in 20,644 patients (6–45 years old) included in the Epidemiologic Study of Cystic Fibrosis. We calculated yearly population changes using age-specific medians.ResultsFEV₁% predicted decreased 1–3 points per year for individuals, with maximal decreases in 14–15 year olds. Population changes agreed with individual changes up to age 15; however after age 30, yearly population change approximated zero while individual FEV₁% predicted decreases were 1–2 points per year.ConclusionsAdolescents have the greatest FEV₁% predicted decreases; however, loss of FEV₁ is a persistent risk in 6–45 year old CF patients. Recognizing individual year-to-year changes may improve patient-specific care and may suggest new methods for measuring program quality.     

Innate immunity in cystic fibrosis lung disease

Chronic lung disease determines the morbidity and mortality of cystic fibrosis (CF) patients. The pulmonary immune response in CF is characterized by an early and non-resolving activation of the innate immune system, which is dysregulated at several levels. Here we provide a comprehensive overview of innate immunity in CF lung disease, involving (i) epithelial dysfunction, (ii) pathogen sensing, (iii) leukocyte recruitment, (iv) phagocyte impairment, (v) mechanisms linking innate and adaptive immunity and (iv) the potential clinical relevance. Dissecting the complex network of innate immune regulation and associated pro-inflammatory cascades in CF lung disease may pave the way for novel immune-targeted therapies in CF and other chronic infective lung diseases.     

Continuous glucose monitoring abnormalities in cystic fibrosis youth correlate with pulmonary function decline

Background

To characterize glucose patterns with continuous glucose monitoring (CGM) in cystic fibrosis (CF) and assess relationships between CGM and clinical outcomes.

Measures of body habitus are associated with lung function in adults with cystic fibrosis: A population-based study

BackgroundBody habitus differences may explain some of the variation in lung function between individuals with cystic fibrosis (CF). We tested the hypothesis that measures of lean muscle mass and obesity are independently associated with lung function in CF.MethodsCross-sectional study design using UK CF registry data from 2096 clinically stable adults.ResultsSerum creatinine and BMI were positively and independently associated with FEV₁ and FVC. One standard deviation increment in serum creatinine was associated with an FEV₁ increase of 171 ml (95% confidence intervals CI: + 116 to + 227 ml) in males and 90 ml (95% CI: + 46 to + 133 ml) in females. Compared to the reference group of 20–24.9 kg/m², those with a BMI < 20 kg/m² had lower FEV₁ with values of ? 642 ml (95%CI: ? 784 to ? 500 ml) for males and ? 468 ml (95%CI: ? 564 to ? 372 ml) for females.ConclusionsProspective studies and controlled trials are required to ascertain if these associations have therapeutic potential in modifying disease progression.