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Lung function decline is delayed but not decreased in patients with cystic fibrosis and the R117H gene mutation.

ABSTRACT: BACKGROUND:Patients with cystic fibrosis (CF) experience variable lung disease phenotypes. The R117H mutation is often associated with preserved lung function. Our objective was to compare the rate of lung function decline in patients with the R117H mutation and patients homozygous for the F508del mutation. METHODS:Rate of decline in percentage-of-predicted FEV1 (ppFEV1) was analyzed using the 2006-2010 US CF Foundation Patient Registry. RESULTS:4-year rate of decline was slower in 156 R117H patients compared with 6251 F508del patients (-0.61 vs -2.03 ppFEV1/year, P<0.001). Rates of decline in children were slower in R117H vs F508del patients (6-12-year-olds: +0.73 vs -1.91 ppFEV1/year, P<0.001 and 13-17-year-olds: -1.55 vs -2.66 ppFEV1/year, P=0.046), whereas rates in adults were not significantly different (18-24-year-olds: -1.52 vs -2.12, P=0.26 and ?25-year-olds: -1.17 vs -1.40, P=0.33). CONCLUSIONS:These findings are consistent with a delayed onset, but ultimately similar progression, of lung disease in R117H compared with homozygous F508del patients.

SUBMITTER: Wagener JS

PROVIDER: S-EPMC6547371 | biostudies-literature | 2018 Jul

REPOSITORIES: biostudies-literature

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Lung function decline is delayed but not decreased in patients with cystic fibrosis and the R117H gene mutation.

Wagener Jeffrey S JS Millar Stefanie J SJ Mayer-Hamblett Nicole N Sawicki Gregory S GS McKone Edward F EF Goss Christopher H CH Konstan Michael W MW Morgan Wayne J WJ Pasta David J DJ Moss Richard B RB

Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society 20171031 4

<h4>Background</h4>Patients with cystic fibrosis (CF) experience variable lung disease phenotypes. The R117H mutation is often associated with preserved lung function. Our objective was to compare the rate of lung function decline in patients with the R117H mutation and patients homozygous for the F508del mutation.<h4>Methods</h4>Rate of decline in percentage-of-predicted FEV<sub>1</sub> (ppFEV<sub>1</sub>) was analyzed using the 2006-2010 US CF Foundation Patient Registry.<h4>Results</h4>4-year ...[more]

PMID: 29100868

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Project description:IntroductionCystic fibrosis (CF) is an autosomal recessive disease caused by mutations in the CF transmembrane conductance regulator (CFTR) gene. Approximately 5% of people with CF have residual function (RF) CFTR mutations that result in partially retained CFTR activity. Published literature on disease trajectory among those with RF mutations is limited. In this retrospective study, we characterized lung function decline across different age groups in CFTR modulator-untreated people with CF heterozygous for F508del and an RF mutation (F/RF).MethodsRate of decline in percent predicted forced expiratory volume in 1 s (ppFEV1) was analyzed using data from the US CF Foundation Patient Registry (2006-2014) in F/RF (all), F/RF (excluding R117H), and F508del homozygous (F/F) cohorts. Annual rates of ppFEV1 decline were estimated over 2-year periods based on calendar year. Subgroup analyses by age [6-12 (children), 13-17 (adolescents), 18-24 (young adults), and ≥ 25 years (adults)] were performed.ResultsThe estimated annualized rate of ppFEV1 decline was - 0.70 percentage points per year (95% CI -1.09, -0.30) in the F/RF (all) cohort (N = 1242) versus -1.91 percentage points per year (95% CI -2.01, -1.80) in the F/F cohort (N = 11,916) [difference, 1.29 percentage points per year (95% CI 0.88, 1.70); P < 0.001]. In the F/RF (all) cohort, all age groups demonstrated lung function decline ranging from -0.30 to -1.38. In the F/RF (excluding R117H) cohort, the rate of decline was -1.05 percentage points per year (95% CI -1.51, -0.60) [difference versus F/F cohort, 0.95 percentage points per year (95% CI 0.48, 1.41; P < 0.001); not statistically significant in children and young adults].ConclusionProgressive lung function decline was observed in people with F/RF genotypes across all assessed age groups, reinforcing the importance of early intervention and clinical monitoring to preserve lung function in all people with CF.

Project description:Cystic fibrosis (CF) is a genetic disease resulting in chronic polymicrobial infections of the airways and progressive decline in lung function. To gain insight into the underlying causes of severe lung diseases, we aimed at comparing the airway microbiota detected in sputum of CF patients with stable lung function (S) versus those with a substantial decline in lung function (SD). Microbiota composition was investigated by using culture-based and culture-independent methods, and by performing multivariate and statistical analyses. Culture-based methods identified some microbial species associated with a worse lung function, i.e. Pseudomonas aeruginosa, Rothia mucilaginosa, Streptococcus pneumoniae and Candida albicans, but only the presence of S. pneumoniae and R. mucilaginosa was found to be associated with increased severe decline in forced expiratory volume in 1 second (FEV1). Terminal-Restriction Fragment Length Polymorphism (T-RFLP) analysis revealed a higher bacterial diversity than that detected by culture-based methods. Molecular signatures with a statistically significant odds ratio for SD status were detected, and classified as Pseudomonas, Burkholderia and Shewanella, while for other Terminal Restriction Fragments (T-RFs) no species assignation was achieved. The analysis of T-RFLP data using ecological biodiversity indices showed reduced Evenness in SD patients compared to S ones, suggesting an impaired ecology of the bacterial community in SD patients. Statistically significant differences of the ecological biodiversity indices among the three sub-groups of FEV1 (normal/mild vs moderate vs severe) were also found, suggesting that the patients with moderate lung disease experienced changes in the airway assembly of taxa. Overall, changes in CF airway microbial community associated with a severe lung function decline were detected, allowing us to define some discriminatory species as well as some discriminatory T-RFs that represent good candidates for the development of predictive biomarkers of substantial decline in lung function.

Project description:BackgroundChronic infection and concomitant airway inflammation is the leading cause of morbidity and mortality for people living with cystic fibrosis (CF). Although chronic infection in CF is undeniably polymicrobial, involving a lung microbiota, infection surveillance and control approaches remain underpinned by classical aerobic culture-based microbiology. How to use microbiomics to direct clinical management of CF airway infections remains a crucial challenge. A pivotal step towards leveraging microbiome approaches in CF clinical care is to understand the ecology of the CF lung microbiome and identify ecological patterns of CF microbiota across a wide spectrum of lung disease. Assessing sputum samples from 299 patients attending 13 CF centres in Europe and the USA, we determined whether the emerging relationship of decreasing microbiota diversity with worsening lung function could be considered a generalised pattern of CF lung microbiota and explored its potential as an informative indicator of lung disease state in CF.ResultsWe tested and found decreasing microbiota diversity with a reduction in lung function to be a significant ecological pattern. Moreover, the loss of diversity was accompanied by an increase in microbiota dominance. Subsequently, we stratified patients into lung disease categories of increasing disease severity to further investigate relationships between microbiota characteristics and lung function, and the factors contributing to microbiota variance. Core taxa group composition became highly conserved within the severe disease category, while the rarer satellite taxa underpinned the high variability observed in the microbiota diversity. Further, the lung microbiota of individual patient were increasingly dominated by recognised CF pathogens as lung function decreased. Conversely, other bacteria, especially obligate anaerobes, increasingly dominated in those with better lung function. Ordination analyses revealed lung function and antibiotics to be main explanators of compositional variance in the microbiota and the core and satellite taxa. Biogeography was found to influence acquisition of the rarer satellite taxa.ConclusionsOur findings demonstrate that microbiota diversity and dominance, as well as the identity of the dominant bacterial species, in combination with measures of lung function, can be used as informative indicators of disease state in CF. Video Abstract.

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Lung function decline is delayed but not decreased in patients with cystic fibrosis and the R117H gene mutation.

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Lung function decline is delayed but not decreased in patients with cystic fibrosis and the R117H gene mutation.

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