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      The microbiome in pediatric cystic fibrosis patients: the role of shared environment suggests a window of intervention

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          Abstract

          Background

          Cystic fibrosis (CF) is caused by mutations in the CFTR gene that predispose the airway to infection. Chronic infection by pathogens such as Pseudomonas aeruginosa leads to inflammation that gradually degrades lung function, resulting in morbidity and early mortality. In a previous study of CF monozygotic twins, we demonstrate that genetic modifiers significantly affect the establishment of persistent P. aeruginosa colonization in CF. Recognizing that bacteria other than P. aeruginosa contribute to the CF microbiome and associated pathology, we used deep sequencing of sputum from pediatric monozygotic twins and nontwin siblings with CF to characterize pediatric bacterial communities and the role that genetics plays in their evolution.

          Findings

          We found that the microbial communities in sputum from pediatric patients living together were much more alike than those from pediatric individuals living apart, regardless of whether samples were taken from monozygous twins or from nontwin CF siblings living together, which we used as a proxy for dizygous twins. In contrast, adult communities were comparatively monolithic and much less diverse than the microbiome of pediatric patients.

          Conclusion

          Taken together, these data and other recent studies suggest that as patients age, the CF microbiome becomes less diverse, more refractory to treatment and dominated by mucoid P. aeruginosa, as well as being associated with accelerated pulmonary decline. Our studies show that the microbiome of pediatric patients is susceptible to environmental influences, suggesting that interventions to preserve the community structure found in young CF patients might be possible, perhaps slowing disease progression.

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          Most cited references14

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          Pseudomonas aeruginosa and other predictors of mortality and morbidity in young children with cystic fibrosis.

          We conducted a registry-based study to determine prognostic indicators of 8-year mortality and morbidity in young children with cystic fibrosis (CF). Patients ages 1-5 years from the 1990 U.S. Cystic Fibrosis Foundation (CFF) National Patient Registry served as the study cohort (N = 3,323). Registry data provided information on baseline characteristics in 1990, 8-year mortality, and clinical outcomes in 1998.P. aeruginosa respiratory infection was found to be a major predictor of morbidity and mortality. The 8-year risk of death was 2.6 times higher in patients who had respiratory cultures positive for P. aeruginosa in 1990 (95% confidence interval 1.6, 4.1) than in children without P. aeruginosa in their respiratory cultures. Culture-positive patients in 1990 also had a significantly lower percent predicted forced expiratory volume in 1 sec (FEV(1)) and weight percentile at follow-up, and they had an increased risk of continued P. aeruginosa respiratory infection and hospitalization for acute respiratory exacerbation in 1998. Among the other predictors of increased morbidity and mortality were lower baseline weight percentiles and number of CF-related hospitalizations during the baseline year.These findings confirm reports from previous smaller studies of outcomes among young children with CF, and highlight the potential to decrease the morbidity and mortality of young patients with CF through early intervention. Copyright 2002 Wiley-Liss, Inc.
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            Clinical outcome after early Pseudomonas aeruginosa infection in cystic fibrosis.

            To determine the clinical consequences of acquiring Pseudomonas aeruginosa infection during early childhood in children with cystic fibrosis (CF). Prospective, observational cohort study of 56 children with CF identified by newborn screening during 1990-92. Each child underwent an annual bronchial lavage during the first 2 to 3 years of life. Clinical outcome was determined at 7 years of age. P aeruginosa infection was diagnosed in 24 (43%) cohort subjects. Four children died before 7 years of age, all of whom had been infected with a multi-resistant, mucoid strain of P aeruginosa (P =.04). In survivors, P aeruginosa infection was associated with significantly increased morbidity as measured by lower National Institutes of Health scores, greater variability in lung function, increased time in the hospital, and higher rates of recombinant human deoxyribonuclease therapy (P <.01). In this young CF cohort, best forced expiratory volume in 1 second was an insensitive measure of increased morbidity. Acquisition of P aeruginosa was common by 7 years of age in this CF birth cohort and was associated with increased morbidity and mortality. An improved disease severity score would improve the evaluation and study of early CF lung disease.
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              VAMPS: a website for visualization and analysis of microbial population structures

              Background The advent of next-generation DNA sequencing platforms has revolutionized molecular microbial ecology by making the detailed analysis of complex communities over time and space a tractable research pursuit for small research groups. However, the ability to generate 105–108 reads with relative ease brings with it many downstream complications. Beyond the computational resources and skills needed to process and analyze data, it is difficult to compare datasets in an intuitive and interactive manner that leads to hypothesis generation and testing. Results We developed the free web service VAMPS (Visualization and Analysis of Microbial Population Structures, http://vamps.mbl.edu) to address these challenges and to facilitate research by individuals or collaborating groups working on projects with large-scale sequencing data. Users can upload marker gene sequences and associated metadata; reads are quality filtered and assigned to both taxonomic structures and to taxonomy-independent clusters. A simple point-and-click interface allows users to select for analysis any combination of their own or their collaborators’ private data and data from public projects, filter these by their choice of taxonomic and/or abundance criteria, and then explore these data using a wide range of analytic methods and visualizations. Each result is extensively hyperlinked to other analysis and visualization options, promoting data exploration and leading to a greater understanding of data relationships. Conclusions VAMPS allows researchers using marker gene sequence data to analyze the diversity of microbial communities and the relationships between communities, to explore these analyses in an intuitive visual context, and to download data, results, and images for publication. VAMPS obviates the need for individual research groups to make the considerable investment in computational infrastructure and bioinformatic support otherwise necessary to process, analyze, and interpret massive amounts of next-generation sequence data. Any web-capable device can be used to upload, process, explore, and extract data and results from VAMPS. VAMPS encourages researchers to share sequence and metadata, and fosters collaboration between researchers of disparate biomes who recognize common patterns in shared data.
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                Author and article information

                Contributors
                Journal
                Microbiome
                Microbiome
                Microbiome
                BioMed Central
                2049-2618
                2014
                28 April 2014
                : 2
                : 14
                Affiliations
                [1 ]Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, 615 Remsen Building, N. College St., Hanover, NH 03755, USA
                [2 ]Division of Pediatric Pulmonary and Sleep Medicine, Duke University Medical Center, 350 Hanes House, DUMC Box 102360, Durham NC, USA
                [3 ]McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, 1800 Orleans St., Baltimore MD, USA
                [4 ]Josephine Bay Paul Center for Comparative Molecular Biology and Evolution, Marine Biological Laboratory, 7 MBL Street, Woods Hole, MA 02543, USA
                [5 ]Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, 202 Remsen Building, N. College St., Hanover, NH 03755, USA
                Article
                2049-2618-2-14
                10.1186/2049-2618-2-14
                4113139
                25071935
                6570b08e-887c-4d2b-b3ec-f9ca15c702dc
                Copyright © 2014 Hampton et al.; licensee BioMed Central Ltd.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                : 1 February 2014
                : 27 March 2014
                Categories
                Short Report

                cystic fibrosis,microbiome,pseudomonas aeruginosa,sputum

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