title: Factors Associated with Worse Lung Function in Cystic Fibrosis Patients with Persistent Staphylococcus aureus.
abstract: BACKGROUND
  Staphylococcus aureus is an important pathogen in cystic fibrosis (CF). However, it is not clear which factors are associated with worse lung function in patients with persistent S. aureus airway cultures. Our main hypothesis was that patients with high S. aureus density in their respiratory specimens would more likely experience worsening of their lung disease than patients with low bacterial loads.
  
  
  METHODS
  Therefore, we conducted an observational prospective longitudinal multi-center study and assessed the association between lung function and S. aureus bacterial density in respiratory samples, co-infection with other CF-pathogens, nasal S. aureus carriage, clinical status, antibiotic therapy, IL-6- and IgG-levels against S. aureus virulence factors.
  
  
  RESULTS
  195 patients from 17 centers were followed; each patient had an average of 7 visits. Data were analyzed using descriptive statistics and generalized linear mixed models. Our main hypothesis was only supported for patients providing throat specimens indicating that patients with higher density experienced a steeper lung function decline (p<0.001). Patients with exacerbations (n = 60), S. aureus small-colony variants (SCVs, n = 84) and co-infection with Stenotrophomonas maltophilia (n = 44) had worse lung function (p = 0.0068; p = 0.0011; p = 0.0103). Patients with SCVs were older (p = 0.0066) and more often treated with trimethoprim/sulfamethoxazole (p = 0.0078). IL-6 levels positively correlated with decreased lung function (p<0.001), S. aureus density in sputa (p = 0.0016), SCVs (p = 0.0209), exacerbations (p = 0.0041) and co-infections with S. maltophilia (p = 0.0195) or A. fumigatus (p = 0.0496).
  
  
  CONCLUSIONS
  In CF-patients with chronic S. aureus cultures, independent risk factors for worse lung function are high bacterial density in throat cultures, exacerbations, elevated IL-6 levels, presence of S. aureus SCVs and co-infection with S. maltophilia.
  
  
  BACKGROUND
  ClinicalTrials.gov NCT00669760.
authors.affiliation: Clinic for Paediatric Pulmonology, Allergology and Neonatology, Hannover, Hannover, Germany.
authors.forename: Sibylle
authors.initials: S
authors.lastname: Junge
authors.affiliation: Institute of Biostatistics and Clinical Research, University Hospital Münster, Münster, Germany.
authors.forename: Dennis
authors.initials: D
authors.lastname: Görlich
authors.affiliation: Department of Medical Microbiology and Infectious Diseases, Erasmus Medical Center Rotterdam, Rotterdam, The Netherlands.
authors.forename: Martijn
authors.initials: M
authors.lastname: den Reijer
authors.affiliation: Institute of Medical Informatics and Biometrics, Technical University Dresden, Dresden, Germany.
authors.forename: Bärbel
authors.initials: B
authors.lastname: Wiedemann
authors.affiliation: Clinical Research Group, Clinic for Paediatric Pulmonology, Allergology and Neonatology, Medizinische Hochschule Hannover, Hannover, Germany.
authors.forename: Burkhard
authors.initials: B
authors.lastname: Tümmler
authors.affiliation: CF-Center Innsbruck, Department of Child and Adolescent Health, Medical University of Innsbruck, Innsbruck, Austria.
authors.forename: Helmut
authors.initials: H
authors.lastname: Ellemunter
authors.affiliation: Department of Paediatrics, University Hospital Münster, Münster, Germany.
authors.forename: Angelika
authors.initials: A
authors.lastname: Dübbers
authors.affiliation: Department of Paediatrics, Clemenshospital Münster, Münster, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Küster
authors.affiliation: Ruhr University, Paediatric Clinic at St Josef Hospital, Bochum, Germany.
authors.forename: Manfred
authors.initials: M
authors.lastname: Ballmann
authors.affiliation: Ruhr University, Paediatric Clinic at St Josef Hospital, Bochum, Germany.
authors.forename: Cordula
authors.initials: C
authors.lastname: Koerner-Rettberg
authors.affiliation: Department of Paediatrics, University Hospital Essen, Essen, Germany.
authors.forename: Jörg
authors.initials: J
authors.lastname: Große-Onnebrink
authors.affiliation: Paediatricians "Kinderärztliche Ambulanz", Hamburg, Germany.
authors.forename: Eberhardt
authors.initials: E
authors.lastname: Heuer
authors.affiliation: Paediatricians "Kinderärztliche Ambulanz", Hamburg, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Sextro
authors.affiliation: CF Center, Department of Paediatrics, Jena University Hospital, Jena, Germany.
authors.forename: Jochen G
authors.initials: JG
authors.lastname: Mainz
authors.affiliation: Department of Paediatrics, University Clinics Dresden, Dresden, Germany.
authors.forename: Jutta
authors.initials: J
authors.lastname: Hammermann
authors.affiliation: Department of Pediatrics, University Clinics Tübingen, Tübingen, Germany.
authors.forename: Joachim
authors.initials: J
authors.lastname: Riethmüller
authors.affiliation: Department of Pediatrics, University Clinics Tübingen, Tübingen, Germany.
authors.forename: Ute
authors.initials: U
authors.lastname: Graepler-Mainka
authors.affiliation: Department of Paediatric Pulmonology and Immunology, Charité Universitätsmedizin Berlin, Campus Virchow Klinikum, Berlin, Germany.
authors.forename: Doris
authors.initials: D
authors.lastname: Staab
authors.affiliation: University Hospital Halle, Halle, Germany.
authors.forename: Bettina
authors.initials: B
authors.lastname: Wollschläger
authors.affiliation: Children's Hospital Osnabrück, Osnabrück, Germany.
authors.forename: Rüdiger
authors.initials: R
authors.lastname: Szczepanski
authors.affiliation: Department of Paediatrics, University of Düsseldorf, Düsseldorf, Germany.
authors.forename: Antje
authors.initials: A
authors.lastname: Schuster
authors.affiliation: Park Schönefeld Clinics, Kassel, Germany.
authors.forename: Friedrich-Karl
authors.initials: FK
authors.lastname: Tegtmeyer
authors.affiliation: Ruhrlandklinik, Essen, Germany.
authors.forename: Sivagurunathan
authors.initials: S
authors.lastname: Sutharsan
authors.affiliation: University Clinics Leipzig, Leipzig, Germany.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Wald
authors.affiliation: Center for Laboratory Medicine, University Hospital Münster, Münster, Germany.
authors.forename: Jerzy-Roch
authors.initials: JR
authors.lastname: Nofer
authors.affiliation: Department of Medical Microbiology and Infectious Diseases, Erasmus Medical Center Rotterdam, Rotterdam, The Netherlands.
authors.forename: Willem
authors.initials: W
authors.lastname: van Wamel
authors.affiliation: Institute of Medical Microbiology, University Hospital Münster, Münster, Germany.
authors.forename: Karsten
authors.initials: K
authors.lastname: Becker
authors.affiliation: Institute of Medical Microbiology, University Hospital Münster, Münster, Germany.
authors.forename: Georg
authors.initials: G
authors.lastname: Peters
authors.affiliation: Institute of Medical Microbiology, University Hospital Münster, Münster, Germany.
authors.forename: Barbara C
authors.identifier: http://orcid.org/0000-0001-5155-3383
authors.initials: BC
authors.lastname: Kahl
mesh_terms: D000293:Adolescent; D000328:Adult; D000907:Antibodies, Bacterial / Q000276:immunology; D058491:Bacterial Load; D002648:Child; D060085:Coinfection; D003550:Cystic Fibrosis / Q000150:complications* / Q000175:diagnosis / Q000503:physiopathology*; D018450:Disease Progression; D005260:Female; D005541:Forced Expiratory Volume; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology; D015850:Interleukin-6 / Q000378:metabolism; D008297:Male; D009297:Nasal Mucosa / Q000382:microbiology; D011446:Prospective Studies; D012129:Respiratory Function Tests; D013183:Sputum / Q000382:microbiology; D013203:Staphylococcal Infections / Q000188:drug therapy / Q000209:etiology* / Q000503:physiopathology*; D013211:Staphylococcus aureus / Q000187:drug effects / Q000276:immunology; D055815:Young Adult
chemical_list: D000907:Antibodies, Bacterial; D007074:Immunoglobulin G; D015850:Interleukin-6