title: Towards Improving Point-of-Care Diagnosis of Non-malaria Febrile Illness: A Metabolomics Approach.
abstract: BACKGROUND
  Non-malaria febrile illnesses such as bacterial bloodstream infections (BSI) are a leading cause of disease and mortality in the tropics. However, there are no reliable, simple diagnostic tests for identifying BSI or other severe non-malaria febrile illnesses. We hypothesized that different infectious agents responsible for severe febrile illness would impact on the host metabolome in different ways, and investigated the potential of plasma metabolites for diagnosis of non-malaria febrile illness.
  
  
  METHODS
  We conducted a comprehensive mass-spectrometry based metabolomics analysis of the plasma of 61 children with severe febrile illness from a malaria-endemic rural African setting. Metabolite features characteristic for non-malaria febrile illness, BSI, severe anemia and poor clinical outcome were identified by receiver operating curve analysis.
  
  
  RESULTS
  The plasma metabolome profile of malaria and non-malaria patients revealed fundamental differences in host response, including a differential activation of the hypothalamic-pituitary-adrenal axis. A simple corticosteroid signature was a good classifier of severe malaria and non-malaria febrile patients (AUC 0.82, 95% CI: 0.70-0.93). Patients with BSI were characterized by upregulated plasma bile metabolites; a signature of two bile metabolites was estimated to have a sensitivity of 98.1% (95% CI: 80.2-100) and a specificity of 82.9% (95% CI: 54.7-99.9) to detect BSI in children younger than 5 years. This BSI signature demonstrates that host metabolites can have a superior diagnostic sensitivity compared to pathogen-detecting tests to identify infections characterized by low pathogen load such as BSI.
  
  
  CONCLUSIONS
  This study demonstrates the potential use of plasma metabolites to identify causality in children with severe febrile illness in malaria-endemic settings.
authors.affiliation: Telethon Kids Institute, University of Western Australia, Perth, Australia.
authors.forename: Saskia
authors.initials: S
authors.lastname: Decuypere
authors.affiliation: Department of Clinical Sciences, Institute of Tropical Medicine, Antwerp, Belgium.|Center for Molecular and Vascular Biology, KU Leuven, Leuven, Belgium.
authors.forename: Jessica
authors.initials: J
authors.lastname: Maltha
authors.affiliation: Department of Biomedical Sciences, Institute of Tropical Medicine, Antwerp, Belgium.
authors.forename: Stijn
authors.initials: S
authors.lastname: Deborggraeve
authors.affiliation: School of Chemistry, Manchester Institute of Biotechnology, University of Manchester, Manchester, United Kingdom.
authors.forename: Nicholas J W
authors.initials: NJ
authors.lastname: Rattray
authors.affiliation: Clinical Research Unit Nanoro-IRSS-CRUN, Nanoro, Burkina Faso.
authors.forename: Guiraud
authors.initials: G
authors.lastname: Issa
authors.affiliation: Clinical Research Unit Nanoro-IRSS-CRUN, Nanoro, Burkina Faso.
authors.forename: Kaboré
authors.initials: K
authors.lastname: Bérenger
authors.affiliation: Clinical Research Unit Nanoro-IRSS-CRUN, Nanoro, Burkina Faso.
authors.forename: Palpouguini
authors.initials: P
authors.lastname: Lompo
authors.affiliation: Clinical Research Unit Nanoro-IRSS-CRUN, Nanoro, Burkina Faso.
authors.forename: Marc C
authors.initials: MC
authors.lastname: Tahita
authors.affiliation: Metabolomics Australia and Bio21 Institute of Molecular Sciences and Biotechnology, University of Melbourne, Melbourne, Australia.
authors.forename: Thusitha
authors.initials: T
authors.lastname: Ruspasinghe
authors.affiliation: Metabolomics Australia and Bio21 Institute of Molecular Sciences and Biotechnology, University of Melbourne, Melbourne, Australia.
authors.forename: Malcolm
authors.initials: M
authors.lastname: McConville
authors.affiliation: School of Chemistry, Manchester Institute of Biotechnology, University of Manchester, Manchester, United Kingdom.
authors.forename: Royston
authors.initials: R
authors.lastname: Goodacre
authors.affiliation: Clinical Research Unit Nanoro-IRSS-CRUN, Nanoro, Burkina Faso.
authors.forename: Halidou
authors.initials: H
authors.lastname: Tinto
authors.affiliation: Department of Clinical Sciences, Institute of Tropical Medicine, Antwerp, Belgium.|Department of Immunology and Microbiology, KU Leuven, Leuven, Belgium.
authors.forename: Jan
authors.initials: J
authors.lastname: Jacobs
authors.affiliation: Telethon Kids Institute, University of Western Australia, Perth, Australia.
authors.forename: Jonathan R
authors.initials: JR
authors.lastname: Carapetis
mesh_terms: D000293:Adolescent; D000349:Africa; D002648:Child; D002675:Child, Preschool; D003955:Diagnostic Tests, Routine / Q000379:methods*; D005260:Female; D005335:Fever of Unknown Origin / Q000175:diagnosis*; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D013058:Mass Spectrometry / Q000379:methods*; D055432:Metabolomics / Q000379:methods*; D019095:Point-of-Care Systems; D012424:Rural Population