Towards Improving Point-of-Care Diagnosis of Non-malaria Febrile Illness: A Metabolomics Approach

PLoS Negl Trop Dis. 2016 Mar 4;10(3):e0004480. doi: 10.1371/journal.pntd.0004480. eCollection 2016 Mar.

Abstract

Introduction: 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.

Methodology: 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.

Principal findings: 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.

Publication types

  • Evaluation Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Africa
  • Child
  • Child, Preschool
  • Diagnostic Tests, Routine / methods*
  • Female
  • Fever of Unknown Origin / diagnosis*
  • Humans
  • Infant
  • Infant, Newborn
  • Male
  • Mass Spectrometry / methods*
  • Metabolomics / methods*
  • Point-of-Care Systems*
  • Rural Population

Grants and funding

This work was supported by a Telethon Kids Institute small grant & a Merit Award of the Department of Health Western Australia to SDec, JRC, MM and TR; the Institute of Tropical Medicine Belgium to JM, JJ, GI, KB, PL, MCT and HT; the UK Medical Research Council to NJWR and RG; and the Flemish Ministry of Sciences (EWI, SOFI grant) to SDeb and JJ. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.