title: Host Biomarkers Are Associated With Response to Therapy and Long-Term Mortality in Pediatric Severe Malaria.
abstract: Background.Host responses to infection are critical determinants of disease severity and clinical outcome. The development of tools to risk stratify children with malaria is needed to identify children most likely to benefit from targeted interventions.Methods.This study investigated the kinetics of candidate biomarkers of mortality associated with endothelial activation and dysfunction (angiopoietin-2 [Ang-2], soluble FMS-like tyrosine kinase-1 [sFlt-1], and soluble intercellular adhesion molecule-1 [sICAM-1]) and inflammation (10 kDa interferon γ-induced protein [CXCL10/IP-10] and soluble triggering receptor expressed on myeloid cells-1 [sTREM-1]) in the context of a randomized, double-blind, placebo-controlled, parallel-arm trial evaluating inhaled nitric oxide versus placebo as adjunctive therapy to parenteral artesunate for severe malaria. One hundred eighty children aged 1-10 years were enrolled at Jinja Regional Referral Hospital in Uganda and followed for up to 6 months.Results.There were no differences between the 2 study arms in the rate of biomarker recovery. Median levels of Ang-2, CXCL10, and sFlt-1 were higher at admission in children who died in-hospital (n = 15 of 180;P< .001,P= .027, andP= .004, respectively). Elevated levels of Ang-2, sTREM-1, CXCL10, and sICAM-1 were associated with prolonged clinical recovery times in survivors. The Ang-2 levels were also associated with postdischarge mortality (P< .0001). No biomarkers were associated with neurodisability.Conclusions.Persistent endothelial activation and dysfunction predict survival in children admitted with severe malaria.
authors.affiliation: Sandra A. Rotman Laboratories, Sandra Rotman Centre for Global Health, University Health Network-Toronto General Hospital, University of Toronto, Canada; Department of Pediatrics, Indiana University School of Medicine, Indianapolis.
authors.forename: Andrea L
authors.initials: AL
authors.lastname: Conroy
authors.affiliation: Sandra A. Rotman Laboratories, Sandra Rotman Centre for Global Health, University Health Network-Toronto General Hospital, University of Toronto, Canada; Division of Pediatric Infectious Diseases, University of Alberta, Edmonton, Canada.
authors.forename: Michael
authors.initials: M
authors.lastname: Hawkes
authors.affiliation: Sandra A. Rotman Laboratories, Sandra Rotman Centre for Global Health , University Health Network-Toronto General Hospital, University of Toronto , Canada.
authors.forename: Chloe R
authors.initials: CR
authors.lastname: McDonald
authors.affiliation: Sandra A. Rotman Laboratories, Sandra Rotman Centre for Global Health , University Health Network-Toronto General Hospital, University of Toronto , Canada.
authors.forename: Hani
authors.initials: H
authors.lastname: Kim
authors.affiliation: Sandra A. Rotman Laboratories, Sandra Rotman Centre for Global Health , University Health Network-Toronto General Hospital, University of Toronto , Canada.
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Higgins
authors.affiliation: Sandra A. Rotman Laboratories, Sandra Rotman Centre for Global Health , University Health Network-Toronto General Hospital, University of Toronto , Canada.
authors.forename: Kevin R
authors.initials: KR
authors.lastname: Barker
authors.affiliation: Department of Pediatrics , Jinja Regional Referral Hospital.
authors.forename: Sophie
authors.initials: S
authors.lastname: Namasopo
authors.affiliation: Department of Paediatrics and Child Health , Mulago Hospital and Makerere University , Kampala , Uganda.
authors.forename: Robert O
authors.initials: RO
authors.lastname: Opoka
authors.affiliation: Department of Pediatrics , Indiana University School of Medicine , Indianapolis.
authors.forename: Chandy C
authors.initials: CC
authors.lastname: John
authors.affiliation: Department of Medicine , University of Washington , Seattle.
authors.forename: W Conrad
authors.initials: WC
authors.lastname: Liles
authors.affiliation: Sandra A. Rotman Laboratories, Sandra Rotman Centre for Global Health, University Health Network-Toronto General Hospital, University of Toronto, Canada; Tropical Disease Unit, Division of Infectious Diseases, Department of Medicine, University of Toronto, Canada.
authors.forename: Kevin C
authors.initials: KC
authors.lastname: Kain
keywords: angiopoietin-2; mortality; pediatric; sTREM-1; severe malaria