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Published on: June 8, 2017
Host Biomarkers Are Associated With Response to Therapy and Long-Term Mortality in Pediatric Severe Malaria
Andrea L Conroy1, Michael Hawkes2, Chloe R McDonald3
1Sandra 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.
Insights
Biomarkers like angiopoietin-2 (Ang-2) indicate severe malaria risk in children. Persistent endothelial dysfunction predicts survival, aiding in targeted interventions for better clinical outcomes.
Area of Science:
- Pediatrics
- Infectious Diseases
- Biomarkers
Background:
- Host responses to infection critically influence disease severity.
- Risk stratification tools are needed for children with severe malaria to guide interventions.
Purpose of the Study:
- Investigate candidate biomarkers of mortality, endothelial activation/dysfunction, and inflammation in children with severe malaria.
- Assess biomarker kinetics in a trial of inhaled nitric oxide versus placebo as adjunctive therapy.
Main Methods:
- 180 children (1-10 years) with severe malaria were enrolled in a randomized, placebo-controlled trial in Uganda.
- Kinetics of angiopoietin-2 (Ang-2), sFlt-1, sICAM-1, CXCL10/IP-10, and sTREM-1 were measured.
- Follow-up extended up to 6 months to assess outcomes including mortality and recovery.
Main Results:
- Higher admission levels of Ang-2, CXCL10, and sFlt-1 were observed in children who died.
- Elevated Ang-2, sTREM-1, CXCL10, and sICAM-1 correlated with prolonged clinical recovery in survivors.
- Ang-2 levels predicted postdischarge mortality; no biomarkers were linked to neurodisability.
Conclusions:
- Persistent endothelial activation and dysfunction are key predictors of survival in pediatric severe malaria.
- Specific biomarkers may aid in identifying children at higher risk for mortality and prolonged recovery.
Abstract:
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. 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. 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, and P = .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. Persistent endothelial activation and dysfunction predict survival in children admitted with severe malaria.
