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Published on: October 6, 2015
Combinations of host biomarkers predict mortality among Ugandan children with severe malaria: a retrospective
Laura K Erdman1, Aggrey Dhabangi, Charles Musoke
1SA Rotman Laboratories, McLaughlin-Rotman Centre for Global Health, Toronto General Hospital-University Health Network, University of Toronto, Toronto, Ontario, Canada.
Insights
Novel host biomarkers, including soluble TREM-1 and soluble Flt-1, accurately predict death in children with severe malaria. Combinations of these biomarkers offer a promising prognostic tool for identifying high-risk pediatric patients.
Area of Science:
- Pediatric Infectious Diseases
- Clinical Biomarkers
- Malaria Pathogenesis
Background:
- Severe malaria is a major cause of childhood mortality in Africa.
- Predicting fatal outcomes in severe malaria at presentation is challenging.
- Host inflammatory responses and endothelial activation are key in severe malaria.
Purpose of the Study:
- To identify host biomarkers that accurately predict mortality in children with severe malaria.
- To evaluate the predictive accuracy of individual and combined biomarkers.
Main Methods:
- Plasma samples from children with uncomplicated malaria, cerebral malaria, and severe malarial anemia were analyzed.
- Levels of 13 biomarkers (e.g., angiopoietin-2, vWF, ICAM-1, Flt-1, TREM-1) were measured using ELISA.
- Receiver operating characteristic (ROC) curve analysis and classification tree analysis were employed to assess predictive accuracy.
Main Results:
- Six biomarkers (angiopoietin-2, ICAM-1, Flt-1, procalcitonin, IP-10, TREM-1) showed good discrimination between survivors and non-survivors.
- A six-biomarker score achieved 95.7% sensitivity and 88.8% specificity for predicting death.
- A three-biomarker model demonstrated 100% sensitivity and 92.5% specificity.
Conclusions:
- Novel host biomarkers (soluble TREM-1, soluble Flt-1) for pediatric severe and fatal malaria were identified.
- Simple biomarker combinations accurately predicted death in an African pediatric population.
- Combinatorial biomarker strategies show potential as prognostic tests for severe malaria, requiring further validation.
Background:
Severe malaria is a leading cause of childhood mortality in Africa. However, at presentation, it is difficult to predict which children with severe malaria are at greatest risk of death. Dysregulated host inflammatory responses and endothelial activation play central roles in severe malaria pathogenesis. We hypothesized that biomarkers of these processes would accurately predict outcome among children with severe malaria.
Methodology/Findings:
Plasma was obtained from children with uncomplicated malaria (n = 53), cerebral malaria (n = 44) and severe malarial anemia (n = 59) at time of presentation to hospital in Kampala, Uganda. Levels of angiopoietin-2, von Willebrand Factor (vWF), vWF propeptide, soluble P-selectin, soluble intercellular adhesion molecule-1 (ICAM-1), soluble endoglin, soluble FMS-like tyrosine kinase-1 (Flt-1), soluble Tie-2, C-reactive protein, procalcitonin, 10 kDa interferon gamma-induced protein (IP-10), and soluble triggering receptor expressed on myeloid cells-1 (TREM-1) were determined by ELISA. Receiver operating characteristic (ROC) curve analysis was used to assess predictive accuracy of individual biomarkers. Six biomarkers (angiopoietin-2, soluble ICAM-1, soluble Flt-1, procalcitonin, IP-10, soluble TREM-1) discriminated well between children who survived severe malaria infection and those who subsequently died (area under ROC curve>0.7). Combinational approaches were applied in an attempt to improve accuracy. A biomarker score was developed based on dichotomization and summation of the six biomarkers, resulting in 95.7% (95% CI: 78.1-99.9) sensitivity and 88.8% (79.7-94.7) specificity for predicting death. Similar predictive accuracy was achieved with models comprised of 3 biomarkers. Classification tree analysis generated a 3-marker model with 100% sensitivity and 92.5% specificity (cross-validated misclassification rate: 15.4%, standard error 4.9%).
Conclusions:
We identified novel host biomarkers of pediatric severe and fatal malaria (soluble TREM-1 and soluble Flt-1) and generated simple biomarker combinations that accurately predicted death in an African pediatric population. While requiring validation in further studies, these results suggest the utility of combinatorial biomarker strategies as prognostic tests for severe malaria.
