Combinations of host biomarkers predict mortality among Ugandan children with severe malaria: A retrospective case-control study

Erdman, Laura K., Dhabangi, Aggrey, Musoke, Charles, Conroy, Andrea L., Hawkes, Michael, Higgins, Sarah, Rajwans, Nimerta, Wolofsky, Kayla T., Streiner, David L., Liles, W. Conrad, Cserti-Gazdewich, Christine M. and Kain, Kevin C. (2011) Combinations of host biomarkers predict mortality among Ugandan children with severe malaria: A retrospective case-control study. PLoS One, 6 2: 1-11. doi:10.1371/journal.pone.0017440


Author Erdman, Laura K.
Dhabangi, Aggrey
Musoke, Charles
Conroy, Andrea L.
Hawkes, Michael
Higgins, Sarah
Rajwans, Nimerta
Wolofsky, Kayla T.
Streiner, David L.
Liles, W. Conrad
Cserti-Gazdewich, Christine M.
Kain, Kevin C.
Title Combinations of host biomarkers predict mortality among Ugandan children with severe malaria: A retrospective case-control study
Journal name PLoS One   Check publisher's open access policy
ISSN 1932-6203
Publication date 2011-02-01
Sub-type Article (original research)
DOI 10.1371/journal.pone.0017440
Open Access Status DOI
Volume 6
Issue 2
Start page 1
End page 11
Total pages 11
Place of publication San Francisco CA , United States
Publisher Public Library of Science
Language eng
Formatted abstract
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.
Keyword Plasmodium-falciparum malaria
Tumor-necrosis-factor
Endothelial growth-factor
Cerebral malaria
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2012 Collection
School of Medicine Publications
 
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Created: Sun, 20 Mar 2011, 10:03:07 EST