Abstract
BackgroundSevere and cerebral malaria are associated with endothelial activation. Angiopoietin-1 (ANG-1) and angiopoietin-2 (ANG-2) are major regulators of endothelial activation and integrity. The aim of this study was to investigate the clinical utility of whole blood angiopoietin (ANG) levels as biomarkers of disease severity in Plasmodium falciparum malaria.MethodsThe utility of whole blood ANG levels was examined in Thai patients to distinguish cerebral (CM; n = 87) and severe (non-cerebral) malaria (SM; n = 36) from uncomplicated malaria (UM; n = 70). Comparative statistics are reported using a non-parametric univariate analysis (Kruskal-Wallis test or Chi-squared test, as appropriate). Multivariate binary logistic regression was used to examine differences in whole blood protein levels between groups (UM, SM, CM), adjusting for differences due to ethnicity, age, parasitaemia and sex. Receiver operating characteristic curve analysis was used to assess the diagnostic accuracy of the ANGs in their ability to distinguish between UM, SM and CM. Cumulative organ injury scores were obtained for patients with severe disease based on the presence of acute renal failure, jaundice, severe anaemia, circulatory collapse or coma.ResultsANG-1 and ANG-2 were readily detectable in whole blood. Compared to UM there were significant decreases in ANG-1 (p < 0.001) and significant increases in ANG-2 (p < 0.001) levels and the ratio of ANG-2: ANG-1 (p < 0.001) observed in patients with SM and CM. This effect was independent of covariates (ethnicity, age, parasitaemia, sex). Further, there was a significant decrease in ANG-1 levels in patients with SM (non-cerebral) versus CM (p < 0.001). In participants with severe disease, ANG-2, but not ANG-1, levels correlated with cumulative organ injury scores; however, ANG-1 correlated with the presence of renal dysfunction and coma. Receiver operating characteristic curve analysis demonstrated that the level of ANG-1, the level of ANG-2 or the ratio of ANG-2: ANG-1 discriminated between individuals with UM and SM (area under the curve, p-value: ANG-2, 0.763, p < 0.001; ANG-1, 0.884, p < 0.001; Ratio, 0.857, p < 0.001) or UM and CM (area under the curve, p-value: ANG-2, 0.772, p < 0.001; ANG-1, 0.778, p < 0.001; Ratio, 0.820, p < 0.001).ConclusionsThese results suggest that whole blood ANG-1/2 levels are promising clinically informative biomarkers of disease severity in malarial syndromes.
Highlights
Severe and cerebral malaria are associated with endothelial activation
This study focused on the predictive value of ANG-1 and ANG-2 levels in whole blood, since unprocessed whole blood obtained by finger prick is a preferred clinical specimen for point-of-care testing [15]
ANG-1 was positively associated with renal dysfunction (Spearman's rho, p-value: 0.243, p = 0.007) and coma (Spearman's rho, p-value: 0.370, p < 0.0001). These results demonstrate that whole blood ANG-1 and ANG-2 levels are robust biomarkers of severe and cerebral malaria
Summary
Severe and cerebral malaria are associated with endothelial activation. The definitive diagnosis of severe and cerebral malaria is challenging due to the non-specific nature of the clinical presentation and the confounder of incidental parasitaemia in malaria-endemic areas [3]. These factors may result in misdiagnosis and adverse outcomes due to the failure to treat other life-threatening infections [2,3]. A rapid point-of-care test that accurately identifies patients with severe or cerebral malaria, or those at risk of progressing to these syndromes, would be of clinical and public health utility. Limited prognostic or diagnostic laboratory tools for severe malaria are currently available
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