Abstract
BackgroundLimited tools exist to identify which individuals infected with Plasmodium falciparum are at risk of developing serious complications such as cerebral malaria (CM). The objective of this study was to assess serum biomarkers that differentiate between CM and non-CM, with the long-term goal of developing a clinically informative prognostic test for severe malaria.Methodology/Principal FindingsBased on the hypothesis that endothelial activation and blood-brain-barrier dysfunction contribute to CM pathogenesis, we examined the endothelial regulators, angiopoietin-1 (ANG-1) and angiopoietin-2 (ANG-2), in serum samples from P. falciparum-infected patients with uncomplicated malaria (UM) or CM, from two diverse populations – Thai adults and Ugandan children. Angiopoietin levels were compared to tumour necrosis factor (TNF). In both populations, ANG-1 levels were significantly decreased and ANG-2 levels were significantly increased in CM versus UM and healthy controls (p<0.001). TNF was significantly elevated in CM in the Thai adult population (p<0.001), but did not discriminate well between CM and UM in African children. Receiver operating characteristic curve analysis showed that ANG-1 and the ratio of ANG-2∶ANG-1 accurately discriminated CM patients from UM in both populations. Applied as a diagnostic test, ANG-1 had a sensitivity and specificity of 100% for distinguishing CM from UM in Thai adults and 70% and 75%, respectively, for Ugandan children. Across both populations the likelihood ratio of CM given a positive test (ANG-1<15 ng/mL) was 4.1 (2.7–6.5) and the likelihood ratio of CM given a negative test was 0.29 (0.20–0.42). Moreover, low ANG-1 levels at presentation predicted subsequent mortality in children with CM (p = 0.027).Conclusions/SignificanceANG-1 and the ANG-2/1 ratio are promising clinically informative biomarkers for CM. Additional studies should address their utility as prognostic biomarkers and potential therapeutic targets in severe malaria.
Highlights
Greater than 500 million Plasmodium falciparum malaria infections are estimated to occur each year, only a small proportion of patients progress to severe and potentially fatal complications such as cerebral malaria (CM) [1,2,3,4]
ANG-1 levels are decreased and ANG-2 levels increased in the serum of cerebral malaria patients compared to uncomplicated patients and healthy controls In Thailand, serum ANG-1 levels were significantly lower in adults with CM compared to either adults with uncomplicated malaria (UM) or healthy controls, and in adults with UM compared to healthy controls (Figure 1A; Kruskal-Wallis: p,0.001)
Serum ANG-2 levels were significantly increased in adults with CM compared to adults with UM or healthy controls, as well as in adults with UM compared to healthy controls (Figure 1A; Kruskal-Wallis: P,0.001)
Summary
Greater than 500 million Plasmodium falciparum malaria infections are estimated to occur each year, only a small proportion of patients progress to severe and potentially fatal complications such as cerebral malaria (CM) [1,2,3,4]. The mechanisms underlying CM are poorly understood, and limited prognostic tools are available to determine which infected individuals will progress to cerebral complications [5,6,7,8]. Several studies have examined the correlation of serum markers, such as cytokines, with severe and complicated malaria. Elevated levels of TNF have been associated with severe malaria [9,10,11,12,13,14] and were identified as a predictor of mortality in CM [10,11]. Limited tools exist to identify which individuals infected with Plasmodium falciparum are at risk of developing serious complications such as cerebral malaria (CM). The objective of this study was to assess serum biomarkers that differentiate between CM and non-CM, with the long-term goal of developing a clinically informative prognostic test for severe malaria
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