Sandra A. Rotman Laboratories, McLaughlin-Rotman Centre for Global Health, University Health Network-Toronto General Hospital, University of Toronto, Toronto, Canada.
PLoS One. 2010 Dec 29;5(12):e15291. doi: 10.1371/journal.pone.0015291.
Differentiating cerebral malaria (CM) from other causes of serious illness in African children is problematic, owing to the non-specific nature of the clinical presentation and the high prevalence of incidental parasitaemia. CM is associated with endothelial activation. In this study we tested the hypothesis that endothelium-derived biomarkers are associated with the pathophysiology of severe malaria and may help identify children with CM.
Plasma samples were tested from children recruited with uncomplicated malaria (UM; n = 32), cerebral malaria with retinopathy (CM-R; n = 38), clinically defined CM without retinopathy (CM-N; n = 29), or non-malaria febrile illness with decreased consciousness (CNS; n = 24). Admission levels of angiopoietin-2 (Ang-2), Ang-1, soluble Tie-2 (sTie-2), von Willebrand factor (VWF), its propeptide (VWFpp), vascular endothelial growth factor (VEGF), soluble ICAM-1 (sICAM-1) and interferon-inducible protein 10 (IP-10) were measured by ELISA. Children with CM-R had significantly higher median levels of Ang-2, Ang-2:Ang-1, sTie-2, VWFpp and sICAM-1 compared to children with CM-N. Children with CM-R had significantly lower median levels of Ang-1 and higher median concentrations of Ang-2:Ang-1, sTie-2, VWF, VWFpp, VEGF and sICAM-1 compared to UM, and significantly lower median levels of Ang-1 and higher median levels of Ang-2, Ang-2:Ang-1, VWF and VWFpp compared to children with fever and altered consciousness due to other causes. Ang-1 was the best discriminator between UM and CM-R and between CNS and CM-R (areas under the ROC curve of 0.96 and 0.93, respectively). A comparison of biomarker levels in CM-R between admission and recovery showed uniform increases in Ang-1 levels, suggesting this biomarker may have utility in monitoring clinical response.
These results suggest that endothelial proteins are informative biomarkers of malarial disease severity. These results require validation in prospective studies to confirm that this group of biomarkers improves the diagnostic accuracy of CM from similar conditions causing fever and altered consciousness.
在非洲儿童中，由于临床症状不具有特异性，且偶然发生寄生虫血症的情况很常见，因此难以将脑型疟疾（CM）与其他严重疾病的原因区分开来。CM 与内皮细胞激活有关。在这项研究中，我们检验了一个假设，即内皮衍生生物标志物与严重疟疾的病理生理学有关，并且可能有助于识别患有 CM 的儿童。
我们检测了患有单纯性疟疾（UM；n=32）、伴有视网膜病变的脑型疟疾（CM-R；n=38）、无视网膜病变的临床定义性脑型疟疾（CM-N；n=29）或非疟疾发热性疾病伴意识障碍（CNS；n=24）的儿童的血浆样本。通过 ELISA 检测血管生成素-2（Ang-2）、Ang-1、可溶性 Tie-2（sTie-2）、血管性血友病因子（VWF）、其前肽（VWFpp）、血管内皮生长因子（VEGF）、可溶性细胞间黏附分子-1（sICAM-1）和干扰素诱导蛋白 10（IP-10）的入院水平。与 CM-N 相比，CM-R 患儿的中位 Ang-2、Ang-2:Ang-1、sTie-2、VWFpp 和 sICAM-1 水平显著升高。与 UM 相比，CM-R 患儿的中位 Ang-1 水平显著降低，中位 Ang-2:Ang-1、sTie-2、VWF、VWFpp、VEGF 和 sICAM-1 水平显著升高，与因其他原因引起发热和意识改变的儿童相比，中位 Ang-1 水平显著降低，中位 Ang-2、Ang-2:Ang-1、VWF 和 VWFpp 水平显著升高。Ang-1 是区分 UM 和 CM-R 以及 CNS 和 CM-R 的最佳鉴别标志物（ROC 曲线下面积分别为 0.96 和 0.93）。比较 CM-R 入院和康复时的生物标志物水平发现，Ang-1 水平呈均匀升高，表明该生物标志物可能有助于监测临床反应。
这些结果表明，内皮蛋白是疟疾严重程度的信息生物标志物。这些结果需要在前瞻性研究中进行验证，以确认这组生物标志物是否可以提高类似引起发热和意识改变的疾病中 CM 的诊断准确性。
