Global and Tropical Health Division, Menzies School of Health Research, Darwin, NT, Australia.
Infectious Diseases Society Sabah-Menzies School of Health Research Clinical Research Unit, Kota Kinabalu, Sabah, Malaysia.
Emerg Microbes Infect. 2018 Jun 6;7(1):106. doi: 10.1038/s41426-018-0105-2.
Plasmodium knowlesi occurs throughout Southeast Asia, and is the most common cause of human malaria in Malaysia. Severe disease in humans is characterised by high parasite biomass, reduced red blood cell deformability, endothelial activation and microvascular dysfunction. However, the roles of intravascular haemolysis and nitric oxide (NO)-dependent endothelial dysfunction, important features of severe falciparum malaria, have not been evaluated, nor their role in acute kidney injury (AKI). In hospitalised Malaysian adults with severe (n = 48) and non-severe (n = 154) knowlesi malaria, and in healthy controls (n = 50), we measured cell-free haemoglobin (CFHb) and assessed associations with the endothelial Weibel-Palade body (WPB) constituents, angiopoietin-2 and osteoprotegerin, endothelial and microvascular function, and other markers of disease severity. CFHb was increased in knowlesi malaria in proportion to disease severity, and to a greater extent than previously reported in severe falciparum malaria patients from the same study cohort. In knowlesi malaria, CFHb was associated with parasitaemia, and independently associated with angiopoietin-2 and osteoprotegerin. As with angiopoietin-2, osteoprotegerin was increased in proportion to disease severity, and independently associated with severity markers including creatinine, lactate, interleukin-6, endothelial cell adhesion molecules ICAM-1 and E-selectin, and impaired microvascular reactivity. Osteoprotegerin was also independently associated with NO-dependent endothelial dysfunction. AKI was found in 88% of those with severe knowlesi malaria. Angiopoietin-2 and osteoprotegerin were both independent risk factors for acute kidney injury. Our findings suggest that haemolysis-mediated endothelial activation and release of WPB constituents is likely a key contributor to end-organ dysfunction, including AKI, in severe knowlesi malaria.
疟原虫 knowlesi 分布于整个东南亚地区，是马来西亚最常见的人类疟疾病原体。人类的严重疾病表现为高寄生虫生物量、红细胞变形能力降低、内皮细胞激活和微血管功能障碍。然而，严重恶性疟原虫感染中血管内溶血和一氧化氮（NO）依赖性内皮功能障碍的作用，以及它们在急性肾损伤（AKI）中的作用，尚未得到评估。在因严重（n=48）和非严重（n=154）疟原虫 knowlesi 疟疾住院的马来西亚成年人以及健康对照组（n=50）中，我们测量了无细胞血红蛋白（CFHb），并评估了其与内皮 Weibel-Palade 体（WPB）成分血管生成素-2 和骨保护素、内皮和微血管功能以及其他疾病严重程度标志物的关联。CFHb 在疟原虫 knowlesi 中与疾病严重程度成正比增加，并且比来自同一研究队列的严重恶性疟原虫患者中先前报道的更为显著。在疟原虫 knowlesi 中，CFHb 与寄生虫血症相关，并且与血管生成素-2 和骨保护素独立相关。与血管生成素-2 一样，骨保护素与疾病严重程度成正比增加，并且与包括肌酐、乳酸、白细胞介素-6、内皮细胞黏附分子 ICAM-1 和 E-选择素在内的严重程度标志物以及微血管反应性受损独立相关。骨保护素也与 NO 依赖性内皮功能障碍独立相关。在严重疟原虫 knowlesi 患者中发现 88%发生急性肾损伤。血管生成素-2 和骨保护素都是急性肾损伤的独立危险因素。我们的研究结果表明，溶血介导的内皮激活和 WPB 成分的释放可能是严重疟原虫 knowlesi 导致终末器官功能障碍（包括 AKI）的关键因素。
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