Abstract
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.
Highlights
The monkey parasite Plasmodium knowlesi is an important emerging zoonotic infection in Southeast Asia, and is the most common cause of human malaria in Malaysia[1, 2] and regions of western Indonesia[3, 4]
We have recently reported that, as with falciparum malaria, disease severity in knowlesi malaria is Barber et al Emerging Microbes & Infections (2018)7:106 associated with parasite biomass, endothelial activation, and microvascular dysfunction[10], as well as reduced red blood cell (RBC) deformability[11]
Intravascular haemolysis is increased in knowlesi malaria in proportion to disease severity, and to a greater extent than that seen in falciparum malaria
Summary
The monkey parasite Plasmodium knowlesi is an important emerging zoonotic infection in Southeast Asia, and is the most common cause of human malaria in Malaysia[1, 2] and regions of western Indonesia[3, 4]. In contrast to P. falciparum, P. knowlesi-attributed coma has not been reported to-date, and endothelial cytoadherence, a key pathogenic feature of severe falciparum malaria, does not appear to occur[8, 9]. We have recently reported that, as with falciparum malaria, disease severity in knowlesi malaria is Barber et al Emerging Microbes & Infections (2018)7:106 associated with parasite biomass, endothelial activation, and microvascular dysfunction[10], as well as reduced red blood cell (RBC) deformability[11]. The roles of intravascular haemolysis and nitric oxide (NO)-dependent endothelial dysfunction, important features of severe falciparum malaria[12,13,14,15,16], have not yet been reported
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