人畜共患寄生虫诺氏疟原虫患严重疟疾的风险接近恶性疟原虫。在严重的恶性疟疾中,中性粒细胞活化有助于炎症发病机制,包括急性肺损伤。尚未研究中性粒细胞活化在重症知识疟疾发病机理中的作用。我们评估了213例知识假单胞菌单感染患者(138例非严重,来自马来西亚的75例严重)和49例疟原虫阴性对照。中性粒细胞活化标志物(可溶性中性粒细胞弹性蛋白酶[NE],通过显微镜和免疫测定对外周血中的瓜氨酸化组蛋白[CitH3]和循环中性粒细胞胞外陷阱[NET])进行定量。研究结果与疟疾严重程度相关,ALI临床标准,寄生虫生物量的生物标志物,溶血,和内皮激活。中性粒细胞活化随着疾病的严重程度而增加,重度疟疾和NE对照的中位数高于非重度疟疾(380[IQR:210-930]ng/mL,236[139-448]ng/mL,218[134-307]ng/mL,分别)和CitH3(8.72[IQR:3.0-23.1]ng/mL,4.29[1.46-9.49]ng/mL,1.53[0.6-2.59]ng/mL,分别)[所有p<0.01]。与对照组相比,重症疟疾的NETs较高(126/μL[IQR:49-323]vs51[20-75]/μL,p<0.001)。在非严重疟疾中,出院后中性粒细胞活化显著下降(p<0.03).在严重疾病中,NET,NE,和CitH3与寄生虫血症相关,无细胞血红蛋白和血管生成素-2(所有Pearson的r>0.24,p<0.05)。有ALI患者血浆NE和血管生成素-2高于无ALI患者(p<0.008);中性粒细胞增多与ALI风险增加相关(aOR3.27,p<0.01)。总之,中性粒细胞活化在ALI中增加,并且在知识疟疾中与疾病严重程度成比例,与内皮激活有关,并可能有助于疾病的发病机制。在严重的知识疟疾中,有必要进行辅助疗法以调节中性粒细胞活化的试验。
The risk of severe malaria from the zoonotic parasite Plasmodium knowlesi approximates that from P. falciparum. In severe falciparum malaria, neutrophil activation contributes to inflammatory pathogenesis, including acute lung injury (ALI). The role of neutrophil activation in the pathogenesis of severe knowlesi malaria has not been examined. We evaluated 213 patients with P. knowlesi mono-infection (138 non-severe, 75 severe) and 49 Plasmodium-negative controls from Malaysia. Markers of neutrophil activation (soluble neutrophil elastase [NE], citrullinated histone [CitH3] and circulating neutrophil extracellular traps [NETs]) were quantified in peripheral blood by microscopy and immunoassays. Findings were correlated with malaria severity, ALI clinical criteria, biomarkers of parasite biomass, haemolysis, and endothelial activation. Neutrophil activation increased with disease severity, with median levels higher in severe than non-severe malaria and controls for NE (380[IQR:210-930]ng/mL, 236[139-448]ng/mL, 218[134-307]ng/mL, respectively) and CitH3 (8.72[IQR:3.0-23.1]ng/mL, 4.29[1.46-9.49]ng/mL, 1.53[0.6-2.59]ng/mL, respectively)[all p<0.01]. NETs were higher in severe malaria compared to controls (126/μL[IQR:49-323] vs 51[20-75]/μL, p<0.001). In non-severe malaria, neutrophil activation fell significantly upon discharge from hospital (p<0.03). In severe disease, NETs, NE, and CitH3 were correlated with parasitaemia, cell-free haemoglobin and angiopoietin-2 (all Pearson\'s r>0.24, p<0.05). Plasma NE and angiopoietin-2 were higher in knowlesi patients with ALI than those without (p<0.008); neutrophilia was associated with an increased risk of ALI (aOR 3.27, p<0.01). In conclusion, neutrophil activation is increased in ALI and in proportion to disease severity in knowlesi malaria, is associated with endothelial activation, and may contribute to disease pathogenesis. Trials of adjunctive therapies to regulate neutrophil activation are warranted in severe knowlesi malaria.