糖萼破裂与恶性疟原虫疟疾的严重疾病和致命结局相关。
Glycocalyx Breakdown Is Associated With Severe Disease and Fatal Outcome in Plasmodium falciparum Malaria.
机构信息
Global and Tropical Health Division, Menzies School of Health Research, Darwin, Northern Territory, Australia.
Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore.
出版信息
Clin Infect Dis. 2019 Oct 30;69(10):1712-1720. doi: 10.1093/cid/ciz038.
BACKGROUND
Interactions between the endothelium and infected erythrocytes play a major role in the pathogenesis of falciparum malaria, with microvascular dysfunction and parasite sequestration associated with worsening outcomes. The glycocalyx is a carbohydrate-rich layer that lines the endothelium, with multiple roles in vascular homeostasis. The role of the glycocalyx in falciparum malaria and the association with disease severity has not been investigated.
METHODS
We prospectively enrolled Indonesian inpatients (aged ≥18 years) with severe (SM) or moderately severe (MSM) falciparum malaria, as defined by World Health Organization criteria, and healthy controls (HCs). On enrollment, blood and urine samples were collected concurrently with measurements of vascular nitric oxide (NO) bioavailability. Urine was assayed for glycocalyx breakdown products (glycosaminoglycans) using a dimethylmethylene blue (GAG-DMMB) and liquid chromatography-tandem mass spectrometry (GAG-MS) assay.
RESULTS
A total of 129 patients (SM = 43, MSM = 57, HC=29) were recruited. GAG-DMMB and GAG-MS (g/mol creatinine) were increased in SM (mean, 95% confidence interval: 3.98, 2.44-5.53 and 6.82, 5.19-8.44) compared to MSM patients (1.78, 1.27-2.29 and 4.87, 4.27-5.46) and HCs (0.22, 0.06-0.37 and 1.24, 0.89-1.59; P < 0.001). In SM patients, GAG-DMMB and GAG-MS were increased in those with a fatal outcome (n = 3; median, interquartile range: 6.72, 3.80-27.87 and 12.15, 7.88-17.20) compared to survivors (n = 39; 3.10, 0.46-4.5 and 4.64, 2.02-15.20; P = 0.03). Glycocalyx degradation was significantly associated with parasite biomass in both MSM (r = 0.48, GAG-DMMB and r = 0.43, GAG-MS; P < 0.001) and SM patients (r = 0.47, P = 0.002 and r = 0.33, P = 0.04) and inversely associated with endothelial NO bioavailability.
CONCLUSIONS
Increased endothelial glycocalyx breakdown is associated with severe disease and a fatal outcome in adults with falciparum malaria.
背景
内皮细胞与感染的红细胞之间的相互作用在恶性疟原虫病的发病机制中起着重要作用，微血管功能障碍和寄生虫隔离与病情恶化有关。糖萼是一种富含碳水化合物的层，位于内皮细胞上，在血管稳态中具有多种作用。糖萼在恶性疟原虫病中的作用及其与疾病严重程度的关系尚未得到研究。
方法
我们前瞻性地招募了印度尼西亚住院患者（年龄≥18 岁），这些患者患有严重（SM）或中度严重（MSM）的恶性疟原虫病，符合世界卫生组织的标准，并招募了健康对照组（HCs）。在入组时，同时采集血液和尿液样本，并测量血管中一氧化氮（NO）生物利用度。使用二甲亚甲基蓝（GAG-DMMB）和液相色谱-串联质谱（GAG-MS）测定尿液中的糖萼分解产物（糖胺聚糖）。
结果
共招募了 129 名患者（SM = 43 名，MSM = 57 名，HC = 29 名）。与 MSM 患者（1.78，1.27-2.29 和 4.87，4.27-5.46）和 HCs（0.22，0.06-0.37 和 1.24，0.89-1.59；P <0.001）相比，SM 患者的 GAG-DMMB 和 GAG-MS（g/mol 肌酐）升高（平均值，95%置信区间：3.98，2.44-5.53 和 6.82，5.19-8.44）。在 SM 患者中，与幸存者（n = 39；3.10，0.46-4.5 和 4.64，2.02-15.20）相比，死亡结局（n = 3；中位数，四分位距：6.72，3.80-27.87 和 12.15，7.88-17.20）患者的 GAG-DMMB 和 GAG-MS 升高（P = 0.03）。糖萼降解与 MSM 患者（r = 0.48，GAG-DMMB 和 r = 0.43，GAG-MS；P <0.001）和 SM 患者（r = 0.47，P = 0.002 和 r = 0.33，P = 0.04）的寄生虫生物量均显著相关，与内皮细胞 NO 生物利用度呈负相关。
结论
内皮糖萼分解增加与恶性疟原虫病成人严重疾病和致命结局有关。
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