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脓毒症是因感染反应失调而导致的危及生命的器官功能障碍,其发病率和死亡率很高。根据柳叶刀杂志最新报道,2017年全球记录的脓毒症病例为4890万例,与脓毒症相关的死亡为1100万例,约占全球所有死亡病例的20%[1]。发达国家如美国每年脓毒症病例约为170万例,与脓毒症相关的死亡约27万例[2]。在低收入及中等收入的国家,脓毒症更是重症监护病房(ICU)患者的主要死亡原因,死亡率高达80%[3]。世界卫生组织已经认识到脓毒症对全球健康的重大威胁,并加强了对脓毒症的预防、诊断和治疗[4]。尽管如此,脓毒症的死亡率依然很高,主要原因之一是目前并没有诊断脓毒症的金标准,临床缺乏早期诊断和病情预测的手段。传统的标准微生物培养方法非常耗时,且有相当比例的假阴性结果。降钙素原(PCT)是唯一写进临床指南的脓毒症标志物,可用于指导抗生素的使用,但并不具有独立诊断的能力。C反应蛋白(CRP)作为传统的炎性指标,其诊断特异性较差。为了给临床提供准确及时的诊断及预后标准,脓毒症标志物一直是研究热点。本文对近年来关注度较高的、新的脓毒症候选生物标志物进行了综述,主要包括急性期蛋白、可溶性受体、非编码RNA和其他候选标志物。
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本文综述的急性期蛋白、可溶性受体、非编码RNA和其他的标志物的作用及效能如表1所示。早期诊断和正确治疗是降低脓毒症病死率的关键。但由于脓毒症病理生理机制复杂,个体差异较大,体征和症状无特异性,早期诊断极为困难。目前被研究的诊断标志物主要参与先天免疫反应的初始发病机制,预后标志物通常与脓毒症引起的器官功能障碍有关。这些候选标志物在脓毒症发病机制中的作用以及最佳联合使用策略,都需要进一步的研究,以供将来的临床使用。
表 1 脓毒症生物标志物作用及效能比较
分类 标志物 作用 效能 参考文献 AUC 临界值 敏感性(%) 特异性(%) 急性期蛋白 PTX-3 诊断新生儿脓毒症 0.875 ? 100 94.3 [6] 诊断新生儿脓毒症 0.995 5.6 μg/L 98.3 96.7 [7] 预测28天死亡率 0.69 ? ? ? [9] 预测脓毒症休克 0.798 15877 pg/ml 50 100 [10] 预测28天死亡率 0.78 49.9 ng/ml 83.3 64.2 [11] ADM 诊断脓毒症 0.85 1.5 pg/ml 83 76.47 [12] 预测器官衰竭 0.69 75 pg/ml ? ? [13] 诊断脓毒症 0.731 ? ? ? [14] 预测总死亡率 0.655 1.4 nmol/L 81.1 39.8 可溶性受体 Presepsin 诊断脓毒症 0.792 380 pg/ml 83.5 62.2 [18] 预测30天死亡率 0.683 556 pg/ml 73.1 59.6 诊断免疫功能低下患者的脓毒症 0.87 1248 pg/ml 66 100 [19] sTREM-1 诊断脓毒症 0.97 60 ng/ml 96 89 [25] 诊断脓毒症 0.868 108.9 pg/ml 83 81 [26] 预测脓毒症死亡率 0.74 180 pg/ml 86 70 [29] 预测脓毒症休克 0.823 222.5 pg/ml 59.5 93.3 [30] 预测脓毒症死亡率 0.64 954.4 pg/ml 54.5 78 [31] SuPAR 诊断脓毒症 0.89 5.58 pg/ml 96 72.2 [33] 预测脓毒症病情恶化 0.66 ? 90 20 [35] 预测脓毒症死亡率 ? 5.2 ng/ml ? ? [36] 诊断脓毒症 0.83 7.5 pg/ml 76 78 [32] 预测死亡率 0.78 9.6 pg/ml 74 70 鉴别脓毒症与CIRS 0.81 7.5 pg/ml 67 82 MicroRNA miRNA-16a 诊断新生儿脓毒症 0.968 3.164 88 98 [36] miR-328 诊断脓毒症 0.926 0.305 87.6 86.36 [37] miR-10a 诊断脓毒症 0.804 0.18 65 85.7 [39] 预测28天死亡率 0.699 ? ? ? miR-223 诊断脓毒症 0.924 ? ? ? [40] 预测28天死亡率 0.711 ? ? ? miR-21-3p 预测脓毒症并发急性肾损伤 0.962 ? 97 91.4 [42] lncRNA lncRNA MALAT1 诊断脓毒症 0.91 1.895 83.33 85 [47] 预测脓毒症休克 0.836 3.665 70.37 92.42 预测脓毒症死亡率 0.886 3.62 81.82 89.47 lncRNA ZFAS1 诊断脓毒症 0.814 ? 92.1 63.5 [48] 预测脓毒症死亡率 0.628 ? 92.1 35.5 lncRNA NEAT1 诊断脓毒症 0.785 ? ? ? [49] 预测28天死亡率 0.726 ? ? ? lnc-MEG3 诊断脓毒症 0.887 ? ? ? [51] 预测28天死亡率 0.704 ? ? ? lncRNA TUG1 诊断脓毒症 0.846 ? ? ? [40] 预测28天死亡率 0.705 ? ? ? 其他 Calprotectin 诊断脓毒症 0.79 1.3 ng/l 81 56 [52] 诊断脓毒症 0.91 ? ? ? [53] nCD64 诊断新生儿脓毒症 0.925 41.60% 94.7 93.6 [55] 诊断脓毒症 0.879 8 MFI 75 89.4 [56] 预测28天死亡率 0.85 5.45 MFI 93.3 65.3 诊断脓毒症 0.922 43% 85.6 93 [57] 肠道微生物群 诊断迟发性脓毒症 0.78 ? ? ? [58] Angiopoietin 2 预测脓毒症休克 0.631 9047 pg/ml 42.31 88.24 [61] Angiopoietin 2/1 预测28天死亡率 0.736 3.2 69.8 70.6 [62]
Recent advances in biomarkers of sepsis
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摘要: 脓毒症可以导致危及生命的器官功能障碍,是危重患者死亡的主要原因之一。脓毒症的早期诊断与正确治疗是降低病死率的关键,但目前尚无诊断的金标准。理想的脓毒症生物标志物应该具有早期诊断和预测不良预后的能力,且具有较好的敏感性和特异性。脓毒症的候选生物标志物众多,本文重点综述了急性期蛋白、可溶性受体、非编码RNA和其他近期关注度较高的候选标志物的最新进展。Abstract: Sepsis can cause life-threatening organ dysfunction and is one of the leading causes of death in critically ill patients. Early diagnosis and correct treatment of sepsis are the key to reducing the fatality, however, there is no golden standard for diagnosis at present. The ideal sepsis biomarker can be used for early diagnosis and predicting poor prognosis with good sensitivity and specificity. There are many candidate biomarkers for sepsis. This article reviews the latest developments on acute phase proteins, soluble receptors, non-coding RNAs and other candidate biomarkers of sepsis that attracted more recent attention.
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表 1 脓毒症生物标志物作用及效能比较
分类 标志物 作用 效能 参考文献 AUC 临界值 敏感性(%) 特异性(%) 急性期蛋白 PTX-3 诊断新生儿脓毒症 0.875 ? 100 94.3 [6] 诊断新生儿脓毒症 0.995 5.6 μg/L 98.3 96.7 [7] 预测28天死亡率 0.69 ? ? ? [9] 预测脓毒症休克 0.798 15877 pg/ml 50 100 [10] 预测28天死亡率 0.78 49.9 ng/ml 83.3 64.2 [11] ADM 诊断脓毒症 0.85 1.5 pg/ml 83 76.47 [12] 预测器官衰竭 0.69 75 pg/ml ? ? [13] 诊断脓毒症 0.731 ? ? ? [14] 预测总死亡率 0.655 1.4 nmol/L 81.1 39.8 可溶性受体 Presepsin 诊断脓毒症 0.792 380 pg/ml 83.5 62.2 [18] 预测30天死亡率 0.683 556 pg/ml 73.1 59.6 诊断免疫功能低下患者的脓毒症 0.87 1248 pg/ml 66 100 [19] sTREM-1 诊断脓毒症 0.97 60 ng/ml 96 89 [25] 诊断脓毒症 0.868 108.9 pg/ml 83 81 [26] 预测脓毒症死亡率 0.74 180 pg/ml 86 70 [29] 预测脓毒症休克 0.823 222.5 pg/ml 59.5 93.3 [30] 预测脓毒症死亡率 0.64 954.4 pg/ml 54.5 78 [31] SuPAR 诊断脓毒症 0.89 5.58 pg/ml 96 72.2 [33] 预测脓毒症病情恶化 0.66 ? 90 20 [35] 预测脓毒症死亡率 ? 5.2 ng/ml ? ? [36] 诊断脓毒症 0.83 7.5 pg/ml 76 78 [32] 预测死亡率 0.78 9.6 pg/ml 74 70 鉴别脓毒症与CIRS 0.81 7.5 pg/ml 67 82 MicroRNA miRNA-16a 诊断新生儿脓毒症 0.968 3.164 88 98 [36] miR-328 诊断脓毒症 0.926 0.305 87.6 86.36 [37] miR-10a 诊断脓毒症 0.804 0.18 65 85.7 [39] 预测28天死亡率 0.699 ? ? ? miR-223 诊断脓毒症 0.924 ? ? ? [40] 预测28天死亡率 0.711 ? ? ? miR-21-3p 预测脓毒症并发急性肾损伤 0.962 ? 97 91.4 [42] lncRNA lncRNA MALAT1 诊断脓毒症 0.91 1.895 83.33 85 [47] 预测脓毒症休克 0.836 3.665 70.37 92.42 预测脓毒症死亡率 0.886 3.62 81.82 89.47 lncRNA ZFAS1 诊断脓毒症 0.814 ? 92.1 63.5 [48] 预测脓毒症死亡率 0.628 ? 92.1 35.5 lncRNA NEAT1 诊断脓毒症 0.785 ? ? ? [49] 预测28天死亡率 0.726 ? ? ? lnc-MEG3 诊断脓毒症 0.887 ? ? ? [51] 预测28天死亡率 0.704 ? ? ? lncRNA TUG1 诊断脓毒症 0.846 ? ? ? [40] 预测28天死亡率 0.705 ? ? ? 其他 Calprotectin 诊断脓毒症 0.79 1.3 ng/l 81 56 [52] 诊断脓毒症 0.91 ? ? ? [53] nCD64 诊断新生儿脓毒症 0.925 41.60% 94.7 93.6 [55] 诊断脓毒症 0.879 8 MFI 75 89.4 [56] 预测28天死亡率 0.85 5.45 MFI 93.3 65.3 诊断脓毒症 0.922 43% 85.6 93 [57] 肠道微生物群 诊断迟发性脓毒症 0.78 ? ? ? [58] Angiopoietin 2 预测脓毒症休克 0.631 9047 pg/ml 42.31 88.24 [61] Angiopoietin 2/1 预测28天死亡率 0.736 3.2 69.8 70.6 [62] -
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