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ACM

Advances in Clinical Medicine

2161-8712

Scientific Research Publishing

10.12677/ACM.2023.134752

ACM-63752

ACM20230400000_68907489.pdf

医药卫生

脓毒症生物标志物研究进展 Research Progress in Biomarkers of Sepsis

敖

玉培

²¹胡

怀东

²¹

重庆医科大学附属第二医院，重庆

null

04042023

130453125317

2014

This work is licensed under the Creative Commons Attribution International License (CC BY). http://creativecommons.org/licenses/by/4.0/

脓毒症目前定义为由宿主对感染的免疫反应失调引起的危及生命的器官功能障碍，通常可归因于细菌感染，但病毒、真菌或寄生虫引起的感染也可能导致脓毒症。如果不及早发现并及时处理，可能导致感染性休克、多器官衰竭和死亡。据统计，脓毒症发病率及死亡率极高，是重症医学科危重症患者死亡的主要原因，且对于幸存者，也导致生活质量严重下降。因此，及时诊断及治疗脓毒症，成为医疗卫生工作的重点。但目前尚无法建立金标准或有效的指标来明确识别脓毒症患者。近年来，关于脓毒症相关生物标志物的研究取得了较大的进展，对脓毒症的早期识别有着较高的灵敏性和特异性。本项研究就几种生物标志物在感染及脓毒症的发生、发展中的研究进展进行阐述。 Sepsis is currently defined as life-threatening organ dysfunction caused by dysregulation of the host’s immune response to infection and can often be attributed to bacterial infection, but infections caused by viruses, fungus, or parasites can also cause sepsis. If not detected early and treated promptly, it will lead to septic shock, multiple organ failure, and death. According to statistics, the incidence and mortality of sepsis are extremely high, which is the main cause of death for critically ill patients in the Department of Intensive Care Medicine, and for survivors, it also leads to a serious decline in the quality of life. Therefore, timely diagnosis and treatment of sepsis has become the focus of medical and health work. However, there is currently no gold standard or effective indicator to clearly identify patients with sepsis. In recent years, great progress has been made in the research on sepsis-related biomarkers, and it has high sensitivity and specificity for the early recognition of sepsis. This study describes the research progress of several biomarkers in the occurrence and development of infection and sepsis.

脓毒症，生物标志物, Sepsis Biomarkers

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关键词

脓毒症，生物标志物

Research Progress in Biomarkers of Sepsis

Yupei Ao, Huaidong Hu^*

The Second Affiliated Hospital of Chongqing Medical University, Chongqing

Received: Mar. 7^th, 2023; accepted: Apr. 1^st, 2023; published: Apr. 11^th, 2023

ABSTRACT

Sepsis is currently defined as life-threatening organ dysfunction caused by dysregulation of the host’s immune response to infection and can often be attributed to bacterial infection, but infections caused by viruses, fungus, or parasites can also cause sepsis. If not detected early and treated promptly, it will lead to septic shock, multiple organ failure, and death. According to statistics, the incidence and mortality of sepsis are extremely high, which is the main cause of death for critically ill patients in the Department of Intensive Care Medicine, and for survivors, it also leads to a serious decline in the quality of life. Therefore, timely diagnosis and treatment of sepsis has become the focus of medical and health work. However, there is currently no gold standard or effective indicator to clearly identify patients with sepsis. In recent years, great progress has been made in the research on sepsis-related biomarkers, and it has high sensitivity and specificity for the early recognition of sepsis. This study describes the research progress of several biomarkers in the occurrence and development of infection and sepsis.

Keywords:Sepsis, Biomarkers

This work is licensed under the Creative Commons Attribution International License (CC BY 4.0).

http://creativecommons.org/licenses/by/4.0/

1. 引言

脓毒症首先于1989由Roger Bone及其团队提出 [1] 。1992年，一个国际共识小组首次将脓毒症定义为全身炎症反应综合征(SIRS)。除了确立SIRS标准外，还定义了脓毒症、重度脓毒症、脓毒性休克、脓毒症诱发的低血压和多器官功能障碍综合征 [2] 。2016年，脓毒症被定义为由宿主对感染反应失调导致的危及生命的器官功能障碍，使用顺序器官功能衰竭评估(SOFA)评分，对怀疑感染或者可疑感染的患者，当SOFA评分 ³ 2分时，可诊断为脓毒症；对于可疑感染的患者，若满足快速SOFA (qSOFA)评分中两项及以上(收缩压 ≤ 100 mmHg、呼吸频率 ≥ 22次/分、意识改变)，可进一步行SOFA评分评估是否存在器官功能衰竭 [3] 。据世界卫生组织统计，2017年全世界有约4890万例脓毒症病例和110万脓毒症相关死亡病例，是约占全球死亡总人数的20%，且近一半脓毒症病例发生在儿童中 [4] 。即使幸存者，生活质量同样受到了较大的影响，常伴有神经肌肉无力、功能状态下降、抑郁、焦虑和创伤后应激综合征等 [5] 。因此，及时准确地诊断脓毒症对于扭转其不利的临床病程至关重要。

目前对于诊断脓毒症缺乏快速可靠的诊断标准，标准血培养被认为诊断脓毒症的可靠手段，但存在周转时间长(微生物生长到可检测水平需要6小时至5天，药物敏感度测试需要额外的24~48小时)，灵敏度低，需要样本量大等缺陷；SIRS标准、SOFA评分和快速SOFA (qSOFA)评分主要针对于预测结局，对于早期诊断的特异性和敏感性较低 [6] [7] 。因此，在临床中，对于脓毒症的诊断及治疗，具有一定的滞后性，造成感染进一步进展，甚至对全身器官造成不可逆的损伤，甚至导致死亡。因此，如何早期预测脓毒症的发生及发展，成为及时有效治疗脓毒症、提高预后、减少死亡发生的关键。

2. 脓毒症生物标志物

脓毒症生物标志物可指示脓毒症的存在与否或严重程度，对指导抗生素治疗，评估治疗疗效及脓毒症的恢复起重要作用，同时可预测脓毒症相关并发症发生。近年来，脓毒症标志物在血液、唾液、尿液、细胞外囊泡中均得到广泛的研究，尽管这些生物标志物都不能周到地满足脓毒症生物标志物的所有理想特征，但在临床实践中展示出了较强的实用性 [8] [9] [10] [11] [12] 。现就几种生物标志物在脓毒症的发生、发展中的研究进展进行阐述。

2.1. C反应蛋白(CRP)

CRP是一种由224个氨基酸组成的五聚体蛋白，由肝细胞分泌入血液中，是目前最广泛使用和研究的生物标志物之一。血清CRP水平在炎症和感染时可增加，其对各种类型的炎症(包括急性胰腺炎、过敏性休克)敏感性较高，但对细菌感染的特异性较低 [13] [14] 。CRP可在任何组织损伤起初的6~72小时内发生从10至100倍迅速而剧烈的变化，因此，CRP可作为炎症水平刺激程度或器官功能障碍程度较低阶段的敏感性指标。但随着全身炎症和器官功能障碍的进一步加重，CRP接近于临界，随着炎症进一步加重，也无法进一步升高，故CRP对全身炎症和器官功能障碍的进展的预测价值较低 [15] [16] 。

目前，在临床实践中认为，CRP ≥ 10 mg/L作为诊断脓毒症有较好的敏感性和特异性 [17] 。但在其他非感染性疾病中，同样存在CRP ≥ 10 mg/L。一项研究对370名连续住院的成年患者进行了CRP检测，发现细菌感染(120 mg/L)，炎症性疾病(65 mg/L)，实体瘤(46 mg/L)，非细菌感染(32 mg/L)和心血管疾病(6 mg/L)之间的中位CRP值显着差异 [18] 。另外，许多生理等其他因素(例如年龄，性别，体重指数，运动，饮食，睡眠，药物使用等)同样可影响CRP值。因此，尽管细菌感染患者CRP水平较高，但仅根据一个较高的CRP值来区分是否存在细菌感染是不可靠的，需进一步结合临床表现及其他辅助检查。

2.2. 降钙素原(PCT)

PCT是甲状腺C细胞合成的含有116个氨基酸的多肽，由单核细胞和肝细胞产生的降钙素原前体蛋白，健康人血清PCT浓度通常在0.5 ng/mL以下，其对细菌感染特异性较高 [13] 。当暴露于细菌内毒素后，机体在2~4小时内PCT水平急剧上升，6~8小时内达到平台，24小时后恢复正常水平。但由于其生理范围极低，对于炎症水平刺激程度或器官功能障碍程度较低的阶段，PCT升高并不明显，导致其预测早期感染灵敏性较低 [13] [19] 。另外，严重病毒感染和非感染性炎症反应与PCT增加无关，或仅轻度升高 [19] 。PCT在对于指导脓毒症治疗及改善患者预后中也起到较大作用，研究表明，当PCT低于基线的80%或低于0.5 ng/ml时，使用停止抗生素可有效地缩短抗菌治疗时间、以及抗生素相关不良事件和感染并发症，如多重耐药微生物和艰难梭菌感染的发生 [20] [21] 。多项证据表明，相比于CRP，PCT对于检测成人脓毒症以及评估严重程度的临床价值较高，且PCT的升高，在一定程度上可以提示感染反应失调导致的全身器官的损害进一步加重 [22] [23] 。同样，对于新生儿脓毒症的预测和诊断，PCT有更好的准确性更好 [24] 。另有研究表明，经验性抗生素治疗开始后36小时内的CRP和PCT系列测量结果正常，可以高概率排除新生儿早期脓毒症的存在 [25] 。

2.3. 穿透素-3 (PTX3)

PTX-3是一种急性期蛋白，是由白细胞介素-1、肿瘤坏死因子α和Toll样受体激动剂等细胞因子强烈诱导在树突状细胞、单核细胞、内皮细胞或中性粒细胞等多种细胞中表达 [26] 。在一项纳入了213名脓毒症和脓毒性休克的重症医学科患者研究中，通过在第1、3和8天测量PTX-3，降钙素原和白细胞介素-6的血浆水平，最终证明，PTX-3与较高的乳酸水平、APACHE II以及SOFA评分相关(p = 0.0001)。脓毒症或脓毒性休克患者的PTX-3水平始终显著高于对照组(p ≤ 0.001)。血浆PTX-3水平能够在第1、3和8天显著区分脓毒症和脓毒性休克(p = 0.0001)，且其预测价值于PCT相当 [27] 。另有两项荟萃研究，分别纳入16项研究(3001名脓毒症患者)和17项研究(3658名脓毒症患者)，最终证明，严重脓毒症患者的PTX-3水平明显高于轻度脓毒症患者，非存活患者的PTX-3水平明显高于存活患者，PTX-3水平升高显著增加了全因死亡的风险 [28] 。

2.4. 长链非编码RNA(lncRNA)

lncRNA是指长度超过200 nt的非编码RNA (ncRNA)，许多研究表明，lncRNA通过调节不同的信号通路来调节败血症，例如激活核因子κB (NF-κB)的Toll样受体(TLR)信号通路，从而引发败血症的炎症反应 [29] 。许多研究发现，在脓毒症过程中或暴露于细菌脂多糖(LPS)后，人单核细胞，心肌细胞和肾小管上皮细胞中lncRNA的表达发生了不同程度的改变 [29] [30] 。lncRNA不仅参与脓毒症发生过程，还通过不同的机制参与脓毒症诱导的多器官系统衰竭的发生，包括心血管功能障碍、急性肺损伤和急性肾损伤 [31] [32] [33] 。NEAT1，MALAT1，THRIL，XIST，MIAT和TUG1是参与脓毒症相关并发症病理学的lncRNA [31] 。不同的lncRNA在不同的脓毒症过程中表达不同。体外通过使用LPS刺激的外周血单核细胞(PBMC)，NEAT1的表达迅速增加，并在2小时达到峰值，而PCT需要12~48小时才能达到峰值，表明NEAT1是感染期间的早期反应因子 [29] 。一项纳入392受试者的研究发现，与健康对照组相比，脓毒症患者的长非编码转移相关肺腺癌转录本1 (lnc-MALAT1)和microRNA (miR)-125a增加，并与APACHE-II评分、SOFA评分、血清肌酐、CRP、TNF-α、IL-1β、IL-6和IL-8呈正相关。lnc-MALAT1/miR-125a轴也是28日死亡风险增加的预测指标 [34] 。lncRNA MALAT1通过下调miR-150-5p以增加IL-6，TNF-α和NF-κB信号通路的表达，导致心肌细胞LPS给药下的脓毒症相关炎症反应。MALAT1还与p38 MAPK/NF-kB和miR-125b相互作用，加重脓毒症的心脏炎症和功能障碍 [35] 。目前lncRNA在脓毒症及其诱导的器官功能衰竭中的作用尚未得到充分探索，仍需进一步研究来阐明其中的机制。

2.5. 单核细胞分布宽度(MDW)

单核细胞分布宽度是一种血清学参数，描述了循环单核细胞的大小分布，是最近一种新兴的脓毒症生物标志物。一项对506名入住重症医学科的成年患者进行前瞻性研究发现，脓毒症或脓毒症休克患者的MDW值明显高于无脓毒症组。在发生重症医学科获得性脓毒症的患者中，MDW显示从21.33 (19.47~21.72)增加到29.19 (27.46~31.47)。且MDW的增加不受脓毒症病因的影响。在脓毒症幸存者中，从第一次到住院结束，MDW值下降 [36] 。在一项国际性、前瞻性队列研究中，纳入了1517名脓毒症患者，最终证实MDW联合WBC检测脓毒症的准确性与CRP相似，并超过了PCT，从而确定了MDW对早期脓毒症预测和诊断的临床价值 [37] 。当与SIRS标准(心动过速、呼吸急促、白细胞计数异常或体温)或qSOFA标准结合使用时，MDW异常(>20.0)增加了脓毒症概率，而正常MDW降低了脓毒症概率。单核细胞分布宽度作为SIRS和qSOFA参数的补充，可帮助早期、快速的识别脓毒症 [38] 。同时，另有研究表明，MDW对鉴别血培养假阳性有一定的借鉴意义 [39] 。MDW是一项新的脓毒症预测参数，目前研究中已证明其有巨大的临床价值，且其易于获得，在临床中有较大的应用前景。

3. 小结与展望

目前，多项生物标志物已在脓毒症的早期预测、诊断和预后中展示了较好的灵敏性和特性行，对临床实践提供了较好的参考价值。但同时，每一种生物标志物都有各自的不足于缺陷，需要我们不断去探索其他潜在生物标志物进而寻求理想的生物指标物。理想的脓毒症生物标志物应具有诊断和预测价值(高灵敏度、高特异性)，供体变异性低，可在快速且经济高效的床旁测定，并经得起多中心试验的验证。几种脓毒症生物标志物联合应用可提高诊断的灵敏性于特异性，但仍需大量的研究证实，因此，理想的脓毒症生物标志物仍需我们积极探索。

文章引用

敖玉培,胡怀东. 脓毒症生物标志物研究进展Research Progress in Biomarkers of Sepsis[J]. 临床医学进展, 2023, 13(04): 5312-5317. https://doi.org/10.12677/ACM.2023.134752

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