脓毒症相关生物标志物的研究进展
Research Progress on Sepsis-Related Biomarkers
DOI: 10.12677/ACM.2024.141237, PDF, HTML, XML, 下载: 208  浏览: 382 
作者: 王 淞:新疆医科大学研究生院,新疆 乌鲁木齐;陆金帅*:新疆维吾尔自治区人民医院苏州路院区急诊科,新疆 乌鲁木齐
关键词: 脓毒症生物标志物早期诊断Sepsis Biomarkers Early Diagnosis
摘要: 脓毒症是发病率和死亡率都极高的疾病。脓毒症的临床表现无特异性且发病机制也极其复杂,这导致了脓毒症的早期诊断变得困难。临床上及早的诊断脓毒症,及时地给予抗生素治疗,可以挽救患者的生命。所以寻找简便、特异性和敏感性都高的生物标志物,对于脓毒症的早期诊断、预后判断都极为重要。本文对目前临床上已使用的生物标志物,和一些新发现的有潜力的生物标志物予以综述。
Abstract: Sepsis is a disease with extremely high morbidity and mortality. The clinical manifestations of sep-sis are nonspecific, and the pathogenesis is extremely complex, which makes early diagnosis of sep-sis difficult. Early clinical diagnosis of sepsis and timely antibiotic treatment can save the patient’s life. Therefore, finding simple, specific, and sensitive biomarkers is extremely important for early diagnosis and prognosis of sepsis. This article reviews the biomarkers currently used clinically and some newly discovered potential biomarkers.
文章引用:王淞, 陆金帅. 脓毒症相关生物标志物的研究进展[J]. 临床医学进展, 2024, 14(1): 1652-1657. https://doi.org/10.12677/ACM.2024.141237

1. 引言

脓毒症(Sepsis)是宿主对感染反应失调导致的严重器官功能障碍,并伴有组织和器官的严重损伤,直至感染性休克、多器官功能衰竭(MODF)和死亡 [1] 。脓毒症是一种可能危及生命的疾病,在全球发病率很高,2017年全球有近5000万人确诊患有脓毒症,估计有1100万人死于脓毒症。严重脓毒症患者的死亡率约为30%~50%,脓毒症休克患者的死亡率超过50% [2] 。在临床上,标准血培养技术一直是诊断脓毒症的金标,但血培养在许多临床实验室中仍然是一个劳动密集型且耗时的过程 [3] ,并且其培养的成功率较低,需多次取样培养以提高阳性率,耽误患者病情延误治疗。因此,寻找灵敏度、特异度高的生物标志物能在临床实践中起到重要辅助作用,在脓毒症的诊断、治疗和预后评估中发挥重要作用。本文对目前临床上已使用的生物标志物,和一些新发现的有潜力的生物标志物予以综述。

2. 降钙素原(Procalcitonin, PCT)

PCT是降钙素激素的前体,降钙素由甲状腺中的C细胞产生,在较小程度上由全身其他神经内分泌细胞产生。PCT在胎儿发育的早期就在中枢神经系统中表达,但PCT本身的功能尚不清楚;它在甲状腺中转化为降钙素,一种参与钙稳态的激素。由于PCT在正常生理条件下几乎只在甲状腺中产生,因此在健康患者血清中通常检测不到 [4] 。在细菌感染期间,PCT水平在2~6小时内迅速升高,6~24小时达到高峰 [5] ,这使得PCT成为区分细菌性感染和非细菌性感染的早期生物标志物。一项对101名患有全身炎症反应综合征(SIRS)且预计住院时间为24小时的重症监护病房(ICU)患者进行的前瞻性研究显示,脓毒症和培养阳性患者的PCT水平较高,以PCT浓度为1 ng/ml为临界值,脓毒症的敏感性为0.89,特异性为0.94 [6] 。PCT除了可以早期识别脓毒症,在使用抗生素治疗中,PCT还可以帮助临床医生了解如何使用抗生素以及使用多长时间。有研究发现,当PCT水平从峰值浓度下降80%或降至0.5 ng/ml已被证实是缩短抗生素疗程的一种方法 [7] 。PCT已是医学领域广泛应用的生物标记物。然而有研究发现 [2] ,PCT检测的AUC值为0.882,灵敏度和特异度分别为79.76%和91.36%;而IL-10 + IL-17 + PCT的AUC值为0.976,灵敏度和特异度分别为91.67%和96.30%,IL-10 + IL-17 + PCT三者联合的AUC、灵敏度、特异度均高于单独使用PCT,表明PCT联合其他生物标志物可以更好的诊断脓毒血症。

3. 肝素结合蛋白(Heparin-Binding Protein, HBP)

HBP又称azurocidin或CAP37,是一种中性粒细胞衍生的颗粒蛋白,是脓毒症的重要诊断和预测生物标志物。HBP预先储存在中性粒细胞的分泌囊泡和嗜天青颗粒中,并在中性粒细胞表面的b2整合素交联,当感染时中性粒细胞被激活其中的HBP被释放,HBP的释放导致内皮通透性增加,它可以通过诱导细胞骨架重排,导致血管和中性粒细胞外渗和聚集,从而放大全身炎症反应 [8] 。Kahn等人 [9] 的研究发现,感染且伴有器官功能障碍患者的血浆HBP水平明显高于非感染患者。患者功能障碍的器官数量越多,其血浆HBP水平越高。在非感染患者中,HBP水平总体较低,这些分析表明,HBP在检测脓毒症引起的器官功能障碍方面具有良好的性能。一项前瞻性队列研究发现,非休克脓毒症患者的HBP水平明显高于局部感染患者(p < 0.01)。此外,脓毒性休克患者的HBP水平明显高于无休克的脓毒症患者(p < 0.01)。脓毒症患者HBP (临界值 ≥ 28.1 ng/mL)的ROC曲线下面积(AUC)为0.893,高于临界值 ≥ 2.05 ng/mL的PCT (0.856)和临界值 ≥ 151.9 mg/L的CRP (0.699),以HBP ≥ 28.1纳克/毫升为临界值,诊断脓毒症的敏感性为84.9%,特异性为78.3% [10] 。另有研究发现 [11] ,在出现脓毒症休克或器官功能障碍之前的72小时,患者的血清HBP水平就已升高,这表明HBP可作为脓毒症患者的早期诊断生物标志物。Han等人的一项模型研究,他们运用统计分析方法来评估qSOFA评分、HBP标记和其他临床指标之间的相关性。研究将数据分为训练集和验证集,并开发了三个基于实验室标记的模型(qSOFA-NLR评分、qSOFA-CRP评分和qSOFA-HBP评分)来预测死亡率。研究结果显示qSOFA-HBP模型在预测脓毒症患者死亡风险方面表现出较好的判别能力,其性能远高于qSOFA-NLR评分、qSOFA-CRP评分和单独使用qSOFA评分 [12] 。但该研究并未提及单独使用HBP评估脓毒症患者28天死亡率的能力。Katsaros等人的研究发现 [13] ,单一的HBP和PCT不能预测28 d病死率;两者联合应用的敏感性、特异性、阳性预测值和阴性预测值分别为44.8%、81.8%、17.3%和94.6%。类似的结果表明HBP可以作为脓毒症的诊断生物标志物,但独立预测脓毒症患者的死亡率效果却不佳,或许是他们的研究样本太少,在评估脓毒症死亡率方面有待进一步探索。

4. 白介素-6 (IL-6)

白细胞介素-6 (IL-6)是一种促炎细胞因子,由T淋巴细胞、成纤维细胞、内皮细胞和单核细胞合成 [14] 。IL-6会吸引白细胞和急性期蛋白参与炎症清除过程 [15] 。IL-6在免疫反应和炎症反应调节中发挥重要作用 [16] 。IL-6是先天性免疫和适应性免疫所必需的,是有效清除病原体所必需的,在人体中具有重要的生理作用,可调节急性期反应、造血、新陈代谢率、脂质平衡和神经发育 [17] 。Takahashi等人的研究中,IL-6诊断脓毒症的敏感性和特异性分别为0.861和0.806 (95%置信区间[CI]:0.735~0.913),因此,血清IL-6水平的测量有助于脓毒症患者的感染诊断 [18] 。Shao等人的研究中,IL-6用于脓毒症鉴别诊断时,其曲线下面积AUC为0.881,当IL-6水平超过7 pg/mL时,鉴别诊断脓毒症的敏感性为72.5%,特异性为100.0%,表现出较高的诊断效率。还能用于鉴别革兰阴性菌与革兰阳性菌,革兰阴性菌的IL-6水平较革兰阳性菌高 [19] 。Song等人的研究中发现,IL-6对脓毒症和感染性休克的诊断和预后价值均优于PCT [14] 。Yu等人研究显示,IL-6与脓毒症患者的死亡率没有显着相关性 [20] ,然而在Song、Ling等人 [14] [21] 的研究中,IL-6是所有炎症指标中预测脓毒症28天内死亡的唯一独立危险因素,IL-6与脓毒症患者的死亡率相关。IL-6在预测脓毒症患者预后方面存在争议,还需要未来进一步研究。

5. CD64

中性粒细胞CD64是一种IgG Fc部分的高亲和力受体。中性粒细胞CD64属于免疫球蛋白超家族,主要存在于单核细胞、巨噬细胞和树突状细胞等抗原递呈细胞表面。当人体受到感染或存在大量细菌内毒素时,中性粒细胞会接触到脂多糖(LPS)、补体系统分子、IL-8、IL-12、IFN-γ、TNF-α、粒细胞集落刺激因子和其他细胞因子。这些分子会刺激CD64的表达,并在一定时期内保持稳定 [22] 。在静息中性粒细胞的CD64表达量较低,但一旦被刺激因子激活,其表达量会迅速增加10倍,在4到6小时内达到峰值 [23] ,具有早期检测感染的能力。它在未激活的中性粒细胞上以低浓度表达,但在败血症过程开始时可显著增加,CD64诊断脓毒症,其敏感性为94.7%,特异性为93.6%,曲线下面积(AUC) 0.925 [24] ,这表明CD64在脓毒症的诊断中起作用。每天监测重症患者的CD64表达有助于诊断ICU获得性感染,从而促进及时的抗生素治疗。在临床实践中,灵敏度高的生物标志物可作为“排除”相关疾病的工具。考虑到这一点,CD64比其他标记物更敏感,可作为一种用于检测脓毒症中低概率患者的脓毒症的工具 [25] 。尽管CD64在脓毒症检测方面具有优势,但有研究发现,CD64的纳入截止值有所不同,导致的原因可能是实验室方法、采样时间和参与者年龄的差异导致的,在未来研究中,应该在先确定该生物标志物在不同人群中的最佳截止值,以获得最佳的研究结果 [23] 。

6. 可溶性CD14亚型(Presepsin)

可溶性CD14亚型(Presepsin)是一种新型的脓毒症生物标志物。Presepsin是大小为13 kDa,是CD14的可溶性N端片段 [26] 。Presepsin是在脓毒症期间,循环细菌蛋白酶裂解CD14后产生的,在病原体刺激后从免疫细胞表面脱离而释放 [27] 。Presepsin水平在感染后2小时内增加,并在3小时内达到峰值 [28] 。一项meta分析显示,在诊断新生儿败血症中,Presepsin的敏感性0.94、特异性1.0、受试者工作曲线下面积(AUC) 99%,且Presepsin在722 μg/L截止水平下获得的敏感性和特异性高于其在539 μg/L截止水平下的敏感性和特异性,较高的敏感性和特异性,表明presepsin可单独用于诊断和排除新生儿败血症 [27] 。在一研究中,研究者分别记录了脓毒症患者入院第1天、第3天、第六天的血清中Presepsin、PCT、CRP、WBC值,发现脓毒症死亡组的Presepsin值显著高于存活组,而PCT、CRP和WBC值死亡组与存活组中没有显著差异。说明动态监测患者Presepsin可以预测脓毒症患者的预后 [29] 。Aliu-Bejta等人,在对成年人脓毒症患者的研究中发现,Presepsin值高于110 ng/ml与感染性休克显着相关(p = 0.003)。在设定的截止值为110 ng/mL时,敏感性和特异性分别为0.727和0.617。当截止值高于110 ng/mL,计算得出的ROC曲线下面积(AUC)为0.703,且presepsin与SOFA评分有强相关性 [30] ,说明Presepsin不仅有诊断脓毒症的效能,还可以评估脓毒症患者的严重程度。Lee等人的研究发现,对于脓毒症患者,预测30天死亡率的最佳presepsin水平截止值为821 pg/mL (p = 0.005)。具有较高presepsin水平(≥821 pg/mL)的患者的死亡率显着高于具有较低presepsin水平(<821 pg/mL)的患者(对数秩检验;p = 0.004)。在多变量Cox比例风险模型中,presepsin可以预测脓毒症病例的30天死亡率(风险比,1.003;95%置信区间:1.001~1.005;p = 0.042) [31] ,这表明Presepsin是败血症和败血性休克患者30天死亡率的独立危险因素。然而,presepsin的水平受肾功能的影响,由于肾功能受损,Presepsin的高值可能会持续存在。急性肾损伤也可能与血清presepsin水平有关,在诊断脓毒症时应患者的肾功能计算presepsin的截止值提高诊断准确性 [32] 。

7. 总结

虽然新型的生物标志物越来越多,但目前应用于临床实践的生物标志物少,且特异性、灵敏度也欠佳。新型生物标志物能尽早运用于临床诊疗活动中,可以及早发现脓毒症,做到早发现、早诊断、早治疗,以提高脓毒症患者的生存率。

NOTES

*通讯作者。

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