中华急诊医学杂志  2023, Vol. 32 Issue (9): 1278-1283   DOI: 10.3760/cma.j.issn.1671-0282.2023.09.026
血清淀粉样蛋白A在急重症感染患者中的意义
孙宝妮 , 李萍 , 裴红红 , 潘龙飞     
西安交通大学第二附属医院急诊科,西安 710004

急性期反应是脊椎动物为对抗感染性和炎性损伤等刺激的防御机制,这种急性应答主要由内源性细胞因子白细胞介素(interleukin, IL)-1β、IL-6和肿瘤坏死因子-α(tumor necrosis factor-α, TNF-α)驱动,在巨噬细胞和其他白细胞中由与Toll样受体(Toll like receptor, TLR)结合的外源性因子(病毒或细菌)诱导。除了全身性和代谢性改变,如发热、纳差,这些细胞因子也会诱导肝脏合成急性期蛋白。SAA是人类重要的急性期蛋白之一,生理状态下血清浓度约为1~2 μg/mL,急性期反应的最初24~48 h内浓度可增加100~1 000倍[1]。SAA作为一种敏感的急性期蛋白,已被证实在感染性疾病的早期诊断、鉴别诊断、严重程度判断及预后评估中有重要的价值,且浓度不受抗炎药物、免疫抑制剂、肾上腺皮质激素等因素的影响。近年来,SAA在感染性疾病中的应用越来越引起临床关注。本文主要就SAA结构、表达及其在急重症感染患者中的意义做一综述。

1 SAA的基因及蛋白结构 1.1 SAA的基因结构

人类SAA基因位于11号染色体p15.1区域,大小为150 kb,包含SAA1、SAA2、SAA3和SAA4四种基因。除了含3个外显子、2个内显子的SAA3基因,其余SAA基因由4个外显子和3个内含子组成[1]。SAA1和SAA2启动子区域包含核因子κB(nuclear factor kappa-B, NF-κB)和NF-IL6转录因子识别序列,能够被IL-1β、IL-6和TNF-α诱导激活[2]。SSA1和SSA2含有等位基因SAA1α、SAA1β、SAA1γ、SSA2α和SAA2β。SAA3位于SAA4基因下游,大小为110 kb,最初认为它是一个假基因。SSA4位于SAA2基因下游,仅9 kb,与其他SSA基因不同之处在于其启动子区域仅包含截短的NF-κB识别序列,没有IL-6识别序列。

1.2 SAA的蛋白结构

不同的SSA基因编码不同的蛋白质:SSA1、SSA2、SSA3和SSA4。成熟SAA1和SSA2蛋白由104个氨基酸构成,彼此间相同序列超过90%。起初认为SAA3基因几乎不表达,然而Larson等[3]在两个人类乳腺上皮细胞系中检测到SAA3mRNA,预测其编码由42个氨基酸构成的多肽。SAA3是非人类哺乳动物SAA的主要表达形式,在牛、马和羊的初乳中已经检测到相当水平的全长SAA3蛋白[4]。成熟SAA4蛋白由112个氨基酸多肽构成,52%的SAA4氨基酸序列和SAA1α相同。与主要在炎症发生时诱导的SAA1和SAA2蛋白不同,SAA4蛋白存在于血液中[5]。因此,SAA4被称为“结构型SAA”或“C-SAA”,SAA1和SAA2被称为“急性期SAA”或“A-SAA”。A-SAA是与高密度脂蛋白(high-density lipoprotein, HDL)结合的主要载脂蛋白,从而部分取代载脂蛋白A1。

2 SAA的表达特点

和其他急性期蛋白一样,SAA合成的主要部位是肝脏,A-SAA表达主要由IL-1ß、IL-6和TNF-α所诱导。这些细胞因子可以相互或与糖皮质激素协同作用,极大地促进A-SAA产生[6]。SAA mRNA和(或)蛋白质,A-SAA和(或)SAA4在正常人体组织中均有特异性表达,主要在上皮组织中表达。生理状态下血清SAA浓度差异很大,这种差异可能是亚临床感染或炎症的结果,也可能是用于检测血清SAA的抗体缺乏特异性引起。SAA与HDL的结合可能掩盖抗体识别的表位,导致对SAA浓度的低估。其他可能影响SAA浓度的因素有性别、年龄、妊娠和体重指数。健康人血清SAA浓度约为1~2 µg/mL,各种疾病如急性细菌或病毒感染、炎症和自身免疫疾病、肿瘤、创伤和手术期间SAA浓度增加,可升高至10~500 µg/mL,甚至达1 mg/mL[7]

3 SAA在急重症感染患者中的意义

感染性疾病是急诊科常见疾病之一,严重感染,尤其是脓毒症,其发病率、病死率形势严峻,2017年全球统计脓毒症患者约为4 890万,其中死亡约1 100万,占全球死亡人数的19.7%[8]。早期识别感染、明确病原体类型和疾病进展,对急重症感染患者治疗和预后评估具有重要意义。感染生物标志物能够帮助医生快速判断感染的存在以及推断可能导致感染的致病原,是目前研究的热点。临床广泛应用的标志物包括C反应蛋白(c-reactive protein, CRP)和降钙素原(procalcitonin, PCT)。CRP是一种重要的急性期反应蛋白,是感染早期诊断的常用指标之一。研究显示,CRP鉴别细菌或病毒感染的特异度不高,评估疾病转归的特异度不高,对重症感染、血流感染的预测价值有限;全身细菌感染或炎症侵袭时,PCT会在2~4 h内升高,治疗有效后迅速下降,可作为细菌感染的特异性标志物,但PCT在病毒感染中一般不升高,局部细菌感染、慢性炎症以及轻微感染也不会导致PCT变化[9]。SAA在急性感染时迅速升高,随着疾病好转迅速下降,可作为急重症感染患者以及新型冠状病毒感染(corona virus disease 2019, COVID-19)患者的诊断、病情危重程度评估及预后判断的敏感指标[10-11]

3.1 SAA对感染的诊断价值

机体发生感染时,血清SAA会在4~6 h内迅速升高,清除病原体后则迅速降至正常水平。SAA对轻微炎症刺激比CRP更敏感,可用于病毒感染,以及非侵入性和早期侵入性细菌感染的诊断[12]。病毒感染时,SAA浓度是CRP浓度的5~11倍,细菌感染时,SAA浓度变化与CRP相似。

在病毒感染过程中,血清SAA比CRP消失的更快。无论CRP水平有无显著变化,SAA似乎都是临床上急性病毒感染有用的炎症标志物[13]。SAA联合CRP检测可区分合并感染与细菌感染[14]。有研究证实,与CRP、PCT相比,SAA用于诊断肺部病毒感染和肺部细菌感染的AUC最大,分别为0.825和0.943,当将SAA与CRP、PCT联合应用时,可用于肺部病毒感染和肺部细菌感染的早期诊断[15]。但值得注意的是,当SAA/CRP比值高于8.44时,SAA比CRP更能预测炎症[16]。另外,基于SAA、铁蛋白和中性粒细胞百分比的评分系统也有助于从不明原因发热中区分细菌感染,对减少抗生素的过度使用有积极的作用[17]。而将SAA1与PCT、CRP、肝素结合蛋白联合应用时,可显著提高在感染初期后者的诊断价值[18]

研究报道,在细菌感染早期,PCT的诊断价值优于CRP、IL-6和SAA,是诊断发热患者细菌感染的一个有价值的标志物[19]。然而,另有研究显示,针对老年肺炎,SAA、CRP、PCT均无法准确诊断[20]。但是,针对脓毒症,SAA的诊断敏感度和特异度均较高[21]。尤其与CRP和PCT相比,监测术后第一天不同时间点SAA对腹腔脓毒症的诊断具有更高的准确度和敏感度[22]。因此,虽然PCT对脓毒症具有较高的临床应用价值,但SAA对脓毒症的早期诊断价值也值得肯定,可作为脓毒症早期诊断的可靠指标[23]

SAA还可用于预测卒中后感染,有助于识别不会发展为感染的患者,以避免不必要的抗生素治疗[24]。SAA是预测卒中相关性肺炎的潜在标志物,脑卒中发病48 h时,如SAA > 25.15 mg/dL,对卒中相关性肺炎早期诊断的敏感度为80%、特异度为96%[25]。SAA可作为自发性细菌性腹膜炎的诊断标志物,其最佳截断值为9.25 μg/mL时具有较高的敏感度和特异度[26]。SAA对急性阑尾炎也有较好的诊断价值,诊断急性阑尾炎的敏感度和特异度分别为87%和74%[27],SAA和PCT对急性阑尾炎的诊断价值优于CRP[28]。另外,对于晚期人类免疫缺陷病毒感染患者,其SAA水平的升高有助于早期识别活跃的巨细胞病毒感染:当SAA > 3 mg/L时,对巨细胞病毒感染的敏感度为100%、特异度为40%[29]

围绕儿童的相关研究表明,血清SAA、PCT、CRP在呼吸道感染患儿中高表达,在细菌性肺炎患儿中表达水平最高,三者联合检测具有较高的诊断价值,可有效鉴别儿童呼吸道感染病原[30]。SAA和中性粒细胞/淋巴细胞(neutrophil to lymphocyte ratio, NLR)在儿童甲型流感的早期诊断中价值较高,可用于病情监测和疗效评价[31]。SAA也是诊断儿童早期肺炎支原体感染的特异性标志物[32]。另外,SAA也是对早产儿迟发型脓毒症进行早期诊断的可靠标志物,其敏感度达100%、特异度为93%,且阳性预测值为96%[33]。SAA也可作为新生儿早发型脓毒症的炎症标志物,其诊断准确性优于CRP[34]。无论是在首次怀疑脓毒症还是在脓毒症发病后8~96 h,SAA对新生儿脓毒症的诊断均具有较高的准确度,与同期PCT和CRP相似[35],而将SAA与PCT、超敏C反应蛋白(hypersensitive c-reactive protein, hs-CRP)联合应用则对新生儿脓毒症具有较高的诊断价值[36]

3.2 SAA对病情危重程度的评估价值

研究显示,SAA有助于监测肺炎的严重程度,与胸部X线透光度评分相一致,且有助于判断患者是否可能发展为ARDS。SAA水平随病情加重而升高,随疾病恢复而下降[37]。SAA是慢性阻塞性肺病急性加重患者病情评估的生物标志物,其用于预测急性呼吸衰竭的敏感度高于CRP,可作为患者诊断和治疗的有效指标[38-39]。SAA与慢性阻塞性肺病稳定期患者频繁加重独立相关,可用于预测稳定期患者的病情进展[40]。另有研究发现,SAA是反映急性胰腺炎患者严重程度的早期标志物,其预测价值优于CRP[41]。此外,SAA联合IL-6、IL-18、格拉斯哥评分可提高对急性胰腺炎是否发展至重症的临床诊断的准确性[42]

在围绕儿童相关疾病的研究显示,SAA和CRP可作为评估儿童流感严重程度的潜在指标,重型B型流感患儿SAA、CRP水平及重型A型流感患儿SAA水平较非重型流感患儿显著升高[43]。SAA也可用于新生儿脓毒症的鉴别和病情监测,并可作为鉴别细菌培养阳性与细菌培养阴性脓毒症的生物标志物[44]。Liu等[45]研究报道,SAA有助于减少NICU抗生素使用的强度和持续时间,SAA水平与细菌感染的严重程度密切相关,能敏感地反映抗生素治疗的疗效和新生儿的病情变化;SAA在早期新生儿脓毒症中对抗生素治疗48~96 h甚至96~144 h的疗效监测比PCT更有价值。SAA与CRP或PCT联合使用有助于优化脓毒症患儿的抗生素使用,从而减少低细菌感染风险患儿的过度治疗[46]。然而,另有研究报道,单独应用SAA并未对判断儿童感染性疾病的严重程度提供额外的信息,而SAA/CRP比值却可能是重症感染的一个预测指标,死亡儿童SAA/CRP比值显著低于存活儿童[47]

3.3 SAA对疾病转归的预测价值

动态分析SAA水平有助于急性胰腺炎预后判断,重症急性胰腺炎患者SAA升高更明显,且24 h内SAA水平更高[48]。SAA升高是急性白血病合并细菌感染患者不良预后的危险因素,SAA联合CRP及白细胞分化抗原14指数对该病患者不良预后具有预测价值[49]。关于肺炎合并呼吸窘迫综合征患儿的研究显示,SAA越高,预后越差[50]。SAA预测儿童呼吸机相关性肺炎的敏感度达100%、特异度为93%,而联合改良临床肺部感染评分后,其诊断特异度可提高到100%;SAA对死亡的预测敏感度为100%、特异度为89%[51]

SAA在脓毒症患者预后评估中的价值,不同的研究结论也不尽相同。早期研究报道,脓毒性休克患者血清SAA和CRP具有很强的相关性,但不能很好的预测患者发生器官功能障碍和死亡[52]。Townsend等[53]研究也显示,SAA水平高低可能与脓毒性休克患者死亡无关。然而Yu等[54]却发现,SAA可有效预测脓毒症患者的死亡风险。监测SAA水平有助于早期评估脓毒症患者的病情,有助于及时采取积极有效的干预手段,从而降低患者病死率[55]。研究表明,与hs-CRP、PCT相比,SAA诊断脓毒症及脓毒性休克的敏感度最高,对患者预后也有较好的预测价值[56]。随着脓毒症和脓毒性休克的发生,SAA水平明显升高,当SAA为189.06 mg/L时其诊断脓毒症性休克的敏感度和特异度最佳,分别是75%和88%;当高达224.8 mg/L时,其预测脓毒性休克患者28 d死亡的敏感度为65%、特异度为87%;如果将其与快速序贯器官功能衰竭评分(quick sequential organ failure assessment, qSOFA)联合应用,可显著提高对脓毒性休克的预测及诊断价值[57]

3.4 SAA用于评估COVID-19患者的危重程度及预后

研究发现,单独应用SAA,或与其他炎症反应标志物联合应用,均可有效预测COVID-19患者病情严重程度[58]。SAA、IL-6可作为COVID-19患者辅助诊断指标,两者联合效能更佳,可有效预测病情严重程度[59]。SAA与感染严重程度呈正相关,联合铁蛋白、CRP检测对COVID-19感染的发生及病情严重程度判断具有指导意义[60]。SAA截断值为92.90 ng/mL时,预测COVID-19严重程度的敏感度为95.8%,特异度为53.7%,AUC为0.712;当SAA升高但CRP不高时,提示患者的病情尚可,但如果SAA和CRP均升高且NLR也较高则提示患者可能为严重感染[61]。另外一项Meta分析显示,SAA水平与COVID-19患者病情的严重程度和病死率呈显著正相关,有助于对患者的病情进行风险分层和监测[62]。SAA也是预测COVID-19病情恢复情况的预测指标,而CRP不能有效预测COVID-19的恢复情况[63]。相比SAA呈持续上升趋势的患者,SAA呈下降趋势的患者的预后较好[64]

4 结语

在急重症感染患者中,就单一SAA升高而言,可能无法区分是感染性还是非感染性疾病,也无法区分是何种病原体感染,需结合临床表现和其他感染生物标志物综合分析。多种标志物联合检测对感染早期鉴别诊断的价值更高。近年来,研究开始趋向于探索SAA在众多疾病中的作用机制及其生物学功能。随着生命科学与高通量检测技术的发展,SAA研究的深入,其在急重症感染患者诊断、病情监测及治疗领域将发挥更大价值。

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