血液指标区分儿童急性阑尾炎严重程度的研究进展
Research Progress of Blood Indexes in Differentiating the Severity of Acute Appendicitis in Children
DOI: 10.12677/HJS.2022.112008, PDF, HTML, XML, 下载: 300  浏览: 733 
作者: 高 恺, 郭春宝*:重庆医科大学附属儿童医院普外创伤外科,国家儿童健康与疾病临床医学研究中心,儿童发育疾病研究教育部重点实验室,重庆
关键词: 复杂性阑尾炎血液指标Complicated Appendicitis Blood Index
摘要: 阑尾炎是儿童常见的腹部外科急症之一。在许多情况下,儿童阑尾炎的精确诊断仍具有挑战性。依据术中情况及术后组织病理学分型,急性阑尾炎被分为急性非复杂性阑尾炎(UA)和复杂性阑尾炎(CA)。阑尾切除一直以来是AA治疗的金标准,但目前有研究表明,部分UA患儿保守治疗效果良好,故在术前区分阑尾炎的不同严重程度十分必要。本研究基于血液指标,探索其在区分急性阑尾炎严重程度中的应用,结果表明:CRP、PCT、SAA、FIB、PLT、PLR、DD、PT、血钠、血清总胆红素,以及一些新的指标如DLAC、PTX3、FA、DNI在诊断CA中有意义。
Abstract: Appendicitis is one of the most common abdominal surgical emergencies in children. Accurate diagnosis of appendicitis in children remains challenging in many cases. Acute appendicitis was divided into acute uncomplicated appendicitis (UA) and complicated appendicitis (CA) according to the intraoperative condition and postoperative histopathological classification. Appendectomy has always been the gold standard for AA treatment, but current studies have shown that conservative treatment in some children with UA has a good effect, so it is necessary to distinguish different severity of appendicitis before surgery. This study explores its application in differentiating the severity of acute appendicitis based on blood indicators. The results show that: CRP, PCT, SAA, FIB, PLT, PLR, DD, PT, serum sodium, serum total bilirubin, and some new Indicators such as DLAC, PTX3, FA, DNI are meaningful in diagnosing CA.
文章引用:高恺, 郭春宝. 血液指标区分儿童急性阑尾炎严重程度的研究进展[J]. 外科, 2022, 11(2): 43-50. https://doi.org/10.12677/HJS.2022.112008

1. 引言

儿童急性阑尾炎(AA)是指阑尾发生的炎症,其终生发病风险为7%~9% [1] [2]。阑尾炎的病因目前仍不是十分清楚,通常认为是由于阑尾管腔梗阻可引起阑尾炎(常由粪石、淋巴样增生或粪便残渣嵌顿所致;寄生虫、异物及阑尾或盲肠肿瘤引起的阻塞较少见)。最近研究指出遗传因素和环境影响等因素可能是阑尾炎的危险因素 [3] [4]。

临床上依据术中及术后病理学检查,可将AA分为复杂性阑尾炎(CA)和非复杂性阑尾炎(UA) [1] [2]。非复杂性阑尾炎是指单纯的发炎性阑尾炎,没有坏疽穿孔,可能需要手术,也可以表现为轻度炎症,可以自行消退 [5],也可以用抗生素治疗。复杂性阑尾炎是指更严重类型,迅速发展为坏疽、穿孔或两者兼而有之。现代诊断的目的是首先依据患儿的病史、症状、体征、实验室检查及影像学检查确认或排除阑尾炎的诊断,其次当怀疑阑尾炎时,对阑尾炎的严重程度进行分层。如何在保持高精确度的同时限制伤害(如成像辐射)的最佳策略尚未达成共识。

目前认为阑尾切除是阑尾炎治疗的金标准,一些作者提出阑尾有可能成为肠道菌群细菌的储存库,在细菌感染后重新定殖肠道。有文献报道称,非复杂性阑尾炎有自行消退或使用抗生素治疗好转的可能,应根据AA的不同类型选择合适的治疗方案 [6]。血液指标是入院时的常规检验指标,具有较好的客观性、普适性和简便性。在诊断阑尾炎不同严重程度时,已有研究表明,血液指标可以增加区分不同程度阑尾炎的敏感性 [7]。

血液指标通常分为血液一般检查、止血与血栓检验、血液生化检验、血清学与免疫学检测。有利于阑尾炎诊断的血液一般检验常包括白细胞(WBC)、淋巴细胞计数(L)、中性粒细胞计数(N)、血小板计数(PLT)、平均血小板体积(MPV)与红细胞分布宽度(RDW)。其中有些指标之间的比值也发现对阑尾炎的诊断可能存在一定的帮助。止血与血栓检验常包括血小板计数(PLT)、平均血小板体积(MPV)、血浆D-二聚体、血浆纤维蛋白、凝血酶原时间(PT)、活化部分凝血活酶时间(APTT)、血小板平均体积与淋巴细胞比值(MPVLR)。血液生化检验常包括血清总胆红素和血清钠离子浓度。血清学与免疫学检测常包括C反应蛋白(CRP)、降钙素原(PCT)、血清淀粉样蛋白A (SAA)以及白介素6 (IL-6)、白介素8 (IL-8)等细胞因子。现就血液指标在儿童阑尾炎不同严重程度中的应用进行综述。

2. 血液一般检验

2.1. 白细胞(WBC)计数

急性阑尾炎中WBC计数检查是最早和最常用的诊断方法。不同报道中WBC诊断阑尾炎的敏感性和特异性差异很大,分别为65%~85%和32%~82%。CA患者白细胞计数高于UA患者两者之间存在差异性, [8]。有研究指出,在诊断阑尾炎时,WBC > 10.0 × 109/L患者与WBC < 10.0 × 109/L患者相比,危险比(HR)为2.42 [9]。白细胞(WBC)计数在AA患者中普遍升高,但白细胞计数升高对UA与CA的鉴别没有预测价值。

2.2. 中性粒细胞计数(ANC)

ANC是一种常用的炎症标志物,据报道,嗜中性粒细胞计数大于75%诊断AA的准确性为88.82%,敏感性为88.03%,特异性为92.86% [8]。在区分UA与CA中,ANC未表现出显著作用。

2.3. 中性粒细胞与淋巴细胞比值(NLR)

中性粒细胞计数突出活跃和持续的炎症,而淋巴细胞计数突出调节途径,两者的比值NLR在诊断急性阑尾炎中的预测价值已经被一些作者研究过,NLR提供了关于两种不同的免疫和炎症途径的信息,这可能使其成为预测阑尾炎及其严重程度的潜在标记物 [10] [11] [12] [13]。NLR水平的升高会发生在阑尾炎症的早期阶段,在85%~95%有严重感染过程的患者中NLR水平会继续升高,截断值在5~8之间 [13]。多项研究与Meta分析表明,CA患者NLR显著增高,8.8是诊断复杂性阑尾炎的临界值,敏感性为76.92%,特异性为100%,AUC为0.91 [11] [14]。

2.4. 红细胞分布宽度(RDW)

RDW水平升高与红细胞生成受损或红细胞降解相关,具体机制尚不清楚,但可能与炎症、氧化应激有关。在急性阑尾炎中,存在着氧化应激和促氧化/氧化防御系统的失衡,其中炎症细胞因子使内皮细胞生成一氧化氮减少,对红系祖细胞产生抑制作用,使红细胞生成受损,从而RDW增加。血清一氧化氮和氧化应激升高还可以导致红细胞降解,增加红细胞活性氧大量过早进入外周循环,改变红细胞膜的蛋白和离子通道,从而导致RDW的升高 [15] [16]。在迹象成人阑尾炎的研究中,ROC曲线分析表明,RDW在诊断AA的最佳分界点是15.6%,敏感性为47%,特异性为67%,(曲线下面积(AUC):0.62 [17]。尽管较高的RDW可能有助于AA的诊断,但目前已有证据未表明RDW是预测阑尾炎穿孔的有效指标。

3. 血栓与止血的检验

3.1. 血小板计数(PLT)

炎症性疾病可引起PLT的活化,通常表现为PLT计数、血小板分布宽度(PDW)和平均血小板体积(MPV)的变化,可反映包括AA在内的多种疾病的炎症反应及疾病活动性。有研究指出,CA患者的平均PLT与UA患者存在显著差异,PLT可作为CA与UA鉴别的指标 [18]。

3.2. 平均血小板体积(MPV)

MPV是血小板功能和活化的标志,已被证明可以反映炎症的严重程度。在心脑血管疾病、类风湿关节疾病及其他炎性疾病中,MPV有明显变化。在对一项2142例患者的回顾性分析中,与健康受试者相比,AA患者的MPV显著低于对照组。因此,MPV在AA诊断中是有用的 [19],但其敏感性和特异性较低 [20]。另一项关于450例患者的Meta分析表明,MPV在CA组似乎有所减少,但不存在显著差异 [19]。故现有证据表明,MPV在AA诊断中有效,但在区分CA与UA中未展现出令人满意的效果。

3.3. 血浆纤维蛋白原(FIB)

当发生感染、损伤后炎症或与血管破裂相关的疾病时,FIB浓度可增加数倍,通常,它们通过不同的配体–受体相互作用结合和激活多种免疫细胞,从而导致局部产生炎症细胞因子 [21] [22]。不同的研究表明,在CA组患儿中,FIB平均水平为6.18 g/L显著高于UA组。其诊断CA的特异性为0.82%,敏感性为0.74%,当FIB水平超过5.0 g/L时,对预测CA发生的AUC为0.87 [23]。当FB水平为>4.0 g/L时,敏感性为0.87%,特异性为0.71% [24]。FIB对CA诊断具有较高的敏感性和特异性。

3.4. 血小板淋巴细胞比(PLR)

PLR是血小板计数与淋巴细胞计数的比值,可能是急性感染、心血管事件和癌症的预后指标。有文献报道,PLR在诊断UA与CA中,两组间具有显著差异,AUC为0.653~0.722 [14] [25],故PLR可能在区分阑尾炎严重程度中有效。

3.5. 血浆D-二聚体(DD)

DD是纤维蛋白溶解的降解产物,当发生血栓或炎症反应常常增加,尽管DD更常用于血栓栓塞和肺栓塞的诊断,但在诊断CA中的可能原因为阑尾梗阻、随后的缺血以及伴随这些事件的炎症反应可增加血液中DD的含量。最近的研究表明,在CA患者中,DD诊断的截断值为230 ng/Ml,AUC为0.93,具有较高的预测价值,可作为诊断CA的良好指标 [26]。

3.6. 凝血酶原时间(PT)

感染和炎症可以导致凝血功能从不明显的实验室改变到严重的弥散性血管内凝血(DIC) [20] [27]。研究表明,革兰氏阴性杆菌可引起AA患儿血浆内毒素浓度较高,尤其在CA中,内毒素浓度与凝血因子VII(FVII)呈负相关,与PT呈正相关。随着阑尾炎的严重程度,PT显著延长,当>12.7秒时,诊断CA的敏感性为75.92%,特异性较低为42.66%,AUC为0.617 [27]。这表明它的延长对识别CA特别有帮助。

4. 血液生化检验

4.1. 血清钠

CA引起低钠血症的生理病理原因尚未确定,可能是白介素6等细胞因子介导的早期全身炎症反应 [28] [29],引起抗利尿激素分泌增加而引起 [30] [31]。低钠血症(血清钠 < 135 mmol/L)在CA组31.4%,139/443)显著高于UA组(3.8%, 26/690) (p < 0.0001)。术前血清钠用于区分CA与UA的AUC为0.76,诊断的敏感性为31.4%,特异性为95.7% [31]。

4.2. 血清总胆红素

在AA中,阑尾壁完整性受损导致细菌和内毒素从阑尾腔转移到门静脉系统,炎症细胞因子及内毒素可能到达肝脏,导致肝内胆汁淤积,这可以解释胆红素水平升高与阑尾炎的严重程度相关。在UA和CA中,总胆红素诊断的特异性分别为的0.82%,敏感性为0.70% [32]。这表明,在UA与CA中,总胆红素是较特异的标记物 [32]。与胆红素水平 < 0.6 mg/dL的患者相比,胆红素水平 > 1.0 mg/dL的患者发生CA的危险比(HR)为2.04 [9]。在AA患儿中,当总胆红素明显升高时,发生CA的可能性较大 [33]。

5. 血清学与免疫学检测

5.1. C-反应蛋白(CRP)

CRP是一种临床常用的非特异性的炎症标志物,主要由白介素6 (IL-6)、白介素1 (IL-1)和肿瘤坏死因子α (TNF-α)等细胞因子刺激产生。在最初的6~8小时增加,大约48小时后达到峰值。CRP的功能包括通过经典补体途径激活补体以及调节吞噬细胞功能,这些特性表明它在感染因子和受损细胞的调理中发挥作用。炎症或组织破坏消退后,CRP水平迅速下降,其消除半衰期估计为4~9小时,这使其成为一种有用的疾病活动标记物 [34]。CRP水平在AA中升高与感染的严重程度有关 [35]。CRP在诊断AA的敏感性和特异性分别为58%~93%和28%~82%,在诊断CA的敏感性为83%~90% [34] [36]。CRP > 0.5 mg/dL的患者比<0.5 mg/dL的患者发生CA的风险高2.53倍 [9]。

5.2. 降钙素原(PCT)

在炎症过程中,PCT的产生与微生物抗原,特别是内毒素的直接刺激有关,并与特定的细胞因子如IL-1、IL-6和TNF-α间接刺激有关 [37]。有研究发现,由革兰氏阴性细菌引起的感染比由革兰氏阳性细菌引起的感染刺激产生更多的降钙素原,PCT是微生物感染炎症性宿主反应的生物标志物,会随着感染的严重程度成比例地增加 [35]。降钙素原浓度在诱导后2~3小时升高,6~12小时达到高峰。如果刺激停止,降钙素原浓度逐渐降低,并在5~7天恢复到基线水平。PCT对CA的诊断更为确定,其综合敏感性为62% (33%至~84%),特异性为94% (90%至~96%),AUC为0.94 (0.91~0.96) [38]。

5.3. 血清淀粉样蛋白A (SAA)

SAA在炎症细胞因子(如TNF-α、IL-1、IL-6等)激活后2~3小时内升高,2~3天达到一个峰值,5~7天恢复正常。SAA由一系列在不同炎症过程中分泌的载脂蛋白组成,一旦进入体循环,就迅速与细菌脂多糖结合,并合并到高密度脂蛋白(HDL)颗粒中,中和外来有毒产物并改变胆固醇代谢,SAA可刺激炎症部位吞噬细胞和淋巴细胞的趋化和粘附。通过这些发挥抗炎作用。研究表明,在CA组与UA组中,SAA预测CA的AUC为0.96,当SAA > 10 mg/L时,敏感性为100%,特异性为61%;当SAA > 45 mg/L的敏感性为86%,特异性为83% [39]。这表明SAA是CA的独立预测因子。

5.4. 五聚聚3 (PTX3)

PTX3是一种急性炎症反应物,血清中PTX3基础水平一般低于2 ng/mL,但在炎症过程中,该反应物的循环水平可能是其基础值的3~5倍,在6~8 h时达到峰值 [40],PTX3水平与疾病活动相关 [41]。PTX-3在A中的研究表明,当PTX-3 > 9.56 ng/mL对预测CA的敏感性为92.9%,特异性为87.1%,曲线下面积为0.820 [42]。

5.5. 胎球蛋白A (Fetuin-A, FA)

FA是一种胰岛素依赖的内源性酪氨酸激酶受体抑制剂,主要在肝脏中合成。有报道称血清水平在应对感染和炎症时降低,发挥抗炎介质的作用。有研究表明,FA在UA组平均值为223 mg/dL,CA组为161 mg/dL,两组间存在显著的差异性,这表明FA也可能作为一种负性炎症介质在AA的病理生理中发挥作用 [43] [44]。

6. 其他血液指标

6.1. D-乳酸(DLAC)

DLAC是由细菌代谢产生,它可能是胃肠道细菌过度生长的特异性血清标志物 [34] [45]。当阑尾炎症引起粘膜损伤时,细菌增殖的代谢产物进入循环导致血清DLAC水平升高,由于哺乳动物没有代谢DLAC所需的酶系统,所以可以通过肝脏并进入外周循环。当发生肠道穿孔时,DLAC可以进入腹腔被网膜等组织被吸收进入外周循环 [46]。DLAC在CA组中明显明显高于UA组。当DLAC大于2.5 mg/dL时,敏感性为96%,特异性为87%。DLAC水平可帮助临床医生预测阑尾炎的类型 [45] [47]。

6.2. σ中性粒细胞指数(DNI)

DNI是一种新的炎症标志物,在感染早期,中性粒细胞向感染起源部位的迁移受到细胞因子和趋化因子的限制,导致未成熟的中性粒细胞进入循环以弥补活性中性粒细胞的不足 [48]。DNI是外周血循环中未成熟粒细胞与总中性粒细胞的比值,研究表明,在UA与CA组中,DNI分别0%和2.2%,存在显著差异,预测CA发生的AUC为0.738 [49]。

6.3. 循环纤维细胞百分比(CFP)

CFP是来源于骨髓的造血细胞,在炎症和愈合过程中都有重要作用。已被证明在肠系膜疾病的发病机制中发挥关键作用。一项在成人AA患者中的研究表明,CFP诊断AA的敏感性为68.2%,特异性为68.5%,AUC为0.7 [50]。目前暂无证据表明CFP在区分CA中的能力。

关于阑尾炎的血液指标研究众多,而且新的指标也在不断出现,目前研究表明,在区分UA与CA中,NLR、PLT、FIB、PLR、DD、PT、血清钠、血清总胆红素、CRP、PCT、SAA、PTX-3、FA、DLAC、DNI能区分阑尾炎严重程度,但具体每个血液指标在预测儿童阑尾炎严重程度中的预测效力以及临床中如何通过血液指标客观的预测阑尾炎的发生概率仍没有具体的阐述。在之后的研究中,我们可以建立一个包含血液指标的预测模型,通过分析给各个指标赋予参数,使其可以综合评估阑尾炎的严重程度,并且方便临床应用。关于新的血液指标在儿童AA患者中的应用研究不是很多,仍需要前瞻性、多中心和大样本的研究来进一步清楚血液指标对于CA鉴别的作用。

NOTES

*通讯作者。

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