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通讯作者:

吉宁飞,E-mail:jiningfei@163.com

中图分类号:R562.25

文献标识码:A

文章编号:1007-4368(2022)05-734-06

DOI:10.7655/NYDXBNS20220522

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目录contents

    摘要

    哮喘是一种以慢性气道炎症为特点的异质性疾病,而嗜酸粒细胞性哮喘是基于气道炎症分型中最常见的一种亚型。作为诱导痰的替代生物标志物,血嗜酸粒细胞、呼出气一氧化氮、血清骨膜蛋白等被广泛应用于嗜酸粒细胞性哮喘的研究,但这些生物标志物预测嗜酸性气道炎症的能力饱受争议,联合使用或许能提高诊断的准确度。此外,随着组学技术的开展以及对疾病发病机制的深入认识,未来新型生物标志物有望应用于临床。

    Abstract

    Asthma is a heterogeneous disease characterized by chronic airway inflammation. Eosinophilic asthma is the most common subtype based on airway inflammatory classification. As alternative biomarkers for induced sputum,blood eosinophil, fractional exhaled nitric oxide,and serum periostin have been widely used in the study of eosinophilic asthma,but their ability to predict eosinophilic airway inflammation is controversial. Combined use of two or more biomarkers may improve the accuracy of diagnosis. In addition,with the development of omics technology and the in ⁃depth understanding of the pathogenesis of asthma,new biomarkers are expected to be applied in clinic in the future.

  • 哮喘是一类具有不同病理生理特征、临床表现、病理和预后的异质性疾病。从气道炎症的角度可分为4种类型:嗜酸粒细胞性哮喘(eosinophilic asthma,EA)、中性粒细胞哮喘、混合性粒细胞哮喘和寡粒细胞性哮喘,其中以EA最为常见[1]。诱导痰细胞是识别哮喘气道炎症的金标准,文献中常将EA定义为痰嗜酸粒细胞比例>1%~3%的哮喘[2]。近年来EA越来越受到关注,有研究显示部分EA患者尽管吸入高剂量糖皮质激素(激素)但气道嗜酸性炎症仍持续存在,与更严重的疾病程度和预后相关[3]。聚类分析显示,这类患者成年起病,无特应性,常合并慢性鼻窦炎及鼻息肉,存在持续的气流受限[4]。目前,新型靶向2型炎症的生物制剂能够精准化治疗特定表型(如EA)的哮喘患者,对高特异性、可重复且易于测量的生物标志物的需求也愈加明显。诱导痰嗜酸粒细胞可预测哮喘急性发作以及调整吸入性糖皮质激素(inhaled corticosteroid,ICS)的剂量[5-6],但技术要求较高且耗时,需配备专门的实验室和操作人员。支气管组织活检和支气管肺泡灌洗液能直接反映气道嗜酸粒细胞炎症,但这些方法具有侵入性、价格昂贵的缺点,在基层医疗机构中不能广泛使用。一些非侵入性的生物标志物包括外周血嗜酸粒细胞、呼出气一氧化氮(fractional ex⁃ haled nitric oxide,FeNO)和骨膜蛋白(periostin)等成为潜在的替代标志物,但其预测嗜酸性气道炎症的能力仍存在争议。本文就EA的生物标志物作一综述。

  • 1 外周血嗜酸粒细胞

  • 外周血嗜酸粒细胞一直是痰嗜酸粒细胞的良好替代指标[7]。有研究显示血嗜酸粒细胞计数在150个/μL及以上能准确预测痰嗜酸粒细胞增多,敏感性为85%,特异性为75%[8]。同样,Schleich等[9] 提出血嗜酸粒细胞识别痰嗜酸粒细胞≥3%的理想界值为188个/μL,敏感性为72%,特异性为73%。还有研究将截断值设定在300个/μL[5] 甚至更高[10]。关于血嗜酸粒细胞计数作为嗜酸粒细胞炎症的截断值尚未达成共识。一项病例对照研究显示,外周血嗜酸粒细胞增多与哮喘严重程度和症状控制不佳相关,但与肺功能减退无明显关联[7]。血嗜酸粒细胞可以预测哮喘急性发作[11] 并识别出对抗白介素(IL)⁃5单抗治疗有应答的人群[12],但用于指导2型生物制剂治疗的阈值是可变的(从150~400个/μL不等),取决于哮喘常规用药和使用的生物制剂[13]

  • 外周血嗜酸粒细胞的测量具有简便、可重复的优点,但因其相对较高的假阴性率和假阳性率,仍不能完全代替痰嗜酸粒细胞[10]。Hastie等[5] 发现血嗜酸粒细胞计数>300个/μL时识别嗜酸粒细胞表型的准确度只有63%,阳性预测值50%。这种低准确度可能是因为哮喘患者血嗜酸粒细胞的高度变异性[14]。考虑到血嗜酸粒细胞在生物制剂的选择方面有着不可或缺的作用,重复测量血嗜酸粒细胞是有必要的[14]

  • 2 FeNO

  • 一氧化氮(nitric oxide,NO)是气道上皮细胞表达的一氧化氮合酶合成的一种反应性分子[2],经口测量的NO又称FeNO。多项研究表明,FeNO与痰嗜酸粒细胞呈正相关[615]。2011年美国胸科协会指出FeNO<25/20ppb(成人/儿童)提示患者存在非嗜酸粒细胞炎症,对激素治疗不敏感;反之,FeNO> 50/35ppb(成人/儿童)提示存在嗜酸粒细胞炎症,对激素治疗有效[16]。FeNO不仅可以辅助诊断哮喘,还能指导哮喘抗炎治疗[16-17]。一项Meta分析显示,基于FeNO指导哮喘治疗可降低哮喘发作风险,但对哮喘控制和肺功能无明显影响[18]。最近,Fielding等[19] 使用7项随机对照试验的数据进行个体患者数据分析发现,基于FeNO指导治疗的模式对于未接受白三烯受体拮抗剂治疗且不肥胖的哮喘患者可能更有效。高FeNO水平的重症哮喘患者存在明显的嗜酸性气道炎症、严重的气流受限和气道重塑,也存在频繁的急诊就诊[20]。在重症哮喘患者中观察到的FeNO与嗜酸粒细胞之间的联系可能是由于激素抵抗或上皮细胞的持续激活,后者是NO合成的主要部位,也是嗜酸性趋化因子的来源[21]。Abe等[22] 连续3年测量100例重症哮喘患者的FeNO值,发现FeNO水平持续在50ppb以上与病情恶化有关。此外,FeNO还可预测重症EA患者对生物制剂,如奥马珠单抗(omalizumab)、美泊利单抗(mepo⁃ lizumab)和贝那利珠单抗(benralizumab)等的治疗反应[23]

  • 与诱导痰相比,FeNO具有快速、简便、安全、重复性好的优点。但FeNO的测定易受过敏、年龄、激素用量、食物饮料、昼夜节律、吸烟等多种因素的影响。Nanda等[24] 研究发现在5~7d内多次测量FeNO的平均值比单次测量值能更好地反映痰嗜酸粒细胞水平。

  • 3 骨膜蛋白

  • 骨膜蛋白是一种与纤维化有关的分泌型基质蛋白,重组IL⁃4和IL⁃13在培养的支气管上皮细胞和成纤维细胞中可上调骨膜蛋白的表达[25]。在哮喘患者中,骨膜蛋白的表达水平与网状基底膜厚度相关[25]。血清骨膜蛋白是哮喘嗜酸性气道炎症的生物标志物,与痰嗜酸粒细胞和激素治疗反应相关[25-26]。以25ng/mL为分界值,血清骨膜蛋白可有效区分嗜酸粒细胞低和高的个体,敏感性为57%,特异性为85%,阳性预测值为93%[25]。然而,研究结果显示,在两个独立的哮喘队列中,与血嗜酸粒细胞和FeNO相比,血清骨膜蛋白在鉴别嗜酸粒细胞性炎症(痰嗜酸粒细胞≥3%)和非嗜酸粒细胞性炎症方面的准确度最低[27]。尽管诊断EA的能力相对较弱,血清骨膜蛋白可预测哮喘患者的固定气流受限[28] 以及新型生物制剂的疗效[2629]。在一项人源化抗IL⁃13单抗(lebrikizumab)的Ⅱ期临床试验中,治疗前血清骨膜蛋白水平较高的哮喘患者使用lebrikizumab后肺功能的改善比骨膜蛋白水平较低的患者更明显[29]

  • 相较于其他2型炎症生物标志物,血清骨膜蛋白的实验室标本处理和分析工作缺乏标准化流程,且易受年龄、吸烟、体重指数(body mass index, BMI)、合并症等因素的影响[2630],因此对于结果的解读需谨慎。

  • 4 免疫球蛋白E(immunoglobulin E,IgE)

  • IgE通过Fc区与肥大细胞上的FcεR Ⅰ受体或B淋巴细胞和嗜酸粒细胞上的FcεR Ⅱ受体结合,释放炎症介质,在过敏反应中发挥重要作用[1331]。IgE与痰嗜酸粒细胞相关[5-6],但其诊断嗜酸粒细胞性哮喘的效力可能劣于FeNO和血嗜酸粒细胞。Wester⁃ hof等[32] 通过受试者工作特征曲线比较血嗜酸粒细胞、FeNO和总IgE 3种生物标志物预测痰嗜酸粒细胞增多的准确度发现,总IgE的曲线下面积(area un⁃ der the curve,AUC)最小。Good等[33] 通过支气管镜检查以鉴定哮喘表型,也发现总IgE水平与支气管肺泡灌洗液或活检标本中的嗜酸粒细胞缺乏相关性,尽管这部分有嗜酸粒细胞证据的患者大多(> 80%)过敏原皮肤试验阳性。

  • 血清总IgE虽不能预测哮喘患者的临床应答,但抗IgE治疗可显著减少气道和外周血嗜酸粒细胞[34]。对这一矛盾可能的解释是与抗IgE下调肥大细胞、嗜碱性粒细胞和树突状细胞表面的FcεRⅠ有关,表达FcεRⅠ细胞的减少限制过敏原诱导的IgE介导的反应,进而阻止细胞因子的释放和嗜酸粒细胞在气道中的募集[2]。此外,抗IgE治疗还可以通过降低气道树突状细胞水平促进Th2分化、嗜酸粒细胞存活和募集所必需的2型细胞因子减少。

  • 5 血嗜酸粒细胞、FeNO、血清骨膜蛋白和总IgE的组合

  • Korevaar等[6] 纳入32项研究的荟萃分析显示,使用单一的替代生物标志物将导致大量假阳性或假阴性。不难理解,EA发病机制复杂、涉及不同的分子途径,而不同的生物标志物可能代表不同的2型气道炎症途径。因此,两个或两个以上生物标志物的组合或许可以提高检测嗜酸性气道炎症的敏感性和特异性。

  • Westerhof等[32] 联合使用FeNO和血嗜酸粒细胞显著提高了诊断EA的准确度,但将总IgE加入FeNO和血嗜酸粒细胞的组合时,AUC值无明显变化。而Hastie等[5] 联合使用血嗜酸粒细胞、FeNO和IgE并未提高EA诊断的准确度。同样,Wagener等[27] 将血嗜酸粒细胞、FeNO和血清骨膜蛋白3个标志物组合在一起时,没有发现任何改善。在指导治疗方面, Malerba等[35] 研究发现,与传统策略(基于临床症状) 相比,联合FeNO和痰嗜酸粒细胞调整ICS剂量可提高EA控制水平以及减少急性发作。正在进行中的英国医学研究理事会的难治性哮喘分层计划(RASP⁃ UK)旨在探索重症哮喘的新型生物标志物分层策略,以改善重症哮喘患者的临床管理和靶向治疗,其结果在未来将提供更多的信息[36]

  • 6 嗜酸粒细胞阳离子蛋白和嗜酸粒细胞源性神经毒素

  • 嗜酸粒细胞阳离子蛋白(eosinophil cationic pro⁃ tein,ECP)和嗜酸粒细胞源性神经毒素(eosinophil⁃ derived neurotoxin,EDN)是嗜酸粒细胞活化的标志,被认为是哮喘2型炎症的潜在生物标志物[37-38]。一项美泊利单抗治疗重症EA的Ⅲ期临床试验的事后分析[39] 结果显示,EDN和ECP可预测第1秒用力呼气容积(forced expiratory volume in first second, FEV1)的改善,同时高基线EDN亚组的哮喘急性发作频率较低基线EDN亚组下降更明显。但研究者指出,EDN的预测能力很大程度上是由于其与基线外周血嗜酸粒细胞的相关性。最近,有研究显示血清EDN可用于评估EA的严重程度[40]。An等[41] 发现EDN比血嗜酸粒细胞计数能更好地反映哮喘控制状况(AUC 0.726 vs.0.628,P=0.024)。

  • 7 呼吸组学、基因组学、蛋白组学、脂质组学等

  • “组学(omics)”反映了一种基于从单个样本获取大规模数据集的实验范式,目的是识别疾病的生物标志物和/或阐明新的功能或病理机制[42]。测量呼出气冷凝物中的挥发性有机化合物(volatile or⁃ ganic compound,VOC)称为“呼吸组学”。呼出气中含有数千种VOC的复杂气体混合物,它们来自全身和局部的代谢、炎症和氧化过程[43]。目前用于分析VOC的技术包括气相色谱⁃质谱(gas chromatography⁃ mass spectrometry,GC ⁃ MS)和电子鼻(electronic nose,eNose)。GC⁃MS作为一种化学分析技术,通过与先前建立的参考库比较单个化合物的质量与电荷比以识别出呼吸样本中的单个成分;电子鼻则是类似哺乳动物嗅觉的多传感器设备,其对VOC混合物中的多种化合物具有交叉反应,产生由VOC混合物驱动并具有其特征的传感器响应模式[43],缺点是不能对呼出气的化学成分进行精确分析。研究显示,电子鼻技术能够区分哮喘和对照组,其准确度与FeNO和痰嗜酸粒细胞相当,并且预测哮喘患者对激素的反应优于痰嗜酸粒细胞和FeNO[44]。Schleich等[45] 在一项前瞻性队列研究中使用GC⁃MS分析发现,己烷和2⁃己酮能很好地识别EA,其准确度与血嗜酸粒细胞和FeNO相当。此外,FeNO、血嗜酸粒细胞和VOCs的组合对EA显示出较好的预测能力 (AUC为0.9)。

  • 除上述呼吸组学可应用于炎症表型的识别,还有其他组学技术在开展。 Rossios等[46]发现痰IL1RL1(也称为IL33R或ST2)基因表达与重症EA相关。Schofield等[47] 采用无偏标记定量质谱和拓扑数据分析方法对206例哮喘患者的痰上清液蛋白质组进行分析,发现有10种蛋白(组蛋白H4、玻璃体凝集素、富含组氨酸的糖蛋白、免疫球蛋白重常数g3、补体C3、转甲状腺素、血清转铁蛋白、α⁃1⁃抗胰蛋白酶、半乳糖凝集素⁃3结合蛋白和ezrin)能较好地预测EA表型。Gai等[48] 使用液相色谱⁃质谱法测定血清代谢甘油磷脂谱,结果显示痰嗜酸粒细胞≥ 3%组血清溶血磷脂酰甘油水平明显高于痰嗜酸粒细胞<3%组,提示血清溶血磷脂酰甘油可能是EA的一个生物标志物。

  • 8 分子途径相关标志物

  • 在过敏性EA中,Th2细胞是哮喘病理生理的驱动因素,但近年来的研究表明,在成人起病的非过敏性EA中,2型固有淋巴细胞(group 2innate lymphoid cell,ILC2)扮演着重要角色[49]。ILC2是一群不表达谱系标志物(不表达T、B、NK、肥大及嗜碱性粒细胞等谱系标志物),并且缺乏抗原识别受体的细胞群,在IL⁃33、IL⁃25和/或胸腺基质淋巴细胞生成素的刺激下产生大量IL⁃5和IL⁃13,介导2型固有免疫[49]。研究显示,ILC2在哮喘患者外周血中增加[50],且重症EA患者的痰和外周血中ILC2水平比轻症哮喘患者高[51]。Liu等[52] 研究发现外周血淋巴细胞ILC2的百分比(%ILC2)诊断EA的准确度略优于血嗜酸粒细胞和FeNO。以0.076%ILC2为界值,检测嗜酸性气道炎症的敏感性为67.7%,特异性为95.3%,提示ILC2可能是EA的潜在生物标志物。一项前瞻性研究结果显示,ILC2与外周血嗜酸粒细胞百分比呈正相关,但与肺功能无关[53]。目前,关于ILC2能否替代诱导痰诊断EA以及其在预测激素治疗反应和疾病预后方面尚需进一步研究。

  • 综上所述,无创、易获取、可重复的生物标志物将极大地简化和改善哮喘的诊断和治疗。单一的生物标志物并不能有效捕捉复杂的生物网络,两种或两种以上生物标志物的联合也许能提高诊断的准确度(如血嗜酸粒细胞和FeNO的组合)。此外,随着对EA发病机制的进一步认识以及组学等新技术的开展,确定新的、更上游的嗜酸粒细胞炎症生物标志物将为EA患者带来理想的靶向治疗。最后,考虑到部分生物标志物的不稳定性[14],未来的研究应着眼于这些炎症性生物标志物在长时间内的纵向变异性,以更好地应用于临床。

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