Advances in Clinical Medicine
Vol. 13  No. 03 ( 2023 ), Article ID: 62844 , 7 pages
10.12677/ACM.2023.133593

小气道功能障碍与哮喘控制

易良琴1,2,3,4,罗征秀1,2,3,4*

1重庆医科大学附属儿童医院呼吸科,重庆

2国家儿童健康与疾病临床医学研究中心,重庆

3儿童发育疾病研究教育部重点实验室,重庆

4儿科学重庆市重点实验室,重庆

收稿日期:2023年2月17日;录用日期:2023年3月14日;发布日期:2023年3月21日

摘要

哮喘是常见的慢性气道炎症性疾病,炎症可累及整个气管–支气管树,近年来,小气道被认为是炎症累及和气流阻塞的主要部位,小气道功能障碍是持续性哮喘的特征,与疾病恶化和控制不良相关,但目前指南尚缺少小气道管理相关内容。本文就小气道功能障碍与哮喘控制关系做一综述,以期提升对小气道功能障碍在哮喘控制中作用的认知水平,为哮喘指南的完善提供支持性证据。

关键词

哮喘控制,小气道功能障碍

Small Airway Dysfunction and Asthma Control

Liangqin Yi1,2,3,4, Zhengxiu Luo1,2,3,4*

1Department of Respiratory, Children’s Hospital of Chongqing Medical University, Chongqing

2National Clinical Research Center for Child Health and Disorders, Chongqing

3Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing

4Chongqing Key Laboratory of Pediatrics, Chongqing

Received: Feb. 17th, 2023; accepted: Mar. 14th, 2023; published: Mar. 21st, 2023

ABSTRACT

Asthma is a common chronic airway disease. Inflammation in asthma can involve the entire trachea-bronchial tree. Recent years, small airways have been accepted to be the main site of inflammation and major reason of airflow obstruction. And small airway dysfunction is confirmed as a characteristic of persistent asthma, which is related to exacerbation and control. However, in asthma guidelines, little information is stressing the role of small airway. In this review article, we focused on the relationship between small airway dysfunction and asthma control, pointed out the influence of small airway dysfunction in poor asthma control and stressed the importance of its management, in order to provide supporting evidence for asthma guideline.

Keywords:Asthma Control, Small Airway Dysfunction

Copyright © 2023 by author(s) and Hans Publishers Inc.

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

哮喘是一种常见的慢性呼吸道疾病,影响全球约3.39亿人,其患病率逐年上升 [1] [2]。尽管表明哮喘控制是一个可实现的目标,但在临床及研究发现,相当一部分哮喘患者仍处于哮喘控制不佳状态 [3] [4],我国哮喘控制率约28.5%,低于发达国家哮喘控制水平 [5]。哮喘控制不佳与患者病情加重、生活质量受损和个人医疗保健负担增加相关 [6] [7],了解影响哮喘控制不佳的危险因素并及时干预对实现哮喘最佳临床控制至关重要。既往研究已经证实患过敏性鼻炎、治疗依从性差和吸入治疗方法错误等是导致哮喘控制不佳的危险因素 [8] [9] [10] [11]。近年来,越来越多的证据提示小气道功能障碍与哮喘发作及恶化相关 [12] [13] [14]。研究表明在哮喘早期阶段小气道已有不同程度受累,持续性小气道炎症是导致哮喘控制不佳的重要危险因素 [12] [13] [14] [15],然而现有哮喘指南并未提及小气道功能障碍(small airway dysfunction, SAD)在哮喘中的作用及如何对其管理 [11] [16] [17] [18]。因此,本文就目前关于小气道功能障碍对哮喘控制水平的影响做一综述,以期为识别小气道功能障碍在哮喘控制中的重要性提供依据。

2. 小气道功能障碍

小气道被定义为气管内径 ≤ 2 mm,壁上不含软骨,从第8级支气管延伸至周围肺组织的气道 [19]。正常情况下,小气道对气道阻力的贡献很小,在成人中小气道阻力仅占总气道阻力的10%~20%,通常被称为肺的“沉默区” [20]。然而小气道面积大,受炎症累及时,可提供相当大的气道阻力。小气道功能障碍的患病率因生理评估手段不同而呈现差异,总体而言,成人哮喘中小气道功能障碍患病率约50%~60% [21],儿童哮喘中约为20%~30% [22] [23]。多项研究表明,重度哮喘患者小气道功能障碍患病率最高 [12],且与更严重气道高反应性、更差的哮喘控制水平、更频繁的哮喘病情恶化有关 [12] [13] [14]。

3. 小气道功能的评估方法

目前尚缺乏标准化、统一化小气道测量方法,SAD也缺乏评估金标准。全球哮喘倡议(GINA)提出常规肺通气功能仍是评价肺功能的首选方法,第1秒用力呼气容积(FEV1)是评估患者气道阻塞的金标准 [11],然而,FEV1不能敏感地评估小气道功能。用力呼出50%肺活量时的瞬间呼气流量(FEF 50%),用力呼出75%肺活量时的瞬间呼气流量(FEF 75%)和用力呼出25%~75%肺活量间的平均呼气流量(FEF 25%~75%,也称最大呼气中期流量,MMEF)是常用来反应小气道功能指标 [24],此三项指标中有两项低于正常值下限(<65%预计值)可提示SAD [24]。近年来,随脉冲震荡试验(Impulse oscillometry, IOS)、体积描记法(Body plethysmography)、呼出气一氧化氮(Fractional exhaled nitric oxide, FeNO)、重复呼吸氮冲洗法(Multiple breath nitrogen washout test, MBNW)、影像学等专业测试在临床实践中陆续开展,发现IOS能更敏感地识别小气道功能障碍,更有潜力运用于临床监测 [25] [26]。

IOS是通过脉冲波在不同振动频率下检测呼吸道不同部位气道阻力,在5 Hz时的气道阻力(R5)代表总气道阻力,20 Hz时的气道阻力(R20)代表中心气道阻力,R5~R20代表小气道阻力,5 Hz时的电阻抗(X5)和电抗下面积(AX)也是反应小气道功能的重要参数,当小气道出现阻塞时其值可显著增加 [27] [28]。在成人,当R5~R20 > 0.07 kPa/L∙s提示有SAD [13],部分研究也以R5~R20 > 0.03 kPa/L∙s作为成人SAD评估标准 [29] ;在儿童中,R5~R20的界限值因不同年龄段而呈现出差异 [23] [30],目前尚无统一判定SAD的IOS标准。

体积描记法是一种静态评估肺过度充气和空气滞留的方法,小气道狭窄引起气流阻塞,气道过早关闭导致空气滞留,因此残气量(residual volume,RV)增加和RV/肺总量(total lung capacity, TLC)升高(>0.3)提示存在SAD,当慢肺活量(slow vital capacity)-用力肺活量(forced vital capacity, FVC) > 10%可提示小气道的过早关闭 [31] [32]。

FeNO是一种有效的非侵入性检测Th2介导的气道炎症的方法,可根据数学模型分为支气管NO和肺泡NO(CaNO)两部分,CaNO被认为与小气道的炎症有良好相关性 [33],但目前这一数学模型的准确性和应用行仍存在争议。

MBNW可用于评估小气道通气异质性,通过受试者重复吸入纯氧至TLC,再呼气至残气位,多次分析每一阶段呼出氮气浓度的变化,从而计算出通气不均及肺清除率指标。气道传导通气不均指标Scond和气体交换肺腺泡通气不均指标 Sacin的升高以及反应肺清除率的肺清除指数(LCI)的降低可提示小气道病变,其中LCI被认为是一种最稳定反小气道功能的参数 [34] [35]。

4. 小气道功能障碍与哮喘的进展相关

哮喘患者中,气道炎症和结构改变是引起气流受限的重要因素,由于小气道提供的阻力相对小,在哮喘早期尤其未出现典型临床症状前,已有的小气道阻塞可能未被临床检测出,提示临床对SAD的识别不够,这可能是哮喘进展的危险因素之一 [36]。出生队列研究证实 [37],在儿童期肺功能下降发生成年期哮喘患者中,FVC和FEV1处于正常水平时,FEF 25%~75%已出现了不同程度降低。横断面研究发现 [38],从儿童期即有持续性哮喘的患儿比成年期发病的哮喘患者病情更严重,肺功能水平更差,有更多SAD的证据,提示持续性炎症反应对小气道累及更重。小气道功能障碍能成功预测学龄前喘息发生青春期哮喘,其中IOS相关小气道功能指标降低与青春期持续性肺功能异常相关 [39]。Skylogiann等发现中重度过敏性鼻炎患儿支气管舒张试验后存在小气道功能障碍,是随访5年内哮喘发生的有效预测指标 [40]。在无哮喘症状且FEV1及支气管激发试验正常的哮喘患儿中,SAD是未来哮喘恶化的危险因素 [41]。以上研究表明,小气道功能障碍可在大气道功能下降前出现,其可独立于大气道的影响并长期存在,持续的小气道功能障碍加速了哮喘患者的肺功能下降,使得哮喘病情更加严重,症状频繁发作。

5. 小气道功能障碍与哮喘控制相关

们使用不同检测手段来评估小气道功能障碍与哮喘控制之间关系。Takeda等 [42] 使用IOS评估了哮喘患者小气道功能障碍,并探讨其与哮喘症状及哮喘控制的关系,发现R5~R20增加与更频繁的呼吸困难独立相关,X5与哮喘控制不佳相关。Shi等 [30] 发现R5~R20和AX可用来区分哮喘控制和未控制患者,当前哮喘控制稳定的学龄儿童中R5~R20,AX降低,在未来的8~12周内有哮喘控制不佳风险。Galant等发现 [43],由R5~R20,AX,X5定义的SAD与患儿发生哮喘控制不佳一致相关,存在SAD也提示患儿有哮喘控制不佳风险。Farah的研究 [44] [45] 表明了哮喘控制不佳组患者的Scond和Sacin值高于控制良好组的哮喘患者,Scond和Sacin值的增加与一年内哮喘加重的次数显著相关,是哮喘控制不佳的独立危险因素。Puckett等人 [46] 将学龄期–青春期的哮喘儿童根据肺泡和支气管NO的浓度将其分组研究,发现在各组间FEV1的值未见差异,但肺泡NO水平升高的患者比肺泡和支气管NO水平正常的患者或仅支气管NO水平升高的患者哮喘控制更差,此外肺泡NO水平升高的患者出现更频繁的哮喘恶化。也有研究者在使用大剂量吸入性糖皮质激素(inhaled corticosteroids, ICS)治疗的患者中观察到肺泡NO浓度与哮喘控制之间的并无相关性,这可能与大剂量ICS抑制呼出气NO水平有关 [47]。ATLANTIS这项最大的多国研究中证明了SAD对哮喘的作用 [12] :91%的哮喘患者均发现有异常的小气道功能指标,SAD存在于所有按GINA哮喘病情严重程度分级中,以常规肺通气功能和IOS等指标形成的SAD结构方程评分与哮喘控制,恶化,病情严重程度显著相关,其一年随访数据 [14] 表明通过FEF 25%~75%,IOS,MBNW等测量的SAD与哮喘控制、恶化和生活质量纵向相关。

总的来说,上述证据提示随着小气道受累越重,哮喘控制不良的比率增多,哮喘恶化也更加频繁,同时也证实在SAD的检出上除常规肺通气功能外,使用IOS和其他检测手段重要性。

6. 小气道功能障碍的治疗对哮喘控制的影响

哮喘的治疗主要是控制气道炎症,ICS是哮喘患者抗炎治疗的基石 [11] [18],然而大多数吸入疗法不能充分到达小气道。针对小气道功能障碍的治疗通常是增加ICS的剂量或联用舒张支气管的药物以使ICS沉积到远端气道,或使用小颗粒二丙酸倍氯米松氢氟烷吸入器(HFA),以期增加药物的肺部沉积率,或联合白三烯受体拮抗剂(LTRA)治疗,从而最大程度的改善气道的炎症,达到哮喘控制 [48] [49] [50]。

Farah等人 [45] 研究影响哮喘控制变化情况的因素,发现小气道功能障碍是ICS剂量上调后哮喘控制良好或ICS剂量下调后哮喘控制不佳的独立危险因素;在对重度难治性哮喘患儿行肌注皮质类固醇治疗4周后,LCI和FeNO指标得到明显改善,且两者改善呈一致性关系,而其他肺通气功能参数无明显改变,这提示了小气道炎症可能是常规ICS治疗无反应哮喘患儿气流阻塞的主要原因 [51]。与大颗粒ICS治疗相比,使用HFA联合超细颗粒二丙酸倍氯米松/福莫特罗(ICS/LABA)治疗的哮喘患者,其哮喘控制良好的比例更高,哮喘症状恶化的频率更低 [52] [53] [54]。对使用超细颗粒ICS/LABA治疗的哮喘患者随访3个月,发现IOS相关小气道功能指标及哮喘控制水平得到明显改善 [55] [56]。与安慰剂相比,使用孟鲁司特治疗的哮喘患儿,症状的好转与肺残气量、肺泡NO降低和AX的改善相关,与FEV1,FEV1/FVC无关 [57]。最近一项对接受至少一月孟鲁司特维持治疗的轻度持续性哮喘控制良好的学龄期儿童中,在停用孟鲁司特两周后,并未观察到哮喘控制不佳比例增加、IOS相关的小气道功能指标恶化及FENO增加的变化 [58],但该项研究仅随访了短时间内肺功能及哮喘症状变化,仍需相关纵向研究随访评估小气道功能改变情况与哮喘控制之间的关系。

7. 结论

综上,SAD与哮喘患者的症状恶化、控制不佳相关,对病情发展有重要影响。尽管有有效的治疗方法,部分哮喘患者病情仍然控制不佳,这可能与SAD在哮喘中作用认识不足有关。除常规肺通气功能外有很多适用于评估SAD的方法,IOS在评估SAD与哮喘控制及治疗方面较常规肺功能更好,研究结果也较多,能更好地用于检测小气道功能。目前哮喘指南尚缺少针对小气道功能管理这部分内容,似乎需迫切完善相关建议与实施,提高临床医生对SAD的认识,从而早期识别和针对性地治疗,达到哮喘控制的目的和减少病情恶化的发生。

文章引用

易良琴,罗征秀. 小气道功能障碍与哮喘控制
Small Airway Dysfunction and Asthma Control[J]. 临床医学进展, 2023, 13(03): 4129-4135. https://doi.org/10.12677/ACM.2023.133593

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  59. NOTES

    *通讯作者。

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