咳嗽的诊断与治疗指南(2015)
中华结核和呼吸杂志, 2016,39(5) : 323-354. DOI: 10.3760/cma.j.issn.1001-0939.2016.05.003

咳嗽是呼吸专科门诊和社区门诊患者最常见的症状,在国内专科门诊中,慢性咳嗽患者约占三分之一以上。咳嗽病因复杂且涉及面广,特别是胸部影像学检查无明显异常的慢性咳嗽,因诊断不明确,很多患者常反复进行各种检查,或者长期大量使用抗菌药物和镇咳药物,收效甚微并产生诸多不良反应,对患者的工作、学习和生活质量造成严重影响,同时也带来了严重的经济负担[1,2,3,4,5]

为了进一步规范我国急、慢性咳嗽的诊断和治疗,指导咳嗽的临床和基础研究,中华医学会呼吸病学分会哮喘学组组织相关专家,于2005年制定了中国"咳嗽的诊断和治疗指南(草案)"[6]并于2009年进行了修订[7]。我国咳嗽指南的制定主要根据国内咳嗽研究结果和临床实践,同时参考了美国胸科医师协会(ACCP)、欧洲呼吸协会(ERS)以及日本、澳大利亚等国家发布的咳嗽指南[8,9,10,11],在结构和内容上具有鲜明的中国特色。指南制定以来,对临床实践起到了良好的指导作用,显著提高了国内的咳嗽诊治水平。近年来,国内外对咳嗽发病机制、病因分布、诊断与治疗研究取得了许多新的进展,为进一步完善指南,及时反映国内外相关研究结果,中华医学会呼吸病学分会哮喘学组于2014年启动了2009年版"咳嗽的诊断和治疗指南"的修订工作。为适应指南发展的要求,本次指南修订首次采用了循证医学方法,检索了大量文献,形成了众多的推荐意见。新版指南主要增加和修订了以下几方面的内容:(1)指南制定方法和循证方法的介绍。(2)对原有的章节进行了更新和扩展。(3)增加了咳嗽的评估。(4)增加了咳嗽的中医中药治疗。(5)增加了儿童慢性咳嗽的病因分布特点与治疗原则。(6)增加了慢性咳嗽的少见病因。(7)介绍了不明原因咳嗽(难治性咳嗽,咳嗽高敏综合征)等相关问题。

一、方法学介绍

1."指南"目标人群:咳嗽患者。

2."指南"目标用户:任何等级医院的呼吸专科医生、内科医生、中医科医生、全科医生、儿科医生及其他相关科室人员。

3."指南"工作组人员组成:由呼吸内科专家、耳鼻咽喉头颈外科专家、儿科专家、中医科专家、消化科专家、循证医学专家、临床流行病学专家以及相关专业的研究生和医学编辑共同组成。

4.文献检索选用数据库:(1)英文:Pubmed/Medline,Embase和Cochrane Library;(2)中文:中国生物医学文献数据库、万方数据库、中国知网和中文科技期刊全文数据库。检索时间截止至2015年6月。针对每个具体临床问题,首先分别由同一专题的两个工作小组独立检索文献,根据纳入和排除标准进行文献筛选;然后制定统一的文献评价表格,由呼吸病学专业的临床医生和研究生对文献进行初评,初评不能确定的文献由指南工作组集中评价;最后指南工作组再次集中,文献逐篇进行复评。

5.证据质量和推荐强度:本指南采用的证据质量和推荐强度分级标准,主要是结合ACCP 2006年"咳嗽诊断和管理循证实践指南"所采用的分级标准[8,12]和GRADE(grading of recommendations assessment, development and evaluation)方法[13],具体见表1。证据质量分为"高、中、低和极低"4个等级,分别用A、B、C和D表示;将推荐意见分为"强推荐、弱推荐和没有明确推荐意见"3个级别,分别用1、2和3表示。

表1

证据质量和推荐强度分级标准

表1

证据质量和推荐强度分级标准

证据质量(等级) 解释
A 证据来自高质量的RCT或者系统评价/Meta分析
B 证据来自有研究缺陷的RCT或低质量的系统评价/Meta分析、高质量的观察性研究
C 证据来自非随机、病例对照或其他观察性研究
D 专家意见
推荐强度(等级) 解释
1 强推荐
2 弱推荐
3 没有明确推荐意见

证据群(evidence body)质量评价方法主要是根据GRADE方法,随机对照试验开始被定为高质量证据,观察性研究被定为低质量证据,然后根据是否存在研究缺陷、不一致性、间接性、不精确性和发表偏倚5种降级因素,或是否存在效应量大、剂量反应和所有合理的混杂偏倚增加对估计效应的把握度3种升级因素,综合评价后由关键结局对应的证据质量来确定最后证据质量等级。如果纳入证据是已发表的系统评价/Meta分析,则其质量评价采用AMSTAR量表进行评价,在11项条目中满足9条者确定为高质量的系统评价/Meta分析。

推荐方向和强度根据综合证据质量、利弊平衡、患者价值观和意愿,以及资源花费来确定[13]。指南制定小组召开多次全体共识会议,对每个具体问题和干预措施进行了充分的讨论。最后通过修改后的德尔菲法和GRADE表格进行投票表决。投票需遵守以下规则[14]:第一,对持续存在分歧的部分,推荐或反对某一干预措施至少需要获得50%的参与者认可,且持相反意见的参与者比例需低于20%,未满足此项标准将不产生推荐意见。第二,一个推荐意见被列为强推荐而非弱推荐,则需要得到至少70%的参与者认可。

6.利益关系与冲突的声明:本指南制定过程中,所有参与本指南专家研讨会的专家、指南工作组成员均已签署书面声明,与医药企业不存在指南相关的利益冲突。

7.指南实施中的有利因素和不利因素估计:(1)有利因素:①随着循证医学的思想在中国呼吸科医生中的普及和深入,对高质量的循证指南的客观需求日益提高;②咳嗽是临床上患者求诊最常见的症状,大量患者得不到有效诊治,严重影响患者的生活质量,并造成沉重的经济负担,咳嗽循证诊治指南有着很好的临床应用需求;③前两版咳嗽指南的推广应用为本次指南的实施奠定了良好基础。(2)不利因素:①鉴于不同层次的临床医生对指南的重要性以及推荐意见理解的差异,全面推广、宣传和实施本指南尚需时日;②有些单位尚未开展支气管激发试验、诱导痰细胞学检查、咳嗽频率监测和24 h食管pH值-多通道阻抗监测等检查,这些条件的限制可能会对本指南的推广和应用造成一定的影响。

8.指南的更新:计划每3~5年对指南进行更新。

9.指南修订专家组成员、秘书组成员及评议专家成员:名单详见文后。

10.指南设有专有名词英文缩写中英对照表以便读者阅读,具体见表2

点击查看表格
表2

专有名词英文缩写中英对照表

表2

专有名词英文缩写中英对照表

英文缩写 英文全拼 中文
AC atopic cough 变应性咳嗽
ACEI angiotensin converting enzyme inhibitor 血管紧张素转换酶抑制剂
CCIQ chronic cough impact questionnaire 慢性咳嗽影响问卷
CHS chronic cough hypersensitivity syndrome 慢性咳嗽高敏综合征
CQLQ cough-specific quality of life questionnaire 咳嗽专用生活质量问卷
CST cough suppression therapy 咳嗽抑制性治疗
CVA cough variant asthma 咳嗽变异型哮喘
DTT dithiothreitol 二硫苏糖醇
EB eosinophilic bronchitis 嗜酸粒细胞性支气管炎
FeNO fractional exhaled nitric oxide 呼出气一氧化氮
FEV1 forced expiratory volume in first second 第一秒用力呼气容积
GERC gastroesophageal reflux-related cough 胃食管反流性咳嗽
GerdQ gastroesophageal reflux disease questionnaire 胃食管反流病问卷
ICS inhaled corticosteroid 吸入性糖皮质激素
LCQ leicester cough questionnaire 莱切斯特咳嗽问卷
OSA obstructive sleep apnea 阻塞性睡眠呼吸暂停
PBB protracted bacterial bronchitis 迁延性细菌性支气管炎
PEF peak expiratory flow 呼气峰流量
PIC postinfectious cough 感染后咳嗽
PNDS postnasal drip syndrome 鼻后滴流综合征
PPI proton pump inhibitor 质子泵抑制剂
SAP symptom association probability 症状相关概率
SPT skin prick test 皮肤点刺试验
TRP transient receptor potential 瞬时受体电位通道蛋白
TRPA1 transient receptor potential ankyrin 1 瞬时受体电位锚蛋白亚型1
TRPV1 transient receptor potential vanilloid 1 瞬时受体电位香草酸亚型1
UACS upper airway cough syndrome 上气道咳嗽综合征
VAS visual analogue scale 视觉模拟评分
VPIC viral postinfectious cough 病毒感染后咳嗽
二、咳嗽的定义、分类与发生机制

咳嗽是机体的防御性神经反射,有利于清除呼吸道分泌物和有害因子,但频繁剧烈的咳嗽会对患者的工作、生活和社会活动造成严重影响。咳嗽通常按时间分为3类:急性咳嗽、亚急性咳嗽和慢性咳嗽。急性咳嗽<3周,亚急性咳嗽为3~8周,慢性咳嗽>8周[6]。咳嗽按性质又可分为干咳与湿咳。建议以每天痰量>10 ml作为湿咳的标准。不同类型的咳嗽具有不同的病因分布特点。慢性咳嗽病因较多,通常根据胸部X线检查有无异常可分为两类:一类为X线胸片有明确病变者,如肺炎、肺结核、支气管肺癌等;另一类为X线胸片无明显异常,以咳嗽为主要或唯一症状者,即通常所说的慢性咳嗽,此类咳嗽为本指南讨论的重点内容。国内慢性咳嗽患者以30~40年龄段最多,男女比例接近,而欧美地区以50~60年龄段最多[15],且女性比例明显高于男性。慢性咳嗽和空气污染密切相关[16,17,18,19]

非自主咳嗽反射由完整的咳嗽反射弧参与完成,咳嗽反射弧由咳嗽外周感受器、迷走传入神经、咳嗽高级中枢、传出神经及效应器(膈肌、喉、胸部和腹肌群等)构成。刺激支配气管、肺的C纤维以及对机械、酸敏感的有髓机械受体(Aδ纤维),能够直接诱发咳嗽。此外,分布于上气道、咽喉、食管的迷走神经受到刺激亦可能导致咳嗽的发生[20]。咳嗽受延髓咳嗽中枢控制,大脑皮层对此具有调节作用。咳嗽高敏感性是慢性咳嗽重要的病理生理机制[21,22,23],其机制与瞬时受体电位(TRP)通路如TRPV1以及TRPA1激活、气道炎症、神经通路及咳嗽中枢的易化有关[24,25,26,27,28]

慢性咳嗽可引起心血管、消化、神经、泌尿、肌肉骨骼等多个系统的并发症,如尿失禁、晕厥、失眠、焦虑等[2,29]

三、病史与实验室检查

通过仔细询问病史和体格检查能缩小咳嗽的诊断范围,提供病因诊断线索,甚至得出初步诊断并进行经验性治疗,或根据病史提供的线索选择有关检查,从而能更快地明确病因诊断[30]

1.询问病史:

询问咳嗽的持续时间、时相、性质、音色以及诱发或加重因素、体位影响、伴随症状等,了解痰液量、颜色及性状等和有无吸烟史、职业或环境刺激暴露史、服用ACEI类药物或其他药物史等对诊断具有重要价值[7](1D)。有特殊职业接触史应注意职业性咳嗽的可能。咳嗽可按持续时间分为急性、亚急性或慢性咳嗽,缩小诊断范围[7]。急性咳嗽主要为普通感冒与急性气管-支气管炎,亚急性咳嗽最常见的病因为感染后咳嗽(postinfectious cough,PIC)。咳嗽发生的时相亦有一定的诊断价值,夜间咳嗽为主的患者应首先考虑咳嗽变异型哮喘(cough variant asthma,CVA)的诊断[31,32](2B)。干咳主要见于非感染性咳嗽,湿咳则以感染性咳嗽多见,特别是痰量较多、咳脓性痰者,应首先考虑呼吸道感染性疾病[7,32](2C)。慢性支气管炎常咳白色黏液痰,并以冬、春季咳嗽为主。痰中带血或咳血者应考虑结核、支气管扩张和肺癌的可能。有过敏性疾病史和家族史者应注意排除过敏性鼻炎和支气管哮喘(哮喘)相关的咳嗽。伴随鼻塞、流涕、喷嚏、鼻后滴流感、咽后黏液附着感等,应首先考虑上气道咳嗽综合征(upper airway cough syndrome,UACS)的可能[32](2C)。伴随反酸、嗳气、胸骨后烧灼感等症状或者餐后咳嗽加重应考虑胃食管反流性咳嗽(gastroesophageal reflux-related cough,GERC)的诊断[32,33](2C)。

2.体格检查:

包括体型、鼻、咽、喉、气管、肺部等,双肺呼吸音及有无哮鸣音、湿啰音和爆裂音。肥胖体形者应注意睡眠呼吸暂停(OSA)或胃食管反流(GER)合并慢性咳嗽的可能。多数慢性咳嗽患者无异常体征。体格检查闻及呼气期哮鸣音时,提示哮喘。肺底闻及Velcro啰音,应考虑间质性肺疾病。如闻及吸气期哮鸣音,要警惕中心型肺癌或支气管结核。此外也应注意有无心界扩大、早搏、器质性杂音等心脏体征。

3.相关辅助检查:

主要包括影像学检查,诱导痰细胞学检查,肺功能检查和气道高反应性检查,FeNO检查,24 h食管pH值-多通道阻抗监测等。(1)影像学检查:建议将X线胸片作为慢性咳嗽的常规检查(2D)。如发现明显病变,根据病变特征选择相关检查。X线胸片如无明显病变,则按慢性咳嗽诊断流程进行检查(见附件1)。X线胸片如有可疑病变时,可进一步进行CT检查。胸部CT检查有助于发现纵隔前后肺部病变、肺内小结节、气管壁增厚、气管管壁钙化、气管狭窄、纵隔淋巴结肿大等,对于一些胸部X线检查不易发现的病变,一些少见的慢性咳嗽病因如支气管结石、复发性多软骨炎、支气管异物等具有重要诊断价值(1D)。高分辨率CT有助于诊断早期间质性肺疾病和非典型支气管扩张。怀疑鼻窦炎时,首选鼻窦CT检查[34](2D)。应避免短期内反复的X线检查。(2)肺功能检查:肺功能检查主要包括肺通气功能检查、支气管激发试验,对慢性咳嗽的病因诊断具有重要价值,推荐作为常规检测项目[35,36,37](1B),支气管激发阳性是诊断CVA的重要标准。无条件行支气管激发试验的医院也可监测PEF变异率[38,39](1B),PEF平均变异率>10%则支持CVA的诊断。(3)诱导痰细胞学检查:慢性咳嗽病因诊断和气道炎症最重要的一种无创检查方法,安全性和耐受性较好[40,41,42,43](1C)。诱导痰嗜酸粒细胞增高是诊断嗜酸粒细胞性支气管炎(eosinophilic bronchitis,EB)的主要指标(1B),亦可用于CVA的辅助诊断[40](1C)。诱导痰检测有助于指导ICS应用,使慢性咳嗽患者获益[41,42,43](1C)。建议采用单一浓度的高渗盐水进行超声雾化,但应尽量避免在48 h内对患者行多次诱导痰检查[44,45,46](1C)。(方法见附件2)。(4)FeNO水平检查:这是近年来开展的一项无创气道炎症检查技术,FeNO增高(>32 ppb)提示嗜酸粒细胞性炎症或激素敏感性咳嗽可能性大[47,48,49,50,51,52,53,54]。但FeNO筛查慢性咳嗽相关嗜酸粒细胞性炎症敏感性不高,大约40%的嗜酸粒细胞增高的患者FeNO水平正常[51,52,54,55,56](2C)。(5)变应原皮试和血清IgE检查:检测患者是否存在特应质和确定变应原类型,有助于变应性疾病(如过敏性鼻炎和变应性咳嗽)的诊断。约60%~70%的CVA和30%的EB患者存在特应质[31,57]。(6)24 h食管pH值-多通道阻抗监测:这是目前判断胃食管反流的最常用和最有效的方法。通过动态监测食管pH值的变化,获得24 h食管pH值<4的次数、最长反流时间、食管pH值<4占监测时间百分比等6项参数,最后以DeMeester积分表示反流程度。结合食管腔内阻抗可以识别弱酸或弱碱等非酸性反流。检查时实时记录反流相关症状,以获得反流与咳嗽症状的相关概率(symptom association probability,SAP),确定反流与咳嗽的关系(方法见附件3)。弱酸或弱碱等非酸反流检查需采用食管腔内阻抗监测(2C)。(7)支气管镜检查:不作为慢性咳嗽的常规检查,但对于常规检查未明确病因或针对常见病因治疗无效的不明原因慢性咳嗽患者,支气管镜检查可用于诊断或排除气道腔病变导致的咳嗽病因,如支气管肺癌、异物、结核、复发性多软骨炎等[10,58,59,60,61](2C)。(8)其他检查:外周血嗜酸粒细胞增高提示变应性疾病,但多数CVA和EB患者的外周血嗜酸粒细胞均在正常范围内。外周血嗜酸粒细胞显著增高(>20%)提示寄生虫感染、嗜酸粒细胞性肺炎。

四、咳嗽诊断原则与流程

急性咳嗽和亚急性咳嗽的诊断流程请参见第六部分和第七部分。

慢性咳嗽的病因诊断应遵循以下几条原则[5](1D):(1)重视病史,包括耳鼻咽喉和消化系统疾病病史、职业和环境因素暴露史、吸烟史及用药史。如有职业和环境因素暴露史、吸烟史及用药史,停止暴露或用药后咳嗽缓解则可明确诊断。(2)根据病史选择有关检查,由简单到复杂。EB、CVA是慢性咳嗽的最常见病因,约占国内慢性咳嗽病因的50%[62],因此建议将通气功能检查、支气管激发试验和诱导痰细胞学检查作为慢性咳嗽的一线检查[7,40,63](2B)。建议将FeNO检查作为诱导痰细胞学检查的补充手段[47,48,49,50,51,52,53](2C)。24 h食管pH值-多通道阻抗监测是诊断GERC的重要方法,但由于耗时费力,成本较高,建议列为二线检查(2D)。(3)先考虑常见病,后考虑少见病。慢性咳嗽患者应首先考虑UACS、CVA、EB、GERC、变应性咳嗽(atopic cough,AC)等常见病因的可能[37,62,64,65,66,67,68,69]。支气管镜检查仅对一些少见慢性咳嗽病因具有诊断价值。(4)诊断和治疗两者应同步或顺序进行。如检查条件不具备时,根据临床特征进行诊断性治疗,并根据治疗反应确定咳嗽病因[30],治疗无效时再选择有关检查(2C)。如有典型的鼻炎、鼻窦炎症状或鼻后滴流症状、体征,可先按UACS进行治疗。如有典型胃食管反流相关症状或进食后咳嗽,则先按GERC进行治疗。(5)治疗有效是明确病因诊断的前提。治疗部分有效但未完全缓解,应评估影响疗效的因素和是否存在其他慢性咳嗽的复合病因(2C),如UACS合并GERC、CVA或EB,GERC合并EB或CVA等。(6)治疗无效时应评估是否诊断错误,治疗力度和时间是否足够,有无影响治疗疗效的因素,如职业或环境暴露因素(2C)。

慢性咳嗽病因诊断流程图见附件1。

五、咳嗽的评估

咳嗽的评估主要包括视觉模拟评分、咳嗽症状积分、生活质量测评、咳嗽频率监测及咳嗽敏感性检测等,有助于病情评估及疗效观察[29,70]

1.VAS评分系统具有两个特点:

由患者根据自己的感受在标记0~10 cm的直线上划记相应刻度以表示咳嗽的程度,也可采用从0~100 mm标记。与咳嗽症状积分相比,VAS的评分等级划分更细,有助于治疗前后的纵向比较[29,70,71]

2.咳嗽症状积分:

采用咳嗽症状积分表进行相对量化的症状评分,用于咳嗽程度和疗效的临床评定。咳嗽症状积分表分为日间积分和夜间积分两部分,但不同级别之间不容易区分[29,70,71],具体见表3

点击查看表格
表3

咳嗽症状积分表

表3

咳嗽症状积分表

分值 日间咳嗽症状积分 夜间咳嗽症状积分
0 无咳嗽 无咳嗽
1 偶有短暂咳嗽 入睡时短暂咳嗽或偶有夜间咳嗽
2 频繁咳嗽,轻度影响日常活动 因咳嗽轻度影响夜间睡眠
3 频繁咳嗽,严重影响日常活动 因咳嗽严重影响夜间睡眠
3.咳嗽生活质量测评:

针对咳嗽的专用量表主要为慢性咳嗽影响问卷(CCIQ),包括咳嗽专用生活质量问卷(CQLQ)、莱切斯特咳嗽问卷(LCQ),均表现出良好的信度、效度及反应度,在系统评价咳嗽程度和疗效过程中逐渐显示其重要作用[29,71,72,73,74,75,76,77,78,79,80,81],推荐采用中文版LCQ对咳嗽相关生活质量进行评估[77](1A)。

4.咳嗽频率监测:

咳嗽症状积分、VAS评分和咳嗽生活质量测评仍为主观评价工具。咳嗽频率监测是对患者一定时间内发生的咳嗽频次、强度及其特征所进行的客观记录和分析,是客观评估咳嗽病情及疗效观察的理想方法[82,83,84]。受患者的主观耐受性影响,咳嗽频率不一定与患者自我感知的咳嗽严重程度呈正比。国内尚无此类仪器,临床应用受限。

5.咳嗽敏感性检查:

可用于药物的疗效判断和咳嗽机制的研究,尚不是临床常规检测项目。通过雾化方式使受试者吸入一定量的刺激物气溶胶颗粒,刺激相应的咳嗽感受器而诱发咳嗽,并以激发咳嗽≥2次或≥5次的吸入物浓度(C2和C5)作为咳嗽敏感性的指标。常用辣椒素吸入进行咳嗽激发试验(方法见附件4)。国内正常人辣椒素激发试验C5参考值≥125 μmol/L[22]。咳嗽敏感性增高是慢性咳嗽的重要特征,UACS、CVA、EB、AC及GERC等均可能出现咳嗽敏感性增高,以GERC和AC更为显著[23]。另外,病毒感染后咳嗽(viral postinfectious cough,VPIC)的咳嗽敏感性也会明显升高[21,85]。采用咳嗽激发试验评估咳嗽敏感性的安全性、耐受性和可重复性好,有助于识别咳嗽高敏患者,可作为定量评估慢性咳嗽的客观指标,但不能取代主观指标来评估咳嗽频率和严重程度[21,85,86,87,88,89]。女性咳嗽敏感性较男性高[90,91]

六、急性咳嗽的诊断与治疗

急性咳嗽的诊断主要应注意区分是否伴有重症疾病。根据病史、体格检查和选择相关检查进行鉴别。急性咳嗽有可能是一些严重疾病的征象,如急性心肌梗死、左心功能不全、肺炎、气胸、肺栓塞及异物吸入[92,93,94,95,96,97]。急性咳嗽的常见病因主要有普通感冒和急性气管-支气管炎。哮喘、慢性支气管炎和支气管扩张等原有疾病的加重也可导致咳嗽加重或急性咳嗽。此外,环境因素或职业因素暴露越来越多地成为急性咳嗽的原因。

(一)普通感冒

病毒感染是感冒的主要病因[96,98,99]。感冒诊断主要依靠病史与体格检查,通常不需要进行病毒培养、血清学检测、痰液检查或影像学检查(1D)[96,100]。临床表现除咳嗽外,还伴有其他上呼吸道相关症状,如流涕、喷嚏、鼻塞和鼻后滴流感、咽喉刺激感或不适,可伴发热,全身症状少见[94,98,99,100,101,102,103]。普通感冒的咳嗽常与鼻后滴流有关。流行性感冒除了咳嗽症状外,发热、肌痛等全身症状亦是常见表现[101,102,103,104]

普通感冒以对症治疗为主。(1)抗生素应用无法缩短感冒病程或减轻症状,且可能伴随不良反应。因此,感冒患者不推荐常规使用抗菌药物[96,105,106,107,108,109](1A)。(2)减充血剂:成人患者单剂应用减充血剂能够短时间缓解鼻塞症状,不良反应发生率低且程度较轻。减充血剂与第一代抗组胺药物联合应用能明显缓解咳嗽症状[110,111,112](1A)。(3)抗组胺药:单用第一代抗组胺药治疗无明显临床获益,不推荐单独使用[113,114,115,116](1A)。第一代抗组胺药如马来酸氯苯那敏(2~4 mg/次,3次/d)等联合减充血剂能够改善成人及青少年的感冒相关打喷嚏、鼻塞等多种症状,但应注意不良反应,儿童处方需谨慎[113,115,116](2A)。(4)解热镇痛药类:解热镇痛药主要针对普通感冒患者的发热、咽痛和全身酸痛等症状(1A)。对乙酰氨基酚是临床上使用最为广泛的解热镇痛药之一。以咳嗽等呼吸道症状为主要表现而无发热、头痛、肌痛症状的普通感冒患者,不建议使用非甾体类抗炎药物治疗[100,117,118,119,120,121,122,123](1A)。(5)镇咳药物:咳嗽剧烈者,必要时可使用中枢性或外周性镇咳药。对于普通感冒所致的咳嗽患者,中枢性止咳药物(如右美沙芬、可待因)缓解咳嗽的效果有限,不推荐常规使用[100,114,116,124](2D)。推荐由第一代抗组胺药物、减充血剂联合镇咳药物的复方制剂治疗伴有咳嗽的普通感冒[100,116,125,126,127,128,129,130](1A)。(6)异丙托溴胺:鼻喷剂能够改善成人以及青少年感冒患者的流涕和喷嚏症状,但需警惕鼻干、鼻充血和鼻衄等不良反应[131,132](2A)。中医中药治疗感冒有一定的效果,但缺乏高质量的临床研究数据[133,134]

(二)急性气管-支气管炎

急性气管-支气管炎是由于生物性或非生物性因素引起的气管-支气管黏膜的急性炎症。病毒感染是最常见的病因,鼻病毒和流感病毒多见,少部分可由细菌引起[99,135,136,137,138,139,140,141]。冷空气、粉尘及刺激性气体也可引起此病。大部分患者呈自限性。婴幼儿和年老体弱者有可能发展为迁延性支气管炎。

1.临床表现:

起病初期常有上呼吸道感染症状。随后咳嗽可渐加剧,伴或不伴咳痰,伴细菌感染者常咳黄脓痰。急性气管-支气管炎常呈自限性,全身症状可在数天内消失,但咳嗽、咳痰一般持续2~3周。X线检查无明显异常或仅有肺纹理增加。体格检查双肺呼吸音粗,有时可闻及湿性或干性啰音。

2.诊断与鉴别诊断:

诊断主要依据临床表现,通常无需进行病毒培养、血清学检测或痰液检查[136,142,143,144](1D)。咳嗽持续3周以内,伴或不伴咳痰,根据临床症状和(或)影像学检查排除感冒、肺炎、哮喘、慢性阻塞性肺疾病(慢阻肺)急性加重后,应考虑急性支气管炎诊断[96,142,144,145,146,147,148,149](1D)。考虑急性支气管炎诊断的患者,如心率≤100次/min、呼吸频率≤24次/min、体温≤38 ℃且胸部无异常体征者肺炎可能性小[96,147,150,151,152](3C)。

3.治疗:

治疗原则以对症处理为主。剧烈干咳者可适当应用镇咳剂,有痰而不易咳出者使用祛痰剂或黏痰溶解剂可在一定程度上缓解咳嗽症状[153,154,155,156,157,158](1B)。缓释愈创甘油醚可缓解急性呼吸道感染的症状[153,155,156](2A)。国外证据表明疑诊为急性支气管炎的患者,不必常规给予抗生素治疗,因其治疗效果不明确[96,105,107,147,159,160,161,162,163,164,165,166,167](1A)。对于咳黄脓痰的急性支气管炎患者,推荐给予抗生素治疗(1D)。急性支气管炎患者,若不给予抗生素治疗,应向患者解释,因为许多患者根据先前的经验与期望,常诉求接受抗生素治疗[168,169,170,171,172,173,174](1B)。如有细菌感染,如咳脓性痰或外周血白细胞增高者,可依据感染的病原体及药物敏感试验选择抗菌药物。在未得到病原菌阳性结果之前,可选用β-内酰胺类、喹喏酮类等口服抗菌药物[7]。不必常规使用β2受体激动剂,而伴咳喘的成人急性支气管炎,使用β2受体激动剂可能受益[175](2A)。目前仍没有高质量证据证实中草药对于治疗急性支气管炎的有效性和安全性[176,177]

七、亚急性咳嗽的诊断与治疗

亚急性咳嗽最常见的原因是PIC,其次为CVA、EB、UACS等[178,179](1B)。在处理亚急性咳嗽时,首先要明确咳嗽是否继发于先前的呼吸道感染,并进行经验性治疗。治疗无效者,再考虑其他病因并参考慢性咳嗽诊断流程进行诊治。单纯依靠感冒或上呼吸道感染的病史和患者的咳嗽症状诊断感染后咳嗽可能会造成EB、CVA的漏诊[178],建议有条件时应进行支气管激发试验和诱导痰细胞学检查(2C)。一些所谓"顽固性感染后咳嗽"可能为EB、CVA和GERC[178]

当呼吸道感染的急性期症状消失后,咳嗽仍然迁延不愈,多表现为刺激性干咳或咳少量白色黏液痰,通常持续3~8周,X线胸片检查无异常[103,179,180,181],称之为PIC,其中以病毒感冒引起的咳嗽最为常见,又称为"感冒后咳嗽"。既往有PIC病史和咳嗽敏感性增加的患者更容易发生PIC[178,180]

PIC常为自限性,多能自行缓解,但也有部分患者咳嗽顽固,甚至发展为慢性咳嗽。病毒感染后咳嗽不必使用抗菌药物治疗。对部分咳嗽症状明显的患者建议短期应用镇咳药、抗组胺药加减充血剂等。复方甲氧那明治疗PIC有效[182](2C)。孟鲁司特对感染后咳嗽治疗无效,不建议使用[183](2B)。ICS治疗PIC效果不确切,不建议使用[184,185](2B)。中医认为PIC系风邪犯肺、肺气失宣所致,治疗宜疏风宣肺、止咳利咽,采用麻黄、紫苏叶、地龙、枇杷叶及紫苏子等组成的苏黄止咳胶囊对PIC治疗有效[186](2C)。

迁延性感染性咳嗽,常由肺炎支原体和肺炎衣原体引起,亦可由细菌引起,致病菌常为流感嗜血杆菌和肺炎链球菌,多见于婴幼儿及年老体弱者[187,188,189]。血清学抗体检测是诊断支原体/衣原体感染的最有效的手段,有助于临床早期诊断,可作为常规辅助检查[190,191](1C)。血冷凝集素≥1∶64,急性期和恢复期双份血清支原体IgM抗体滴度呈4倍增长,表明近期有支原体感染[190](2D)。衣原体血清抗体效价≥4倍或单次抗体滴度IgM≥1∶16或IgG≥1∶512对衣原体感染有诊断意义。肺炎支原体和肺炎衣原体引起的迁延性感染性咳嗽使用大环内酯类或喹喏酮类抗菌药物治疗有效[7](2C)。由革兰阳性球菌引起的迁延性感染性咳嗽可使用阿莫西林或者头孢菌素类药物,疗程需2~3周[192,193](2B)。

青少年、成人咳嗽患者中,百日咳血清抗体滴度较高时,应考虑百日咳感染的可能性[194,195,196](2C)。根据百日咳的典型症状,如阵发性咳嗽、咳嗽后呕吐以及吸气相喘息症状来诊断百日咳感染价值有限[197,198](2A)。抗百日咳毒素抗体IgG(anti-PT-IgG)、PCR、细菌培养在百日咳诊断中具有一定价值[199,200,201,202,203,204](2C)。

一旦诊断百日咳,应尽早(起病后1~2周卡他期内)开始大环内酯类药物治疗,虽然治疗不能改变疾病进程,但能够降低疾病的传染性[11,205](1B)。对于非卡他期(迁延期)百日咳患者,不建议使用抗生素治疗[206](1A)。不建议使用皮质类固醇、β2-肾上腺素受体激动剂、百日咳特异性免疫球蛋白和抗组胺剂药物治疗百日咳[207](1A)。

八、常见慢性咳嗽病因的诊断与治疗

慢性咳嗽的诊断应首先考虑CVA、UACS、EB和GERC等常见病因(1A)。国内慢性咳嗽病因调查结果显示,AC亦是慢性咳嗽的常见病因,上述疾病约占慢性咳嗽病因的70%~95%[62,64,66,67,68,69]。多数慢性咳嗽与感染无关[208],因此应避免滥用抗菌药物治疗(1C)。

(一)UACS(PNDS)

由于鼻部疾病引起分泌物倒流鼻后和咽喉等部位,直接或间接刺激咳嗽感受器,导致以咳嗽为主要表现的临床综合征称鼻后滴流综合征(postnasal drip syndrome,PNDS)。由于目前无法明确上呼吸道相关的咳嗽是否由鼻后滴流直接刺激或是炎症刺激上呼吸道咳嗽感受器所致,2006年美国咳嗽诊治指南建议用UACS替代PNDS[209]。有关PNDS的概念,及是否应用上气道疾病来替代PNDS及其与咳嗽的联系仍然存在异议[210]。部分具有典型鼻后滴流症状和体征的患者,使用PNDS的诊断更为直观、形象。因此,本指南仍保留PNDS这一名词。

UACS/PNDS是引起慢性咳嗽最常见病因之一,其基础疾病以鼻炎、鼻窦炎为主,需在针对性治疗或经验治疗有效后确认[62,211,212,213](1B)。除了鼻部疾病外,UACS/PNDS可能还与咽喉部的疾病有关,如慢性咽喉炎、慢性扁桃体炎等[7,211]。咽喉部疾病引起的慢性咳嗽可能与喉咳嗽高敏感性有关[214,215]

1.临床表现:

(1)症状:除咳嗽、咳痰外,可表现鼻塞、鼻腔分泌物增加、频繁清嗓、咽后黏液附着及鼻后滴流感。变应性鼻炎还表现为鼻痒、喷嚏、水样涕及眼痒等。鼻-鼻窦炎常有鼻塞和脓涕等症状,也可伴有面部疼痛/肿胀感和嗅觉异常等[216]。(2)体征:变应性鼻炎的鼻黏膜主要表现为苍白或水肿,鼻道及鼻腔底可见清涕或黏涕。非变应性鼻炎的鼻黏膜多表现为肥厚或充血样改变,部分患者口咽部黏膜可呈鹅卵石样改变或咽后壁附有黏脓性分泌物。(3)辅助检查:慢性鼻窦炎的影像学检查征象为鼻窦黏膜增厚、鼻窦内液平面等。咳嗽具有季节性提示与接触特异性变应原(例如花粉、尘螨)有关,变应原检查有助于诊断。慢性鼻窦炎涉及多种类型,如病毒性、细菌性、真菌性和过敏性鼻窦炎,部分合并鼻息肉。怀疑鼻窦炎时,首选CT检查,必要时行鼻内镜、变应原和免疫学检查等。

2.诊断:

UACS/PNDS涉及鼻、鼻窦、咽、喉等多种基础疾病,症状及体征差异较大且多无特异性,因此,必须综合病史、体征及相关检查,在除外合并下气道疾病、GERC等复合病因的情况下针对基础疾病进行治疗,咳嗽得以缓解,诊断方能确定。UACS/PNDS诊断建议参考以下标准[6](2C):(1)发作性或持续性咳嗽,以白天为主,入睡后较少;(2)有鼻部和(或)咽喉疾病的临床表现和病史;(3)辅助检查支持鼻部和(或)咽喉疾病的诊断;(4)针对病因治疗后咳嗽可缓解。

3.治疗:

依据导致UACS/PNDS的基础疾病而定。(1)病因治疗:1)对于非变应性鼻炎以及普通感冒,治疗首选第一代抗组胺药和减充血剂(1A),大多数患者在初始治疗后数天至2周内起效。2)变应性鼻炎患者首选鼻腔吸入糖皮质激素和口服第二代抗组胺药治疗[217](1A)。鼻吸入激素包括布地奈德、丙酸氟地卡松和糠酸莫米松等。第二代抗组胺药常用的有氯雷他定、地氯雷他定及枸地氯雷他定等。若无第二代抗组胺药,第一代抗组胺药亦有同样效果,但嗜睡等不良反应较明显。白三烯受体拮抗剂治疗过敏性鼻炎有效[218,219](1A)。症状较重、常规药物治疗效果不佳的变应性鼻炎,特异性变应原免疫治疗可能有效,但起效时间较长[217,220,221](2B)。3)慢性鼻窦炎:①慢性鼻窦炎患者鼻窦分泌物细菌培养以金黄色葡萄球菌或表皮葡萄球菌、肺炎球菌为主,但要注意的是多数情况下为定植菌,可能与急性发作有关,另外培养菌群可有细菌生物膜形成[222,223]。细菌性鼻窦炎多为混合感染,抗感染是重要治疗措施。抗菌谱应覆盖革兰阳性菌、阴性菌及厌氧菌,急性发作者不少于2周,慢性建议酌情延长使用时间。常用药物为阿莫西林/克拉维酸、头孢类或喹诺酮类[5]。②长期低剂量大环内酯类抗生素对慢性鼻窦炎的治疗作用证据有限[224,225],不建议作为常规治疗(3B)。③联合鼻吸入糖皮质激素,疗程3个月以上。推荐鼻用激素治疗伴有鼻息肉的慢性鼻窦炎,可避免不必要的手术[226](1A)。对于合并鼻息肉的慢性鼻窦炎患者,口服激素序贯局部鼻吸入激素的治疗效果优于单用鼻吸入激素治疗[227](2A)。④药物治疗还是手术治疗的效果更佳,目前尚无定论[228]。内科治疗效果不佳时,建议咨询专科医师,必要时可经鼻内镜手术治疗[229](2B)。(2)对症治疗:①局部减充血剂可减轻鼻黏膜充血水肿,有利于分泌物的引流,缓解鼻塞症状,但不宜长期应用,需要警惕其导致药物性鼻炎的不良反应。鼻喷剂疗程一般<1周[230,231,232,233](1B),建议联合第一代口服抗组胺药和减充血剂,疗程2~3周[234,235,236,237,238](2D)。②黏液溶解剂(羧甲司坦/厄多司坦)治疗慢性鼻窦炎可能获益[239,240,241](2B)。③生理盐水鼻腔冲洗作为慢性鼻窦炎及慢性鼻炎的辅助治疗措施,安全性佳,但其有效性仍有待进一步证实[242,243,244,245,246]。避免或减少接触变应原有助于减轻变应性鼻炎的症状。

(二)CVA

CVA是哮喘的一种特殊类型,咳嗽是其唯一或主要临床表现,无明显喘息、气促等症状或体征,但存在气道高反应性。CVA是慢性咳嗽的最常见病因[37,64,66,67,68,69],国内多中心调查结果显示约占慢性咳嗽原因的三分之一[62]。有些哮喘患者肺功能已有明显下降,但咳嗽仍为唯一症状或主要症状,也有部分典型哮喘患者在喘息症状缓解后,咳嗽成为主要症状[247]

1.临床表现:

主要表现为刺激性干咳,通常咳嗽比较剧烈,夜间及凌晨咳嗽为其重要特征[32]。感冒﹑冷空气、灰尘及油烟等容易诱发或加重咳嗽,但其他原因的慢性咳嗽也同样存在这些诱发因素[32]

2.诊断:

应根据慢性咳嗽病史及特点、支气管激发试验和抗哮喘治疗的有效性综合分析做出诊断。支气管舒张剂治疗有效缓解咳嗽是CVA的一个重要临床特征,但仍有部分(约30%)哮喘患者对单纯支气管舒张剂治疗反应不佳,不建议将支气管舒张剂治疗有效作为一条诊断标准[248,249](2B)。但PEF平均变异率可作为一条诊断标准[250]。诱导痰嗜酸粒细胞增高和FeNO增高有助于CVA的诊断[40,47,50,53]

推荐采用以下诊断标准(1A):(1)慢性咳嗽,常伴有明显的夜间刺激性咳嗽。(2)支气管激发试验阳性,或PEF平均变异率>10%,或支气管舒张试验阳性。(3)抗哮喘治疗有效。

3.治疗:

CVA治疗原则与典型哮喘相同。(1)ICS联合支气管舒张剂治疗比单用ICS或支气管舒张剂治疗能更快速和有效地缓解咳嗽症状[251,252]。推荐使用吸入糖皮质激素和支气管舒张剂(β2受体激动剂)的复方制剂(1B),如布地奈德/福莫特罗、氟替卡松/沙美特罗。建议治疗时间至少8周以上,部分患者需要长期治疗(2D)。(2)如果患者症状或气道炎症较重,或对吸入激素治疗反应不佳时,建议短期口服糖皮质激素治疗(10~20 mg/d,3~5 d)(2C)。如果口服激素治疗无效,需注意是否存在诊断错误,支气管激发试验假阳性或其他疾病,如早期的嗜酸性肉芽肿性多血管炎,或存在一些影响疗效的因素。(3)白三烯受体拮抗剂治疗CVA有效,能够减轻患者咳嗽症状、改善生活质量并减缓气道炎症[253,254,255,256,257](2B)。少数对ICS治疗无效的患者,使用白三烯受体拮抗剂治疗可能有效。治疗疗程及对气道炎症的抑制作用仍有待进一步研究。(4)中医认为CVA与风邪犯肺、肺气失宣有关,治疗宜疏风宣肺、止咳利咽,采用苏黄止咳胶囊治疗有效[258](2B)。

4.预后:

部分CVA患者会发展为典型哮喘,病程长、气道反应性高、诱导痰嗜酸粒细胞高是发展为典型哮喘的危险因素。长期吸入激素可能有助于预防典型哮喘的发生[259,260,261](2B)。

(三)EB

EB是慢性咳嗽的常见病因,约占慢性咳嗽病因的13%~22%[37,65,66,69]。EB以气道嗜酸粒细胞浸润为特征,痰嗜酸粒细胞增高,但气道炎症范围较局限,平滑肌内肥大细胞浸润密度低于哮喘患者,其炎症程度、氧化应激水平均不同程度低于CVA患者[262,263,264,265]。大约三分之一患者合并变应性鼻炎[57,65]

1.临床表现:

主要为慢性刺激性咳嗽,常是唯一的临床症状,干咳或咳少许白色黏液痰,多为白天咳嗽,少数伴有夜间咳嗽。患者对油烟、灰尘、异味或冷空气比较敏感,常为咳嗽的诱发因素。患者无气喘、呼吸困难等症状。肺通气功能和呼气峰流速变异率正常,无气道高反应。

2.诊断:

EB临床表现缺乏特征性,部分临床表现类似CVA,体格检查无异常发现,痰嗜酸粒细胞增高是主要诊断依据。国内正常人诱导痰嗜酸粒细胞比例<2.5%[63]。FeNO检测诊断EB的敏感性较低,增高(FeNO>32 ppb)提示嗜酸粒细胞性相关慢性咳嗽(如EB或CVA)[48,50,52,54](2C)。既往有接触面粉、异氰酸和氯氨等引起EB的报道[266,267,268,269,270,271](2C),因此EB诊断时要考虑职业因素。EB的诊断必须结合病史,诱导痰(或支气管灌洗液)嗜酸粒细胞计数、气道反应性测定和激素治疗有效等综合判断(1B)。推荐以下诊断标准:(1)慢性咳嗽,表现为刺激性干咳或伴少量黏痰。(2)X线胸片正常。(3)肺通气功能正常,无气道高反应性,呼气峰流速平均周变异率正常。(4)痰细胞学检查嗜酸粒细胞比例≥2.5%。(5)排除其他嗜酸粒细胞增多性疾病。(6)口服或吸入糖皮质激素有效。

3.治疗:

EB对糖皮质激素治疗反应良好,治疗后咳嗽很快消失或明显减轻。建议首选ICS治疗,持续应用8周以上(2C)。初始治疗可联合应用泼尼松口服每天10~20 mg,持续3~5 d[7]。如果小剂量糖皮质激素无效,应注意是否存在嗜酸粒细胞增高有关的全身性疾病,如嗜酸粒细胞增高综合征,嗜酸性肉芽肿性多血管炎等。

4.预后:

半数以上的EB患者治疗缓解后会复发,合并鼻炎和持续性嗜酸粒细胞炎症是复发的危险因素[57]。国外报道少数EB患者可发展为慢性气流阻塞性疾病(哮喘或慢阻肺)[272,273,274]。中国对EB患者的长期随访研究结果显示其肺功能保持稳定,表明EB不是慢性气道阻塞性疾病的前期阶段,而是独立疾病[57]

(四)GERC

因胃酸和其他胃内容物反流进入食管,导致以咳嗽为突出表现的临床综合征,属于胃食管反流病的一种特殊类型,是慢性咳嗽的常见原因[35,62,64,65,66,67]。发病机制涉及微量误吸、食管-支气管反射、食管运动功能失调、植物神经功能失调与气道神经源性炎症等,目前认为食管-支气管反射引起的气道神经源性炎症起着主要作用[275,276,277,278]。除胃酸反流以外,部分患者还与弱酸或弱碱等异常非酸反流(如胆汁反流)有关。

1.临床表现:

除咳嗽外,40%~68%的GERC患者可伴反酸、胸骨后烧灼感及嗳气等典型反流症状,但也有不少患者以咳嗽为唯一的表现[33,279]。咳嗽大多发生在日间和直立位以及体位变换时,干咳或咳少量白色黏痰。进食酸性、油腻食物容易诱发或加重咳嗽[33,280]

2.建议采用以下诊断标准(2C):

(1)慢性咳嗽,以白天咳嗽为主。(2)24 h食管pH值-多通道阻抗监测DeMeester积分≥12.70[281],和(或)SAP≥80%[282]。症状指数≥45%可用于GERC的诊断[283]。但需要注意,少部分合并或以非酸反流(如胆汁反流)为主的患者,其食管pH值监测结果未必异常。食管pH值监测联合腔内阻抗能识别包括非酸反流在内的所有胃食管反流,是目前最灵敏可靠的GERC诊断手段。(3)抗反流治疗后咳嗽明显减轻或消失。

24 h食管pH值监测正常不能排除GERC,因为患者可能存在非酸或弱酸反流,或间歇性反流(2C)。对于没有条件进行24 h食管pH值-多通道阻抗监测的慢性咳嗽患者,如果其具有(1)患者有明显的进食相关性咳嗽,如餐后咳嗽、进食咳嗽等。(2)患者伴有典型的胸骨后烧灼感、反酸等反流症状或胃食管反流病问卷(GerdQ)≥8分。(3)排除CVA、UACS、EB等慢性咳嗽的常见原因,或按这些疾病治疗效果不佳等特征时应考虑GERC的可能,可进行诊断性治疗[7,32,284](2B)。推荐采用PPI试验[285](2C):服用标准剂量质子泵抑制剂(如奥美拉唑20~40 mg,2次/d),诊断性治疗时间不少于2周。抗反流治疗后咳嗽消失或显著缓解,可以临床诊断GERC。相比于24 h食管pH值-多通道阻抗监测等检查更经济简单[285],但特异性较低。

存在异常反流客观证据的慢性咳嗽患者,经标准抗反流药物治疗无效则应考虑非酸反流等因素引起的难治性GERC,亦可能咳嗽与反流无关或为复合病因引起的慢性咳嗽[286,287,288,289](2C)。

3.治疗:

(1)调整生活方式:体重超重患者应减肥,避免过饱和睡前进食,避免进食酸性、辛辣和油腻食物,避免饮用咖啡、酸性饮料及吸烟,避免剧烈运动(2D)。(2)制酸药:推荐抗酸疗法作为GERC的标准治疗方法[290,291,292](1A)。常选用质子泵抑制剂(如奥美拉唑、兰索拉唑、雷贝拉唑及埃索美拉唑等)或H2受体拮抗剂(雷尼替丁或其他类似药物),其中质子泵抑制剂的抑酸效果和症状缓解速度更佳,但需餐前半小时或1 h服用[293],治疗疗程至少8周。(3)促胃动力药:大部分GERC患者有食管运动功能障碍,建议在制酸药的基础上联合促胃动力药,如多潘立酮、莫沙必利等[294](1D)。

经上述治疗效果欠佳时,应考虑治疗药物的剂量及疗程是否足够,或是否存在复合病因。治疗无效者,建议再行24 h食管pH值-多通道阻抗监测,以判断是否为治疗力度不足或其他原因导致的咳嗽(2C)。难治性GERC可使用巴氯芬治疗,但存在着一定程度的嗜睡、困倦等不良反应[287,295,296,297](2C)。常规剂量PPI治疗无效时,加大PPI治疗剂量可能有效[298,299,300,301](2A)。使用某种PPI治疗无效时,换用其他的PPI可能有效[302](2C)。在常规剂量PPI基础上,加用H2受体拮抗剂能使部分难治性胃食管反流或夜间酸反流的症状得到改善[303](2C)。必要时咨询相关专科医师共同研究治疗方案,少数内科治疗失败的严重反流患者,抗反流手术治疗(主要为经腹腔镜胃底黏膜折叠术)或内镜治疗可能有效[304,305,306,307,308,309,310,311,312,313,314,315](2C),目前尚无内镜治疗与药物治疗直接比较的数据。因术后并发症及复发等问题,对手术指征应严格把握。建议在严格抗反流内科治疗后,咳嗽仍不能缓解,严重影响患者生活质量,24 h食管pH值-多通道阻抗监测结果显示仍然存在严重的反流,方考虑手术治疗(2D)。

(五)AC

临床上某些慢性咳嗽患者,具有特应质,痰嗜酸粒细胞正常,无气道高反应性,糖皮质激素及抗组胺药物治疗有效,将此类咳嗽定义为变应性咳嗽。国内研究结果显示,变应性咳嗽是慢性咳嗽的常见原因[37,62,66,69]。慢性咳嗽患者如果支气管激发试验阴性,痰嗜酸粒细胞不高,应考虑AC的可能(2C)。其发病机制有待进一步明确。日本报道了真菌(担子菌)定植作为变应原引起的慢性咳嗽(fungal associated cough),抗真菌治疗有效[316]。其他国家和地区有无真菌相关性咳嗽尚待证实。

1.临床表现:

刺激性干咳,多为阵发性,白天或夜间均可咳嗽,油烟、灰尘、冷空气、讲话等容易诱发咳嗽,常伴有咽喉发痒。通气功能正常,无气道高反应性,诱导痰细胞学检查嗜酸粒细胞比例正常。

2.建议采用以下诊断标准(2C):

(1)慢性咳嗽,多为刺激性干咳。(2)肺通气功能正常,支气管激发试验阴性。(3)诱导痰嗜酸粒细胞不增高。(4)具有下列指征之一:①有过敏性疾病史或过敏物质接触史。②变应原皮试阳性。③血清总IgE或特异性IgE增高。(5)糖皮质激素或抗组胺药治疗有效。

3.治疗:

糖皮质激素或抗组胺药物治疗有效。吸入糖皮质激素治疗4周以上,初期可短期口服糖皮质激素(3~5 d)(2C)[7,10]

九、其他慢性咳嗽病因的诊断与治疗
(一)慢性支气管炎(chronic bronchitis)

定义:咳嗽、咳痰连续2年以上,每年累积或持续至少3个月,并排除其他引起慢性咳嗽的病因。咳嗽、咳痰一般晨间明显,咳白色泡沫痰或黏液痰,加重期亦有夜间咳嗽。

在社区流行病学调查中慢性支气管炎是常见疾病,然而在专科门诊诊治的慢性咳嗽患者中,慢性支气管炎只占少数。造成这种差异的原因可能与目前慢性支气管炎的诊断缺乏客观标准,在流行病学调查时易将许多其他病因引起的慢性咳嗽患者误诊为慢性支气管炎有关。作为慢阻肺的一个特殊表型-慢性支气管炎型慢阻肺,慢性咳嗽、咳痰可与增加急性加重发病率及死亡率相关[317,318]

亚洲地区的研究结果表明,慢性支气管炎急性发作患者多为流感嗜血杆菌、卡他莫拉菌、肺炎球菌、肺炎克雷伯菌、铜绿假单胞菌和不动杆菌感染,应对当地细菌耐药情况进行流行病学调查并指导抗生素选择[319,320,321,322,323](1B)。莫西沙星、左氧氟沙星,因其广谱抗菌活性且药物相关不良事件少,已成为慢性支气管炎急性发作时的主要治疗药物[319,321,322](2B)。

(二)支气管扩张症(bronchiectasis)

由于慢性炎症引起气道壁破坏,导致不可逆性支气管扩张和管腔变形,主要病变部位为亚段支气管。典型临床表现为慢性咳嗽、大量咳脓痰及间断性咯血,常合并慢性鼻窦炎。典型病史者诊断并不困难,无典型病史的轻度支气管扩张症则容易误诊。X线胸片改变(如卷发样征)对诊断有提示作用,怀疑支气管扩张症时,最佳诊断方法为胸部高分辨率CT[324,325,326](1C)。

不推荐稳定期支气管扩张症患者常规吸入激素[326,327,328,329,330,331,332,333],但对存在慢性气流阻塞或气道高反应性的稳定期纤维化支气管扩张症患者,联合吸入ICS+LABA或LAMA可改善慢性咳嗽症状[324,325,334](1A)。体位引流对支气管扩张患者具有一定的作用(2D)。对于重度支气管扩张症患者,静脉抗生素治疗可能有助于减轻咳嗽症状和急性加重,建议在患者情况差和需要住院治疗时,或所感染的病原菌对口服抗生素治疗无反应,或口服抗生素治疗失败时应用[332,335,336](2B)。大环内酯类药物有助于改善稳定期支气管扩张症患者症状、减少急性加重风险,但要注意长期应用的细菌耐药性及药物毒副作用等问题[337,338,339,340,341](2B)。不推荐常规应用吸入性气道黏液溶解剂[342](1A)。他汀类药物[343,344](2B)、甘露醇吸入也可能有助于支气管扩张症治疗,但不推荐常规临床应用[345,346,347,348](2B)。

(三)气管-支气管结核(bronchial tuberculosis)

国内气管-支气管结核在慢性咳嗽中并不罕见,多数合并肺结核,也有不少患者仅表现为单纯性支气管结核,其主要症状为慢性咳嗽,可伴有低热、盗汗、消痩等结核中毒症状,部分患者咳嗽是其唯一的临床表现,体格检查有时可闻及局限性吸气期干啰音。X线胸片无明显异常改变,临床上容易误诊及漏诊[349,350,351,352,353]

对怀疑气管-支气管结核的患者应首先进行痰涂片找抗酸杆菌。部分患者结核杆菌培养可阳性。X线胸片的直接征象不多,可发现气管、主支气管的管壁增厚、管腔狭窄或阻塞等病变。CT检查(特别是高分辨率CT)显示支气管病变征象较X线胸片更为敏感,尤其能显示叶以下支气管的病变,可以间接提示诊断。支气管镜检查是确诊气管-支气管结核的主要手段,镜下常规刷检和组织活检阳性率高[354](2C)。治疗原则参考有关结核指南进行。

(四)ACEI和其他药物诱发的咳嗽

咳嗽是ACEI类降压药物的常见不良反应,发生率约5%~25%,在慢性咳嗽中的比例约为1.7%~12%[355,356,357,358,359,360]。ACEI引起咳嗽的独立危险因素包括:吸烟史、ACEI引起咳嗽的既往史[361]、东亚人(华人)[362]等,与年龄、性别[363]和ACEI剂量无关[364]

停用ACEI后咳嗽缓解可以确诊。通常停药1~4周后咳嗽消失或明显减轻[365]。对于既往出现过或现在有可能是ACEI相关咳嗽的患者,可用血管紧张素Ⅱ受体拮抗剂替代ACEI类药物治疗原发病(2D)。

除了ACEI,亦有麦考酚酸吗乙酯,呋喃妥因,异丙酚,β-受体阻断剂,来氟米特,辛伐他汀,γ-干扰素,奥美拉唑等亦可引起咳嗽的个案报道[29,366,367,368]

(五)支气管肺癌(bronchogenic carcinoma)

咳嗽常为中心型肺癌的早期症状和常见症状,发生率为25%~86%不等[369,370,371]。早期普通X线检查常无异常,故容易漏诊、误诊。因此在详细询问病史后,对有长期吸烟史,出现刺激性干咳、痰中带血、胸痛及消瘦等症状或原有咳嗽性质发生改变的患者,应高度怀疑肺癌的可能,进一步进行影像学检查和支气管镜检查(2D)。肺癌咳嗽的治疗关键在于原发灶的治疗,放疗、化疗、射频消融术及手术切除肺部肿瘤能够缓解肺癌患者的咳嗽症状[372,373,374](1A)。肺癌手术后咳嗽是临床上常见问题,机制不清。甲磺司特可缓解肺癌术后的咳嗽[370,375](2C)。顽固性咳嗽可用中枢性或周围性止咳药对症治疗。

(六)心理性咳嗽(psychologic cough)

心理性咳嗽是由于患者严重心理问题引起,又称为习惯性咳嗽、心因性咳嗽。儿童相对常见。在精神疾病分类中,没有心理性疾病分类的诊断名词,发病机制可能不是单一的心理因素,而与中枢调节紊乱有关,因此称之为中枢性咳嗽可能更为合理[376]。典型表现为日间咳嗽,专注于某一事物及夜间休息时咳嗽消失,常伴随焦虑症状。多种心理因素,如感觉、信念、情绪、学习及习惯方式等可导致咳嗽,临床应予以重视[377]

目前心理性咳嗽的诊断系排它性诊断,缺乏特异性诊断标准,只有在慢性咳嗽的常见病因和少见病因排除后才能考虑此诊断。对于儿童心理性咳嗽患者,暗示疗法、心理疏导等心理治疗措施可获益[378,379,380,381,382,383](2B)。可以短期应用止咳药物辅助治疗。对年龄大的患者可适当应用抗焦虑或抗忧郁等精神类药物,辅以心理干预治疗。儿童患者应注意与抽动秽语综合征相鉴别。

(七)其他少见和罕见慢性咳嗽病因

少见和罕见慢性咳嗽病因所占比例不高,但涉及病因繁多,表4列举了一些国内外文献报道的慢性咳嗽少见和罕见病因[59,384,385,386,387,388,389,390,391,392,393,394,395,396,397,398,399,400,401,402,403,404,405,406,407,408,409,410,411,412,413,414,415,416,417,418,419,420,421,422]

点击查看表格
表4

慢性咳嗽少见病因

表4

慢性咳嗽少见病因

上气道疾病 声门下多形性腺瘤、声门下黏膜相关组织淋巴瘤、喉癌、会咽发育不全、舌根异位涎腺、扁桃体肿大、悬雍垂过长、OSA
气管疾病 气管支气管软化症、骨化性支气管病、复发性软骨炎、巨大气管支气管征、气管狭窄、支气管内错构瘤、气管憩室、支气管异物、气管腺样囊腺癌、气管支气管淀粉样变、支气管结石
肺部疾病 肺泡微结石症、肺间质纤维化、肺泡蛋白沉积症、淋巴管肌瘤病、肺朗格汉斯细胞组织细胞增生症
纵隔疾病 心脏副神经节瘤、心包囊肿、胸腺瘤、创伤后假性主动脉瘤、心律失常及左心功能不全、食管囊肿、食管肿瘤、霍奇金淋巴瘤、纵隔脂肪过多症
其他 颈椎病、肝海绵状血管瘤、迷走神经球瘤、乳糜泻、舌下异位甲状腺、外耳道耵聍、胸膜子宫内膜异位症
十、不明原因慢性咳嗽(unexplained chroniccough),慢性咳嗽高敏综合征(chronic coughhypersensitivity syndrome,CHS)

多数慢性咳嗽患者可以获得明确的病因诊断并在针对性治疗后咳嗽可缓解。然而,有一部分慢性咳嗽患者在进行了全面检查、治疗之后,病因仍无法明确。既往将这一类咳嗽归为不明原因慢性咳嗽,又称为特发性咳嗽。不明原因慢性咳嗽的诊断原则:必须经过系统的慢性咳嗽病因检查,排除已知的慢性咳嗽病因,针对慢性咳嗽病因治疗无效的情况下,方可考虑不明原因慢性咳嗽。这类患者以中年女性多见,常以上呼吸道感染作为起病的首发因素,主要表现为慢性刺激性干咳,伴咽痒或异物感,对油烟、灰尘、异味及冷空气敏感,有时讲话及紧张亦会引起咳嗽,对目前的常规治疗无效,严重影响患者生活质量。由于这些患者普遍存在咳嗽高敏感性,近年来提出一个新的诊断名词"咳嗽高敏综合征",用于描述此类慢性咳嗽患者[423]。临床诊断不明原因慢性咳嗽需慎重,应在进行了慢性咳嗽相关的检查和相关治疗后,咳嗽病因仍不能明确,症状不能缓解者方可考虑。

基于咳嗽高敏综合征的病理生理学特征,治疗应以降低咳嗽敏感性为目的。但目前对咳嗽高敏综合征的治疗选择有限,包括了药物治疗手段及非药物治疗手段。临床研究结果显示神经调节因子类药物加巴喷丁治疗有效[424](2B),其他药物如阿米替林,巴氯芬、卡马西平、普瑞巴林等亦可选用[425](2C)。非药物治疗手段包括语言病理治疗及咳嗽抑制性理疗,统称为咳嗽抑制性治疗(cough suppression therapy,CST)。咳嗽抑制性治疗在改善患者咳嗽相关生活质量,降低咳嗽敏感性及咳嗽频率方面显示出了一定的效果[11,426,427,428,429](2B)。

十一、儿童慢性咳嗽的病因分布特点与治疗原则

儿童慢性咳嗽定义与成人有所不同。通常将咳嗽时间>4周,并以咳嗽为主要症状或唯一症状、胸部X线正常者称之为慢性咳嗽。儿童慢性咳嗽病因分布和成人有所不同,不同年龄阶段儿童的病因分布也有所不同。新生儿和婴幼儿要注意先天性疾病,如气管软化、开口异常、大血管畸形、原发性纤毛不动综合征、支气管扩张症等[430,431,432,433,434,435,436,437,438];<3岁的幼儿,慢性咳嗽应首先考虑呼吸道感染相关疾病(2C)。国外研究结果显示,婴幼儿迁延性细菌性支气管炎(PBB)患病率高,其中近一半患儿存在气管软化,流感嗜血杆菌为主要致病菌[439,440,441,442,443,444](2C),支气管肺泡灌洗液细菌培养对诊断有重要意义。而成人常见的鼻后滴流综合征、咳嗽变异型哮喘均不是婴幼儿慢性咳嗽的常见原因。气道异物为导致儿童慢性咳嗽的重要病因,好发于1~3岁幼儿,对于长期咳嗽,治疗效果欠佳者,注意询问异物吸入病史,并做胸部X线检查,排除异物吸入的可能[445,446,447,448,449](2C)。3岁以后包括哮喘在内的变应性疾病引起的咳嗽逐渐成为常见原因。学龄期儿童慢性咳嗽应首先考虑咳嗽变异型哮喘的可能(2C)。过敏性鼻炎、鼻窦炎和腺样体肥大等均可引起UACS,对因治疗,效果良好[439,443](2C)。EB是成人慢性咳嗽的重要原因之一,但在儿童中的发病情况尚未见报道。有些慢性咳嗽病因成人相对少见,而在儿童比较多见,如非典型病原体(支原体、衣原体)感染和百日咳等引起的慢性咳嗽、异物吸入引起的咳嗽、心因性咳嗽和先天性疾病引起的咳嗽等。由于生理原因,胃食管反流是幼儿的常见现象,健康婴儿胃食管反流发生率高达40%~65%,但是否为幼儿的常见咳嗽原因尚有不同意见。

儿童慢性咳嗽的治疗原则为明确病因,针对病因进行治疗(2D)。如病因不明,或年龄太小无法进行相关检查,可进行经验性治疗或对症治疗。如果治疗后咳嗽症状没有缓解,应重新评估。镇咳药物不宜应用于婴儿。

十二、慢性咳嗽的经验性治疗

上述病因导向的诊断流程是慢性咳嗽诊治成功的基础。但病因诊断需要一定的设备和技术条件,对基层医院或经济条件有限的患者难于实施。因此,当客观条件有限时,经验性治疗可以作为一种替代措施[213,450,451,452,453](2C)。

慢性咳嗽的经验性治疗是指病因诊断不确定的情况下,根据病情和可能的诊断给予相应的治疗措施,通过治疗反应来确立或排除诊断。经验性治疗应遵循以下几条原则。

1.推荐首先针对慢性咳嗽的常见病因进行治疗,国内外研究结果显示,慢性咳嗽的常见病因为CVA、UACS/PNDS、EB、AC和GERC[62,64,208,454](1A)。

2.建议根据病史推测可能的慢性咳嗽病因并进行相应的治疗[453,455](2C)。如患者的主要表现为夜间或凌晨刺激性咳嗽,则可先按CVA进行治疗;咳嗽伴有明显反酸、嗳气、胸骨后烧灼感者则考虑GERC的治疗;如感冒后继发咳嗽迁延不愈,则可按PIC进行处理。咳嗽伴流涕、鼻塞、鼻痒、频繁清喉及鼻后滴流感者,先按UACS/PNDS进行治疗。

3.建议根据临床特征将慢性咳嗽分为激素敏感性咳嗽(包括CVA、EB及AC)、UACS和GERC进行经验治疗,有利于减少经验治疗的盲目性,提高经验治疗的成功率[30](2C)。以患病率为导向的阶梯性、序贯性治疗策略(2C)是一种优先考虑常见、治疗简单和见效快的病因,最后考虑少见、疗程长和起效慢的病因,边诊断边治疗的方案,适用于疾病特征不够典型或多种病因同时存在的情况[10,453,456,457,458,459](1C)。建议将美敏伪麻溶液、复方甲氧那明用于UACS/PNDS、AC和PIC等经验治疗[30](2C)。怀疑激素敏感性咳嗽者,可建议先口服小剂量激素治疗1周,症状缓解后改用ICS或联合β2受体激动剂治疗[30](2C)。

4.咳嗽伴咳脓痰或流脓鼻涕者建议用抗生素治疗(2D)。多数病因与感染无关[62,208,454],经验治疗时应避免滥用抗生素。

5.建议UACS或PNDS、CVA、EB的经验性治疗疗程为1~2周,GERC至少2~4周(2D)。口服糖皮质激素一般不超过1周[7]。治疗有效者,继续按相应咳嗽病因的标准化治疗方案进行治疗。

6.经验治疗有一定的盲目性,应注意排除支气管恶性肿瘤、结核和其他肺部疾病。经验性治疗无效者,建议及时到有条件的医院进行相关检查明确病因[10](2D)。

十三、常用镇咳与祛痰药物

轻度咳嗽不需进行镇咳治疗。咳嗽可由多种原因所致,治疗的关键在于病因治疗,镇咳药物只能起到短暂缓解症状的作用。但严重的咳嗽,如剧烈干咳或频繁咳嗽影响休息和睡眠时,则可适当给予镇咳治疗。痰多患者宜用祛痰治疗。

(一)镇咳药物

一般根据其药理作用机制将镇咳药分为中枢性和外周性两大类。中枢性镇咳药是指作用于延髓咳嗽中枢的一个或多个位点而起到镇咳效果的药物;外周性镇咳药指与咳嗽反射弧上的咳嗽感受器、传入神经、传出神经及效应器部位受体结合产生镇咳效果的药物[3,29,124]

1.中枢性镇咳药:

该类药物对延脑中枢具有抑制作用,根据其是否具有成瘾性和麻醉作用又可分为依赖性和非依赖性镇咳药。前者为吗啡类生物碱及其衍生物,具有十分明显的镇咳作用,由于具有成瘾性,仅在其他治疗无效时短暂使用。后者多为人工合成的镇咳药,如右美沙芬和喷托维林等,临床应用十分广泛。(1)依赖性镇咳药:①可待因(codeine)[3]:直接抑制延脑中枢,止咳作用强而迅速,同时亦具有镇痛和镇静作用,可用于病因不明、治疗效果不佳且剧烈干咳和刺激性咳嗽,尤其是伴有胸痛的干咳。②福尔可定(pholcodine):作用与可待因相似,但成瘾性较之为弱。(2)非依赖性镇咳药:①右美沙芬(dextromethorphan):目前临床上应用最广的镇咳药,作用与可待因相似,但无镇痛和催眠作用,治疗剂量对呼吸中枢无抑制作用,亦无成瘾性。推荐使用含有右美沙芬的复方镇咳药物,对治疗成人慢性咳嗽有一定疗效[460](2A)。②喷托维林(pentoxyverine):作用强度为可待因的1/3,同时具有抗惊厥和解痉作用。青光眼及心功能不全者应慎用。③右啡烷(dextrophan):为右美沙芬的代谢产物,患者的耐受性更好,今后可能取代右美沙芬而用于临床治疗。

2.外周性镇咳药:

也称为末梢镇咳药,通过抑制咳嗽反射弧中的某一环节而起到镇咳作用。这类药物包括局部麻醉药和黏膜防护剂。(1)那可丁(narcodine):阿片所含的异哇琳类生物碱,作用与可待因相当,无依赖性,对呼吸中枢无抑制作用,适用于不同原因引起的咳嗽。(2)苯丙哌林(benproperine):非麻醉性镇咳药,作用为可待因的2~4倍。可抑制外周传入神经,亦可抑制咳嗽中枢。(3)莫吉司坦(moguisteine):外周性非麻醉性镇咳药,作用较强。(4)苯佐那酯(benzonatate):丁卡因衍生物,具有较强的局部麻醉作用,抑制咳嗽反射的传入神经。

(二)祛痰药物

祛痰治疗可提高咳嗽对气道分泌物的清除效率。祛痰药的作用机制包括:增加分泌物的排出量;降低分泌物黏稠度;增强纤毛的清除功能。祛痰药物种类繁多,其有效性除个别药物外尚需更多循证医学证据。常见祛痰药如下。

1.愈创木酚甘油醚(guaifenesin):

美国FDA唯一批准的祛痰药物。可刺激胃黏膜,反射性引起气道分泌物分泌增多,降低痰液黏稠度,并有一定的支气管舒张作用,达到增强黏液排出的效果。常与抗组胺药、镇咳药、减充血剂配伍使用[461,462,463]

2.桃金娘油(myrtol):

桃金娘科树叶的提取物,属于挥发性植物油,主要成分包括桉油精、柠檬烯及α-蒎烯,常用药物为桉柠蒎和标准桃金娘油。能促进气道和鼻窦黏膜纤毛运动,可用于急性支气管炎、慢性支气管炎和鼻窦炎等疾病[464,465]

3.氨溴索(ambroxol)和溴已新(bromhexine):

两者均属于黏液溶解药,氨溴索是溴已新在体内的代谢产物,破坏类黏蛋白的酸性黏多糖结构,使分泌物黏滞度下降,还可促进纤毛运动和增强抗生素在呼吸道的浓度。

4.乙酰半胱氨酸(N-acetylcysteine):

可使黏液糖蛋白多肽链的硫键断裂,降低痰的黏滞度。

5.羧甲司坦(carbocistein):

可使黏蛋白的二硫键断裂,降低分泌物黏滞度。厄多司坦(erdosteine)是其前体药物,口服经代谢产生3个含有游离巯基的代谢产物而发挥药理作用。

6.其他:

高渗盐水及甘露醇吸入可提高气道黏液分泌的水合作用,改善黏液的生物流变学,从而促进黏液清除。联合应用支气管舒张剂可提高部分患者的咳嗽清除能力[345,347]

十四、中医中药治疗

中医学认为,咳嗽既是肺系疾病中的一个症状,又是独立的一种疾病。慢性咳嗽属于中医学"久咳"、"顽咳"的范畴。

咳嗽病名始见于《黄帝内经》,并在咳嗽的病因认识上,提出"五脏六腑皆令人咳,非独肺也"的观点[466]。古人最初对咳嗽分类亦以脏腑命名,这与现代医学慢性咳嗽的解剖学分布观点不谋而合。咳嗽的辩证类型繁多,明代《景岳全书》[467]执简驭繁,将咳嗽分外感咳嗽和内伤咳嗽两大类,一直沿用至今。总之,均是肺失宣降,肺气上逆而作咳嗽。

中医中药对咳嗽的治疗有悠久的历史和丰富的经验,临床上可见有些不明原因顽固性慢性咳嗽经中药治疗后缓解的例子。中医治疗慢性咳嗽的优势,首先是以三因制宜为特征,体现高度个体化、精准化的辨证论治;其次是通过多环节、多靶点的复方发挥效应;第三是遵循"急则治其标,缓则治其本"的原则,是一种标本兼治的综合管理模式。用于治疗咳嗽的中药、中药组方和成药品种繁多[468,469,470]。下面介绍几种临床常用的咳嗽证型及方药[469,471]

【肺阴亏虚证】 干咳,痰少黏白,或声音逐渐嘶哑,口干咽燥,起病缓慢。

治法:养阴清热,润肺止咳。

方药举例:沙参麦冬汤(《温病条辨》)加减:沙参,麦冬,玉竹,天花粉,白扁豆,桑叶,生甘草。

【肺肾阳虚证】 咳嗽声怯,遇寒易发或加重,或伴短气息促,腰酸腿软。

治法:补肺益肾,温阳止咳。

方药举例:小青龙汤(《伤寒论》)合金匮肾气丸(《金匮要略》)加减:麻黄,芍药,细辛,干姜,桂枝,五味子,半夏,地黄,山药,淫羊藿,巴戟天,甘草。

【胃气上逆证】 阵发性呛咳,咳甚时呕吐酸苦水,平卧或饱食后症状加重,可伴嗳腐吞酸、嘈杂或灼痛。此证类同胃食管反流性咳嗽。

治法:降浊化痰,和胃止咳。

方药举例:旋覆代赭汤(《伤寒论》)合半夏泻心汤(《伤寒论》)加减:旋复花,赭石,人参,半夏,生姜,大枣,黄连,黄芩,炙甘草。

【肝火犯肺证】 咳逆阵作,咳时面红目赤,咳引胸痛,随情绪波动增减,常感痰滞咽喉,咯之难出,量少质黏,口干口苦。

治法:清肺泻热,化痰止咳。

方药举例:黄芩泻白散(《症因脉治》)合黛蛤散(《中国药典》)加减:黄芩,桑皮,地骨皮,青黛,蛤壳,甘草。

【风邪伏肺证】 咳嗽阵作,咳伴咽痒,干咳或少痰,咯痰不畅,常因冷热空气、异味、说笑诱发,身无明显寒热。外感常诱发咳嗽加重或复发。舌淡红,苔薄白。

治法:疏风宣肺,止咳化痰。

方药举例:麻黄、紫苏叶、地龙、枇杷叶、紫苏子、蝉蜕、前胡、牛蒡子、五味子。或三拗汤(《太平惠民和剂局方》)合止嗽散(《医学心悟》)加减:炙麻黄,杏仁,桔梗,荆芥,炙紫苑,炙百部,白前,黄芩,甘草。

【风寒袭肺证】 症见咳嗽声重,气急咽痒,咳痰稀薄色白,鼻塞,流清涕,头痛,苔薄白,脉浮或浮紧。

方药举例:止嗽散(《医学心悟》)+玉屏风散(《究原方》)。

【风热犯肺证】 症见咳嗽频剧,喉燥咽痛,咯痰不爽,痰黏或稠黄,鼻流黄涕,口渴,头痛,舌质红,舌苔薄黄,脉浮数或浮滑。

方药举例:银翘散(《温病条辨》)。

目前中医关于咳嗽的治疗多集中在一方一法或专家经验,缺乏严格的循证医学研究数据,证据的级别普遍较低[472]。国内中成药品种繁多,但多数停留在对症治疗的层面,有效组分、治疗指征及不良反应均有待进一步明确。对于"病"与"证"的指征不明确,影响中成药的有效使用,很多中成药只描述中医证候,未指出具体适用于哪些病因,亦未明确哪些是镇咳药,哪些是祛痰药。需要今后采用现代医学方法结合中医药理念,挖掘出更多指征明确、疗效肯定的中药复方或单体制剂。

十五、展望

慢性咳嗽作为临床上一个常见问题,对其病因诊断、治疗及发病机制的研究在西方国家已有30余年的历史,在中国进行系统的研究亦有近15年的时间,在咳嗽的诊断、治疗和发病机制方面取得了系列成果。欧美、英国、日本、澳大利亚等相继制定了咳嗽方面的指南,中国于2005年制定了第一版的咳嗽指南。随着对慢性咳嗽研究的深入,指南的推广应用,中国临床医生对咳嗽病因的认识、诊断和治疗的水平均有了显著的提高。国内已有些单位建立了咳嗽实验室,开展了诱导痰细胞学检查、24 h食管pH值-多通道阻抗监测等,设立了慢性咳嗽亚专科和咳嗽门诊。虽然我们在咳嗽领域取得了很大的进步,我们也面临着不少新的挑战。首先,慢性咳嗽作为临床上的最常见问题,越来越成为广大临床医生关注的问题,但国内研究慢性咳嗽的单位尚不多,需要更多的同道参与慢性咳嗽的研究行列中来。其次,诱导痰细胞学检查的诊断价值和疗效评估价值已得到越来越多的临床医生的认可,国内已有数十家的医院开展了这方面的检查,但总的来说,开展得还不是很普遍。另外,一些慢性咳嗽的诊断治疗及机制问题仍有待于进一步研究明确,如顽固性感染后咳嗽的发病机制和治疗方法,UACS/PNDS的发病机制,咽喉部疾病与UACS的关系,EB/CVA的治疗疗程及其与典型哮喘的关系,GERC的诊断标准及发病机制,空气污染与慢性咳嗽的关系,不明原因咳嗽或难治性咳嗽的治疗,咳嗽高敏感性的机制等。展望未来,任重道远,只有不断努力,才能不断进步。

指南修订专家组成员

指南修订专家组成员(按姓氏拼音排序):蔡绍曦(南方医科大学南方医院)、陈耀龙(兰州大学循证医学中心)、郝创利(苏州大学附属儿童医院)、黄克武(首都医科大学附属北京朝阳医院)、孔灵菲(中国医科大学附属第一医院)、赖克方(呼吸疾病国家重点实验室 广州医科大学附属第一医院 广州呼吸疾病研究所)、林江涛(中日友好医院)、邱忠民(同济大学附属同济医院)、沈华浩(浙江大学医学院附属第二医院)、王长征(第三军医大学新桥医院)、王秋萍(南京军区南京总医院)、张纾难(中日友好医院)、钟南山(呼吸疾病国家重点实验室 广州医科大学附属第一医院 广州呼吸疾病研究所)、周新(上海交通大学附属第一人民医院)

执笔者:赖克方

秘书组成员:罗炜、江梅、谢佳星

指南修订顾问:白春学、陈旻湖、陈萍、杨克虎、殷凯生、钟南山

同行评议专家:陈一强、戴元荣、姜淑娟、江勇、林琳、史利卿、孙德俊、孙志强、吴昌归、吴峰、徐浦生、叶贤伟、朱佳

文献检索人员:包婺平、方章福、华雯、季俊峰、李娟、梁晓婷、林蕊艳、刘宝娟、刘剑、马千里、尚圣云、苏新明、唐小婷、吴明海、夏丽霞、徐镶怀、许丽、杨梦婕、杨爽、于兴梅、余莉、张巧、张惟毅、张永明、钟伯年

致      谢

志谢 辉瑞健康药物部、第一三共制药(上海)有限公司、扬子江药业集团有限公司和阿斯利康制药有限公司给予本研究支持

利益冲突

利益冲突 指南内容的形成不受以上公司的影响

附件1
慢性咳嗽病因诊断流程
点击查看大图

注:(1)ACEI:血管紧张素转换酶抑制剂;FeNO:呼出气一氧化氮;UACS:上气道咳嗽综合征;PNDS:鼻后滴流综合征;CVA:咳嗽变异性哮喘;EB:嗜酸粒细胞性支气管炎;纤支镜:纤维支气管镜;SPT:过敏原皮试;IgE:免疫球蛋白E;GERC:胃食管反流性咳嗽;AC:变应性咳嗽。(2)对于经济条件受限或普通基层医院的患者,可根据病史和咳嗽相关症状进行经验性治疗。如果经验治疗无效,则应及时到有条件的医院进行检查诊断,以免延误病情。(3)aPEF平均变异率>10%,或支气管舒张试验阳性亦可作为诊断标准。bFeNO检查不可作为病因的确诊依据,但可以作为嗜酸粒细胞性炎症相关咳嗽的参考指标

附件2
高渗盐水雾化诱导痰炎症细胞检测方法

通过雾化吸入高渗盐水诱导患者咳出痰液,以检测痰液炎症细胞总数及细胞分类结果,明确患者气道炎症类型和程度,协助诊治及预后观察。

高渗盐水雾化可采用单一浓度法(NaCl浓度:3%或4.5%)或梯度浓度法(NaCl浓度:3%,4%,5%),重症哮喘或儿童可考虑采用生理盐水雾化以减少不良反应。

试剂:高渗盐水,0.1%二硫苏糖醇(DTT)及苏木素-伊红或瑞士染色液等。

检测仪器:超声或压缩雾化器、水浴箱、旋涡或水平振荡器、光学显微镜等。

操作方法:

1.高渗盐水雾化:(1)单一浓度法:①诱导前10 min让患者吸入沙丁胺醇400 μg。②10 min后清水漱口、擤鼻。③高渗盐水雾化吸入10 min,漱口、擤鼻后主动用力咳痰至培养皿。④若患者无痰或痰量不足则重复步骤3,直至咳出足量合格痰标本或雾化总时间达30 min时均终止雾化。(2)梯度浓度法:①诱导前10 min让患者吸入沙丁胺醇400 μg。②10 min后清水漱口、擤鼻。③3%高渗盐水雾化吸入15 min,漱口、擤鼻后主动用力咳痰至培养皿。④若患者无痰或痰量不足则换用4%高渗盐水继续雾化8 min。⑤若患者无痰或痰量不足则换用5%高渗盐水继续雾化7 min后终止诱导程序。⑥雾化期间如患者咳出足量合格痰标本或雾化总时间达30 min时均终止雾化。

2.痰液处理及检测:痰液咳出后应立即处理,4 ℃存放不超过3 h。及时用镊子收集痰栓或不透明痰块,加入2~4倍体积的0.1%的DTT充分混合,裂解10~15 min,37 ℃水浴和水平温和震荡可提高裂解效果,48 μm滤纸或300目尼龙滤网过滤后,常温离心10 min(2 500转/min),弃上清液后PBS重悬沉淀细胞,牛鲍氏计数板计数细胞总数,细胞悬液涂片,HE或瑞士染色,光镜下对400个以上炎症细胞进行分类。

注意事项:(1)重症哮喘或哮喘急性发作患者需联合肺功能及临床症状综合判断是否适合进行高渗盐水雾化。当患者第一秒用力呼气容积(FEV1)占预计值%<60%或喘息症状明显时建议让患者自然咳痰或行生理盐水雾化诱导。(2)实验室须备有哮喘急性发作等不良反应的抢救指引、设备和药物,雾化过程中密切观察患者表现,必要时监测肺功能。(3)激素类、抗过敏药、茶碱等药物可能会对检查结果造成影响,需要停药3 d以上,但在观察治疗随访效果时,检查期间可不停药。

附件3
多通道食管阻抗-pH监测方法

检测仪器:多通道食管阻抗-pH监测仪。

操作方法:(1)检查前将电极先后置于pH值7.00和pH值4.00的标准液中校正,以保证仪器工作的准确性和稳定性。(2)选择通气较好的一侧鼻腔,用2%利多卡因喷雾局部麻醉,先插入食管测压导管,用定点牵拉法确定食管下括约肌位置,然后经鼻置入束缚在一起的6通道阻抗电极导管和pH电极导管入食管内。阻抗电极中心位置分别位于食管下括约肌上缘上方3、5、7、9、15、17 cm处,pH电极位于食管下括约肌上缘上方5 cm处,参考电极固定于胸骨中下段,将阻抗和pH电极连接至多通道食管阻抗-pH监测仪,以50 Hz的频率记录数据。

监测时间:18 h以上。

检测结果分析:分析内容包括酸和非酸反流事件的识别、计数和分类,食团清除时间、食团暴露时间和食管酸清除时间等参数的测量和计算。食管酸暴露程度以DeMeester总积分表示,由6项参数组成:24 h食管pH值<4的次数,反流时间>5 min的次数,最长反流时间,总、立位、卧位pH值<4的时间占监测时间的百分比。同时计算反流与咳嗽的症状相关概率(SAP)。

注意事项:(1)检查前10 h禁食。(2)检查前最后一次用餐时禁食酸性食物。(3)检查前停服制酸剂7 d,停服促胃动力药3 d,全部药物24 h,但随访治疗效果时可不停药检查。(4)患者必须严格按要求准确记录监测日志,所有记录事件的时间必须以监测仪上显示的时间为准。(5)监测期间患者需保持日常生活方式,不限制活动,但禁食酸、辣刺激性食品、饮料和抗酸药物。

附件4
咳嗽激发试验方法

通过雾化方式使受试者吸入一定量的辣椒素气雾溶胶颗粒,诱发其产生咳嗽,以吸入后患者咳嗽≥5次的最低激发浓度(C5)来表示咳嗽的敏感性。

试剂配制:将辣椒素溶解于Tween 80液和100%乙醇中,再溶于8 ml生理盐水,配成0.01 mol/L原液。使用前用生理盐水进行倍比稀释,浓度为1.95、3.9、7.8、15.6、31.2、62.5、125、250、500、1 000 μmol/L。

测定仪器:采用吸气触发的定量吸入装置。压缩空气流速为0.11 L/s,总输出量约为160 mg/min(以生理盐水作标准),单次吸入时间为0.5 s。嘱受试者由残气位缓慢吸气至肺总量位,在吸气上半段定量吸入辣椒素雾化溶液。

操作方法:(1)先吸入雾化生理盐水作为基础对照。(2)随后由最低浓度(1.95 μmol/L)起吸入雾化辣椒素溶液,记录30 s内咳嗽的次数。若不能达到C5标准,再进行下一个浓度的吸入,每次递增浓度1倍。(3)达到C5标准时终止试验,该浓度就是其咳嗽的域值。如果浓度达到1 000 μmol/L,受试者还没出现C5时,应终止试验,其域值浓度记为>1 000 μmol/L。若患者出现明显不适感时(如剧烈胸骨后烧灼感、气促、呼吸困难等),也应立即终止试验。

注意事项:(1)试验所用的溶液须新鲜配制。(2)具有以下情况者不宜进行本试验:孕妇、哮喘急性发作、气胸、近期咯血及严重心脏疾病等患者。(3)在整个过程中受试者应处于平静状态。在吸入刺激物后不要进行说话等有可能会影响咳嗽的行为。

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