1、肺结核肺结核Pulmonary Tuberculosis甄国华甄国华同济医院呼吸内科同济医院呼吸内科概述概述Introduction 结核病是最古老的传染病之一，曾经是无药结核病是最古老的传染病之一，曾经是无药可治（卫生营养疗法）的瘟疫；可治（卫生营养疗法）的瘟疫； Tuberculosis is one of the most ancient infectious disease, and its treatment was inefficient or largely empirical, such as improved nutrition, rest从从20世纪世纪60年代起化学药物治
2、疗是预防和治疗年代起化学药物治疗是预防和治疗结核病最有效方法；结核病最有效方法；Since 1960, chemotherapy has been the most effective prevention and treatment近二十余年来全球结核病的疫情明显回升：近二十余年来全球结核病的疫情明显回升：The epidemic situation of tuberculosis in the world has been increasing in last 20 years（1）客观因素：）客观因素： HIV感染的流行、多重耐药菌感染的流行、多重耐药菌感染的增多、贫困、人口增长和移民等
3、；感染的增多、贫困、人口增长和移民等； Objective factors: HIV, multi-drug-resistant (MDR) organism, poverty, population pressure and immigrant（2）主观因素：缺乏对结核病流行回升的警惕性）主观因素：缺乏对结核病流行回升的警惕性和结核病控制复杂性的深刻认识、放松对结核病控和结核病控制复杂性的深刻认识、放松对结核病控制工作的管理、削弱对结核病控制工作的投入等。制工作的管理、削弱对结核病控制工作的投入等。 Subjective factors: lack of the guard against
4、the increasing of the tuberculous incidence; lack of the recognition of the complexity, slackening the management, and reducing the funding for tuberculosis control.对策对策国家结核病防治规划国家结核病防治规划Strategy-National tuberculosis control program核心内容：全程督导短程化学治疗核心内容：全程督导短程化学治疗Key point: directly observed treatmen
5、t short-course，DOTS流行病学流行病学 Epidemiology1 全球疫情全球疫情 Global epidemic situation The WHO estimates that there are 7.9 million new clinical cases each year, 1.8 million deaths each year and 1.8 billion persons infected in the world. 22个结核病高负担、高危险性国家，其中包括个结核病高负担、高危险性国家，其中包括中国中国 22 countries of heavy burde
6、n and danger of tuberculosis, including China2 我国疫情我国疫情 Epidemic situation in China （1）高感染率）高感染率 High infection rate （2）高患病率）高患病率 High morbidity rate （3）高耐药率）高耐药率 High drug resistance rate （4）死亡人数多）死亡人数多 Large number of deaths （5）递降率低）递降率低 Low degradation rate （6）中青年患病多）中青年患病多 Large number of young
7、and middle-age patients （7）地区患病率差异大）地区患病率差异大 Big difference of morbidity rate among regions （8）实施）实施DOTS项目的地区患病率低项目的地区患病率低 Lower morbidity rate in the region practicing DOTS program结核分枝杆菌结核分枝杆菌Tubercle bacilliMycobacterium tuberculosis Discovered by Dr. Koch in 1882Acid-fastAFB - Ziehl-Nielson stain
8、分类上属于放线菌目、分支杆菌科、分支杆菌属，分类上属于放线菌目、分支杆菌科、分支杆菌属，包括包括人型、牛型、非洲型和鼠型人型、牛型、非洲型和鼠型4类。类。Categorization: Actinomycetales, Mycobacteriaceae, Mycobacterium, and named Mycobacterium tuberculosis complex, including Human, bovine, aficanum, and murine 1 多形性多形性 Polymorphism2 抗酸性抗酸性 抗酸染色阳性可作为镜检依据抗酸染色阳性可作为镜检依据 Acid fas
9、tness acid-fast staining positive3 生长缓慢生长缓慢 培养时间长，增殖一代培养时间长，增殖一代15-20小时，小时，28周在培养基上形成菌落。周在培养基上形成菌落。 Slow growth culture peroid is long, 2-8 weeks 4 抵抗力强抵抗力强 注意消毒灭菌方法注意消毒灭菌方法 Strong power of resistance 70% alcohol, ultraviolet 5 菌体结构复杂菌体结构复杂 Complex structure of cell wall结核病在人群中的传播结核病在人群中的传播The trans
10、mission of tuberculosis among population1 传染源传染源 Infection sources2 传播途径传播途径 Route of transmission3 易感人群易感人群 Susceptible population 4 影响传染性的因素影响传染性的因素 Factors affecting infection5 化学治疗对结核病传染性的影响化学治疗对结核病传染性的影响 Affecting the tuberculous infection by chemotherapy结核病的发生与发展结核病的发生与发展Pathogenesis of tuberc
11、ulosis肺结核病自然过程示意图肺结核病自然过程示意图1 原发性结核和继发性结核原发性结核和继发性结核Primary tuberculosis and secondary tuberculosis2 结核病细胞免疫和迟发型变态反应结核病细胞免疫和迟发型变态反应 Cell mediated immunity (CMI) and delayed type hypersensitivity (DTH) 2至至3天后天后局部红肿、局部红肿、深溃疡，深溃疡，播散至全播散至全身，死亡身，死亡初次给予少量结核菌感染初次给予少量结核菌感染, 46周后再给予同等量结核周后再给予同等量结核菌感染：菌感染：+10
12、至至14天后天后局部红肿、局部红肿、浅溃疡，浅溃疡，愈合愈合Koch phenomenon初次即给予一定量结核菌感染初次即给予一定量结核菌感染病理学病理学Pathology1 基本病理变化基本病理变化1 Basic pathological change（1）渗出）渗出 (1) Effusion（2）增生）增生 (2) HyperplasiaTuberculous Granulomas（3）干酪样坏死）干酪样坏死 Caseous necrosis2 病理变化转归病理变化转归2 Pathological change渗出渗出增生增生干酪样干酪样坏死坏死抵抗力下降抵抗力下降抵抗力增强抵抗力增强变态
13、反应强烈变态反应强烈纤维化纤维化硬结硬结钙化钙化液化、形液化、形成空洞成空洞临床表现临床表现Clinical manifestation症状症状SymptomsnPulmonary symptomsnSystemic symptoms（1）呼吸系统症状）呼吸系统症状 Pulmonary symptoms咳嗽、咳痰咳嗽、咳痰Cough, sputumCough is the commonest respiratory symptom, usually nonproductive but persistent, or sputum being mucoid or purulent with som
14、e haemoptysis. 咯血咯血HaemoptysisThe haemoptysis is often in small amount but can occasionally be in large amount if a bronchial artery erodes into a cavity. 胸痛胸痛 Chest pain or pleuritic pain Dull chest pain can be associated with mediastinal lymphadenopathy, or pleuritic pain may accompany pleural dis
15、ease. 呼吸困难呼吸困难DyspneaDyspnea is often a late symptom, occurring only if significant lung disease, or pleural effusion, has developed. （2）全身症状）全身症状 Systemic symptoms发热、乏力、不适、盗汗、纳差、消瘦等发热、乏力、不适、盗汗、纳差、消瘦等nThe general symptoms include fever, fatigue, malaise, night sweat, anorexia, weight loss, et al. nT
16、he fever is usually low-grade, and can become hectic, along with increasing weight loss and night sweats, as disease progresses. 体征体征Physical signs湿罗音，实变体征，局限性哮鸣音，气管移位湿罗音，实变体征，局限性哮鸣音，气管移位nClinical signs from the lung are found only in moderate/extensive disease with upper zone crackles or consolidat
17、ion. nA localized wheeze is sometimes heard in endobronchial disease. nTracheal deviation occurs, towards the side of greatest damage in chronic disease. nSign of pleural effusion.(1)临床分型临床分型Clinical classification原发型肺结核原发型肺结核 Primary tuberculosis 原发综合征：病灶、引流淋巴管炎和肺原发综合征：病灶、引流淋巴管炎和肺门淋巴结肿大门淋巴结肿大 Ranke
18、 complex: focus (Ghon lesion), draining lymphangitis and hilar adenopathy血行播散型肺结核血行播散型肺结核 Hematogenous disseminated pulmonary tuberculosisn 急性粟粒型肺结核急性粟粒型肺结核 Acute miliary tuberculosisn 慢性粟粒型肺结核慢性粟粒型肺结核 Cryptic miliary tuberculosisMiliary TB Lung nThe typical chest radiograph shows a diffuse, but eve
19、n, distribution of uniform 1-2mm nodules throughout all the lung fields. nThe early changes of miliary disease are subtle and may be missed, particularly on an overpenetrated film. In suspected cases high-resolution CT of the thorax has a higher sensitivity. 双肺弥漫性粟粒样双肺弥漫性粟粒样改变，呈毛玻璃样改变，呈毛玻璃样继发型肺结核继发型
20、肺结核 Postprimary tuberculosis 浸润性肺结核浸润性肺结核 Infiltrative tuberculosis 空洞性肺结核空洞性肺结核 Cavitary pulmonary tuberculosisCavitary TuberculosisnWhen necrotic tissue is coughed up cavity. nCavitation is typical for large granulomas. nCavitation is more common in the secondary reactivation tuberculosis - upper
21、lobes. 结核球结核球 Tuberculoma右上肺结核球右上肺结核球 干酪样肺炎干酪样肺炎 Caseous pneumonia 纤维空洞性肺结核纤维空洞性肺结核 Fibrotic cavitary tuberculosis结核性胸膜炎结核性胸膜炎 Tuberculous pleurisy其他肺外结核其他肺外结核 Other tuberculosis out of lung 肾结核，肠结核肾结核，肠结核 renal tuberculosis, intestinal tuberculosis 菌阴肺结核菌阴肺结核 Bacterium negative tuberculosis诊断诊断Diag
22、nosis1 诊断方法诊断方法1 Diagnostic method症状体征情况症状体征情况 Symptoms and signs诊断治疗过程诊断治疗过程 The process of diagnosis and treatment肺结核接触史肺结核接触史 Tuberculous contact history（1）病史，症状和体征）病史，症状和体征 History, symptoms and signs胸部胸部X线片线片Chest radiograph胸部计算机断层扫描胸部计算机断层扫描Chest computerized tomographic scanning (CT)Radiograp
23、hic location: most commonly apical and posterior segments of upper lobe, superior segment of lower lobe.(2) 影像学诊断影像学诊断Radiological diagnosis痰标本的收集痰标本的收集 Sputum collection 痰涂片检查痰涂片检查 Sputum smear microscopy培养法（金标准）培养法（金标准） Culture (absolute confirmation)(3) 痰结核分枝杆菌检查痰结核分枝杆菌检查Sputum mycobacterium tube
24、rculosis test药物敏感性测定药物敏感性测定 Drug susceptibility testing其他检测技术：分子探针，抗体检测其他检测技术：分子探针，抗体检测 Other tests：Molecular methods, blood test(4) 纤维支气管镜检查纤维支气管镜检查: 冲洗，刷片和冲洗，刷片和活检活检 Fibreoptic bronchoscopy: washing, brushing and biopsy(5) 结核菌素试验结核菌素试验 Tuberculin skin test旧结核菌素试验旧结核菌素试验, 纯蛋白衍化物试验纯蛋白衍化物试验Old tuberc
25、ulin (OT) test, purified protein derivative (PPD) test方法：左前臂屈侧皮内注射方法：左前臂屈侧皮内注射0.1ml (5IU) Method: left forearm, flexor aspect, intradermal injection 0.1ml (5IU) 时间：时间：48-72小时小时Time: 48-72h结果判断：硬结直径结果判断：硬结直径5mm 为阴性为阴性(-)，5-9mm 为弱阳性为弱阳性(+)，10-19mm为阳性为阳性(+)，20mm或出现水泡和淋巴管炎为强阳性或出现水泡和淋巴管炎为强阳性(+)Result jud
26、gement, according to induration (not erythema) diameter: negative (5mm), weakly positive(5-9mm), positive(10-19mm), strongly positive (20mm or bubble and lymphangitis). 意义：参考意义意义：参考意义nThe tuberculin skin test is only occasionally helpful in making a diagnosis of clinical tuberculosis. It does not di
27、fferentiate between infection (exposure) and disease, particularly in subjects over the age of 35 years .It is much more useful in epidemiological work and contact screening. nThe tuberculin test may be falsely negative, being suppressed in some cases with extensive pulmonary or miliary disease and
28、in those with HIV coinfection, where, because of reduced CD4+ cell counts, anergy to tuberculin can occur in those with active disease or a history of prior infection. nA strongly positive tuberculin test indicates infection but is unhelpful on its own in the presence of a normal examination and che
29、st radiograph, unless in the context of a contact or new immigrant screening investigation. 结核感染结核感染T细胞检测细胞检测(T-SPOT. TB )n利用结核特异抗原（利用结核特异抗原（ESTA-6,CFP-10)，通过酶联免，通过酶联免疫斑点技术（疫斑点技术（ELISPOT)检测受试者体内是否存在结检测受试者体内是否存在结核效应核效应T淋巴细胞，从而判断目前该受试者是否感染结淋巴细胞，从而判断目前该受试者是否感染结核杆菌的方法。核杆菌的方法。n阴性结果阴性结果 提示患者体内不存在针对结核杆菌特异的
30、效应提示患者体内不存在针对结核杆菌特异的效应T细胞。细胞。如出现以下情况如出现以下情况 ，阴性结果不能排除结核杆菌感染的，阴性结果不能排除结核杆菌感染的可能：可能： 1) 因感染阶段不同（如标本是在细胞免疫发生前获取因感染阶段不同（如标本是在细胞免疫发生前获取的）引起的假阴性结果；的）引起的假阴性结果； 2) 少数免疫系统功能不全的情况，如少数免疫系统功能不全的情况，如HIV感染者、肿感染者、肿瘤患者、儿童等；瘤患者、儿童等； 3) 以及其它免疫学、实验非正常操作的差异。以及其它免疫学、实验非正常操作的差异。结核感染结核感染T细胞检测细胞检测(T-SPOT. TB )n阳性结果阳性结果 提示患
31、者体内存在结核杆菌特异的效应提示患者体内存在结核杆菌特异的效应T细胞，患细胞，患者存在结核感染。但是否为活动性结核病，需结合临者存在结核感染。但是否为活动性结核病，需结合临床症状及其它检测指标综合判断。床症状及其它检测指标综合判断。T-SPOT.TB结果不结果不能作为单独或是决定性的诊断结核病的依据。能作为单独或是决定性的诊断结核病的依据。n阳性结果参照以下标准：阳性结果参照以下标准： 空白对照孔斑点数为空白对照孔斑点数为05个且（抗原个且（抗原A或抗原或抗原B斑点斑点数数)-（空白对照孔斑点数）（空白对照孔斑点数）6 空白对照孔斑点数空白对照孔斑点数6-10个时且（抗原个时且（抗原A或抗原或
32、抗原B斑点斑点数）数）2倍空白对照孔斑点数倍空白对照孔斑点数如果上述标准不符合且阳性质控对照孔正常时，检测如果上述标准不符合且阳性质控对照孔正常时，检测结果为结果为“阴性阴性”。结核感染结核感染T细胞检测细胞检测(T-SPOT. TB )诊断要点诊断要点Key points of diagnosis(1)可疑症状患者的筛选可疑症状患者的筛选 Screening patients(2)是否肺结核是否肺结核 Whether or not (X-ray)(3)有无活动性有无活动性 Active or not (X-ray, ESR) (4)是否排菌是否排菌 Discharge bacterium o
33、r not (Sputum microscopy )诊断程序诊断程序Diagnostic procedure（2）痰菌检查记录格式）痰菌检查记录格式 Record form for sputum bacterium screening涂（）涂（） 涂（）涂（）培（）培（） 培（）培（）（无痰）（无痰） （未查）（未查）（3）治疗状况）治疗状况(3) Treatment state1.1.初治初治 Initial treatment 尚未开始抗结核治疗的患者尚未开始抗结核治疗的患者 Not start antituberculosis treatment 正进行标准化疗方案用药而未满疗程的患者正
34、进行标准化疗方案用药而未满疗程的患者 Carry out standard chemotherapy regimen but not finish the course 不规则化疗未满不规则化疗未满1个月的患者个月的患者 Irregular chemotherapy 1 month2.2.复治复治 Retreatment 初治失败的患者初治失败的患者 Initial treatment failure 规则用药满疗程后痰菌又复阳的患者规则用药满疗程后痰菌又复阳的患者 Regular chemotherapy full course but sputum bacterium positive a
35、gain 不规则化疗超过不规则化疗超过1个月的患者个月的患者 Irregular chemotherapy exceed 1 month 慢性排菌患者慢性排菌患者 Chronic discharging bacterium4 记录方式记录方式 Record method依次记录为：结核病分类及亚类、病变部依次记录为：结核病分类及亚类、病变部位及范围、痰菌情况、化疗史、并发症、位及范围、痰菌情况、化疗史、并发症、并存病、手术史并存病、手术史Record in order: classify and subclass, diseased region and scope, sputum state
36、, chemotherapy history, complication, comorbidity, operation historyn继发性继发性肺肺结核结核双上双上涂（涂（+），），复治复治。鉴别诊断鉴别诊断Differential diagnosis1 肺炎肺炎 Pneumonia2 慢性阻塞性肺疾病慢性阻塞性肺疾病 COPD3 支气管扩张支气管扩张 Bronchiectasis4 肺癌肺癌 Lung cancer5 肺脓肿肺脓肿 Lung abscess6 纵隔和肺门疾病纵隔和肺门疾病 Mediastinum and hilar diseases7 其他疾病其他疾病 Other di
37、seases结核病的化学治疗结核病的化学治疗Chemotherapy of Tuberculosis(1) 早期早期 Early(2) 规律规律 Regular(3) 全程全程 Full course(4) 适量适量 Appropriate dosage(5) 联合联合 Combination1 化学治疗的原则化学治疗的原则 Chemotherapy principle(1) 杀菌作用杀菌作用 Bactericidal effect(2) 防止耐药菌产生防止耐药菌产生 Prevent drug-resistance bacteria generating(3) 灭菌灭菌 Sterilizing
38、2 化学治疗的主要作用化学治疗的主要作用 Major effect of chemotherapy3 化学治疗的生物学机制化学治疗的生物学机制 Biological mechanism of chemotherapy A 不断繁殖不断繁殖 B 细胞内菌细胞内菌 （酸性抑制）（酸性抑制） C 偶然繁殖偶然繁殖 D 休眠菌休眠菌异烟肼、利福平、链霉素异烟肼、利福平、链霉素吡嗪酰胺吡嗪酰胺利福平利福平结核杆菌生长速度结核杆菌生长速度慢慢 快快(1) 药物对不同代谢状态和不同部位的结核分枝杆菌群的作用药物对不同代谢状态和不同部位的结核分枝杆菌群的作用 The drugs effects on the
39、mycobacterium tuberculosis of different metabolism state and different site(2) 耐药性耐药性 Drug resistance(3) 间歇化学治疗间歇化学治疗 Intermittent chemotherapy(4) 顿服顿服 Taken at a draught(1) 异烟肼异烟肼（isoniazid, INH, H，0.3 qd）(2) 利福平利福平（rifampin, RFP, R, 0.45 qd）(3) 吡嗪酰胺吡嗪酰胺（pyrazinamide, PZA, Z, 0.5 tid）(4) 乙胺丁醇乙胺丁醇（e
40、thambutol, EMB, E, 0.75 qd）(5) 链霉素链霉素（streptomycin, SM, S, 0.75 5/w）4 常用抗结核病药物常用抗结核病药物 Common antituberculous drug5 统一标准化学治疗方案统一标准化学治疗方案 standard chemotherapy(1) 初治涂阳肺结核治疗方案初治涂阳肺结核治疗方案 Initial treatment for sputum smears positive tuberculosis 每日用药方案每日用药方案 Daily regimen 强化期：强化期：2HRZE Initial phase：2H
41、RZE 巩固期：巩固期：4HR Continuation phase：4HR 间歇用药方案间歇用药方案 Intermittent regimen 强化期：强化期： 2H3R3Z3E3 Initial phase： 2H3R3Z3E3 巩固期：巩固期： 4H3R3 Continuation phase：4H3R3 (2) 复治涂阳肺结核治疗方案复治涂阳肺结核治疗方案 Retreatment for sputum smears positive tuberculosis 每日用药方案每日用药方案 Daily regimen 强化期：强化期：2HRZSE Initial phase：2HRSZE 巩
42、固期：巩固期：46HRE Continuation phase：46HRE 间歇用药方案间歇用药方案 Intermittent regimen 强化期：强化期： 2H3R3Z3S3E3 Initial phase： 2H3R3Z3S3E3 巩固期：巩固期： 4H3R3E3 Continuation phase：4H3R3E3(3) 初治涂阴肺结核治疗方案初治涂阴肺结核治疗方案 Initial treatment for sputum smears negative tuberculosis 每日用药方案每日用药方案 Daily regimen 强化期：强化期：2HRZ Initial phas
43、e：2HRZ 巩固期：巩固期：4HR Continuation phase：4HR 间歇用药方案间歇用药方案 Intermittent regimen 强化期：强化期： 2H3R3Z3 Initial phase： 2H3R3Z3 巩固期：巩固期： 4H3R3 Continuation phase：4H3R36 耐药肺结核耐药肺结核 Drug resistant tuberculosis 缺乏管理导致不规则治疗缺乏管理导致不规则治疗 Lack of management leading to irregular treatment Enforcement of directly observe
44、d treatment short-course (DOTS) strategy7 板式组合药或复合固定剂量组合药板式组合药或复合固定剂量组合药 Combination drugs in plate or compound fixed dosage in caps其他治疗其他治疗Other treatment1 咯血的治疗咯血的治疗 Treatment for haemoptysis(1) 保持呼吸道通畅保持呼吸道通畅 Retain respiratory tract unobstructed(2) 适当镇静、镇咳适当镇静、镇咳 Mitigate and relieving cough app
45、ropriately(3) 垂体后叶素静推、静滴垂体后叶素静推、静滴 Hypophysin iv or iv drop(4) 其它止血药物的使用其它止血药物的使用 Other hemostyptic drug(5) 支气管镜局部止血支气管镜局部止血, 支气管动脉造影及栓塞支气管动脉造影及栓塞, 手术治疗手术治疗 Bronchoscope local haemostasis, bronchial arteriography and embolism, operation2 糖皮质激素的应用糖皮质激素的应用 The using of corticosteroids There is evidenc
46、e to support the addition of corticosteroids to antituberculosis drugs for endobronchial disease in children and there may be a place for them in large pleural effusion, in patients with extensive pulmonary disease such as miliary tuberculosis, and to suppress hypersensitivity reactions to antituber
47、culosis drugs. And tuberculous meningitis also can be treated with steroids. 3 肺结核外科手术治疗肺结核外科手术治疗3 Surgery operation for tuberculosis肺结核与相关疾病肺结核与相关疾病Tuberculosis and correlated diseases1 艾滋病艾滋病 HIV/AIDS Patients who are HIV-positive should be given the standard four-drug regimen unless MDR-TB is sus
48、pected. Coinfected patients who have low CD4+ lymphocyte counts are more likely to have disseminated tuberculosis. Tuberculosis in HIV-positive patients responds just as rapidly as in those who are HIV-negative. Overall, however, HIV-coinfected persons with tuberculosis have a higher mortality than
49、HIV-negative tuberculosis patients. 2 肝炎肝炎 Hepatitis Rifampicin, isoniazid, pyrazinamide are all potentially hepatotoxic, but the addition of pyrazinamide to regimens of rifampicin and isoniazid does not increase the frequency of hepatotoxicity. Patients with known chronic liver disease such as alco
50、holism, chronic active hepatitis or cirrhosis, or known carriers of hepatitis B or C, require both baseline and regular liver function monitoring. Weekly liver function tests for the first 2 weeks followed by 2-weekly tests for the first 2 months are recommended. 3 糖尿病糖尿病 Diabetes Diabetics have bot
