内科学：Pulmonary Tuberculosis

1、Pulmonary Tuberculosis,江德鹏：博士，副教授，副主任医师，硕士生导师，留美学者，重庆市中青年医学高端后备人才。 2000年毕业于上海第二军医大学，本科毕业后于第三军医大学西南医院中心ICU从事重症监护工作6年，后调入重庆医科大学附属第二医院呼吸科工作，已从事临床工作15年，具有多学科工作经历，擅长呼吸危重症的救治。 发表SCI论著4篇，CSCD核心论著10余篇，主持国家自然科学基金1项，其他基金2项。 联系方式 ,Definition,Tuberculosis is a chronic bacterial infection caused by tubercle baci

2、llus and characterized by the formation of granulomas in infected tissues and by cell-mediated hypersensitivity.,Acontagious bacterial infection caused by tubercle bacillus. The lungs are primarily involved, but the infection can spread to other organs. It is characterized by the development of gran

3、uloma in the infected tissues. The patients with TB often have the following symptoms:toxemia syptoms,cough,haemoptysis or blood streaked sputum,Epidemiology,One of the leading infectious disease killers. One third of the worlds population is currently infected with TB. Every second another person i

4、s newly infected with tuberculosis around the world. Each year an estimated 6-8 million people develop clinical disease. Each year 1.2-1.5 million people die of TB.,The incidence of tuberculosis has declined dramatically in developed countries due to improved nutrition,housing,effective drugs,vaccin

5、es. It remains as a problem in poorer countries (about 80% of the world) its overall incidence is increasing worldwide because of the enhanced susceptibility of AIDS patients and the appearance of drug resistant strains.,Etiology,Tubercle bacillus is a rod-shaped, slow-growing, gram-negative, aerobi

6、c bacterium. The cell wall has high acid content, which makes it hydrophobic, resistant to oral fluids.,The M. tuberculosis complex (MTBC) includes four TB-causing mycobacteria: M. tuberculosis var. hominis, M. bovis, M. africanum, and M. microti. M. africanum is not widespread, but it is a signific

7、ant cause of tuberculosis in parts of Africa. M. bovis was once a common cause of tuberculosis, but the introduction of pasteurized milk has largely eliminated this as a public health problem in developed countries.,Because of the surface lipids, the tubercle bacillus cannot be decolorized with acid

8、 alcohol after staining. Heat and fuchsine are usually necessary to accomplish primary staining. Since MTB retains certain stains even after being treated with acidic solution, it is classified as an acid-fast bacillus (AFB).,The most common acid-fast staining techniques are the ZiehlNeelsen stain,

9、which dyes AFBs a bright red that stands out clearly against a blue background. This is an acid fast stain of MTB.,The tubercle bacillus divides every 16 to 20 hours, which is an extremely slow rate compared with other bacteria, which usually divide in less than an hour.,M.Tuberculosis is transmitte

10、d from person to person via the respiratory route. The bacteria are put into the air when a person with TB of the lungs coughs or sneezes. People nearby may breathe in these bacteria and become infected. Adequate ventilation is the most important measure to reduce the infectiousness of the environme

11、nt.,Transmission,Pathogenesis,Infection the initial entry of tubercle bacilli into the previously uninfected lungs elicits a nonspecific acute inflammatory response which accompanied by few or no symptoms. bacilli are then ingested by macrophages and transported to the regional lymph nodes.,numerous

12、 acid fast organisms growed within macrophages. Lots of bright red rods are seen, particularly in macrophages,三种效应T细胞的产生效应分子示意图,CD4+T CD8+T,Th0,Th1：细胞免疫,IL-12,Th2：辅助体液免疫,IL-4,APC 、Th1,Tc（CTL）：细胞毒作用,分化：,Ag,Ag,During the 2-8weeks after primary infection,lymphocytes enter areas of infection,where they

13、elaborate chemotactic factors,interleukins,and lymphokies. Monocytes enter the area and transform into macrophages. tuberculosis granuloma is composed of epithelioid cell Langhans type giant cells caseous necrosis ,and surrounded by lyphocyte.,pathology,1.infiltration 2.caseous necrosis 3.hyperplasi

14、a,granulomas are seen here. They have rounded outlines. The one toward the center of the photograph contains several Langhans giant cells. Granulomas are composed of transformed macrophages called epithelioid cells along with lymphocytes. The localized, small appearance of these granulomas suggests

15、that the immune response is fairly good. caseous necrosis (characterized by complete loss of tissue structure and a texture resembling soft cheese) can be seen in the center.,This is an example of tuberculosis,you can see granulomas of the lung. The pattern of smaller nodules which have a propensity

16、 for upper lobe.,On closer inspection, the granulomas have areas of caseous necrosis. This pattern of multiple caseating granulomas primarily in the upper lobes is most characteristic of secondary tuberculosis.,The transformation of the pathological changes,1.to heal absorption and dissipation Fibro

17、sis and calcification 2. To deteriorate Infiltration Dissolution and dissemination,Clinical findings,Symptoms Physical examination Radiographic features（补） Laboratory Findings Imaging,Symptoms,Constitutional symptoms Fatigue weight loss low fever night sweats,The systemic features of tuberculosis in

18、clude fever in approximately 35% to 80%, malaise, and weight loss; there may be a variety of hematologic abnormalities, especially leukocytosis and anemia.,Pulmonary symptoms Cough Haemotysis Chest pain Dyspnea,Tuberculosis is a very complicated disease. The extent of disease varies from minimal inf

19、iltrates that produce no clinical illness and that are barely discernible on chest radiographs to massive involvement with extensive cavitation and debilitating constitutional and respiratory symptoms.,With the progression of pulmonary tuberculosis,the normal pulmonary architecture is lost.fibrosis,

20、volume loss and upward contraction are typical.however,recently diseased areas may heal with realtively little distruction when effective chemotherapy is adminstered.,The onset may not be accompanied by any of the acute signs but may appear insidiously However,it is incorrect to view this onset as o

21、ne of slow progression. In fact,pulmonary tuberculosis usually reaches its full extent within a few weeks.,Chronic cough is principal respiratory symptom.sputum is usually scant and nonpurulent. Haemoptysis is frequent and is usually limited to blood streaking. sputum.massive,life-threatening haemop

22、tysis is rare.,Specific symptom,Anaphylaxia anergy tuberculosis,Physical examination,Findings on physical examination of the lung in patients with pulmonary tuberculosis are typically few and generally can be appreciated only in the presence of extensive disease.,Crackles may be heard in the area of

23、 involvement, along with bronchial breath sounds, when lung consolidation is close to the chest wall. Amphoric breath sounds may be indicative of a cavity. Findings such as lymph node enlargement, suggestive of extrapulmonary tuberculosis, may also indicate concurrent pulmonary involvement,Radiograp

24、hic features,Radiographic examination of the chest is commonly the first diagnostic study undertaken, after the history and physical examination. The most frequent sites are the apical and posterior segments of the upper lobe and the dorsal segment of the lower lobe. However,in patients with HIV inf

25、ection, a chest radiograph may be normal in up to 11% of patients with positive sputum cultures.,Laboratory Findings,1.Sputum smear microscopy: The first step in the diagnostic sequence is nearly always staining and examining readily available specimens for AFB. However, the sensitivity of microscop

26、ic examination is relatively low. ZiehlNeelsen stain and Kinyoun-stained smears of sputum Auramine fluorochrome stain of sputum smear,Mycobacterium tuberculosis,When the lung is involved, sputum is the initial specimen of choice. if expectorated sputum is not readily available for examination,expect

27、oration may be induced or samples obtained by induction,2.Mycobacterial Culture：Culture in liquid media is considered the current diagnostic gold standard. Culture is an essential step for diagnosis and is necessary for phenotypic drug susceptibility testing. 3. Serologic Tests：Several antigens, inc

28、luding highly purified and recombinant antigens specific for M. tuberculosis complex, have been used in serologic antibody tests with variable results.,4.Fiberoptic bronchoscop: Bronchoscopy has a high yield in the diagnosis of tuberculosis. Bronchoscopic procedures have been especially helpful in t

29、he diagnostic evaluations of patients with HIV infection with negative sputum smear microscopy,5. Pleural fluid cultures: M tuberculosis are positive in less than 25%. 6. Needle biopsy of the pleura: patients with pleural effusions caused by M tuberculosis. 7. Susceptibility testing:the first isolat

30、e of M tuberculosis(when a treatment is failing). 8. ELLISA AND PCR has been used to dianosis,but they are rare applied successfully in routine clinical treatment.,Special examination,Tuberculin skin test PPD test: 0.1 mL of standard purified protein(5 TU) is injected intradermally on the volar surf

31、ace of the forearm.The transverse width(in millimeters) of the induration(red spot) at the skin test site should be recorded after 48-72 hours.,All the people susceptible to tuberculousis should have PPD test: 1. People who have had close day-to-day contact with someone who has active TB disease. (a

32、 family member, friend, or co-worker) 2. People who has symptoms of TB, such as: a cough that hangs on, fever, weight loss,night sweats ,constant tiredness ,loss of appetite. 3. People who have lowered immunity such as HIV infection or certain medical conditions. 4. People who need to give BCG vacci

33、ne.,PPD test (induration),The standard of judgement,48-72h skin node diameter：,1. Negative reaction does not rule out the diagnosis of tuberculosis. 2. False-negative reactions occur: malnutrition； old age ；immunologic or lymphoreticular disorders（HIV infection、Lymphoreticular malignancies ）；cortico

34、steroid or immunosuppressive therapy；chronic renal failure； virus vaccinations or infections； fulminant tuberculosis；improper testing technique； problems with the antigen 3. False-positive reactions:inoculation with BCG,Special examination,IFN- release assays (IGRAs) IFN- release assays (IGRAs) are

35、used for the diagnosis of latent tuberculous infection (LTBI)，Two IGRAs are currently approved in the United States, the QuantiFERON-TB test and the T-SPOT.TB test The IGRAs have several advantages: The tests can be performed in one patient visit, they are more specific in the presence of BCG vaccin

36、ation or infection with nontuberculous mycobacteria, they are not subject to reader variability, and they do not stimulate waned immunity (the booster reaction, described earlier).,1.The QuantiFERON-TB tests：measure the amount of IFN- released from sensitized lymphocytes in whole blood incubated ove

37、rnight with mixtures of M. tuberculosis antigens, ESAT-6 and CFP-10. 2.The T-SPOT-TB tests：utilizes an ELISPOT format to quantify the number of cells in peripheral blood that secrete IFN- when stimulated with ESAT-6 and CFP-10,Clinical classification,1.Primary tuberculosis 2.hematogenous pulmonary t

38、uberculosis,3. secondary pulmonary tuberculosis infiltrative TB cavitary TB tuberculoma caseous pneumonia fibrocavitary TB,4. tuberculous pleurisy 5. extrapulmonary tuberculosis,肺结核病自然过程示意图,the combination of peripheral lung lesion , lymphangitis and hilar lymph node.There is a small tan-yellow subp

39、leural granuloma in the mid-lung field on the right. In the hilum is a small yellow tan granuloma in a hilar lymph node.,Primary tuberculosis,The Ghon complex is seen here at closer range. Primary tuberculosis is the pattern seen with initial infection with tuberculosis in children. Reactivation, or

40、 secondary tuberculosis, is more typically seen in adults.,Usually asymptomatic. A nonspecific pneumonia Hilar lymph node enlargement Bronchial obstruction (Segmental atelectasis) Pleural effusion may be present,Small homogeneous infiltrates (usually in the upper lobe) Hilar and paratracheal lymph n

41、ode enlargement,hematogenous pulmonary tuberculosis,In the past ,hematogenous TB occurred chiefly in infants and adolescent especially in the people with low immune function. Currently, however, except among HIV-infected persons, it is more common among older persons, as a result of endogenous react

42、ivation and bloodstream invasion. Severe toxemia symptoms Dyspnea is rare,Uniform size,density distribution,the bilateral,diffuse small granulomas often contain numerous mycobacterium,Infiltrative tuberculosis,The usual location: apical or posterior segments of the upper lobes; dorsal segments of th

43、e lower lobes. Various radiographic manifestations: fibrocavity -nodules-infiltrates,The TB lesion often locates at posterior or apical segment of the upper lobe or the superior segment of the lower lobe,especially at the apex of lung just as the picture points out.,Caseous necrosis,bilateral upper

44、infiltrates,When there is extensive caseation and the granulomas involve a larger bronchus, it is possible for much of the soft, necrotic center to drain out and leave behind a cavity. Cavitation is typical for large granulomas with tuberculosis. Cavitation is more common in the upper lobes.,cavitar

45、y tuberculosis,Pulmonary cavities may persist even though effective chemotherapy has resulted in apparent cure.cavities, aspergilloma in a chronic tuberculous cavin and bronchiectasis is the common reason haemoptysis.,Pulmonary cavities may persist even though effective chemotherapy has resulted in

46、apparent cure .,tuberculoma,Satellite lisions develop concomitantly. they can usually be recognized on chest X-ray films and are often helpful in distinguishing tuberculosis from pulmonary neoplasms.,caseous pneumonia,Fibrocavitary TB,Cavities may be source of major hemoptysis,especially in the pres

47、ence of continued active disease.persistent terminal pulmonary arteries within cavties may be a source of profound bleeding.,Extensive destruction:widespread cavitation,fibrosis scars,With the progression of pulmonary TB,the normal pulmonary architecture is lost.fibrosis,volume loss,and upward contr

48、action are typical.,pleural tuberculosis,Pleural effusion often appears in pleural tuberculosis. presence of fluid between the visceral and parietal pleura. It can be seen when 300ml of fluid is present on a chest radiograph.,As tuberculosis becomes inactive or Heals,fibrotic scarring becomes appare

49、nt on the chest radiograph.,Fibrotic lessions may develop calcifications. The activity of tuberculosis may be judged from CT.It is never wise to judge tuberculosis to be inactive only on the X ray film.,Diagnosis,1.The diagnosis of latent TB infection (LTBI) LTBI is one of exclusion, based on the fi

50、nding of delayed-type hypersensitivity (DTH) and the absence of active TB. IFN- release assays (IGRAs) and tuberculin skin test (TST) are used for the diagnosis of latent tuberculous infection (LTBI),2.Diagnosis of Pulmonary tuberculosis History and clinical symptoms:fatigue, weight loss, fever, nig

51、ht sweats, cough,or blood sputum Pulmonary infiltrates on chest radiograph, most often apical. Positive tuberculin skin test reaction (most cases). Acid-fast bacilli on smear of sputum or sputum culture positive for Mycobactenum tuberculosis.,Treatment,All proved cases should be reported to local pu

52、blic health departments. (CDC) Treatment of patients should be conducted by skillful physicians. Pay attention to improve nutrition,Hospitalization,not necessary in most patients. Hospitalized patients with active disease require a private room with appropriate ventilation until they become sputum s

53、mear-negative for acid-fast bacilli.,(一) Drug therapy,Tuberculosis requires early, regular, long-time treatment with a combination of special and appropriate drugs.,1.Antituberculosis drugs,First-line drugs Second-line drugs Isoniazid(INH) Kanamycin(KM) Rifampin (RFP) Paminosalacylic acid(PAS) Pyraz

54、inamide(PZA) Amikacin(AM) Ethambutol (EMB) Capreomycin(C) Streptomycin(SM),Tuberculous patients exits in three pools:a metabolically active extracellular pool and relatively metabolically inactive intracellular and necrotic caseum pools. Rifapin and isoniazid are bactericide for extracellular and in

55、tracellular pools TB. Streptomycin is bactericide against extracellular and pyrazinamide are against intracellular organisms.,isoniazid,Isoniazid have been used clinically for 50 years.It is the most efficient bactericide for TB,especial in the early days. isoniazid is bactericide for extracellular

56、and intracellular pools TB. Isoniazid can cross the blood-brain barrier(tubercular meningitis),Side effect:drug hepatitis,peripheral neuritis. Vatamin B6 can be used as the treatment of peripheral neuritis caused by isoniazid,but it will also alleviate the effect of isoniazid.so there are no good so

57、lution to prevent the peripheral neuritis. Isoniazid is also the only choice to prevent the tuberculosis.,Rifampin,isoniazid is bactericidal for extracellular and intracellular pools TB. It is also the most powerful drug in the treatment of TB. Side effect:drug hepatitis, gastroenteric reaction,pyra

58、zimide,pyrazinamide are against intracellular organisms. Pyrazimide has been found to be paticularly useful during the first 2 months of treatment. Pyrazimide can cross the blood-brain barrier Side effect:drug hepatitis, hyperuricemia (arthralgia ),ethambutol,Ethambutol is only bacteriostatic. Side

59、effect:optic neuritis (monitor vision and field of view),Streptomycin,Streptomycin is bactericide against extracellular Side effect: ototoxicity , nephrotoxicity (creatinine urea nitrogen ),Treatment for TB uses antibiotics to kill the bacteria. The three antibiotics most commonly used are rifampicin ,isoniazid and ethambutol .TB requires much longer periods of treatment (around 6 to 12 months) to entirely eliminate mycobacteria from the body.,