4.Pulmonary Tuberculosis

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4.Pulmonary Tuberculosis

  1. 1. 2009/2/26 Definition Epidemiology Etiology Pulmonary Tuberculosis Transmission Progression and development Pathology Clinical manifestations The Department of Respiratory Medicine Laboratory tests and examinations The first affiliated hospital of Sun Yat-sen University Types of pulmonary tuberculosis Diagnosis Kejing Tang, M.D., Ph.D. Differential Diagnosis (self-study) Treatment 唐可京 2009/2/26 【Definition】 【Epidemiology】 A communicable disease caused by Global epidemic status Mycobacterium tuberculosis (tubercle bacillus). TB is one of the world’s deadliest diseases Tuberculosis may involve multiple organs y p g One thi d f th O third of the world’s population (two billion people i t t l) are i f t d ld’ l ti (t billi l in total) infected. such as the lung, liver, spleen, kidney, brain, and bone. Each year, nearly 9 million new cases of TB, half of them are contagious. Pulmonary tuberculosis is the most frequent TB currently holds the seventh place in the global ranking of causes of death. site of involvement. Each year, there are almost 3 million TB-related deaths worldwide. Extrapulmonary tuberculosis is less frequent. TB is the leading killer of people who are HIV infected. Only pulmonary tuberculosis is infectious. It is the single most important bacterial infection and the number one infectious disease killer worldwide. Tang Kejing, SUMS Tang Kejing, SUMS 2009/2/26 2009/2/26 【Epidemiology】 Most TB cases are in India and China(2002) Epidemic status in China Of all individuals infected worldwide, 22% are in China. The characteristics: High infection rate: nearly half of population (550 million) is infected < 1 000 1 000 to 9 999 High Hi h mobidity bidit 10 000 t 99 999 to 100 000 to 999 999 High resistance rate: primary resistance rate 18.6%, acquired ~ 46.5% 1 000 000 or more No Estimate High death rate: about 130 thousand cases died every year Young people and adults are mainly involved Notable difference of mobidity in different areas Low mobidity in areas where DOTS (Directly Observed Treatment, Short-Course) strategy was performed The boundaries and names shown and the designations used on this map do not imply the expression of any opinion whatsoever on the part of the World Tang Kejing, SUMS Health Organization concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted lines on maps represent approximate border lines for which there may not yet be full agreement. © WHO 2002 2009/2/26 1
  2. 2. 2009/2/26 【 Etiology 】 Bionomics of M. tuberculosis (1) 【Etiology】 Microscopic morphology The tubercle bacillus was discovered by Koch in The bacteria are slender, slightly curved 1882. or straight, rod-shaped, non-encapsulated, non-motile bacteria. The Mycobacterium tuberculosis complex belongs y p g The dimensions of the bacilli have been to the family Mycobacteriaceae and includes the reported to be 1-10 μm in length (usually 3-5 μm), subspecies M. tuberculosis, M. africanum, M. bovis and 0.2-0.6 μm in width. Ziehl-Neelsen staining of Mycobacterium tuberculosis and M. microti. growing in culture at 1000x magnification. More than 90% of human pulmonary tuberculosis is Acid fastness caused by M. tuberculosis (and occasionally by M. bovis and M. africanum). Robert Koch Mycobacterium species are classified as acid-fast bacteria because the (1843-1910) waxy cell wall make the mycobacteria have the resistance to decolorization with acid-alcohol solutions after staining with carbol fuchsin Tang Kejing, SUMS 2009/2/26 唐可京 2009/2/26 【 Etiology 】 【 Etiology 】 Bionomics of M. tuberculosis (2) Bionomics of M. tuberculosis (3) Slow-growing Complicated structure The generation time is 15 to 20 hours. Constituents of M. tuberculosis are complex and mainly include Visible colonies on a solid medium usually take 2 to 4 week. lipids, proteins and polysaccharides. Each constituent has its role in the pathogenesis of tuberculosis. tuberculosis Powerful resistance It can survive in a dry state for months or years, in a dark and humid room phospholipids caseous necrosis for months, and in a low temperature condition like -40℃ for years. lipoid substance fatty acid tuberculation To kill: high pressure steam sterilization: 30 minutes at 120℃ (Best way) waxes virulence, acid fastness M. easily destroyed by heat and ultraviolet light (UV) tuberculosis proteins reactinogen of allergy 70% alcohol: within 2 minutes polysaccharides antigen of immune responses 唐可京 2009/2/26 唐可京 2009/2/26 【Transmission】 【Transmission】 Susceptible population Risk factors for tuberculosis include the following: Source of infection The most important source of infection is the patient with (secondary) Poverty, malnourishment, lack of medical facilities pulmonary tuberculosis , and when he/she coughs, sneezes, speaks, Living with those who have active tuberculosis, people with or sings. This person is usually sputum smear-positive. previously active tuberculosis but who have received inadequate chemotherapy Extrapulmonary TB is rarely contagious. Immigrants from high prevalence countries Low income Homeless Route of transmission Crowded living conditions Diseases producing a decrease in immunological status (diabetes, Transmission is by inhalation of droplet nucleus. anticancer chemotherapy, receive immunosuppressive drug, HIV disease) Other routes of transmission such as through digestive tract, skin Health care workers and intrauterine are comparatively rare. Tang Kejing, SUMS Tang Kejing, SUMS 2009/2/26 唐可京 2009/2/26 2
  3. 3. 2009/2/26 【Progression and development】 【Progression and development】 Primary Infection (1) Only 10% of people infected with M. tuberculosis eventually Most common in infants and children, especially in developing countries with high rates of malnutrition and poor medical care. will develop active tuberculosis (when the body’s immune Primary pulmonary tuberculosis results from an initial infection system weakens) y ) with tubercle bacillus through inhalation of droplet nucleus nucleus. Primary Infection Primary syndrome (primary tuberculosis): the lesion of primary infiltration, and the enlargement of tracheobronchial lymph node Postprimary (secondary ) tuberculosis Lymphatic and hematogenous dissemination of tuberculosis typically occurs before the development of an effective immune response. Tang Kejing, SUMS Tang Kejing, SUMS 2009/2/26 2009/2/26 【Progression and development】 【Progression and development】 Primary Infection (2) Immunity and delayed-type hypersensitivity Immunity to tuberculosis: Outcome: Native immunity Acquired immunity—result from primary tuberculous infection or Most lesions of disseminated and primary tuberculosis could heal, vaccination with BCG (Bacillus Calmette-Guerin) although they may remain potential foci for later reactivation when the body immunity function is suppressed. Type of Immunity to tuberculosis: Cell-mediated immunity: provides partial protection. Two types of cells In infants and young children, especially with malnutrition or poor are essential: macrophages and T cells. medical care, dissemination may result in miliary or meningeal Humoral immunity: has no defined role in protection. tuberculosis—illnesses with potential for major mortality. Delayed-type hypersensitivity • a Th1 lymphocyte response to the antigens of the tubercle bacillus, causing cell death and tissue damage or tissue necrosis. • two types of phenomenon: tuberculin (PPD) test, Koch phenomenon Tang Kejing, SUMS 2009/2/26 2009/2/26 【Progression and development】 【Progression and development】 Postprimary (secondary ) tuberculosis (1) Postprimary (secondary ) tuberculosis (2) Occurs after a latent period of months or years following primary It may occur either by infection. Endogenous reactivation: means that dormant bacilli The most common type in adults. persisting in tissues for months or years after primary infection start to multiply. Usually affects the lungs but can involve any part of the body. body Risk factors of reactivation: Patients usually presents obvious clinical symptoms, cavities and bacilli expelled, and are contagious (Most of patients are sputum • Patients with chronic disease causing general debility: smear-positive.) alcoholism, malnutrition and diabetes mellitus Without treatment, 25% of patients are spontaneously cured by • Patients with cellular immunodeficiency: the body’s defence mechanisms, 50% die within 5 years, and HIV infecion, immunosuppressant drug treatment 25% continue to excrete bacilli and remain sources of infection Exogenous reinfection: means a repeat infection in a person for many years before dying. who has already previously had a primary infection. Tang Kejing, SUMS Tang Kejing, SUMS 2009/2/26 3
  4. 4. 2009/2/26 【Pathology】 【Pathology】 Basic pathological findings (1) Basic pathological findings Exudative lesions, proliferative lesions, and caseous necrosis are the basic pathological changes of tuberculosis. Transformation T f ti These pathological changes existed simultaneously and can transform reciprocally. The disease as a whole may fluctuate between periods of exacerbation and remission. Tang Kejing, SUMS Tang Kejing, SUMS 【Pathology】 Tuberculous granuloma 【Pathology】 A typical appearance of proliferative lesions Basic pathological findings (2) At low power magnification. Well-defined granulomas are seen here. The follicle is surrounded by a crown of Exudative lesions lymphocytes; in the centre are two giant cells and a cluster of epithelioid cells. ~ ocurr in the initial or worse duration of tuberculous infection. The localized, small appearance of these granulomas suggests that the immune response Proliferation—shows typically tuberculous granuloma is fairly i f i l good. d ~ ocurrs with strong resistance or in recovery stage of the body. Caseous necrosis ~ appear in the condition of presence of strong toxic tuberculous bacilli At high power magnification. in a large numbers and of hypersensitivity with weak resistance. Langhans giant cell is a committee of macrophages with the nuclei lined up along one edge of the cell. Tang Kejing, SUMS 唐可京 2009/2/26 【Pathology】 【Pathology】 Tuberculous granuloma with caseous necrosis Transformation At low power magnification. The caseating necrosis can be seen in the Before anti-tuberculosis chemotherapy, tuberculosis lesions centre of the photo; at the exterior three represent slow recover, repeated exacerbation, and spread giant cells and epithelioid cells can be seen. easily. Caseating necrosis is a fine-grained , homogeneous, eosinophilic necrosis . This lesion is very specific to tuberculosis. Early exudative lesions: resolve almost completely with chemotherapy. Small areas of proliferative or caseous lesions: may be absorbed to small or gradually become fibrosis. Gross pathologic findings Liquefaction of caseous foci →cavity formation →satellite lesions The caseous necrosis is extensive, and within the lungs cavitation is prominent. Such patients can be highly infectious. Some pulmonary lesions become fibrotic and may later calcify. Tang Kejing, SUMS 唐可京 2009/2/26 4
  5. 5. 2009/2/26 【Clinical Manifestation】 【Clinical Manifestation】 1. Systemic symptoms The onset of the disease is often nonspecific and insidious; 1. Systemic symptoms symptoms often develop slowly, over several weeks. 1. Fever 2. 2 Respiratory symptoms The most common symptom. The fever is a low grade fever and has a characteristic afternoon peak with defervescence at night accompanied by sweats. 3. Signs 2. Fatigue, night sweats, and loss of appetite and weight ~ are systemic symptoms consistent with both pulmonary and 4. Special performance extrapulmonary tuberculosis. 3. Menoxenia Some female patients may have irregular menses Tang Kejing, SUMS Tang Kejing, SUMS 2009/2/26 2009/2/26 【Clinical Manifestation】 【Clinical Manifestation】 2. Respiratory symptoms 3. Signs (self-study) Respiratory symptoms predominate The physical signs in patients with pulmonary tuberculosis are nonspecific. 1. Cough and expectoration cough is the most common symptom. The cough is nonspecific, usually nonproductive but persistent, and it may become Small extent of disease often no abnormal signs in the chest productive of mucopurulent or blood-streaked sputum. Widespread exudative process or caseous necrosis signs of lung consolidation (reinforcement of tactile fremitus dull percussion note, bronchial fremitus, note 2. Hemoptysis can be light, moderate or massive. Sudden massive hemoptysis breathing sound and fine rales) resulting from erosion of a pulmonary artery by an advancing cavity was an occasional terminal event in the pre-drug era but is now seldom seen. Big cavitary process hyperresonant note or tympanic resonance on percussion, and bronchial breathing sound or bottle sound on auscultation. 3. Chest pain usually due to extension of inflammation to the parietal pleura Big extent of fibrosis tracheal deviation toward the affected side, chest wall and often is described as dull and aching or pleuritic in nature. collapse of affected side, dull percussion note, diminished breath sound and moist rales on auscultation. 4. Dyspnea is an uncommon feature; when present, it is usually caused by Tuberculous pleuritis signs of pleural effusion (tracheal deviation away from extensive parenchymal disease, tracheobronchial obstruction, or a large pleural the side of the effusion, bulging of the chest wall, abatement of tactile fremitus, effusion. percussive flatness and absent or attenuated breath sounds on auscultation. Endobronchial tuberculosis local wheezes Tang Kejing, SUMS Tang Kejing, SUMS 2009/2/26 2009/2/26 【Clinical Manifestation】 4. Special performance 【 Laboratory tests and examinations】 Allergic symptoms Tuberculous rheumatism (Poncet's disease): is an immunological reaction to M. tuberculosis with resultant reactive polyarthritis. It is a rare aseptic form of 1. Bacteriological examination arthritis observed in patients with active TB. Follicular keratoconjunctivitis j 2. Radiological 2 R di l i l examination i ti Unresponsive tuberculosis (tuberculous septicemia) 3. Tuberculin skin test Seen in patients with extreme immune suppression. Clinical manifestations: continued high fever, bone marrow suppression or leukemoid reaction. Respiratory symptoms and chest X-ray findings are often not 4. Fiberoptic bronchoscopy obvious or absent. Often misdiagnosed as sepsis, leukemia, typhoid, and other connective tissue diseases. Tang Kejing, SUMS Tang Kejing, SUMS 2009/2/26 2009/2/26 5
  6. 6. 2009/2/26 【 Laboratory tests and examinations】 【 Laboratory tests and examinations】 1. Bacteriological examination 1. Bacteriological examination ② Sputum smear microscopy Key examination in the diagnosis of pulmonary tuberculosis. Because most cases of tuberculosis are pulmonary, examination of In order to detect M. tuberculosis in a sputum sample, in excess of 10,000 sputum is of primary importance. organisms per ml of sputum are required for smear positivity. Other sources: pus, biopsy specimen of lung or bronchus, Acid-fast bacteria seen on smear may represent either M. tuberculosis or nontuberculous mycobacteria. bronchoalveolar lavage fluid Acid-fast staining methods: Ziehl-Neelsen (ZN) stain. ① Collection of sputum samples p , p y p This method is simple, rapid and fairly inexpensive. Reporting on AFB (acid-fast bacilli) Microscopy (by Ziehl-Neelsen) 100% 100% 93% Cumulative Positivity 81% Number of bacilli seen Result reported None per 300 oil immersion fields Negative 50% 1-2 per 100 oil immersion fields report exact number The cumulative positivity of three 3-9 per 100 oil immersion fields + 0% sputum specimens could achieve 100%. 1-9 per 10 oil immersion field ++ First Second Third 1-9 per oil immersion field +++ It is best to obtain a series of early-morning Tang Kejing, SUMS > 9 per oil immersion field ++++ specimens collected on 3 consecutive days. 2009/2/26 【 Laboratory tests and examinations】 【 Laboratory tests and examinations】 1. Bacteriological examination 1. Bacteriological examination ③ Mycobacterial culture Culture of M. tuberculosis has high sensitivity and specificity. Drug sensitivity ④ Molecular biology detection tests can be performed at the same time. Nucleic acid amplification tests As culture is a complicated, relatively costly technique, which is slow to yield The unsatisfactory sensitivity is the major limitation of amplification-based results, it is not suitable for rapid identification of the most potent sources of methods. infection. Culture, supported by microscopy, still remains the gold standard, and Liquid broth cultures require 1 to 3 weeks of incubation for detection of molecular methods only represent a useful support in some cases, to speed up organisms, as compared to solid media, which require 3 to 8 weeks. the diagnosis of TB. fingerprinting DNA fi i ti Commercial automated liquid broth systems (the BACTEC 460 TB system, the BACTEC 960 mycobacterial growth indicator tube (MGIT) system) greatly facilitate mycobacterial culture. Nucleic acid probes High-performance liquid chromatography (HPLC) When growth has occurred on culture, large, rounded, buff- coloured “cauliflower like” colonies are visible to the naked eye on the surface of the culture ⑤ TB antigen and antibody detection medium; they have a dry, rough surface, and are isolated or There is still a need to improve the sensitivity or specificity of confluent, depending on the commercial serological tests. number of bacilli present in the original sample. 【 Laboratory tests and examinations】 【 Laboratory tests and examinations】 2. Radiological examination 2. Radiological examination Important for diagnosis. It is helpful in judging the ranges and characteristics of pulmonary lesions, and is also helpful in evaluating the therapeutic responses. Chest computed tomography Chest X-ray Chest CT is particularly helpful in finding minor or occult A posterior-anterior radiograph of the chest is the standard view used tuberculous lesions, and may also be helpful in differentiating for the detection and description of chest abnormalities. In pulmonary tuberculosis, radiographic abnormalities are often seen in different nodular lesions in the lungs. the apical and posterior segments of the upper lobe or in the superior segments of the lower lobe. However, lesions may appear anywhere in the lungs and may differ in size, shape, density, and cavitation, especially in immunosuppressed persons. Old healed tuberculosis usually presents a different radiographic appearance from active tuberculosis. Infiltration, caseous change and cavitation are considered as active lesions. 唐可京 2009/2/26 唐可京 2009/2/26 6
  7. 7. 2009/2/26 【 Laboratory tests and examinations】 【 Laboratory tests and examinations】 3. Tuberculin skin test (TST) 3. Tuberculin skin test (TST) How to judge the result The standard method of determining whether a person is infected with Less than 5 mm: not significant, or “negative” M. tuberculosis. Between 5 to 9 mm: weakly positive Reagent:5-tuberculin unit (TU) of purified protein derivative (PPD) Where to inject: Intradermal injection. About a third of the way Between 10 to 19 mm: positive down on the volar aspect of the forearm Greater than 20 mm or there are water vacuoles and When to read the result: should be read between 48 and 72 lymphangitis on the injection site: significant positive hours after the injection j How to measure: The reaction should be measured in millimeters How to interpret the result Measure induration of the induration (palpable, raised, hardened area or swelling). The (not erythema) Factors that May Affect the Skin Test Reaction reader should not measure erythema (redness). Type of Reaction Possible causes False-positive Nontuberculous mycobacteria BCG vaccination False-negative HIV infected Overwhelming TB disease Severe or febrile illness Viral infections (e.g. measles, chickenpox) Live-virus vaccinations Immunosuppressive therapy 唐可京 2009/2/26 2009/2/26 【 Laboratory tests and examinations】 4. Fiberoptic bronchoscopy Diagnostic fiberoptic bronchoscopy with transbronchial biopsy and bronchoalveolar lavage (BAL) is an efficient way to obtain diagnostic materials when sputum does not suffice. Tang Kejing, SUMS 唐可京 2009/2/26 【 Types of pulmonary tuberculosis 】 【 Types of pulmonary tuberculosis 】 According to Chinese Medical Association (CMA) (1999), According to Britain and USA, tuberculosis is classified as tuberculosis is classified as five types. two types. 1. Primary pulmonary tuberculosis Primary syndrome and intrathoracic lymphatic tuberculosis 2. Hematogenous disseminated pulmonary tuberculosis 1. Pulmonary tuberculosis Acute, subacute, and chronic ~ Primary or postprimary (second) ~. 3. Postprimary or secondary pulmonary tuberculosis Both categories can lead to hematogenous spreading. Infiltrative, chronic fibro-cavitary pulmonary tuberculosis, and caseous pneumonitis 4. Tuberculous pleuritis 2. Extrapulmonary tuberculosis Tuberculous dry pleurisy, tuberculous exudative pleurisy, and Virtually all organ systems may be affected. tuberculous empyema The sites include lymph nodes, pleura, genitourinary tract, bones 5. Other extrapulmonary tuberculosis and joints, meninges, peritoneum, pericardium, and so on. In order of frequency: genitourinary tract, bones and joints, meninges, peritoneum, and pericardium 2009/2/26 2009/2/26 7
  8. 8. 2009/2/26 【CMA types】 续:【诊断】 1. Primary pulmonary tuberculosis 1. Primary pulmonary tuberculosis Pathology and chest radiograph Occurs in people (most often in children less than 5 years of age) Primary complex who have not had any previous exposure to M. tuberculosis. Typical lesion of primary pulmonary tuberculosis, Includes primary complex and mediastinal lymphadenopathy consists of the primary lesion, lymphangitis (Lymphatic s drain the bacilli to the hilar lymph In the majority of cases ~ is asymptomatic, and goes unnoticed. nodes) and related hilar lymphadenopathy. The primary complex (Ghon focus and ipsilateral hilar lymphadenopathy) Most patients recover completely without sequelae. Some of them may, however, subsequently develop active tuberculosis Mediastinal lymphadenopathy (reactivate) after a period of quiescence . In some cases, isolated ~ may occur without any visible changes in the pulmonary parenchyma. Tang Kejing, SUMS Tuberculosis of intrathoracic lymphonodes 【CMA types】 2. Hematogenous disseminated 2. Hematogenous disseminated pulmonary tuberculosis pulmonary tuberculosis Pathology Includes acute ~ (acute miliary tuberculosis) and subacute or chronic ~. Acute hematogenous disseminated Acute hematogenous disseminated pulmonary tuberculosis pulmonary tuberculosis Occurs most commonly in infants and children, and other immunologically Often demonstrates the miliary pattern of incompetent individuals. extensive, small nodules resembling millet seeds, all The onset often occurs within the first weeks after primary pulmonary tuberculosis. tuberculosis the same size (most of the nodules are 2 mm in In children, there is always widespread dissemination of the granulomas in other diameter) and spread symmetrically over both organs. lungs. If treatment is delayed, the prognosis may be badly affected, as many children have accompanying meningitis. Subacute or chronic hematogenous disseminated pulmonary tuberculosis Subacute or chronic hematogenous disseminated pulmonary often demonstrates extensive, miliary or nodous tuberculosis shadows of variable size, density and distribution, The onset of ~ often develops insidiously without striking clinical symptoms. most frequently in the bilateral upper and middle The body immunity of the patient is relatively good. lung zones, and existing simultaneously with fresh Tang Kejing, SUMS exudations, old indurations and calcified nodules. 2. Hematogenous 【CMA types】 disseminated pulmonary tuberculosis 3. Secondary pulmonary tuberculosis Chest radiograph Acute hematogenous disseminated Characteristic features: pulmonary tuberculosis The lesions can present with a wide variety of radiographic nodules iso-density features and usually be present in the apical or posterior iso-size iso-distribution segment of the upper lobes or the superior segment of the lower lobes. Subacute or chronic hematogenous Usually no intrathoracic lymphadenopathy . disseminated pulmonary tuberculosis Pulmonary lesions are usually localized, but may have nodules aniso-density extensive lung destruction with cavitation or caseous necrosis. ansio-size ansio-distribution Most of patients are sputum smear-positive. Tang Kejing, SUMS 8
  9. 9. 2009/2/26 【CMA types】 【Diagnosis 】 Classifications based on pathology and chest radiograph Infiltrative pulmonary tuberculosis 1. Medical history and clinical manifestations Cavitary pulmonary tuberculosis 2. Diagnostic criteria Tuberculoma Bacillary positive Bacillary-positive pulmonary tuberculosis Caseous pneumonia Bacillary-negative pulmonary tuberculosis Fibro-cavitary pulmonary tuberculosis 3. Judgement of activities 4. Classification and Record mode Tang Kejing, SUMS 2009/2/26 【Diagnosis】 【Diagnosis】 2. Diagnostic criteria 1. Medical history and clinical manifestations Bacillary-positive pulmonary tuberculosis Symptoms and signs Patient can be diagnosed when the sputum smear and/or culture is The symptoms of pulmonary TB may include a productive, prolonged positive with corresponding clinical manifestations and chest X-ray findings. cough (duration of ≥ 3 weeks), chest pain, and hemoptysis. Systemic symptoms of TB include fever, chills, night sweats, appetite loss, weight Bacillary-negative pulmonary tuberculosis loss, and easy fatigability. TB should be considered in persons who have g p Can be diagnosed when examination results of a series of three sputum these symptoms. smear microscopy and one sputum culture are all negative. The physical signs in patients with pulmonary TB are nonspecific. The diagnosis of ~ should be based on criteria as follows: History of TB exposure, infection, or disease ① Typical clinical symptoms and chest radiographic characteristics of Past TB treatment pulmonary TB. Demographic risk factors for TB: ② Exclusion of other non-tuberculous pulmonary diseases clinically. ③ A strong positive PPD-tuberculin (5TU) skin test and/or a positive Country of origin, age, ethnic or racial group, occupation serum anti-tuberculosis antibody. Medical conditions that increase risk for TB disease: ④ Response to diagnostic anti-tuberculosis therapy. HIV infection, use of medications that affect host immunity Tang Kejing, SUMS Having at least three criteria can diagnose as ~ clinically. 2009/2/26 2009/2/26 【Diagnosis】 【Diagnosis】 4. Classification and Record mode 3. Judgement of activities Tuberculosis is classified as five types in China in 1999 Primary pulmonary tuberculosis Patients with pulmonary TB must be identified to be clinically active or Hematogenous disseminated pulmonary tuberculosis inactive, and active patients should receive anti-tuberculosis therapy. Secondary pulmonary tuberculosis Judgement of activities is based on the clinical features, chest X-ray Tuberculous pleurisy findings and sputum bacteria examination. Other extrapulmonary tuberculosis Signs of active pulmonary tuberculosis Recording mode of pulmonary tuberculosis Sputum bacteria positive Pulmonary tuberculosis should be recorded in proper order and based on Chest X-ray: Exudative lesions, exudative and proliferative lesions, Types: five types caseous pneumonia, caseous change and cavitation Affected sites and range: left, right or both lungs Bacteriologic status of sputum: smear (+) / (-) or culture (+) / (-). (No Signs of inactive pulmonary tuberculosis sputum) or (Unexamined if no sputum) Chest X-ray: Proliferative lesions, nodules and fibrotic lesions with well- History of chemotherapy: initial treatment, retreatment demarcated, sharp margins, calcified nodular lesions (calcified For example: granuloma ) or apical pleural thickening • Postprimary pulmonary tuberculosis of right upper lobe with positive sputum smears in initial treatment. Tang Kejing, SUMS 2009/2/26 2009/2/26 9
  10. 10. 2009/2/26 【Differential Diagnosis】 (Self-study) The table shows possible alternative diagnoses. Diagnosis Pointers to the correct diagnosis 【 Treatment】 Other infections, e.g. Bacterial pneumonia usually shorter history, febrile, response to antibiotic Lung abscess cough with large amounts of purulent Chemotherapy of Tuberculosis abscess with fluid level on CXR Pneumocystis carinii often dry, non-productive cough with prominent 1. Principles of anti-tuberculosis chemotherapy dyspnoea 2. Major effects of chemotherapy Chronic obstructive airways risk factor (smoking), chronic symptoms, prominent g 3. Biological mechanisms of chemotherapy py disease di dyspnoea, generalized wheeze, signs of right h d li d h i f i ht heartt failure (e.g. ankle oedema) 4. Frequently used anti-tuberculosis drugs Bronchiectasis coughing large amounts of purulent 5. Standardized tuberculosis treatment regimens Bronchial carcinoma (lung cancer)risk factor (smoking, older age, previous mine-work) 6. Drug resistant pulmonary tuberculosis Asthma intermittent symptoms, generalized expiratory wheeze; symptoms wake the patient at night Surgical treatment Congestive cardiac failure symptoms of heart failure (dyspnoea, orthopnoea, left ventricular failure paroxysmal nocturnal dyspnea, hemoptysis, oedema, epigastric discomfort from hepatic congestion) signs of heart failure Symptomatic treatment Diseases of mediastinum or hilus intrathoracic thyroid (right upper mediastinum ) of lung tumors of lymphatic tissue (middle mediastinum), dermoid cyst,teratoma (anterior mediastinum) Tang Kejing, SUMS Other febrile illness typhus, septicemia and leukemia 2009/2/26 【 Treatment】 【 Treatment】 Chemotherapy of Tuberculosis Chemotherapy of Tuberculosis 1. Principles of anti-tuberculosis chemotherapy 1. Principles of anti-tuberculosis chemotherapy Aims of anti-tuberculosis drug treatment Guiding principles for effective treatment of tuberculosis (1) Early: Early therapy for suspicious or confirmed cases may get (1) to cure the patient of tuberculosis early efficacy, possible complete absorption, and less spreading. (2) to prevent death from active tuberculosis or its late effects (2) Regular: resistance. Regular administration to avoid drug resistance (3) to prevent relapse of tuberculosis (3) Full-termed: Full course of therapy for the long generation time of mycobacteria and their long periods of metabolic inactivity, such therapy (4) to decrease transmission of tuberculosis to others ensure to enhance cure rate and lessen recurrent rate. (5) to prevent the development of acquired drug resistance (4) Adequate: Adequate dosages provide the safest and most effective therapy. (5) Combined chemotherapy: Combined multiple drugs improve efficacy and prevent drug resistance. Tang Kejing, SUMS Tang Kejing, SUMS 2009/2/26 2009/2/26 【 Treatment】 【 Treatment】 Chemotherapy of Tuberculosis 2. Major effects of chemotherapy Chemotherapy of Tuberculosis (1) Bactericidal activity Isoniazid (INH) kills 90% of the total population of bacilli during the first few days of treatment. It is most effective against the metabolically active, The course of therapy is divided into two phases continuously growing bacilli. Rifampicin (RFP) can kill the semidormant bacilli that isoniazid cannot. Pyrazinamide (PZA) kills bacilli in an acid environment inside cells, e.g. macrophages. The initial or intensive phase (2 months)——agents are used in combination to kill rapidly replicating populations of (2) Prevention of drug resistance M. tuberculosis and to prevent the emergence of drug Isoniazid and rifampicin are most effective in preventing resistance to other drugs. resistance Streptomycin (SM) and ethambutol (EMB) are slightly less effective. The continuation phase (4 to 6 months)——utilizing (3) Sterilizing activity sterilizing drugs to kill the less metabolically active and The ability of a drug to kill the last viable, often semidormant, bacterium intermittently replicating populations inside the host. Rifampicin and pyrazinamide are the most effective sterilizing drugs Isoniazid is intermediate Streptomycin (SM) and ethambutol (EMB) are the least effective Tang Kejing, SUMS 2009/2/26 10
  11. 11. 2009/2/26 【 Treatment】 【 Treatment】 3. Biological mechanisms of chemotherapy Chemotherapy of Tuberculosis (1)Anti-tuberculosis drugs act on different bacillary populations in 3. Biological mechanisms of chemotherapy a patient with tuberculosis (2) Drug resistance The best protection against the selection of resistant organisms is the Table. Different bacillary populations in a patient with tuberculosis use of at least two bactericidal drugs to which the organisms are sensitive. Metabolism Location Biological features Active Clinical By giving initial chemotherapy with two or more drugs, the likelihood of state drugs significance drug resistant bacilli surviving in the bacterial population is extremely A Metabolically Extracellular • replicate constantly and INH>>SM Reducing small. group active, bacilli, found rapidly. >RFP>EMB infectiousness continuously principally • strong virulence, big and growing bacilli inside lung infectiousness and changed preventing cavities g into drug-resistant mutant acquired q bacilli easily. resistance (3) I t Intermittent use itt t B Slowly- Intracellular Their multiplication is PZA>>RFP group replicating bacilli bacilli, situated slowed down by the lack of >INH Mainly based on the delayed growing period of M. tuberculosis after inside the oxygen and the acid pH of giving anti-tuberculosis drugs such as Isoniazid and Rifampicin. macrophages the macrophage cytoplasm. Preventing relapse C Semidormant / which replicate in the tissues RFP>>INH group bacilli very slowly and episodically, (persisters) are metabolically inactive. However, they are still alive, (4) Draught and can start to multiply once again as soon as the A high peak concentration of drugs in the serum played a more important immune defence system role in the response to treatment than the maintenance of a continuous weakens inhibitory level of the drug. D dormant bacilli / which fade away and die Generally / group on their own. drug resistent 【 Treatment】 Table . Doses and common adverse reactions to anti-tuberculosis drugs Nomen Abbrevi- Daily dose Intermittent Mechanisms 4. Frequently used proprium ation (g) dose(g) of action Common adverse reactions Isoniazid H,INH 0.3 0.6~0.8 DNA synthesis Peripheral neuropathy, anti-tuberculosis drugs occasional hepatotoxicity Rifampicin R,RFP 0.45~0.6* 0.6~0.9 mRNA Hepatitis, gastrointestinal Isoniazid (INH) synthesis upset, skin eruptions, Streptomycin (SM) thrombocytopenia Discovery of antituberculosis drugs: Streptomycin S,SM 0.75~1.0△ 0.75~1.0 Protein Eighth nerve damage, synthesis nephrotoxicity Pyrazinamide Z,PZA 1.5~2.0 2~3 Bacteriostasis Gastrointestinal upset, 1944: Streptomycin (S, SM) by hepatotoxicity, pyrazinoic acid 1946: p-aminosalicylic acid (P, PAS) hyperuricemia, joint pain Ethambutol E,EMB 0.75 1.0 0.75~1.0** 1.5 2.0 1.5~2.0 RNA synthesis Retrobulbar neuritis, synthes s neur t s, 1950: Ethambutol (E, EMB) 1950 Eth b t l (E Rifampin (RFP) Rifapentine Rif ti hyperuricemia, gout, skin rash, drug fever, gastrointestinal 1951: Isoniazid (H, INH) disturbance 1952: Pyrazinamide (Z, PZA) Para-aminosalicylic P,PAS 8~12*** 10~12 Intermediary Gastrointestinal intolerance, metabolism hepatitis, hypersensitivity 1955: Cycloserine (环丝氨酸) acid Protionamide 1321Th 0.5~0.75 0.5~1.0 Protein Gastrointestinal symptoms, 1956: Ethionamide(乙硫异烟胺)、kanamycin synthesis hepatotoxicity 1962: Capreomycin(卷曲霉素) Ethambutol (EMB) p-aminosalicylic acid (PAS) Kanamycin K,KM 0.75~1.0△ 0.75~1.0 Protein Auditory and vestibular nerve synthesis 1965: Rifampicin (R, RFP) damage, nephrotoxicity Capreomycin Cp,CPM 0.75~1.0△ 0.75~1.0 Protein Auditory and vestibular nerve synthesis damage, nephrotoxicity •*0.45 g if < 50 kg body weight,0.6 g if ≥ 50 kg;dosages of S、Z、Th are also regulated based on body weight; •△ 0.75 g per time for aged people; Pyrazinamide (PZA) •** 25 mg/kg for the initial 2 months; then decreased to 15 mg/kg; Cycloserine •*** separated to twice per day(other drugs: once daily). 【 Treatment】 【 Treatment】 Chemotherapy of Tuberculosis Chemotherapy of Tuberculosis 5. Standardized tuberculosis treatment regimens 6. Drug resistant pulmonary tuberculosis There are many different possible anti-tuberculosis treatment regimens. The recommended treatment regimen for drug resistant pulmonary Directly observed treatment (DOT) is recommended for all patients and is particularly essential when intermittent regimens are used. tuberculosis, especially multidrug-resistance pulmonary tuberculosis (MDR-TB) should include at least 4 or 5 drugs, including 3 drugs which (1) Recommended treatment regimens for new, smear-positive tuberculosis are active or never used previously in the initial phase, and 2 or 3 of the cases, including new smear-negative cases with cavitation or miliary most active and best-tolerated drugs in the continuation phase. tuberculosis ① Daily regimens:2HRZE/4HR An initial phase of at least 3 months should be followed by a ② Intermittent regimens:2H3R3Z3E3/4H3R3 continuation phase of 18 to 21 months. (2) Recommended treatment regimens for smear-positive cases who need to receive re-treatment Available drugs used in drug resistant pulmonary tuberculosis include ① Daily regimens: 2HRZSE/4~6HRE ofloxacin, levofloxacin, prothionamide (1321Th), para-aminosalicylic acid ② Intermittent regimens: 2H3R3Z3S3E3/6H3R3E3 (PAS), amikacin, capreomycin, etc. (3) Recommended treatment regimens for new, smear-negative tuberculosis Directly observed treatment (DOT) should be performed during the cases whole range of treatment. ① Daily regimens: 2HRZ/4HR ② Intermittent regimens: 2H3R3Z3/4H3R3 Tang Kejing, SUMS Tang Kejing, SUMS 2009/2/26 2009/2/26 11

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