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Tuberculosis. A Small Disclaimer… This presentation will NOT teach you everything there is to know about tuberculosis.

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Presentation on theme: "Tuberculosis. A Small Disclaimer… This presentation will NOT teach you everything there is to know about tuberculosis."— Presentation transcript:

1 Tuberculosis

2 A Small Disclaimer… This presentation will NOT teach you everything there is to know about tuberculosis

3 3 TB has affected humans for millennia TB has affected humans for millennia Historically known by a variety of names, including: Historically known by a variety of names, including: Consumption Consumption Wasting disease Wasting disease White plague White plague TB was a death sentence for many TB was a death sentence for many History of TB (1) Vintage image circa 1919 Image credit: National Library of Medicine

4 4 Until mid-1800s, many believed TB was hereditary Until mid-1800s, many believed TB was hereditary 1865 Jean Antoine- Villemin proved TB was contagious 1865 Jean Antoine- Villemin proved TB was contagious 1882 Robert Koch discovered M. tuberculosis, the bacterium that causes TB 1882 Robert Koch discovered M. tuberculosis, the bacterium that causes TB Mycobacterium tuberculosis Image credit: Janice Haney Carr History of TB (2) Scientific Discoveries in 1800s

5 5 Before TB antibiotics, many patients were sent to sanatoriums Before TB antibiotics, many patients were sent to sanatoriums Patients followed a regimen of bed rest, open air, and sunshine Patients followed a regimen of bed rest, open air, and sunshine TB patients who could not afford sanatoriums often died at home TB patients who could not afford sanatoriums often died at home History of TB (3) Sanatoriums Sanatorium patients resting outside

6 6 Breakthrough in the Fight Against TB (1) Drugs that could kill TB bacteria were discovered in 1940s and 1950s Streptomycin (SM) discovered in 1943 Streptomycin (SM) discovered in 1943 Isoniazid (INH) and Isoniazid (INH) and p-aminosalicylic acid (PAS) discovered between 1943 and 1952 p-aminosalicylic acid (PAS) discovered between 1943 and 1952

7 most common and important agent of human disease is M. tuberculosis. most common and important agent of human disease is M. tuberculosis. M. bovis (characteristically resistant to pyrazinamide, once an important cause, currently the cause of a small percentage of cases worldwide) M. bovis (characteristically resistant to pyrazinamide, once an important cause, currently the cause of a small percentage of cases worldwide) M. microti : less virulent and rarely encountered M. microti : less virulent and rarely encountered M. pinnipedii (seals and sea lions in the southern hemisphere and recently isolated from humans ) M. pinnipedii (seals and sea lions in the southern hemisphere and recently isolated from humans ) M. canettii (a rare isolate from East African cases that produces unusual smooth colonies on solid media) M. canettii (a rare isolate from East African cases that produces unusual smooth colonies on solid media)

8 M. tuberculosis is a rod-shaped, non-spore- forming, thin aerobic bacterium measuring 0.5μm by 3 μm M. tuberculosis is a rod-shaped, non-spore- forming, thin aerobic bacterium measuring 0.5μm by 3 μm neutral on Gram's staining. neutral on Gram's staining. once stained, the bacilli cannot be decolorized by acid alcohol due mainly to the organisms high content of once stained, the bacilli cannot be decolorized by acid alcohol due mainly to the organisms high content of mycolic acids, mycolic acids, long-chain cross-linked fatty acids, long-chain cross-linked fatty acids, other cell-wall lipids other cell-wall lipids

9 cell wall, lipids are linked to underlying arabinogalactan and peptidoglycan. This structure confers very low permeability of the cell wall, thus reducing the effectiveness of most antibiotics cell wall, lipids are linked to underlying arabinogalactan and peptidoglycan. This structure confers very low permeability of the cell wall, thus reducing the effectiveness of most antibiotics cell wall, lipoarabinomannan, is involved in the pathogen-host interaction and facilitates the survival of M. tuberculosis within macrophages cell wall, lipoarabinomannan, is involved in the pathogen-host interaction and facilitates the survival of M. tuberculosis within macrophages

10 Microorganisms other than mycobacteria that display some acid fastness include species of Nocardia and Rhodococcus, Legionella micdadei, and the protozoa Isospora and Cryptosporidium Microorganisms other than mycobacteria that display some acid fastness include species of Nocardia and Rhodococcus, Legionella micdadei, and the protozoa Isospora and Cryptosporidium

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12 12 TB is spread person to person through the air via droplet nuclei TB is spread person to person through the air via droplet nuclei M. tuberculosis may be expelled when an infectious person: M. tuberculosis may be expelled when an infectious person: Coughs Coughs Sneezes Sneezes Speaks Speaks Sings Sings Transmission occurs when another person inhales droplet nuclei Transmission occurs when another person inhales droplet nuclei TB Transmission (3)

13 13 TB Transmission (4) Dots in air represent droplet nuclei containing M. tuberculosis

14 SOURCE CASE Only patients with pulmonary tuberculosis can be regarded as infectious. (placenta, skin, milk) Only patients with pulmonary tuberculosis can be regarded as infectious. (placenta, skin, milk) Smear positive Smear positive 1. Cavitary pulmonary disease 2. Endobronchial or laryngeal tuberculosis Coughing(wearing mask with patient) Coughing(wearing mask with patient) Use of chemotherapy (Isoniazide) Use of chemotherapy (Isoniazide) persons with both HIV infection and tuberculosis are less likely to have cavitations, they may be less infectious than persons without HIV co-infection. persons with both HIV infection and tuberculosis are less likely to have cavitations, they may be less infectious than persons without HIV co-infection.

15 A single bacillus in a tiny droplet nucleus is more hazardous than several bacilli in larger airborne particles A single bacillus in a tiny droplet nucleus is more hazardous than several bacilli in larger airborne particles Coughing is the most effective mechanism for generating aerosols that create droplet nuclei. Coughing is the most effective mechanism for generating aerosols that create droplet nuclei. Thin, watery secretions are more easily fragmented into small respirable droplets than is more viscous mucus. Thin, watery secretions are more easily fragmented into small respirable droplets than is more viscous mucus.

16 Masks worn by persons exposed to an infectious source are less effective than are masks worn by patients, because most airborne droplet nuclei are much smaller than their parent droplets. Masks worn by persons exposed to an infectious source are less effective than are masks worn by patients, because most airborne droplet nuclei are much smaller than their parent droplets.

17 prevalence of PPD + among young contacts of patients with newly discovered tuberculosis increased as the radiographic extent of involvement increased prevalence of PPD + among young contacts of patients with newly discovered tuberculosis increased as the radiographic extent of involvement increased contacts of patients who have organisms + in sputum smears have a much higher prevalence of infection contacts of patients who have organisms + in sputum smears have a much higher prevalence of infection patients who had positive sputum smears but who were receiving antituberculosis drugs were much less infectious for guinea pigs than were untreated patients. patients who had positive sputum smears but who were receiving antituberculosis drugs were much less infectious for guinea pigs than were untreated patients.

18 under standard conditions of temperature and humidity indoors : survived under standard conditions of temperature and humidity indoors : survived 60% to 71% for 3 hours, 60% to 71% for 3 hours, 48% to 56% for 6 hours, 48% to 56% for 6 hours, 28% to 32% for 9 hours. 28% to 32% for 9 hours. exposure to ultraviolet radiation kills tubercle bacilli exposure to ultraviolet radiation kills tubercle bacilli

19 close contacts (generally household) 30% are infected, rate of tuberculosis is in the range of 15 per 1000 close contacts (generally household) 30% are infected, rate of tuberculosis is in the range of 15 per 1000 nonclose contacts (generally out-of-household) 15% are infected, 3 per 1000 nonclose contacts develop tuberculosis nonclose contacts (generally out-of-household) 15% are infected, 3 per 1000 nonclose contacts develop tuberculosis Because the risk of tuberculosis is higher among close contacts, they should also be considered high- priority candidates for INH preventive therapy. Because the risk of tuberculosis is higher among close contacts, they should also be considered high- priority candidates for INH preventive therapy.

20 risk of developing disease after being infected depends on endogenous factors, such as the individual's: risk of developing disease after being infected depends on endogenous factors, such as the individual's: innate innate 1- immunologic 2- nonimmunologic defenses, level of function of cell-mediated immunity (CMI) level of function of cell-mediated immunity (CMI)

21 FROM INFECTION TO DISEASE PRIMARY TUBERCULOSIS -common among children (up to 4yr) -may be severe and disseminated -usually not transmissible -within two years after infection PRIMARY TUBERCULOSIS -common among children (up to 4yr) -may be severe and disseminated -usually not transmissible -within two years after infection SECONDARY TUBERCULOSIS -often infectious -late adolescent and early adulthood -women(25-34yr) SECONDARY TUBERCULOSIS -often infectious -late adolescent and early adulthood -women(25-34yr)

22 risk is much higher among HIV-infected persons were due to recent transmission rather than to reactivation of latent infection. one-third of cases of active tuberculosis in some inner-city communities

23 Risk Factors for Active Tuberculosis Recent infection (<1 year) Recent infection (<1 year) Fibrotic lesions (spontaneously healed) Fibrotic lesions (spontaneously healed) Intravenous drug use Intravenous drug use Gastrectomy Gastrectomy Jejunoileal bypass Jejunoileal bypass Posttransplantation period (renal, cardiac) Posttransplantation period (renal, cardiac) Malnutrition and severe underweight Malnutrition and severe underweight Silicosis Lymphoma Leukemia Other malignancy HIV Hemophilia CRF CRF Diabetes(insulin dependent) Diabetes(insulin dependent) Immunosuppresion Immunosuppresion

24 Infection and Macrophage Invasion usually <10% of droplet nuclei reach the alveoli usually <10% of droplet nuclei reach the alveoli Invasion of macrophages results largely from binding of the bacterial cell wall with a variety of macrophage cell-surface molecules Invasion of macrophages results largely from binding of the bacterial cell wall with a variety of macrophage cell-surface molecules Phagocytosis is enhanced by complement activation leading to opsonization of bacilli Phagocytosis is enhanced by complement activation leading to opsonization of bacilli

25 LAM inhibits the intracellular increase of Ca2+. Thus the Ca2+/calmodulin pathway (leading to phagosome-lysosome fusion) is impaired, and the bacilli may survive within the phagosomes LAM inhibits the intracellular increase of Ca2+. Thus the Ca2+/calmodulin pathway (leading to phagosome-lysosome fusion) is impaired, and the bacilli may survive within the phagosomes replication begins and the macrophage eventually ruptures and releases its bacillary contents replication begins and the macrophage eventually ruptures and releases its bacillary contents

26 Virulance of the bacillus lipid rich cell wall lipid rich cell wall glycolipid capsule glycolipid capsule genes confer virulance(katG,rpoV) genes confer virulance(katG,rpoV) number of invading bacilli number of invading bacilli katG gene encodes for catalase/peroxidase enzymes that protect against oxidative stress katG gene encodes for catalase/peroxidase enzymes that protect against oxidative stress rpoV is the main sigma factor initiating transcription of several genes rpoV is the main sigma factor initiating transcription of several genes

27 PATHOGENESIS Host response - tissue damage response(DTH) delayed-type hypersensitivity (DTH) reaction to various bacillary antigens; it destroys unactivated macrophages that contain multiplying bacilli but also causes caseous necrosis of the involved tissues Host response - tissue damage response(DTH) delayed-type hypersensitivity (DTH) reaction to various bacillary antigens; it destroys unactivated macrophages that contain multiplying bacilli but also causes caseous necrosis of the involved tissues -macrophage activating response (T-cell mediated phenomenon) activation of macrophages that are capable of killing and digesting tubercle bacilli -macrophage activating response (T-cell mediated phenomenon) activation of macrophages that are capable of killing and digesting tubercle bacilli

28 Granuloma Formation development of specific immunity and the accumulation of large numbers of activated lymphocytes and macrophages that evolve toward epithelioid and giant cell morphologies development of specific immunity and the accumulation of large numbers of activated lymphocytes and macrophages that evolve toward epithelioid and giant cell morphologies the tissue-damaging response can limit mycobacterial growth within macrophages the tissue-damaging response can limit mycobacterial growth within macrophages growth is inhibited within this necrotic environment by low oxygen tension and low pH growth is inhibited within this necrotic environment by low oxygen tension and low pH some lesions may heal by fibrosis, with subsequent calcification, whereas inflammation and necrosis occur in other lesions. some lesions may heal by fibrosis, with subsequent calcification, whereas inflammation and necrosis occur in other lesions.

29 The Delayed-Type Hypersensitivity Reaction minority of cases, the macrophage-activating response is weak mycobacterial growth can be inhibited only by intensified DTH reactions, which lead to lung tissue destruction. minority of cases, the macrophage-activating response is weak mycobacterial growth can be inhibited only by intensified DTH reactions, which lead to lung tissue destruction. lesions enlarge and the surrounding tissue is progressively damaged cavities are formed liquefied caseous material, containing large numbers of bacilli, is drained through bronchi. lesions enlarge and the surrounding tissue is progressively damaged cavities are formed liquefied caseous material, containing large numbers of bacilli, is drained through bronchi.

30 In young children with poor natural immunity, hematogenous dissemination may result in fatal miliary tuberculosis or tuberculous meningitis In young children with poor natural immunity, hematogenous dissemination may result in fatal miliary tuberculosis or tuberculous meningitis early stages of infection, bacilli are transported by macrophages to regional lymph nodes gain access to the bloodstream and disseminate throughout the body. early stages of infection, bacilli are transported by macrophages to regional lymph nodes gain access to the bloodstream and disseminate throughout the body.

31 CELL MEDIATED IMMUNITY T lymphocyte,mainly Th1(CD4+) T lymphocyte,mainly Th1(CD4+) Local macrophage Local macrophage IL1- IL6 –TNFα- IL2- IFNγ IL1- IL6 –TNFα- IL2- IFNγ Active cell aggregate around lesion and effectively neutralize tubercle bacilli Active cell aggregate around lesion and effectively neutralize tubercle bacilli Caseous necrosis Caseous necrosis Viable bacilli may remain dormant Viable bacilli may remain dormant Healed lesion may undergo calcification (Ranke complex) Healed lesion may undergo calcification (Ranke complex)

32 TST, which is used primarily for the detection of M. tuberculosis infection in persons without symptoms TST, which is used primarily for the detection of M. tuberculosis infection in persons without symptoms related mainly to previously sensitized CD4+ T lymphocytes related mainly to previously sensitized CD4+ T lymphocytes DTH is associated with protective immunity, it by no means guarantees protection against reactivation DTH is associated with protective immunity, it by no means guarantees protection against reactivation previous latent or active tuberculosis may not confer fully protective immunity previous latent or active tuberculosis may not confer fully protective immunity

33 Interferon-γ Release Assays Compared with the tuberculin skin test, the INF-γ release assays have the advantage of : being accomplished with one patient visit, being accomplished with one patient visit, being more specific being more specific in the presence of BCG vaccination in the presence of BCG vaccination infection with nontuberculous mycobacteria, infection with nontuberculous mycobacteria, having less reader variability, having less reader variability, not recalling waned immunity not recalling waned immunity

34 POSSIBLE OUTCOMES Immediate clearance of the organism Immediate clearance of the organism Chronic or latent infection Chronic or latent infection Primary disease Primary disease Reactivation Reactivation

35 Condition associated with reactivation HIV infection HIV infection End stage renal disease End stage renal disease Diabetes mellitus Diabetes mellitus Corticosteroid use Corticosteroid use Diminution in CMI associated with old age Reactivation TB tends to be localized Diminution in CMI associated with old age Reactivation TB tends to be localized

36 Clinical manifeststion Extra pulmonary tuberculosis Extra pulmonary tuberculosis Tuberculous lymphadenitis Tuberculous lymphadenitis Pleural tuberculosis Upper airway tuberculosis Genitourinary tuberculosis Skeletal TB, Pleural tuberculosis Upper airway tuberculosis Genitourinary tuberculosis Skeletal TB, Meningitis & tuberculoma Meningitis & tuberculoma Gastrointestinal, Gastrointestinal, Pericardial Pericardial Miliary or disseminated TB Miliary or disseminated TB Eye TB Eye TB Pulmonary tuberculosis -primary -Secondary Pulmonary tuberculosis -primary -Secondary

37 37 Sites of TB Disease (1) Bacilli may reach any part of the body, but common sites include:

38 38 Sites of TB Disease (2) LocationFrequency Pulmonary TB Lungs Most TB cases are pulmonary Extrapulmonary TB Places other than lungs such as: Larynx Larynx Lymph nodes Lymph nodes Pleura Pleura Brain Brain Kidneys Kidneys Bones and joints Bones and joints Found more often in: HIV-infected or HIV-infected or other other immunosuppressed immunosuppressed persons persons Young children Young children Miliary TB Carried to all parts of body, through bloodstream Rare

39 Module 1 – Transmission and Pathogenesis of Tuberculosis 39 TB Pathogenesis (4) Droplet nuclei containing tubercle bacilli are inhaled, enter the lungs, and travel to small air sacs (alveoli)

40 Module 1 – Transmission and Pathogenesis of Tuberculosis 40 TB Pathogenesis (5) Tubercle bacilli multiply in alveoli, where infection begins

41 Module 1 – Transmission and Pathogenesis of Tuberculosis 41 TB Pathogenesis (6) A small number of tubercle bacilli enter bloodstream and spread throughout body

42 Module 1 – Transmission and Pathogenesis of Tuberculosis 42 TB Pathogenesis (7) LTBI Within 2 to 8 weeks the immune system produces special immune cells called macrophages that surround the tubercle bacilli These cells form a barrier shell that keeps the bacilli contained and under control (LTBI)

43 Module 1 – Transmission and Pathogenesis of Tuberculosis 43 TB Pathogenesis (8) TB Disease If the immune system CANNOT keep tubercle bacilli under control, bacilli begin to multiply rapidly and cause TB disease This process can occur in different places in the body

44 Module 1 – Transmission and Pathogenesis of Tuberculosis 44 LTBI vs. TB Disease Latent TB Infection (LTBI) TB Disease (in the lungs) Inactive, contained tubercle bacilli in the body Active, multiplying tubercle bacilli in the body TST or blood test results usually positive Chest x-ray usually normalChest x-ray usually abnormal Sputum smears and cultures negative Sputum smears and cultures may be positive No symptomsSymptoms such as cough, fever, weight loss Not infectiousOften infectious before treatment Not a case of TBA case of TB

45 Signs and Symptoms of TB Cough for more than three weeks Cough for more than three weeks Coughing up blood Coughing up blood Unexplained weight loss Unexplained weight loss Night sweats Night sweats Fever Fever Feeling tired Feeling tired Not everyone with TB looks really sick…

46 Systemic effcts Fever Fever Malaise Malaise Weight loss Weight loss pancytopenia pancytopenia Leukocytosis Anemia Leukopenia hyponatremia

47 Primary pulmonary tuberculosis Often seen in children Often seen in children Frequently localized to middle and lower lung zone Frequently localized to middle and lower lung zone Paratracheal or hilar lymphadenopathy Paratracheal or hilar lymphadenopathy Progressive primary tuberculosis (cavation) Progressive primary tuberculosis (cavation) Pleural effusion, collapse lung, Bronchectasis Pleural effusion, collapse lung, Bronchectasis Dissemination,may develop milliary tuberculosis and meningitis Dissemination,may develop milliary tuberculosis and meningitis Ghon lesion(healed lesion) Ghon lesion(healed lesion)

48 Secondary tuberculosis Symptom: productive cough, hemoptysis, dyspnea, fever, night sweat Symptom: productive cough, hemoptysis, dyspnea, fever, night sweat Signs: not specific, Signs: not specific, dullness with decreased fermitus (pleural effusion), dullness with decreased fermitus (pleural effusion), rales, rales, sign of consolidation, sign of consolidation, amphoric sound,clubbing amphoric sound,clubbing

49 Chest.x.ray secondary tuberculosis Apical and post. segments of the upper lobes(80- 90%) Apical and post. segments of the upper lobes(80- 90%) Superior segments of lower lobes Superior segments of lower lobes Infiltration and cavitary lesion Infiltration and cavitary lesion Nodules and branching linear densities (tree in bud) Nodules and branching linear densities (tree in bud) Pleural effusion Pleural effusion Solitary nodule(atypical) Solitary nodule(atypical)

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53 Other pulmonary presentation Endobronchial tuberculosis Endobronchial tuberculosis ARDS ARDS Tuberculous pneumonitis (lower lobe) Tuberculous pneumonitis (lower lobe) Lower lobe TB(elderly,diabetes,renal and hepatic dis.,corticosteroid) Lower lobe TB(elderly,diabetes,renal and hepatic dis.,corticosteroid) Tuberculoma (rounded mass lesion) Tuberculoma (rounded mass lesion)

54 Complication of pulmonary TB Massive hemoptysis (rare) Massive hemoptysis (rare) Spontaneous pneumothorax Spontaneous pneumothorax Empyema Empyema Bronchectasis Bronchectasis Extensive pulmonary destruction Extensive pulmonary destruction Tuberculosis of the upper airway(chronic productive cough, hoarseness,dysphagia) Tuberculosis of the upper airway(chronic productive cough, hoarseness,dysphagia)

55 Pleural tuberculosis Hypersensitivity reaction to mycobacterial antigens in pleural space Hypersensitivity reaction to mycobacterial antigens in pleural space Rupture or leakage from subpleural focus of disease Rupture or leakage from subpleural focus of disease Ph.E:dullness to percussion and absence of breath sound Ph.E:dullness to percussion and absence of breath sound

56 Pleural fluid characteristics Exudative (ppl / pserum >0/5) Exudative (ppl / pserum >0/5) Normal or low glucose Normal or low glucose PH<7/2 PH<7/2 Lymph dominant Lymph dominant Mesothelial cell rare Mesothelial cell rare AFB negative in smear AFB negative in smear Fluid culture 30% positive Fluid culture 30% positive Biopsy with culture 70-80% diagnostic Biopsy with culture 70-80% diagnostic ADA, IFN gamma ADA, IFN gamma

57 Miliary (disseminated) tuberculosis Hematogenous spread of tubercle bacilli Hematogenous spread of tubercle bacilli Recent infection or reactivation Recent infection or reactivation Yellowish granuloma up to 2mm Yellowish granuloma up to 2mm

58 Clinical manifestation (miliaryTB ) History: fever, night sweat,anorexia, weakness,weight loss History: fever, night sweat,anorexia, weakness,weight loss PH.E: Hepatomegaly,Splenomegaly, lymphadenopathy, choroidal tubercle, menangismus PH.E: Hepatomegaly,Splenomegaly, lymphadenopathy, choroidal tubercle, menangismus

59 Diagnosis miliary TB CXR :miliary reticonodular pattern CXR :miliary reticonodular pattern Sputum smear negative in 80% Sputum smear negative in 80% Anemia,leukopenia,leukocytosis Anemia,leukopenia,leukocytosis DIC DIC Elevated alk/ph, abnormal liver function test Elevated alk/ph, abnormal liver function test Negative PPD(50%) Negative PPD(50%) BAL and biopsy more positive BAL and biopsy more positive

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64 Clinicopathologic patterns Acute miliary tuberculosis(typical caseating granuloma) Acute miliary tuberculosis(typical caseating granuloma) Cryptic miliary tuberculosis(more chronic, non specific clinical presentation) Cryptic miliary tuberculosis(more chronic, non specific clinical presentation) Non reactive miliary TB(acute septicemic) Non reactive miliary TB(acute septicemic) Risk factor: Age, alcohol abuse, malignancy, renal failure, CTD, diabetes, pregnancy, immunosuppresion Risk factor: Age, alcohol abuse, malignancy, renal failure, CTD, diabetes, pregnancy, immunosuppresion

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66 HIV-associated TB Presentation varies with the stage Presentation varies with the stage Late stage: primary pattern with miliary infiltrate and lymphadenopathy, no cavitation Late stage: primary pattern with miliary infiltrate and lymphadenopathy, no cavitation Higher incidence of extrapulmonary and pleural effusion Higher incidence of extrapulmonary and pleural effusion Sputum smear frequently negative Sputum smear frequently negative Lack of classic granuloma formation Lack of classic granuloma formation

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68 Diagnosis Tuberculosis High index suspicion High index suspicion Chest.x.ray Chest.x.ray AFB Microscopy: AFB Microscopy: three sputum specimens, collected in the early morning three sputum specimens, collected in the early morning Staining with ziehl neelsen or auramine-rhodamine Staining with ziehl neelsen or auramine-rhodamine

69 Diagnosis Culture: Culture: Egg based (lowenstein-jensen), agar based (middelbrook); 4-8 week may be requird for growth 4-8 week may be requird for growth Liquid media with radiometric growth detection (bactec-460) Liquid media with radiometric growth detection (bactec-460) High pressure liquid chromatography of mycolic acid(2-3 week) High pressure liquid chromatography of mycolic acid(2-3 week) Nucleic acid amplification Nucleic acid amplification

70 BCG VACCINATION Derived from an attenuated strain of M.bovis Derived from an attenuated strain of M.bovis Efficacy from 80% to nil Efficacy from 80% to nil Rarely complication: Rarely complication:ulceration, regional lymphadenitis, osteomyelitis,dissemination

71 PPD Purified protein derivative Purified protein derivative PPD 5tu:0/1ml contain 0/0001mg PPD 5tu:0/1ml contain 0/0001mg Mantoax method (interadermaly, volar surface) Mantoax method (interadermaly, volar surface) Wheal 6-10mm Wheal 6-10mm Reaction are read at 48 to72h(transverse diameter of induration in mm) Reaction are read at 48 to72h(transverse diameter of induration in mm) A second skin test administered 1week or more after the first(two-step) A second skin test administered 1week or more after the first(two-step)

72 Measuring TST Record induration (bump) only Record induration (bump) only Measure transverse (across arm) Measure transverse (across arm) Record: Date given, date read, mm Record: Date given, date read, mm

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75 Module 1 – Transmission and Pathogenesis of Tuberculosis 75 TB Classification System (1) ClassTypeDescription 0No TB exposure Not infected No history of TB exposure Negative result to a TST or IGRA 1TB exposure No evidence of infection History of TB exposure Negative result to a TST (given at least weeks after exposure) or IGRA 2TB infection No TB disease Positive result to a TST or IGRA Negative smears and cultures (if done) No clinical or x-ray evidence of active TB disease Based on pathogenesis of TB

76 Module 1 – Transmission and Pathogenesis of Tuberculosis 76 TB Classification System (2) ClassTypeDescription 3TB, clinically active Positive culture (if done) for M. tuberculosis Positive result to a TST or IGRA, and clinical, bacteriological, or x-ray evidence of TB disease 4Previous TB disease (not clinically active) Medical history of TB disease Abnormal but stable x-ray findings Positive result to a TST or IGRA Negative smears and cultures (if done) No clinical or x-ray evidence of active TB disease 5TB suspected Signs and symptoms of TB disease, but evaluation not complete Based on pathogenesis of TB

77 Treatment First line drugs: Rifampin, Isoniazid, Ethambutol, Pyrazinamid, streptomycin First line drugs: Rifampin, Isoniazid, Ethambutol, Pyrazinamid, streptomycin Short course treatment(6 month) Short course treatment(6 month) 2month initial phase (bactericidal): rifampin, isoniazid, ethambutol, pyrazinamide 2month initial phase (bactericidal): rifampin, isoniazid, ethambutol, pyrazinamide 4month continuation (sterilizing): rifampin and isoniazid 4month continuation (sterilizing): rifampin and isoniazid

78 Treatment Pyridoxin (vit B6) should be given to: Pyridoxin (vit B6) should be given to: -ALCOHOLICS -ALCOHOLICS -Malnurished -Malnurished -pregnant and lactating woman -pregnant and lactating woman -chronic renal failure -chronic renal failure -diabetes -diabetes -HIV infection -HIV infection

79 Hepatitis Most common adverse reaction Most common adverse reaction Baseline assessment of liver function in all adult patient Baseline assessment of liver function in all adult patient monitoring monthly : monitoring monthly : Older patient alcoholicspregnancyHIV history of hepatic disease Treatment should be stopped: symptomatic hepatitis or three to five fold elevation LFT Treatment should be stopped: symptomatic hepatitis or three to five fold elevation LFT

80 First Line Drugs INH : Raised LFT Raised LFT Hepatitis Hepatitis Peripheral-neuropathy Peripheral-neuropathy Drug interactions Drug interactions Mild effect on CNS Mild effect on CNS drug induced lupus drug induced lupus RIF: GI-upset,Drug Interactions Hepatitis Thrombocytopenia Rash Interstitial nephritis Flu like

81 PZA: Hepatitis, Rash Hepatitis, Rash GI upset GI upset Arthralgia Arthralgia Hyperuricemia Hyperuricemia rarerly gout rarerly gout EMB: Optic neuritis SM : Ototoxicity Nephrotoxicity

82 Adjunctive corticosteroid Meningitis Meningitis Pericarditis Pericarditis Acute life threatening pulmonary tuberculosis Acute life threatening pulmonary tuberculosis Low serum albumin Low serum albumin Severe weight loss Severe weight loss Adenitis in children Adenitis in children

83 Monitoring response to treatment Sputum culture monthly until become negative Sputum culture monthly until become negative AFB smear conversion may follow culture conversion AFB smear conversion may follow culture conversion If culture not practical,AFB smear should be undertaken at 2,5and 6 months If culture not practical,AFB smear should be undertaken at 2,5and 6 months Culture/smear positive after 3month and smear positive after 5months are indicative treatment failure Culture/smear positive after 3month and smear positive after 5months are indicative treatment failure Serial c.x.ray not recommended,except at the end of treatment Serial c.x.ray not recommended,except at the end of treatment

84 results of susceptibility testing are expected to become available within a few weeks changes in the regimen can be postponed until that time. results of susceptibility testing are expected to become available within a few weeks changes in the regimen can be postponed until that time. If the patient's clinical condition is deteriorating, an earlier change in regimen may be indicated. If the patient's clinical condition is deteriorating, an earlier change in regimen may be indicated. A cardinal rule in the latter situation always add more than one drug at a time to a failing regimen: always add more than one drug at a time to a failing regimen: at least two and preferably three drugs that have never been used and to which the bacilli are likely to be susceptible at least two and preferably three drugs that have never been used and to which the bacilli are likely to be susceptible The patient may continue to take isoniazid and rifampin along with these new agents pending the results of susceptibility tests. The patient may continue to take isoniazid and rifampin along with these new agents pending the results of susceptibility tests.

85 Patients who experience a recurrence after apparently successful treatment (relapses) are less likely to harbor drug-resistant strains than are patients in whom treatment has failed. Patients who experience a recurrence after apparently successful treatment (relapses) are less likely to harbor drug-resistant strains than are patients in whom treatment has failed. If the regimen administered initially does not contain rifampin, the probability of isoniazid resistance is high. If the regimen administered initially does not contain rifampin, the probability of isoniazid resistance is high. begin the treatment of all patients who have relapsed with all four first-line drugs plus streptomycin, pending the results of susceptibility testing. begin the treatment of all patients who have relapsed with all four first-line drugs plus streptomycin, pending the results of susceptibility testing.

86 Drug-Resistant TB M. tuberculosis resistant to individual drugs spontaneous point mutations in the mycobacterial genome M. tuberculosis resistant to individual drugs spontaneous point mutations in the mycobacterial genome there is no cross-resistance among the commonly used drugs there is no cross-resistance among the commonly used drugs probability that a strain will be resistant to two drugs : product of the probabilities of resistance to each drug probability that a strain will be resistant to two drugs : product of the probabilities of resistance to each drug drug-resistant TB is invariably the result of drug-resistant TB is invariably the result of Monotherapy i.e., the failure of the health care provider to prescribe at least two drugs to which tubercle bacilli are susceptible Monotherapy i.e., the failure of the health care provider to prescribe at least two drugs to which tubercle bacilli are susceptible the patient to take properly prescribed therapy the patient to take properly prescribed therapy

87 Drug-resistant TB may be either primary or acquired Drug-resistant TB may be either primary or acquired Primary : develops in a strain infecting a patient who has not previously been treated Primary : develops in a strain infecting a patient who has not previously been treated Acquired : during treatment with an inappropriate regimen Acquired : during treatment with an inappropriate regimen Multidrug-resistant tuberculosis (MDR-TB) defined as resistance to at least isoniazid and rifampin (also known as rifampicin in many countries), defined as resistance to at least isoniazid and rifampin (also known as rifampicin in many countries),

88 Module 1 – Transmission and Pathogenesis of Tuberculosis 88 Mono-resistantResistant to any one TB treatment drug Poly-resistantResistant to at least any 2 TB drugs (but not both isoniazid and rifampin) Multidrug resistant (MDR TB) Resistant to at least isoniazid and rifampin, the 2 best first-line TB treatment drugs Extensively drug resistant (XDR TB) Resistant to isoniazid and rifampin, PLUS resistant to any fluoroquinolone AND at least 1 of the 3 injectable second-line drugs (e.g., amikacin, kanamycin, or capreomycin) Drug-Resistant TB (3)

89 XDR-TB MDR strains that are resistant to : MDR strains that are resistant to : all fluoroquinolones and all fluoroquinolones and at least one of three second-line injectable agents (amikacin, kanamycin, and capreomycin). at least one of three second-line injectable agents (amikacin, kanamycin, and capreomycin). Drug-resistant TB can be prevented by adherence : Drug-resistant TB can be prevented by adherence : the inclusion of at least two bactericidal drugs to which the organism is susceptible the inclusion of at least two bactericidal drugs to which the organism is susceptible the use of fixed-drug-combination products the use of fixed-drug-combination products the verification that patients complete the prescribed course. the verification that patients complete the prescribed course.

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