Tuberculosis

1. Tuberculosis

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

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

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

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

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 Isoniazid (INH) and p-aminosalicylic acid (PAS) discovered between 1943 and 1952 6

7. 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. microti : less virulent and rarely encountered • 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)

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

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

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

14. SOURCE CASE • Only patients with pulmonary tuberculosis can be regarded as infectious. (placenta, skin, milk) • Smear positive • Cavitary pulmonary disease • Endobronchial or laryngeal tuberculosis • Coughing(wearing mask with patient) • 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.

15. 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. • 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.

17. prevalence of PPD + among young contacts of patients with newlydiscovered tuberculosis increased as the radiographic extentof involvement increased • 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.

18. under standard conditions of temperature and humidity indoors : survived • 60% to 71% for 3 hours, • 48% to 56% for 6 hours, • 28% to 32% for 9 hours. • 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 • 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.

20. risk of developing disease after being infected depends on endogenous factors, such as the individual's: • innate 1- immunologic 2- nonimmunologic defenses , • 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 • SECONDARY TUBERCULOSIS -often infectious -late adolescent and early adulthood -women(25-34yr)

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

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

24. Infection and Macrophage Invasion • 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 • 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 • replication begins and the macrophage eventually ruptures and releases its bacillary contents

26. Virulance of the bacillus • lipid rich cell wall • glycolipid capsule • genes confer virulance(katG,rpoV) • number of invading bacilli • katG gene encodes for catalase/peroxidase enzymes that protect against oxidative stress • 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 -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 • the tissue-damaging response can limit mycobacterial growth within macrophages • 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.

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. • 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 • 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+) • Local macrophage • IL1- IL6 –TNFα- IL2- IFNγ • Active cell aggregate around lesion and effectively neutralize tubercle bacilli • Caseous necrosis • Viable bacilli may remain dormant • Healed lesion may undergo calcification (Ranke complex)

32. TST, which is used primarily for the detection of M. tuberculosis infection in persons without symptoms • related mainly to previously sensitized CD4+ T lymphocytes • 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

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 more specific • in the presence of BCG vaccination • infection with nontuberculous mycobacteria, • having less reader variability, • not recalling waned immunity

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

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

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

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

38. Sites of TB Disease (2) 38

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

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

41. TB Pathogenesis (6) A small number of tubercle bacilli enter bloodstream and spread throughout body 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) 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 causeTB disease • This process can occur in different places in the body Module 1 – Transmission and Pathogenesis of Tuberculosis

44. LTBI vs. TB Disease Module 1 – Transmission and Pathogenesis of Tuberculosis

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

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

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

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

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