Pulmmonary tuberculosis


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Pulmmonary tuberculosis

  1. 1. Pulmmonary Tuberculosis
  2. 2. Causative agent (P.T.)• : Mycobacterium tuberculosis• Was an important cause of death prior the antibiotic era• Currently its importance rising again due to - AIDS• - multidrug resistance
  3. 3. Etiology and Pathogenesis (PT)• M. tuberculosis: transmitted by infective droplets• M. bovis: milk diseased cow• M. avium :  avirulent to normal subjects• M. intracellulare:  disseminated infection in 15-24% AIDS patients
  4. 4. Pathogenesis• Mycobacterium - has no known exotoxin, endotoxin, proteolytic enzyme• Pathogenecity of M. tubeculosa is related to ability to:1. escape killing by macrophages2. induce delayed hypersensitivity
  5. 5. Pathogenesis• Induction of delayed hypersensitivity by P.T. attributed to several components of M. tubersulosa cell wall:1. cord factor: surface glycolipid, facilitates cultured mycobacter to grow in cords. a. Pathogenic mycobacter: cord factor positive, Non-pathogenic: cord factor negative:Injection purified cord factor in mice ⇒ granuloma formation2. Lipoarabimannam (LAM): heteropolysaccharide similar to endotoxin in gram negative bacteria.
  6. 6. PathogenesisLAM a. - inhibits macrophage activation by interferon-γ – b. induces macrophages to secrete TNF-α (fever, weight loss, tissue damage) c. induces macrophages to secrete IL-10 suppresses mycobacteria-nduced T-cell proliferation)
  7. 7. Pathogenesis• iii. Complement -activated on surface of mycobacteria may opsonise mycobacteria ⇒ macrophage complement receptor (CR3) (Mac-1 integrin) without triggering the respiratory burst necessary to kill the bacteria.iv. Highly immunogenic Tuberculous heat- shock protein is similar to human ⇒ autoimmune reactions induced by mycobacteria.
  8. 8. Pathogenesis• Mycobacter resides in phagosomes which are not acidified into lysosomes.• Inhibition of acidification is associated with urease secreted by mycobacter.• The development of cell-mediated, type IV, hypersensitivity to the mycobacteria explains the organism’s destructiveness in tissues and also the emergence of resistance the mycroorganism.
  9. 9. Pathogenesis• Initial exposure to the M. tuberculosa ⇒ no-specific inflammatory reaction• After 2-3 weeks: reaction changes to granulomatous, center caseates• The patteren of host response depends on whether the infection is a primary exposure (primary) or it is in a sensitized host (secondary).
  10. 10. Primary Tuberculosis• Disease acquired from initial exposure to M. tuberculosa• Inhaled microorganisms multiply in alveoli, alveolar macrophages can not readily kill the bacteria.• Naïve macrophages can not kill mycobacteria ⇒ multiply, lyse the cell ⇒ infect other macrophages, spread by the blood stream.
  11. 11. Pathogenesis• After a few weeks (2-3) ⇒ development T- cell-mediated immunity.• Mycobacteria-activated T-cells react with macrophages through following ways:• 1. CD4+ helper T-cells secrete interferon-γ• interferon-γ ⇒ activates macrophages ⇒ killing of intracellular mycobacteria2. mycobacter through intermediate nitrogen species.∀ ⇒ epithelioid granuloma formation
  12. 12. Pathogenesis2. CD8+ suppressor T cells ⇒ lyse macrophages infected with mycobacter through Fas-independent pathway.3. CD4-, CD8- (double-negative) T –cells lyse macrophages by Fas-dependent pathway, without killing mycobacteria.
  13. 13. Pathogenesis primary tuberculosis• Mycobacteria can not grow in acidic extracellular environment• ⇒infection is controlled.• Fate of primary tuberculosis: calcification
  14. 14. The Ghon Complex:• first lesion of primary tuberculosis• G.C. consists of - peripheral parenchymal granuloma (often located in lower lobes) (Ghon nodule)• a prominent infected mediastinal (hilar) lymphnode• lymphangitis joining nodule to hilar L. nodeGrossly: Ghon nodule: 1-2 cm ∅
  15. 15. Pathogenesis• Histo: Granuloma, central caseous necrosis.• Clinically: Usualy assymptomatic, localized lesions⇒ healing (`~90% cases).• In occasional cases, however, primary tb• - spreads to other parts of the lung (progressive primary TB) common in children, immunocompromised adults
  16. 16. Pathogenesis• Gross: primary lesion enlarges to lesions ~6 cm ∅ ⇒ cavities occupying most of lower lobes
  17. 17. Secondary TB• This stage results from:• - reactivation of primary pulmonary TB• new infection in a previously sensitized individual• This stage results from:• - reactivation of primary pulmonary TB• new infection in a previously sensitized individual
  18. 18. • new infection in a previously sensitized individual• Initial response to M. tuberculosa is different in patients with secondary TB.• Infection ⇒ latent period⇒ cellular immune response ⇒formation of many granulomas , extensive tissue necrosis• Apical and posterior segments upper lobes most commonly affected
  19. 19. Histology tuberculous granuloma• Gross: Diffuse fibrotic lesions, with caseative necrosis• ⇒ heal and calcify• ⇒ erosion of bronchi⇒drainage caseous material and infectious agents⇒ tuberculous cavity
  20. 20. Tuberculous Cavities• Size: 1- 10 cm• Location: apices of upper lobes• Wall of cavity consists fibrotic material with granulation tissue• Cavity: caseous material with bacilli• On healing: fibrosis with calcifications
  21. 21. Complications of secondary tuberculosis1. milliary TB: presence of multiple, small (size of millet seeds)• granulomas in many organs.• Spread usually haematogenous, mostly from primary pulmonary Tb or from other sites2.Hemopthysis: Bleeding from eroded blood vessel in cavity∀ ⇒ Drowning into one’s own blood.
  22. 22. Complication tuberculous granuloma3. Bronchopleural fistula: rupture of subpleural cavity ⇒ pleural• space ⇒ tuberculous empyema ⇒ pneumothorax4. Intestinal tuberculosis: follows swallowing of tuberculous• material
  23. 23. M.tuberculosis and M. avium intracellulare lesions in AIDS• Mycobacterial infection in AIDS can take three forms depending on degree of immunosuppression• 1. In developing countries where M. tuberculosis is frequent: HIV infected individuals have primary and secondary M. tuberculosis infection with the usual well formed granulomas, composed of epithelioid cells, Langerhan’s giant cells and lymphocytes. In these granulomas acid-fast bacilli are few and difficult to find.
  24. 24. tuberculosis in AIDS2. When HIV patients develop AIDS and are moderately immunocompressed (< 200 CD4+ T helper lymphocytes/ml): infection is mostly from reactivation/re-infection. Because mycobacteria infect T-cells and macrophages, defects in the host immune response to M. tuberculosis may be;
  25. 25. tuberculosis in AIDSa. secondary to the failure of CD4 helper T-lymphocytes to secrete lymphokines that activate macrophages to kill bacteriab. failure of infected helper T- lymphocytes to secrete and mycobacteria infected macrophages to respond to lymphokines.
  26. 26. tuberculosis in AIDS• The relative increase in number of CD8+ cytotoxic T-lymphocytes to cause macrophage destruction in the M. tuberculosa lesions.• ⇒ histologically: granulomas less well formed, are more frequent necrotic, and contain more abundant acid fast bacilli.• Though sputum is positive for mycobacteria in 31-83% of AIDS patients , only 33% react with PPD.
  27. 27. tuberculosis in AIDS• extrapulmonary TB occurs in 70% cases involving LN, blood, CNS, and GIT.• 3. Opportunistic infection with M. avium intracellulare (occurs in severely immunocompromised patients: < 60 CD+ T- lymphocytes) Most organisms originate from GIT though some from RT• Infection usually widely disseminated throughout the reticulo-endothelial system ⇒ enlargement of lymphnodes
  28. 28. tuberculosis in AIDS• There is a large number of mycobacteria in the enlarged nodes.• Granulomas, lymphocytes and tissue destruction are rare