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Pulmmonary tuberculosis
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Pulmmonary tuberculosis

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  • 1. Pulmmonary Tuberculosis
  • 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. Pathogenesis primary tuberculosis• Mycobacteria can not grow in acidic extracellular environment• ⇒infection is controlled.• Fate of primary tuberculosis: calcification
  • 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. 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. Pathogenesis• Gross: primary lesion enlarges to lesions ~6 cm ∅ ⇒ cavities occupying most of lower lobes
  • 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. • 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. 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. 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. 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. Complication tuberculous granuloma3. Bronchopleural fistula: rupture of subpleural cavity ⇒ pleural• space ⇒ tuberculous empyema ⇒ pneumothorax4. Intestinal tuberculosis: follows swallowing of tuberculous• material
  • 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. 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. 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. 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. 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. tuberculosis in AIDS• There is a large number of mycobacteria in the enlarged nodes.• Granulomas, lymphocytes and tissue destruction are rare