Pulmmonary Tuberculosis

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

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

Pathogenesis

• Mycobacterium - has no known exotoxin, endotoxin, proteolytic enzyme

• Pathogenecity of M. tubeculosa is related to ability to:

1. escape killing by macrophages

2. induce delayed hypersensitivity

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.Pathogenic mycobacter: cord factor positive, Non-pathogenic: cord factor negative:

Injection purified cord factor in mice granuloma formation

2. Lipoarabimannam (LAM): heteropolysaccharide similar to endotoxin in gram negative bacteria.

a.

Pathogenesis

LAM a. - inhibits macrophage activation by interferon-– b. induces macrophages to secrete TNF-

(fever, weight loss, tissue damage)

c. induces macrophages to secrete IL-10 suppresses mycobacteria-nduced T-cell proliferation)

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.

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.

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).

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.

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-• interferon- activates macrophages

killing of intracellular mycobacteria2. mycobacter through intermediate nitrogen

species. epithelioid granuloma formation

Pathogenesis

2. 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.

Pathogenesis primary tuberculosis

• Mycobacteria can not grow in acidic extracellular environment

• infection is controlled.

• Fate of primary tuberculosis: calcification

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. node

Grossly: Ghon nodule: 1-2 cm

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

Pathogenesis

• Gross: primary lesion enlarges to lesions ~6 cm cavities occupying most of lower lobes

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

• 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

Histology tuberculous granuloma

• Gross: Diffuse fibrotic lesions, with caseative necrosis

• heal and calcify

• erosion of bronchidrainage caseous material and infectious agents tuberculous cavity

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

Complications of secondary tuberculosis

1. 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 sites

2.Hemopthysis: Bleeding from eroded blood vessel in cavity

Drowning into one’s own blood.

Complication tuberculous granuloma

3. Bronchopleural fistula: rupture of subpleural cavity pleural

• space tuberculous empyema pneumothorax

4. Intestinal tuberculosis: follows swallowing of tuberculous

• material

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.

tuberculosis in AIDS

2. 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;

tuberculosis in AIDS

a. secondary to the failure of CD4 helper T-lymphocytes to secrete lymphokines that activate macrophages to kill bacteria

b. failure of infected helper T-lymphocytes to secrete and mycobacteria infected macrophages to respond to lymphokines.

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.

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

tuberculosis in AIDS

• There is a large number of mycobacteria in the enlarged nodes.

• Granulomas, lymphocytes and tissue destruction are rare