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

6. Pathogenesis
LAM 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 mycobacteria
2. mycobacter through intermediate nitrogen
species.
∀ ⇒ epithelioid granuloma formation

12. 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.

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.
node
Grossly: 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
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.

22. Complication tuberculous
granuloma
3. Bronchopleural fistula: rupture of
subpleural cavity ⇒ pleural
• space ⇒ tuberculous empyema ⇒
pneumothorax
4. 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 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;

25. 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.

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