Pathophysiology of Tuberculosis and it's Complications

This is a presentation on the pathophysiology Tuberculosis , Mechanism of infection and inflammation involved in the disese process

1. INTRODUCTION Tuberculosis (TB) is an ancient disease with a history interwoven with the evolution and migration of mankind. Mycobacterium tuberculosis is thought to have evolved from an early progenitor in East Africa as early as 3300 years ago. By the early 1800s, TB epidemics ravaged much of Europe and North America, resulting in 800 to 1000 deaths per 100 000 population per year .

2. HISTORY OF TB 1700 s TB was called as white plague. Until mid-1800s, many believed TB was hereditary (vampire panic). 1834 Johann schonlein coined the term tuberculosis. 1865 Jean Antoine- Villemin proved TB was contagious. 1882 Robert Koch discovered M. tuberculosis, the bacterium that causes TB. 1943 Selman Waksman developed streptomycin in the treatment of TB. 3

3. EPIDEMIOLOGY India is the highest TB burden country in the world 10.6 million people affected with TB in 2022 globally with almost 1.6 million deaths related to TB. In India 2.59 million affected with TB, 188 per 1 lakh population in 2022. Globally, about 1 million cases of paediatric TB estimated with mortality of about 1 lakh .

4. TUBERCULOSIS It is a chronic specific inflammatory infectious disease caused by mycobacterium tuberculosis in human. Usually attacks the lungs(pulmonary) but it can also affect any parts of the body (extra pulmonary). Organism dormant for decades(latent TB). Reactivation of disease occurs when Immune defenses lowers and become communicable disease. 5

5. RISK FACTORS Crowded living condition Malnutrition Smoking Malignancy Old age Diseases weakens immune system – AIDS Immuno supressive drugs – steroids , TNF antagonists Systemic diseases – DM,CRF,CLD Genetic susceptibility –TLR deficiency, IFN deficiency

6. TRANSMISSION AEROSOL INGESTION INOCULATION

7. TRANSMISSION Infected persons with active TB release the bacteria in air by cough, sneeze, speak, spit. A single sneeze can release upto 40,000 infectious droplets but even 10 bacteria may cause infection. Incubation period varies according to age and risk factors After 3-4 weeks of acquiring infection , person becomes infectious to others.

8. Characteristics of mycobacterium tuberculosis Rod shaped (bacilli) Slow growing Non motile Aerobic 0.2 -0.5µ in D 2-4µ in L Acid fast bacilli

9. CELL WALL Mycolic acid responsible for acid fastness Prevention of phagolysosome formation Virulence Resistant to drying , alkalinity/acidity &many antibiotics

10. PATHOGENESIS Initial macrophage response Replication of bacilli Activation of immune response Cavitation stage.

11. STAGE 1 Early in infection—bacteria enters into airspaces where through phagocyte receptors enter into macrophages and multiply .

12. Replication in macrophages. M. tuberculosis recruits a host protein coronin to the membrane of the phagosome Coronin activates the phosphatase calcineurin, leading to inhibition of phagosome-lysosome fusion. Inhibits maturation of the phagosome and blocks formation of the phagolysosome. Unchecked replication leads to bacteremia and seeding of multiple sites.

13. Primary infection Depends on Number of organisms inhaled Virulence of the organism Immune status of the host

14. IMMUNE RESPONSE Pathogen recognised by innate immune receptors (TLR2 &TLR 9) Lipoarabinomannan binds with TLR2 &TLR 9 ↓ Enhances the innate & adaptive immune response in TB

15. The TH1 response . About 3 weeks after infection, Mycobacterial antigens enter draining lymph nodes displayed to T cells. Differentiation of TH1 cells(secretion of IL-12 by antigen presenting cells) Stimulation of TLR2 by mycobacterial ligands promotes production of IL-12 by dendritic cells. T-helper 1 (TH1) response is mounted that activates macrophages, enabling them to become bactericidal.

16. Pathogenesis

17. Gamma IFN Th1 cells produces IFN-γ stimulates maturation of the phagolysosome in infected macrophages, expose the bacteria to a lethal acidic, oxidizing environment stimulates expression of inducible nitric oxide synthase  NO, reactive nitrogen intermediates mobilizes antimicrobial peptides (defensins) against the bacteria stimulates autophagy

18. Caseating Granuloma IFN-γ differentiate macrophages into the “epithelioid histiocytes” which forms granulomas and Langhans giant cells In many people this response halts the infection before significant tissue destruction or illness occur. In other people the infection progresses due to immunosuppression, and the ongoing immune response results in caseation necrosis or tissue destruction.

19. Tuberculous Granuloma

20. Primary tuberculosis Disease that develops in previously unexposed person. Inhaled bacilli implant in the distal airspaces of the lower part of upper lobe or upper part of the lower lobe 1 -1.5 cm area of grey white inflammation with consolidation develops , called as GHON’s FOCUS, which often caseates Subpleural granuloma (parenchyma) + hilar LN granuloma is called as GHON’s COMPLEX

21. Ghon Complex and Ranke complex

22. Fate of primary tuberculosis Heal by fibrosis  calcification Progressive primary tuberculosis ↓ Primary miliary tuberculosis

23. Secondary tuberculosis The infection of an individual who has been previously infected or sensitized. The infection may be acquired from Endogenous source: reactivation of dormant primary complex. Exogenous source.

24. Course of secondary tuberculosis Heal With Fibrous Scarring And Calcification Tuberculous Pneumonia Secondary Progressive Pulmonary Tuberculosis Tuberculous Caseous Pneumonia Fibro caseous Tuberculosis Miliary Tuberculosis

25. SECONDARY PROGRESSIVE TB Gross: sharply circumscribed, firm, gray white to yellow presents as consolidation of <2 cm D within apical pleura. Micro: coalescent tuberculous granulomas with central caseation necrosis .

26. CASEATING GRANULOMA

27. Fibrocaseous tuberculosis Seen usually in elderly, immunosuppressed people or untreated patients. Apical lesion enlarges with expansion of area of necrosis forming cavity which may either break into bronchus from a cavity with evacuation of caseous material (open fibrocaseous TB ) Break into blood vessel producing hemoptysis

28. Cont.. The cavity provides a favourable environment for the proliferation of a bacilli due to high oxygen tension The open case of secondary TB may implant tuberculous lesion on the mucosal lining of air passages producing endobronchial / endotracheal TB

29. Lung TB - Cavitation

30. Complications of cavitatory secondary TB Extension to pleura producing bronchopleural fistula Tuberculous empyema Thickened pleura Pleural effusions Obliterative fibrous pleuritis

31. Miliary pulmonary tuberculosis Occurs when organisms drain through lymphatics into  lymphatic ducts venous return on the right side of heart pulmonary arteries Lymphatic spread – EB,ET AND LARYNGEAL TB Individual lesions are either microscopic or small, visible (2mm) foci of yellow-white consolidation scattered through the lung parenchyma (resembling millet seeds) Micro: the lesion shows structure of granuloma with minute areas of caseous necrosis.

32. Miliary pulmonary tuberculosis

33. Extrapulmonary tuberculosis In tissues or organs seeded haematogenously . Intestinal (Primary, Secondary, Hyperplastic) Meninges (Tuberculous Meningitis ) Kidneys ( Renal Tuberculosis ) Adrenals (Addison’s Disease ) Bone ( Osteomyelitis ) Vertebrae ( Pott’s Disease ) Fallopian Tube ( Salpingitis )

34. EXTRAPULMONARY TUBERCULOSIS INTESTINAL TB MENINGEAL TB

35. EXTRAPULMONARY TUBERCULOSIS SPLEEN LYMPH NODE

36. EXTRAPULMONARY TUBERCULOSIS POTT’S SPINE TB KIDNEY

37. EXTRAPULMONARY TUBERCULOSIS TB EPIDIDYMO ORCHITIS TB PERICARDITIS

38. TB/AIDS – SYNDEMIC(?) TB is the leading cause of death in AIDS. Low CD4 count is the risk factor. Pulmonary manifestations varies from focal lesion to multiple infiltrates . False negative sputum smears in seropositive patients due to absence of bacterial cell wall destruction as there is reduced T cell mediated immune reaction .