Pathophysiology tubercuslosis

Contains description of Etiology, types, Sign and symptoms, pathogenesis of Granulomatous inflammation and Tuberculosis.

1. Nem Kumar Jain MS (Pharm.) Pharmacology & Toxicology Assistant Professor School of Pharmacy ITM University Gwalior Pathophysiology of Tuberculosis (TB)

2. Observed on 24 March each year, is designed to build public awareness about the global epidemic of tuberculosis (TB) and efforts to eliminate the disease. 24 th March memorialize the day in 1882, when Dr. Robert Koch declared that he had discovered the causative factor of Tuberculosis- Mycobacterium Tuberculosis In 1995 WHO start recognizing World Tuberculosis DAY and continued to sponsor this event till now with distinct themes. Theme of 2020 is It's time to end TB!

3. Granulomatous inflammation Granulomatous inflammation is a distinctive pattern of chronic inflammatory reaction . The formation of Granuloma is a protective defense reaction by the host to chronic infection or foreign material, preventing dissemination and restricting inflammation but eventually causes tissue destruction because of persistence of the poorly digestible antigen Causative Factors: Infectious or non-infectious Ex. Tuberculosis and Syphilis etc

4. Tuberculosis Introduction TB is caused by bacteria,belonging to the genus Mycobacterium . It mainly affects the lungs , but it can affect any part of the body, including the abdomen, glands, bones and nervous system . As per WHO reports(2018), approx. 10 million active TB cases globally India: 2.3 million cases Other common names included “ wasting disease ” and the “ white plague ”. Sign and Symptoms Cough for more than 3 weeks Weight loss/anorexia Malaise Fatigue Low grade Fever Night sweats Hemoptysis (blood stained mucus) Chest pain

5. These form a large group but only three relatives ( Mycobacterium tuberculosis complex) are obligate parasites that can cause TB disease . Mycobacterium: aerobic atypical slender, rod shaped bacteria M. tuberculosis complex: M. tuberculosis, M. bovis, M. africanum They have been found in soil, milk and water (atypical mycobacteria ) Mycobacterium leprae : The cause of leprosy . Other strains which causes TB are M. Avium Complex (MAC): M. avium & M. intracellulare M . bovi s , M . hominis Less common strains which causes TB are M. africanum M. microti M. pinnipeddi M. cannetti Less pathogenic strains are M. abscessus M. fortuitum M. chelonae M. ulcerans Non pathogenic strains are M. smegmatis M.tuberculi also called as Koch’s bacilli or Acid Fast bacilli Etiology

6. Based on anatomical side : Pulmunary TB (lungs) Milliary (Spleen, kidney, liver, brain etc) Based on presence of signs and symptom : Active TB (only shows signs and symptoms). Latent TB (Signs and symptoms absent, Dormant) Based on type of tissue response Primary TB: First time, Childhood TB, Ghon’s complex No Immunization or infection Secondary TB: Re-infection Characteristics of Mycobacterium sp. which makes resultant disease Chronic and necessitates prolong treatment Slow growing Intracellular infection Formation of slow growing granuloma results in destruction of host tissue Biology of Mycobacterium: distinct populations Rapidly growing with high bacillary load Slow growing Spurters Dormant Types and some facts of Tuberculosis

7. MODE OF TRANSMISSION. Human beings acquire infection with tubercle bacilli by one of the following routes: Inhalation of organisms present in fresh cough droplets or in dried sputum from an open case of pulmonary tuberculosis. Ingestion sputum of an open case of pulmonary tuberculosis, or ingestion of bovine tubercle bacilli from milk of diseased cows. Inoculation of the organisms into the skin may rarely occur from infected postmortem tissue. Transplacental route results in development of congenital tuberculosis in foetus from infected mother and is a rare mode of transmission.

8. TYPES OF TUBERCULOSIS Lung is the main organ affected in tuberculosis. Depending upon the type of tissue response and age, the infection with tubercle bacilli is of 2 main types: Primary tuberculosis Secondary tuberculosis

9. PRIMARY TUBERCULOSIS The infection of an individual who has not been previously infected or immunised is called primary tuberculosis or Ghon’s complex or childhood tuberculosis. The most commonly involved tissues for primary complex are lungs and lymph nodes. Other tissues are tonsils and cervical lymph nodes, lesions may be found in small intestine and mesenteric lymph nodes. Progressive primary tuberculosis is particularly high in immunocompromised host e.g. in patients of AIDS. in

10. SECONDARY TUBERCULOSIS The infection of an individual who has been previously infected or sensitised is called secondary, or post-primary or reinfection , or chronic tuberculosis. The infection may be endogenous source such as reactivation of dormant primary complex. exogenous source such as fresh dose of reinfection by the tubercle bacilli. Secondary tuberculosis occurs most commonly in lungs in the region of apex. Other sites and tissues which can be involved are tonsils, pharynx, larynx, small intestine and skin.

11. EXTRA PULMONARY / miliary TUBERCULOSIS RESPIRATORY TUBERCULOSIS PERIPHERAL LYMPH NODES TUBERCULOSIS BONE TUBERCULOSIS JOINTS TUBERCULOSIS PERICARDIAL TUBERCULOSIS

12. HIV-ASSOCIATED TUBERCULOSIS Moreover, HIV-infected individual on acquiring infection with tubercle bacilli develops active disease rapidly (within few weeks) rather than after months or years. Extra-pulmonary tuberculosis is more common in HIV disease and manifests commonly by involving lymph nodes, pleura, pericardium, and tuberculous meningitis. Infection with M. avium - intracellulare ( avia or bird strain) is common in patients with HIV/AIDS.

13. Pathogenesis: Evolution of tubercle

14. When ever the Mycobacterium tuberculi enters body. As it is strictly aerobic it resides in alveoli of lungs. After about 12 hours, there is progressive infiltration by macrophages (C2a C2b) as opsonins The macrophages start phagocytosing the tubercle bacilli and either kill the bacteria or die away themselves. In the latter case, they further proliferate locally as well as there is increased recruitment of macrophages from blood monocytes .

15. As a part of body’s immune response, T and B cells are activated. Activated CD4+T cells develop the cell-mediated delayed type hypersensitivity reaction, while B cells result in formation of antibodies which play no role in body’s defence against tubercle bacilli. In 2-3 days, the macrophages undergo structural changes as a result of immune mechanisms to epithelioid cells.

16. The epithelioid cells in time aggregate into tight clusters or granulomas . Release of cytokines in response to sensitized CD4+T cells and some constituents of mycobacterial cell wall play a role in formation of granuloma . Some of the macrophages form multinucleated giant cells by fusion of adjacent cells. The giant cells may be Langhans ’ type having peripherally arranged nuclei in the form of horseshoe or ring

17. Around the mass of epithelioid cells and giant cells is a zone of lymphocytes, plasma cells and fibroblasts. The lesion at this stage is called hard tubercle due to absence of central necrosis. Within 10-14 days, the centre of the cellular mass begins to undergo caseation necrosis, characterised by cheesy appearance and high lipid content. This stage is called soft tubercle which is the hallmark of tuberculous lesions.

18. The development of caseation necrosis is possibly due to interaction of mycobacteria with activated T cells (CD4+ helper T cells via IFN- γ and CD8+ suppressor T cells directly) Microscopically , caseation necrosis is structure less, eosinophilic and granular material with nuclear debris. The soft tubercle which is a fully-developed granuloma with caseous centre does not favour rapid proliferation of tubercle bacilli. Acid-fast bacilli are difficult to find in these lesions and may be demonstrated at the margins of recent necrotic foci and in the walls of the cavities.

19. Fate of granuloma The caseous material may undergo liquefaction, extend , discharge .: Trsnsmission through sputum In tuberculosis of tissues like bones, joints, lymph nodes and epididymis , sinuses are formed and the sinus tracts are lined by tuberculous granulation tissue: Miliary Tuberculosis May coalesce together enlarging the lesion which is surrounded by progressive fibrosis. In the granuloma enclosed by fibrous tissue, calcium salts may get deposited in the caseous material (dystrophic calcification) and sometimes the lesion may even get ossified over the years .