Tuberculosis (TB) Power Point Presentation.

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1. TUBERCULOSIS Dr. SHAIK KAREEMULLA Associate Professor Department of Pharmacy Practice MMCP, (MMDU)

2. INTRODUCTION: Tuberculosis is the most communicable and infectious disease which is mainly caused by bacteria, Mycobacterium tuberculosis. It is an infection, treated by anti-TB drugs. It is a global problem, with the incidence varying across the world. An increase in reported cases of TB in countries across all continents led the WHO to declare TB as a global emergency. In many countries, it is compounded in those who have co-infection with the human immune deficiency virus HIV. There has been an increase in multi-drug resistant TB. The treatment of MDR-TB is very complex, costlier and also have a longer duration when compared to susceptible treated drugs.

3. TB is easily transmitted from person to person through coughing and sneezing. Adequate and effective treatment is essential for patients to control TB, as the BCG vaccine does not protect against the infection. TB infection usually occurs by the respiratory route. Successful control of TB depends on a close working collaboration between clinical, microbiological, pharmaceutical, infection control and health care professionals involved in TB. EPIDEMIOLOGY : Globally, it is estimated that TB causes 2 million deaths worldwide each year. one-third of the population is affected with the tubercle bacillus. It is the leading cause of death among HIV positive patients. Over 4 million cases of TB are notified annually.

4. It is estimated that 4,40,00 people had MDR-TB world-wide and one-third of these people die annually . ETIOLOGY : TB is caused by tubercle bacilli, which belongs to the genus Mycobacterium. Among the large group, 3 species cause TB. They are M. tuberculosis(98.6%), M. bovis (0.5%), M. africanum (0.9%). Around 15 species other than tuberculosis are recognized as pathogenic, found in soil, milk and water. They are called as atypical bacteria. Robert Koch discovered the microbial cause of TB. TB is highly contagious. The greatest risk of infection is prolong contacts, mainly household contacts . It can’t be acquired from individuals with latent TB infection.

5. Most people with active TB who have received appropriate treatment for at least 2 weeks are non-contagious . MDR-TB is developed during the treatment period or by transmission of MDR bacteria. RISK FACTORS : Close contact of patient with TB, especially those with sputum smear positive pulmonary disease. The following people are at high risk to get active TB which have LTBI. HIV positive Drug abusers Organ transplantation Hemodialysis Immunocompramised people Receiving anti-TNF treatment Silicosis (Lung diseases occurs due to silica or quartz inhaling)

6. PATHOGENESIS : The primary infection will be seen in individuals who were not previously exposed. Immune compromised patients develops TB due to activation of T- cells. This results in the development of pathological lesions such as caseating granulomas (Tissue degeneration). Steps include: 1) ENTRY INTO MACROPHAGES: M. tuberculosis enters the macrophages by phagocytosis i.e., mediated by mannose binding lectin and complement receptors. 2) REPLICATION IN MACROPHAGES : Bacteria inhibits the maturation of phagosomes, blocks the formation of phagolysosome and prevents the attack of lysosomal enzymes.

7. It is done by inhibiting both calcium signals and assembly of proteins which is essential for phagolysosome formation. This stage is associated with bacteremia at multiple sites. At this stage, most of the people are asymptomatic or some patients may have flu like symptoms . 3) INITIATION OF IMMUNITY: Lipoproteins and glycolipids associated with mycobacteria are recognized by innate immune receptors. This initiates and enhances adaptive immune responses to mycobacterium.

8. 4) THE TH1 RESPONSE : After 3 weeks of infection, TH cells are responded and activates the macrophages, enable macrophages to act as bactericidal. This is initiated by mycobacterial antigens after entering into lymph nodes. IL-12 are produced by the antigen presenting cells (APC) and dendritic cells, encounter mycobacteria by T cells differentiation. TH1 MEDIATED MACROPHAGES ACTIVATION AND KILLING OF BACTERIA: TH1 cells produce interferon- gamma. A) It stimulates infected macrophages maturation to phagolysosome and exposing bacteria to lethal acidic environment . B) Stimulates expression of nitric oxide synthase, produces nitric oxide, combines with other oxidants to form reactive nitrogen intermediates and kills mycobacterium.

9. C) It mobilizes antimicrobial peptides against the bacteria. D) Stimulates autophagy, it is a process that destroy damaged organelles and intracellular bacteria . GRANULOMATOUS INFLAMMATION AND TISSUE DAMAGE : In addition, Macrophages stimulated by INF-gamma undergo differentiation and aggregation to form granulomas, fuses to form giant cells. In many people, this reaction may halt the infection, in some patients, infection may progress further due to immuno-suppression or advanced age . Ongoing response lead to caseation necrosis. Activated macrophages secrete TNF and chemokines, promotes to recruit more monocytes. Eventually, necrosis and tissue damage are seen at infected areas.

10. CLINICAL FEATURES : Clinically TB is separated in 2 pathophysiologic types. 1) P rimary tuberculosis: I t develops in previously unexposed and un-sensitized persons. The source of organism is exogenous. 2) Secondary tuberculosis : I t arises in previously sensitized host persons. It appears after many years of primary infection. Early warning signs : According to the Centers for Disease Control and Prevention (CDC), the symptoms of TB include : •Feeling sick, weak •Loss of appetite, weight loss •Chills , fever, night sweats •Severe cough lasting for 3 weeks •Chest pain

11. SYMPTOMS : During a latent stage, TB has no symptoms. When TB is active: cough , fever, and other symptoms appears. TB usually affects the lungs, it also affects other parts of the body, and symptoms will vary accordingly. •The bones: S pinal pain and Joint destruction. •The brain: It can lead to meningitis. •The liver and kidneys: It impairs waste products filtration and leads to blood in the urine. •The heart: It impairs heart's ability to pump blood resulting in cardiac tamponade, a condition that can be fatal.

12. Diagnosis: It can be diagnosed based on symptoms, medical history, assessing the risk, and checking lung sounds. M ost common diagnostic test for TB is a skin test where a small injection of PPD tuberculin is administered just below forearm. Tuberculin is an extract of the TB bacterium. I njection site should be checked after 2-3 days . I f there is a presence of hard , redness and swelling to a specific size, it reveals that patient is suffering from Tuberculosis i.e., provisional diagnosis. Unfortunately , skin test will not give 100 percent accurate diagnosis. MDR TB is more difficult to diagnose when compared to regular TB. TB in children is also difficult to diagnose.

13. O ther tests also be performed to diagnose TB. Blood tests, chest X-rays, and sputum tests are used to test the presence of TB bacteria and were performed along with skin test. TREATMENT : In treating TB, a number of factors are important: Choice of drugs Length of the treatment Co-morbidity especially HIV infection, liver and renal diseases. Adherence to treatment by the patient .

14. RESPIRATORY TB: It affect lungs , pleural cavity, mediastinal lymph nodes, larynx. It can be treated by the following regimen. SIX MONTHS TREATMENT: Rifampicin , Isoniazid , Pyrazinamide and Ethambutol for the initial 2 months (initial phase), reduces bacterial population rapidly and prevent the emergence of drug resistant bacteria. Further 4 months of Rifampicin and Isoniazid (continuation therapy) Combination of tablets is used to prevent accidental missing of drug therapy and minimizing risk of MDR-TB. Pyridoxine in the dose of 10-15 mg should prescribe along with the Isoniazid to reduce the incidence of CNS and peripheral neuropathic effects.

15. LYMPH NODES TB: Previously, 9 months treatment is recommended. Now, standard 6 months regimen is advised, since trials have shown that 6 months treatment is as effective as 9 months treatment. MENINGEAL TB: It can be treated with Rifampicin and Isoniazid for 12 months along with Pyrazinamide , and E thambutol for the first 2 months as it reaches CSF through inflamed meninges. Ethambutol may cause the visual abnormalities. So care should be taken in unconscious patients. Glucocorticoids are also recommended in management with the initiation of anti-TB drugs. But they should be withdrawn within 2-3 weeks. Prednisolone : 20-40 mg in adults 1-2 mg/kg in children upto maximum of 40mg.

16. BONE AND JOINT TB: S pine is the most common site for bone TB. It is treated by 6 months regimen containing Rifampicin and Isoniazid along with pyrazinamide and ethambutol. In some cases, surgery is done to relieve spinal cord compression or to correct spinal deformities. PERICARDIAL TB: It may lead to cardiac tamponade and pericarditis, which are associated with a significant mortality and morbidity. S tandard 6 months regimen is used. G lucocorticoids should also be prescribed in dose of 60mg/day for adults or 1mg/kg/day for children. It should be withdrawn after 2-3 weeks.

17. TREATMENT IN SPECIAL CONDITIONS: IN CHILDREN: D oses should be reduced, prescribed should be administered in correct volumes in appropriate strengths. Ethambutol should not be used frequently as patients may report certain visual disturbances. IN PREGNANCY CONDITION: As there is a risk of TB to foetus , treatment should be started immediately. Standard therapy should be given. Pyridoxine supplementation should also be recommended. RENAL DISEASES : Standard doses of Rifampicin , Isoniazid and P yrazinamide are prescribed. But the dose of ethambutol should be reduced as it is eliminated through renal route.

18. DRUG-RESISTANT TB: I t is considered as a worldwide problem. Drug resistance is an important issue in the management of TB as it may compromise the effectiveness of treatment. I t is also important because bactericidal drugs such as I soniazid and Rifampicin become inactive. Treatment should be individualized and requires a complex regimen that increases the treatment costs. Drug resistance TB may developed during treatment period.

19. DOT THERAPY : Directly Observed Therapy , in which patients taking medications were observed by a health care professional i.e., TB patients residing in streets or homeless patients. RNTCP : R evised N ational TB Control Program was started in 1997. Main ambition is Diagnosis and Treatment for TB are free. The initial objectives of RNTCP are: To achieve and maintain a TB treatment success rate of at least 85% among new sputum positive patients. To achieve and maintain detection of at least 70% of the estimated new sputum positive people in the community.

20. PREVENTION: F ace mask can help to lower the risk of the spreading the disease to other people. Wearing a mask, covering the mouth and ventilating rooms also limits the spread of bacteria. Isolate the patient from community for certain period. TB vaccination: BCG vaccine doesn’t protect against infection, but it prevents from serious diseases such as miliary TB and meningeal TB.

21. Bacille Calmette Guerin Vaccination (BCG): The BCG vaccine contains a live attenuated strain of M. bovis and is 70% to 80 % effective against the most severe forms of TB, such as TB meningitis in children, but is less effective in adults. Public Health England, 2013 UK vaccination strategy targets the at-risk population rather than the entire UK population. In brief, BCG immunization is offered to infants at high risk of TB exposure, children who are contacts of people diagnosed with pulmonary TB and people younger than 35 years who are at occupational risk of TB such as healthcare workers, veterinary staff, prison staff and staff of hostels.

22. Case Study of Tuberculosis: A 50 -year-old man being treated for pulmonary TB, is reviewed in the outpatient clinic at week 4 of his standard antituberculous treatment include (isoniazid , rifampicin, pyrazinamide and ethambutol). He reports feeling uneasy with some increased nausea. Routine blood tests are performed and his alanine transaminase (ALT) has risen from 37 U/L to 230 U/L.

23. NICE guidelines recommendations: National Institute for health Care and Excellence Q1 ) Should the patient treatment be stopped? Ans : Once the ALT has risen to five times the upper limit of normal ( >200 U/L), then medicines should be discontinued . Q2) What is the likely causative medicine? Ans : Unfortunately, all of the drugs used can cause liver toxicity. The least likely cause is ethambutol.

24. Q3) How should the medicines be re-introduced ? Liver function should be monitored to ensure it is returning to baseline. At the same time it is important to assess for factors that increase risk of liver toxicity, such as viral hepatitis . When the ALT is less than two times the upper limit of normal ( < 80 U/L) reintroduction can take place in a sequential fashion starting with ethambutol plus either isoniazid or rifampicin. Pyrazinamide is reintroduced last, because it may be the most likely drug that induces hepatotoxicity. Latest NICE guidelines (NICE, 2016 ) recommend that the reintroduction regimen should take place quickly over no more than 10 days.