Tuberculosis

Pathogenesis and Histopathology

1. PRESENTED BY DR.D.VENKATESH KUMAR 2 ND YR PG TUBERCULOSIS

2. Contents Introduction Classification of mycobacteria Pathogenesis Primary TB Secondary TB Miliary TB Diagnosis Treatment Immunization

3. Introduction Tuberculosis (TB) - leading cause of death - world. 1.8 billion people/year-equal to one-third of the entire world population . In 2014 ,- 9.6 million cases - active TB - resulted in 1.5 million deaths. C urable and preventable

4. HISTORY Tuberculosis-Ancient Disease- Spinal Tuberculosis - Egyptian Mummies History dates to 1550 – 1080 BC Identified by PCR Robert Koch- M. Tuberculosis - discovered - 24 March 1882. Received-Nobel Prize -1905 .

5. Classification of mycobacterium Cultivable 1. Tubercle bacilli Human – MTB Bovine – M. bovis Murine – M. microti Avian – M. avium Cold blooded – M. marinum 2. Mycobacteria causing skin ulcers M. ulcerans M. belnei 3. Atypical Mycobacteria (Runyon Groups) Photochromogens Scotochromogens Nonphotochromogens Rapid growers 4. Johne’s bacillus M. paratuberculosis 5. Saprophytic mycobacteria M. butyricum M. phlei M. stercoralis M. smegmatis Others Non cultivable Lepra bacilli Human – M. leprae Rat – M. leprae murium

6. Mycobacterium differ from other routinely isolated Bacteria Slow-growing -12 to 18 hours ( 20-30 min E.coli ). Hydrophobic- high lipid content in the cell wall. Tend to clump together - impermeable to the usual stains, e.g. Gram's stain Acid-fast bacilli - lipid-rich cell walls-relatively impermeable - various basic dyes unless the dyes-combined with phenol. S ensitive to heat & UV light

7. Forms of TB

8. Predisposing Factors Overcrowding Malnutrition Drugs Inhabitants Medically Underprivileged Resource-poor Communities Chronic Lung Disease Smoking Alcoholism  Diabetes Corticosteroids  Genetic Susceptibility

9. GRANULOMA PATHOGENS I S Bacterial sulfolipids

10. Immunity in Tuberculosis CD 4 T Lymphocytes with Th 1 or Th 2 secrete – 1. Cytokines , 2. Interleukin, 3. Interferon's γ , 4. Tumor necrosis factor . The mechanisms Th 1 secrete – cytokines Activate Macrophages Results in protective Immunity & contain Infection. Th 2 manifests with Delayed Hypersensitivity DTH causes Tissue destruction. and disease will progress.

11. Giant cells

12. Primary Tuberculosis Initial response Events of Primary complex 1. Bacilli are engulfed - Alveolar Macrophages 2. Multiply & give raise-Sub pleural focus TB involve lower lobes & lower part of upper lobes- Ghon’s focus & primary complex .

13. Primary complex The patient will heal & a scar - infected area F ew viable bacilli/spores may remain(particularly - lung ). B acteria-this time goes into-dormant state, as long as- person's immune system remains active & functions normally.

14. Reactivation When a person's immune system-depressed., a secondary reactivation occurs. 85-90 % -cases seen -secondary reactivation type occurs in the lungs Infection activated in Immunosuppressed conditions Eg . HIV infections and AIDS Can produce Meningitis, Miliary tuberculosis, other disseminated Tuberculosis .

15. No progression Healing by fibrosis & calcification Ghons complex after undergoing progressive fibrosis-radiologically detectable calcification- Ranke complex Progressive primary tuberculosis Primary miliary tuberculosis Dissemination to organs like liver, spleen, kidney, ..etc . FATE OF PRIMARY TUBERCULOSIS

16. SECONDARY PULMONARY TUBERCULOSIS The upper parts of both lungs Showed: Gray-white areas of caseation Multiple areas of softening and cavitation

17. Lesion may heal-fibrous scarring & calcification L esions may coalesce together - form large area - TB pneumonia & produce progressive secondary pulmonary tuberculosis Producing pulmonary & extra pulmonary lesions: Tuberculous caseous pneumonia Fibrocaseous tuberculosis Miliary tuberculosis FATE OF SECONDARY PULMONARY TB

18. Extensive infection via hematogenous spread In lung: lesions - either microscopic or small, visible foci (2mm) of yellow white- scattered through out lung parenchyma. Miliary pulmonary disease can cause pleural effusion, tuberculous empyema or obliterative fibrous pleuritis . Extra pulmonary miliary tuberculosis - most prominent - liver , spleen, bone marrow, adrenals, meninges, kidneys, fallopian tubes & epididymis but can involve any organ MILIARY TUBERCULOSIS

19. In tissues or organs seeded - hematogenously Commonly involved organs include: -Intestinal tuberculosis (Tuberculosis peritonitis) -Meninges (Tuberculous meningitis ) -Kidneys (Renal tuberculosis ) - Bones (Osteomyelitis) -Vertebrae (Pott disease) -Fallopian tubes ( Salpingitis ) - Tuberculosis - Lymphadenitis EXTRA PULMONARY TUBERCULOSIS

20. Oral manifestations Oral lesions- any site- tongue most common Other-palate, buccal mucosa, lips, gingiva & floor of the mouth. Irregular, painful, multiple ulcers with undermined border granulating floor usually covered by grey-yellowish exudate, inflamed surrounding tissue.

21. Diffuse involvement-maxilla & mandible-haematogenous spread. TB osteomyelitis - maxilla & mandible-later stages. Biopsy ideal-oral lesion TB-bacilli-oral lesions-too few-direct microscopy.

22. Atypical mycobacteria Occasionally-human TB-atypical myco bacteria-resistance-anti TB drugs. Group 1- Photochromogens Group 2- S cotocromogens Group 3- Non-chromogenic Group 4- Rapid growers.

23. Five patterns of the disease are recognised: I) pulmonary diseas -m. Kansasii or M. Aviumintracellulare . Ii) lymphadenitis - m. Avium-intracellulare or M.Scrofulaceum . Iii) ulcerated skin lesions - m. Ulcerans or M. Marinum . Iv) abscesses - m.Fortuitum or M. Chelonae . V) bacteraemias - m. Avium - intracellulare -seen- Immunosuppressed patients / AIDS Atypical mycobacteria Atypical mycobacteria-acquired-directly from environment, unlike person-to-person transmission -classical TB-disease produce-atypical mycobacteriosis Similar-tuberculosis but-less virulent. Lesions produced-granulomas, nodular collection of foamy cells, or acute inflammation.

24. CLINICAL FEATURES SYMPTOMS

25. HIV Considerations HIV - strongest risk factor-progression to active disease HIV kills CD4 + T Helper cells which normally inhibit M. tuberculosis. HIV interferes with PPD skin test .

26. Assessment and Diagnostic aids A complete history and physical examination . Histopathological examination Tuberculin skin test ( Mantoux test) Chest x-ray Acid-fast bacillus smear & sputum culture - diagnose TB. Smear-ZN - mycobacterium. Bone Marrow Culture

27. Histopathological features Granulomatous inflammation forms both caseating and non caseating tubercles Tuberculous granuloma has the following criteria: Rounded outlines Central caseous necrosis Transformed macrophages termed epithelioid cells Lymphocytes, plasma cells, & fibroblasts Multinucleated giant cells TB - HISTOPATHOLOGICAL EXAMINATION

28. GRANULOMA OF TUBERCULOSIS Collar of lymphocytes, plasma cells Central caseated necrosis Giant multinucleated cells (langhans type E pithliod cells

29. Mantoux test Tubercle bacillus extract (tuberculin), purified protein derivative (PPD)-injected-intradermal layer of the inner aspect - forearm, approx-4 inches-elbow. Result is read 48 to 72 hrs after injection.

30. Culturing Acid Fast Bacilli Slow to grow , Generation time is 14 – 15 hours Grows at 37 c do not grow below 25 c Ph between 6.4 to 7.0

31. CULTURE MEDIA SOLID MEDIA Egg-based Media: Lowenstein-Jensen (LJ) Medium Dorset Medium Serum containing Media: Loeffler’s Medium Potato-based Media: Pawlowsky’s Medium Blood containing Media: Tarshi’s Medium Agar-based Media: Middlebrook 7H10 Middlebrook 7H11 Middlebrook Biplate (7H10/7H11 S Agar).

32. CULTURE MEDIA LIQUID MEDIA BACTEC 12 B Medium BACTEC 460 TB BACTEC 9000 MB BACTEC MGIT 960 EPS Culture System II Middlebrook 7H9 Broth SeptiChek AFB Dubo’s Medium Tween 80 (Sorbitol Mono oleate ) Continuous Monitoring system

33. TB-L.J MEDIUM M.tuberculosis appear dry, rough raised irregular colonies Appear wrinkled C reamy white to yellowish M.bovis appear as flat smooth, moist, white and break up easily

34. ZN-Stain Zn stain-demonstrate-AFB Appear-straight /curved rods – single, pairs or clumps Technique is simple & inexpensive Limited sensitivity(46-78%) Specificity 100%

35. Biochemical Reactions : Niacin Test Arylsulphatase Test Neutral Red Test Catalase-Peroxidase Test Tween 80 Hydrolysis Test Amidase Test Nitrate Reduction Test Thiophene 2-Carboxylic acid Hydrazide (TCH) Test Tellurite Reduction Test

36. DRUGS REGIMEN USED IN ACTIVE TB FIRST LINE DRUGS

37. DRUGS REGIMEN USED IN ACTIVE TB SECOND LINE DRUGS

38. Immuno-prophylaxis Intradermal injection - live attenuated vaccine (BCG). S train causes self limited lesion & induces hypersensitivity & immunity. Coverts tuberculin negative person to positive reactor. Immunity lasts for 10-15 years. Immunity 60-80% Some studies proved BCG is doubtful value in prevention of Tuberculosis.

39. Incidence of oral lesions in TB cases is very less, so each and every persistent and atypical oral lesion must be examined carefully to intercept & prevent the disease early will increase the morbidity and mortality of the patient. Conclusion

40. References Text book of oral pathology, Shafer’s, 7 th Edition Text book of Oral & maxillofacial pathology Neville, Damm , Allen, Bouquot ., 1 st south asia edition. Text book of clinical medicine, DR. S N CHUGH, 3 rd edition Text book of microbiology, C P Baveja , 4 th edition Text book of essential pathology for dental students, harsh mohan 3 rd edition.