Pathogenesis and Histopathology

1. 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.
 Curable 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
mycobacteriumCultivable
1. Tubercle bacilli
a) Human – MTB
b) Bovine – M. bovis
c) Murine – M. microti
d) Avian – M. avium
e) Cold blooded – M. marinum
2. Mycobacteria causing skin ulcers
a) M. ulcerans
b) M. belnei
3. Atypical Mycobacteria (Runyon Groups)
a) Photochromogens
b) Scotochromogens
c) Nonphotochromogens
d) Rapid growers
4. Johne’s bacillus
M. paratuberculosis
5. Saprophytic mycobacteria
a) M. butyricum
b) M. phlei
c) M. stercoralis
d) M. smegmatis
e) Others
Non cultivable
1. Lepra bacilli
a) Human – M. leprae
b) 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.
 Sensitive to heat & UV light

7. Pulmonary
Tuberculosis
• lung
parenchyma-
usually involves-
middle or lower
lung area.
Extra
pulmonary TB
• Other parts-
body- Meninges,
kidneys, bone,
joints,
pericardium, GI
tract & lymph
nodes.
Bovine
tuberculosis
• Disease-affects
animals-cattle -
may sometimes be
transmitted to
man.
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
PA
TH
O
GE
NS
I
S
Bacterial sulfolipids

10. Immunity in Tuberculosis
CD4 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
 Few viable bacilli/spores may remain(particularly - lung).
 Bacteria-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
 Lesions 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- Scotocromogens
 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 FEATURESSYMPTOMS

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
1. A complete history and physical examination.
2. Histopathological examination
3. Tuberculin skin test (Mantoux test)
4. Chest x-ray
5. Acid-fast bacillus smear & sputum culture -diagnose TB.
6. Smear-ZN - mycobacterium.
7. Bone Marrow Culture

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

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

31. Culturing Acid Fast Bacilli
 Slow to grow ,
 Generation time is 14 – 15 hours
 Grows at 370c do not grow
below 250c
 Ph between 6.4 to 7.0

32. 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).

33. 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

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

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

36. 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

37. DRUGS REGIMEN USED IN ACTIVE TB
FIRST LINE DRUGS

38. DRUGS REGIMEN USED IN ACTIVE TB
SECOND LINE DRUGS

39. Immuno-prophylaxis
 Intradermal injection - live attenuated vaccine (BCG).
 Strain 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.

40. 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

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