My presentation on review of epidemiology,aetiology and Pathogenesis of Mycobacterium tuberculosis in the department of respiratory medicine,BSMMU

1. • An Overview ofAn Overview of
Epidemiology ,Epidemiology ,
Aetiology andAetiology and
Pathogenesis ofPathogenesis of
TuberculosisTuberculosis
Presenter-Presenter-
Dr.S.A.R.AshiqDr.S.A.R.Ashiq
ChoudhuryChoudhury

2. Introduction
• The word ‘Tuberculosis’ came from ‘Tuberculum (Latin)’
+ ‘osis (English)’
• Other names: Phthisis (Greek; meaning consumption),
Great white plague (due to TB epidemic in Europe in 17th
century,Scrofula (Cervical lymphadenitis caused by
Mycobacterium tuberculosis), Pott’s disease.
• Tuberculosis is an airborne infectious disease caused by
bacilli called the ‘Mycobacterium tuberculosis’
• This is one of the commonest health problems in ourThis is one of the commonest health problems in our
country. It has also become a serious problem incountry. It has also become a serious problem in
developed countries like USA, UK, because of emergingdeveloped countries like USA, UK, because of emerging
of AIDS.of AIDS.

3. History of Tuberculosis
• TB was documented in Egypt, India, and China as early
as 5,000, 3,300, and 2,300 years ago. Typical skeletal
abnormalities, including Pott’s deformities, were found in
Egyptian and Andean mummies and were also depicted
in early Egyptian and pre-colombian art.
  Clinical features of Pulmonary tuberculosis were well
described by Hipocrates in about 400 BC.
  The TB epidemic in Europe, later known as the “Great
White Plague”, probably started at the beginning of the
17th century and continued for the next 200 years.

4. • Image of Nespaheran, an Egyptian mummy from the
time of the 21st Dynasty with spinal TB

5. History of Tuberculosis (contd.)
• Hermann Brehmer (1826-1889) a Silesian
botany student suffering from TB, was instructed
by his doctor to seek out a healthier climate. He
traveled to the Himalayas where he studied the
mountain’s flora. He returned home cured and
began to study medicine. In 1854, he presented
his medical dissertation saying Tuberculosis is a
Curable Disease. Brehmer then opened an in-
patient hospital in Gorbersdorf, where patients
received good nutrition and fresh air

7. • In 1882,Renowned German physician and
Microbiologist Robert Koch discovered the
organism of TB- ‘Mycobacterium Tuberculosis’
• He said ‘from my numerous observation I
conclude that these tubercle bacilli occur in all
tuberculous disorders and they are
distinguishable from all other micro organisms.’

10. • Epidemiology-Global Scenerio

12. Epidemiology-Global Scenario
Nearly one-third of the global population (over 2 billion people) are
infected with Mycobacterium tuberculosis and thus at risk of
developing the disease.
It causes ill health among millions of people each year and ranks as
the second leading cause of death from an infectious disease
worldwide after HIV virus.
One third of the world population has latent TB. More than 90% of
the global Tb cases and deaths occur in the developing countries.
About 75% cases are in the economically productive age group(15-
54 years)

14. Epidemiology-Global Scenario
(contd.)
Of the 8.6 million incident cases an estimated .
53 million were children and 2.9 million occurred
among women
In 1993 the World Health Organization (WHO)
declared TB as a global emergency and
recommended a standard strategy of control of
the disease known as ‘DOTS’ or Directly
observed treatment short-course.

15. Epidemiology-Situation in
Bangladesh
• Tuberculosis is a major public health problem in Bangladesh since
long. Bangladesh ranks sixth among the 22 high TB burden
countries.
• According to WHO, the annual estimated incidence for all cases is
225 per 100,000 population per year. The prevalence (all cases) is
estimated to be 434 per 100,000 population.
• The estimated TB mortality is 45 per 100,000 population per year.
• The extent of anti-TB drug resistance in Bangladesh is not well
known. No nation-wide drug-resistance survey was conducted.
However, limited surveys conducted by the Damien Foundation and
the International Centre for Diarrheal Diseases Research,
Bangladesh (ICDDR,B) showed an overall MDR-TB prevalence rate
of 2%-5.5%

17. TB infection and TB Disease
• TB infection:
TB spreads from person to person through airborne particles that contain
M.tuberculosis called droplet nuclei (size of droplet nuclei .5-5 micro meter,)
TB bacilli stay suspended in the air as droplets. Healthy people become
infected with TB through inhalation of the droplets containing TB bacilli
inhalation fewer than 10 bacteria can cause an infection.
Around 90% of the infected people don’t progress to TB disease because of
their immunity.
`People with TB infection usually –don’t have symptoms
-don’t feel sick
-cannot spread TB to others
-may have a positive skin
test(Mantoux test)

18. TB infection and TB disease
(contd.)
• TB disease:
• Around 10% of the people infected with
TB bacilli may progress to TB disease in
their lifetime. TB disease means TB
infection plus presence of signs and
symptoms of TB

19. Aetiology and classification
The term ‘Mycobacterium’ comes from greek word
‘Myces’ which means long filament. Other name:
Tubercle bacilli, koch’s bacilli
M. tuberculosis divides every 15–20 hours, which is
extremely slow compared to other bacteria, which tend
to have division times measured in minutes (Escherichia
coli can divide roughly every 20 minutes). It is a
small bacillus that can withstand weak disinfectants and
can survive in a dry state for weeks. Its unusual cell wall,
rich in lipids (e.g., mycolic acid), is likely responsible for
this resistance and is a key virulence factor

21. Classification of Mycobacteria

22. Classification of Mycobacteria
• On the basis of it’s disease producing
capability The Mycobacteria are classified
into-
Non pathogenic Mycobacteria: eg: M.phlei
(found on grass), M.butericum (found on
butter)
Pathogenic Mycobacteria

23. Classification of Mycobacteria
(contd.)
• Pathogenic Mycobacteria
 pathogenic to animal: M.bovis
 Pathogenic to humans: These are again
sub classified into
a) Obligate pathogen: M.tuberculosis,
M.africanum, M.ulcerens, M.leprae
b) Opportunistic pathogen: These are also
called atypical Mycobacteria or
Mycobacteria other than tuberculosis.

24. Classification of Mycobacteria
(contd.)
On the basis of their rate of growth in the culture
media Opportunistic pathogens are subdivided
into two categories :
a) Slow growers: They take more than 7 days to
produce colony in the culture medium. Ex:
M.avium intercellularae, M.kansasii,
M.scrofulaccum.
b) Rapid growers: produce colony in the culture
medium less than 7 days. Ex: M.fortuitum

25. Classification of Mycobacteria
(contd.)
• Again slow growers are subdivided into:
a) photochromogen: They produce colony in
presence of light. Ex: M.kansasii
b) Scotochromogen: They produce colony in
presence of darkness. Ex: M.scrofulaccum.
c) Non-chromogen: Those atypical slow grower
mycobacteria who don’t produce pigmented
colony in presence or absence of light. Ex:
M.avium intercellularae.

27. Difference between Typical and Atypical
mycobacterium

28. Pathogenesis

29. Pathogenesis
 Agent: Mycobacterium tuberculosis
 Host: Human
 Name of clinical illness: Tuberculosis
 Reservoir of infection: open cases of
tuberculosis
 Source of infection:
1) Sputum containing the bacteria
2) Pregnant mother’s blood

30. Pathogenesis(contd.)
• Mode of infection:
1) Droplet inhalation
2) Congenital transmission
 Portal of entry: a) nose b) mouth
 Incubation period: few months to few
years

31. Mode of transmission

32. Evolution of the disease
• On the basis of the exposure of mycobacterium
to human the pathogenesis of tuberculosis is
divided into two types:
1) Primary tuberculosis: It means TB occurring in a
person exposed to mycobacterium for the first
time.
2)Secondary tuberculosis: TB occurring in a
person who has already been exposed to
mycobacterium previously.

33. Evolution of the disease (contd.)
• Mycobacterium tuberculosis has neither enzyme
nor toxin ( both exotoxin and endotoxin)
• Mycobacterium tuberculosis can not itself cause
tissue damage. Tissue damage is due to
inflammatory response against M.tuberculosis.
• Commonest sites of primary tuberculosis:
1) Lower part of the upper lobe or upper part of
the lower lobe.
2) Tonsil 3) Intestine 4) skin (remember the
mnemonic LIST)

34. Evolution of the disease (contd.)
The bacilli after localization in the lungs are attacked by neutrophil first
|
But they are unable to kill the bacilli and the bacteria escape
|
Now the bacteria engulfed or phagocytosed by macrophages
|
In the cytoplasm of the macrophages,the bacteria survive because aspecial
molecule on the cell wall of the mycobacteria called‘ sulphatides’ prevents
the fusion of lysosome with phagosome
|
As a result of which, at the site of primary localization there is local
accumulation of multiplying bacteria surrounded by huge number of
macrophages
|
This is called “Ghon focus”
•

36. Evolution of the disease (contd.)
From this primary site of localization, the bacilli are drained
by macrophages to the regional lymph nodes
|
In the lymph node there is a formation of simple foci of
infection
|
This results in lymphadenopathy at the regional
lymphnodes
|
Ghon focus together with regional lymphadenopathy is
called “Ghon complex”

39. Evolution of the disease (contd.)
• Macrophages act as antigen presenting cell and
present the antigens of mycobacteria via its
MHC-II to CD4+T-helper-0 cell
|
• At the same time macrophage liberate IL-12 and
CD4+Th-0 cell to CD4+Th-1 cell
|
This CD4+Th-1 cells are sensitized to the
antigens of mycobacteria

40. Evolution of the disease (contd.)
Some of the CD4+Th-1 cells become effecter T-Helper
cells and some become memory T cell.
Effecter T cells go to action immediately but memory
CD4+helper T cells remain dormant.
They will become active in future when expose to the
mycobacterial antigen again
Such a person who is carrying memory T helper cell is
called sensitized person. It can be detected by Manteaux
test which is a type Iv hypersensitivity reaction.

41. Activated effecter CD4+helper T cell releases
the following cytokines namely-
i. IFN-gamma-it causes
a) Macrophages to become more efficient
killer of mycobacteria
b) Macrophages to become better antigen
presenting cell
c) Macrophages to liberate two cytokines;
PDGF and TGF-beta, these in turn activate
fibroblast to synthesize collagen fibers.

42. ii) IL-2: acts in an autocrine and paracrine manner on macrophages
and causes gathering of huge number of macrophages at the site of
infection.
iii) TNF-alpha and Lymphotoxin (TNF-beta):
These two cytokines liberated from the CD4 T helper-1 cell act on
endothelium of the regional blood vessels and causes vasodialation
and increase in the local blood volume by releasing prostacycline.
They also liberates IL-8 which in turn causes chemotaxis of
lymphocytes and monocytes at the foci of infection
All thsese ultimately cause formation of a special structure at the site
of infection called “Granuloma”

44. • At the center of granuloma, there is a mixture of dead
tissue, macrophages and bacilli. Lipid from the dead
tissue gives cheesy appearance and this type of
necrosis is called “caseation necrosis”
Surrounding the necrotic area at the center there are
numerous macrophages.
Some of the macrophages change their shape and
become epitheloid cells and others fuse to form multi
nucleated giant cells
The entire structure is surrounded by lymphocytes and
lymphocytes are surrounded by collagen fibres.

47. Advantages of the formation of granuloma:
 There is formation of the collagen wall which prevents
the dissemination of tubercle bacilli throughout the body.
 In the granuloma there are a large number of
macrophages. These metabolically active macrophages
consume a huge amount of oxygen and liberates
metabolically acidic end products. As a result of this
anoxia + acidosis develops
 In this adverse condition the mycobacteria which are
obligate aerobes either die or become dormant.

48. • Consequence of Granuloma formation:
a) In about 75% of the cases there is
healing by scar formation or calcification
occurs.
b) Not all mycobacteria get killed. Some
continue to live in a dormant manner and
become activated in the future to
produce post primary tuberculosis.

49. c) In a small number of cases specially in
infants and children the primary foci of
infection don’t heal and continue to
produce severe life threatening
complications such as:
TB meningitis
TB pleurisy
TB disease of spine
TB disease of the kidney etc.

51. • Rupture of blood vessel by eroding the vessel
wall with resultant haematogenous
dissemination of the bacilli to the different
organs of the body gives rise to numerous
granulomatous leisons in these internal organs.
• These leisons give the apperance of “Millet
seeds” in the x-ray. Such type of tuberculosis is
known as Milliary Tuberculosis.

53. Post primary/secondary
tuberculosis:
 Occurs in persons who have already
exposed to mycobacterium before.
 Post primary TB can be occurred by
i) Re infection ii) Re activation of old
dormant foci
In most of the cases reactivation occurs
more often.

54. • Reactivation mainly occurs in a person
suffering from a disease causing
immunusuppression such as:
 DM
Measles
AIDS
Anti-cancer therapy
PEM

55. • Site:
Reactivation of dormant foci of the lung
can occur in any area but most frequently
in the upper lobe- due to high ventilation-
perfusion ratio.
The pathogenesis is almost same as the
primary one but there is more tissue
destruction.

56. WHY?

57. o Because of existing memory T-cell in the pre-
sensitized person the immune response is more
vigorous in post primary tuberculosis and
macrophage and Monocyte liberate more tissue
destructing proteases.
o There is more excessive caseous necrosis in
post primary tuberculosis than primary
tuberculosis
o Due to liberation of excessive Tumour necrosis
factor alpha, there is fever and wasting due to
lypolysis.

58. • In post primary tuberculosis there is extensive
cavitation of the lung.
• Such a person who has a tubercular cavitary
leison within the lung may be in direct contact
with the respiratory passage and called “open
case tuberculosis”
• When a person who have a tubercular cavitary
leison within the lung but are not in a direct
contact with the respiratory passage is called
“Closed case tuberculosis”

61. • Bacilli from post primary tubercular leison
spread mostly along the bronchial tree
and minimally along the Haematogenous
or Lymphatic route.
• Sometimes it goes up to the larynx then
and swallowed. After swallowing this
bacilli are ingested in the intestine and
cause “Intestinal TB”

62. • If the post primary leison in the lung directly
communicate with the pleural cavity then
produce- Broncho pleural fistula.
• Tubercular leison in the Kidney becomes re
activated,goes to the bladder and give rise to i)
Cystits ii) Epididymis
• Post primary TB of skin may become extensive
and may involve skin of the neck and results in
“Lupus Vulgaris”

63. Difference between primary and post primary TB:Difference between primary and post primary TB:
CharacterCharacter PrimaryPrimary Post primaryPost primary
1)1) DefinitionDefinition It is defined as infection ofIt is defined as infection of
an individual lackingan individual lacking
previous contact withprevious contact with
TB-bacilliTB-bacilli
Post primary TB is that phase ofPost primary TB is that phase of
TB infection that arises in aTB infection that arises in a
previously sensitized individualpreviously sensitized individual
& the bacilli is derived from& the bacilli is derived from
exo or endogenous sourceexo or endogenous source
2) Age2) Age Mostly childrenMostly children Young adultsYoung adults
3) Source of infection3) Source of infection Mostly childrenMostly children Young adultsYoung adults
4) Site4) Site Usually at the bases of lungsUsually at the bases of lungs Usually at the apex of the lungsUsually at the apex of the lungs
5) Hilar lymphnodes5) Hilar lymphnodes InvolvedInvolved Not involvedNot involved
6) Spread6) Spread By lymphatics &By lymphatics &
haematogenoushaematogenous
Along tissue spacesAlong tissue spaces
7) Local lesion7) Local lesion Minimal local lesion (GhonsMinimal local lesion (Ghons
focus)focus)
Mainly localized lesionMainly localized lesion
(Caseation & Cavitation)(Caseation & Cavitation)
8) Cellular response8) Cellular response Slow & mainly exudativeSlow & mainly exudative
lesionlesion
Rapid & mainly productiveRapid & mainly productive
lesionlesion
9) Healing9) Healing By calcificationBy calcification By fibrosisBy fibrosis

64. THANK YOU