•An Overview ofAn Overview of Epidemiology , Epidemiology , Aetiology and Aetiology and Pathogenesis of Pathogenesis of TuberculosisTuberculosis

Presenter-Presenter-Dr.S.A.R.Ashiq Dr.S.A.R.Ashiq ChoudhuryChoudhury

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 our This is one of the commonest health problems in our country. It has also become a serious problem in country. It has also become a serious problem in developed countries like USA, UK, because of emerging developed countries like USA, UK, because of emerging of AIDS.of AIDS.

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.

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

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

• 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.’

• Epidemiology-Global Scenerio

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)

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.

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%

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)

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

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

Classification of Mycobacteria

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

Classification of Mycobacteria (contd.)

• Pathogenic Mycobacteria pathogenic to animal: M.bovis Pathogenic to humans: These are again

sub classified intoa) Obligate pathogen: M.tuberculosis,

M.africanum, M.ulcerens, M.lepraeb) Opportunistic pathogen: These are also

called atypical Mycobacteria or Mycobacteria other than tuberculosis.

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

Classification of Mycobacteria (contd.)

• Again slow growers are subdivided into:a) photochromogen: They produce colony in

presence of light. Ex: M.kansasiib) 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.

Difference between Typical and Atypical mycobacterium

Pathogenesis

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

Pathogenesis(contd.)

• Mode of infection:1) Droplet inhalation2) Congenital transmission Portal of entry: a) nose b) mouth Incubation period: few months to few

years

Mode of transmission

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.

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)

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”

•

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”

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

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.

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.

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”

• 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.

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.

• 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.

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 meningitisTB pleurisyTB disease of spineTB disease of the kidney etc.

• 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.

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 fociIn most of the cases reactivation occurs

more often.

• Reactivation mainly occurs in a person suffering from a disease causing immunusuppression such as:

DMMeaslesAIDSAnti-cancer therapyPEM

• 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.

WHY?

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.

• 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”

• 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”

• 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”

Difference between primary and post primary TB:Difference between primary and post primary TB:CharacterCharacter PrimaryPrimary Post primaryPost primary1)1) DefinitionDefinition It is defined as infection of It is defined as infection of

an individual lacking an individual lacking previous contact with previous contact with TB-bacilliTB-bacilli

Post primary TB is that phase ofPost primary TB is that phase ofTB infection that arises in aTB infection that arises in a previously sensitized individual previously 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 children Mostly 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 lymphnodes 5) Hilar lymphnodes InvolvedInvolved Not involvedNot involved

6) Spread6) Spread By lymphatics & By lymphatics & haematogenoushaematogenous

Along tissue spacesAlong tissue spaces

7) Local lesion 7) Local lesion Minimal local lesion (GhonsMinimal local lesion (Ghons focus)focus)

Mainly localized lesion Mainly localized lesion (Caseation & Cavitation)(Caseation & Cavitation)

8) Cellular response8) Cellular response Slow & mainly exudativeSlow & mainly exudative lesionlesion

Rapid & mainly productive Rapid & mainly productive lesionlesion

9) Healing9) Healing By calcification By calcification By fibrosisBy fibrosis

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