2. CONTENT- 1
1. INTRODUCTION
2. HISTORY
3. CAUSATIVE ORGANISM
4. MORPHOLOGY
5. STAINING & IDENTIFICATION METHODS
6. ACID-FAST STAINING METHOD
7. MODE OF TRANSMISSION
8. ATYPICAL MYCOBACTERIUM
9. SPREAD OF TUBERCULOSIS
10. HIV ASSOCIATED TUBERCULOSIS
11. EVOLUTION OF TUBERCLE
12. HYPERSENSITIVITY IN TUBERCULOSIS
13. EPIDEMIOLOGY OF TUBERCULOSIS
14. IMMUNISATION AGAINST TUBERCULOSIS
3. CONTENT (2)
• CLASSIFICATION OF TUBERCULOSIS
• PULMONARY TUBERCULOSIS
• FATE OF PRIMARY TUBERCULOSIS
• SECONDARY PULMONARY TUBERCULOSIS
• FATE OF SECONDARY PULMONARY
TUBERCULOSIS
• FIBROCASEOUS TUBERCULOSIS
• TUBERCULOUS CASEOUS PNEUMONIA
• MILIARY TUBERCULOSIS
• INTESTINAL TUBERCULOSIS
• CLINICAL FEATURES OF TUBERCULOSIS
• DIAGONOSIS OF TUBERCULOSIS
• TREATMENT OF TUBERCULOSIS
• MEDICATIONS OF TUBERCULOSIS
4. INTRODUCTION
DEFINITION - It’s an infectious bacterial disease characterized by the
growth of nodules (tubercles) in the tissues, especially the lungs.
SCIENTIFIC NAME - Mycobacterium tuberculosis
TISSUE RESPONSE - Tissue response in tuberculosis represents
classical example of chronic granulomatous inflammation in humans.
Caseous necrosis in T.B. is most common site of dystrophic
calcification.
5. HISTORY
● Hansen (1868) discovered the first member of
the genus (i.e. lepra bacillus).
● Robert Koch (1882) isolated the mammalian
tubercle bacillus and Johne (1895) described
M.paratuberculosis (Johne's bacillus) causing
chronic enteritis in cattle.
● Tubercle bacillus or Koch’s bacillus (named
after discovery of the organism by Robert Koch
in 1882) called Mycobacterium tuberculosis
causes tuberculosis in the lungs and other
tissues of the human body. Robert Koch
6. CAUSATIVE ORGANISM
● Mycobacterium tuberculosis is the causative organism.
● The organism is a strict aerobe and thrives best in
tissues with high oxygen tension such as in the apex of
the lung.
● Out of various pathogenic strains for human disease
included in Mycobacterium tuberculosis complex,
currently most common is M. tuberculosis hominis
(human strain),while M. tuberculosis bovis (bovine strain)
used to be common pathogen to human beings.
7. MORPHOLOGY OF CAUSATIVE ORGANISM
● Mycobacteria are slender,straight or
slightly curved bacilli with rounded
ends, occurring singly,in pairs or in
small clumps and it sometimes show
branching filamentous forms
resembling fungal mycelium.
● It measures, 1-4 μm x 0.2 - 0.8
μm(average 3 μm x 0.3 μm) in size.
● These bacilli are acid-fast, non-sporing,
non-capsulated and non-motile.
8. STAINING AND IDENTIFICATION METHODS
1. Acid fast (Ziehl-Neelsen) staining.
2. Fluorescent dye methods.
3. Culture of the organism from sputum in
Lowenstein-Jensen (L.J.) medium for 6 weeks.
4. Guinea pig inoculation method by subcutaneous injection
of the organisms.
5. Molecular methods such as PCR are the most recent
methods.
9. ACID-FAST OR (ZIEHL-NEELSAN) STAINING
METHOD
● Ziehl-Neelsen staining is useful to study
the morphology of these organisms. With
this stain, tubercle bacilli are seen in bright
red (acid-fast), while the tissue cells and
other organisms are stained blue.
● The acid fastness of the tubercle bacilli is
due to mycolic acids, cross-linked fatty
acids and other lipids in the cell wall of the
organism making it impermeable to the
usual stains. Fig: Mycobacterium tuberculosis
visualization using the Ziehl–Neelsen
stain.
10. ● It takes up stain by heated carbol fuchsin and resists
decolourisation by acids and alcohols (acid fast and alcohol
fast) and can be decolourised by 20% sulphuric acid (compared
to 5% sulphuric acid for decolourisation for M. leprae which are
less acid fast).
● False positive AFB staining is seen due to Nocardia,
Rhodococcus, Legionella, and some protozoa such as Isospora
and Cryptosporidium.
11. MODE OF TRANSMISSION
Human beings acquire infection with tubercle bacilli by one of the following
routes -
1. Inhalation of organisms present in fresh cough droplets or in dried sputum
from an open case of pulmonary tuberculosis.
2. Ingestion of the organisms leads to development of tonsillar or intestinal
tuberculosis. This mode of infection of human tubercle bacilli is from
self-swallowing of infected sputum of an open case of pulmonary tuberculosis,
or ingestion of bovine tubercle bacilli from milk of diseased cows.
3. Inoculation of the organisms into the skin may rarely occur from infected
postmortem tissue.
13. ATYPICAL MYCOBACTERIUM (NON-TUBERCULOUS
MYCOBACTERIUM)
● The term atypical mycobacteria or non-tuberculous mycobacteria is used for
mycobacterial species other than M. tuberculosis complex and M. leprae.
● Non-tuberculous mycobacteria are widely distributed in the environment
and are, therefore, also called as environmental mycobacteria.
● They too are acid fast.
● Occasionally,human tuberculosis may be caused by atypical
mycobacteria which are nonpathogenic to guinea pigs and resistant to
usual antitubercular drugs.
● This is further classified and studied as:-Rapid growers and Slow
growers.
14. SPREAD OF TUBERCULOSIS
The disease spreads in the body by various routes:-
1. Local spread - This takes place by macrophages carrying the bacilli into the
surrounding tissues.
2. Lymphatic spread - Tuberculosis is primarily an infection of lymphoid tissues. The
bacilli may pass into lymphoid follicles of pharynx, bronchi, intestines or regional lymph
nodes resulting in regional tuberculous lymphadenitis which is typical of childhood
infections.
3. Haematogenous spread - This occurs either as a result of tuberculous bacillaemia
because of the drainage of lymphatics into the venous system or due to caseous
material escaping through ulcerated wall of a vein.
15. 4. By the natural passages - Infection may spread from:
i) lung lesions into pleura (tuberculous pleurisy);
ii) transbronchial spread into the adjacent lung segments;
iii)tuberculous salpingitis into peritoneal cavity (tuberculous
peritonitis);
iv) infected sputum into larynx (tuberculous laryngitis);
v) swallowing of infected sputum (ileocaecal tuberculosis);
vi) renal lesions into ureter and down to trigone of bladder.
16. HIV-ASSOCIATED TUBERCULOSIS
● HIV-infected individuals have very high incidence of tuberculosis
all over the world. Vice-versa, rate of HIV infection in patients of
tuberculosis is very high.
● HIV-infected individual on acquiring infection with tubercle bacilli
develops active disease rapidly rather than after months or years.
● Extra-pulmonary tuberculosis is more common in HIV disease and
manifests commonly by involving lymph nodes, pleura,
pericardium, and tuberculous,meningitis.
17. EVOLUTION OF TUBERCLE
The sequence of events which take place
when tubercle bacilli are introduced into
the tissue are as under -
● When the tubercle bacilli are injected
intravenously into the guinea pig, the bacilli
are lodged in pulmonary capillaries where
an initial response of neutrophils is evoked
which are rapidly destroyed by the
organisms.
18. Continue...
● After about 12 hours, there is progressive infiltration by macrophages. This is
due to coating of tubercle bacilli with serum complement factors C2a and C3b
which act as opsonins and attract the macrophages.
● The macrophages start phagocytosing the tubercle bacilli and either kill the
bacteria or die away themselves.
● As a part of body’s immune response, T and B cells are activated. Activated
CD4+T cells develop the cell mediated delayed type hypersensitivity reaction,
while B cells result in formation of antibodies which play no role in body’s
defence against tubercle bacilli.
19. Continue...
● In 2-3 days, the macrophages undergo structural changes as a result of
immune mechanisms-the cytoplasm becomes pale and eosinophilic and their
nuclei become elongated and vesicular. These modified macrophages
resemble epithelial cells and are called epithelioid cells.
● The epithelioid cells in time aggregate into tight clusters or granulomas.
Release of cytokines in response to sensitised CD4+T cells and some
constituents of mycobacterial cell wall play a role in formation of granuloma.
● Some of the macrophages form multinucleated giant cells by fusion of
adjacent cells. The giant cells may be Langhans’ type.
20. Continue...
● Around the mass of epithelioid cells and giant cells is a zone of lymphocytes,
plasma cells and fibroblasts. The lesion at this stage is called hard tubercle
due to absence of central necrosis.
● Within 10-14 days, the centre of the cellular mass begins to undergo
caseation necrosis, characterised by cheesy appearance and high lipid
content. This stage is called soft tubercle which is the hallmark of tuberculous
lesions.
● The soft tubercle which is a fully-developed granuloma with caseous centre
does not favour rapid proliferation of tubercle bacilli. Acid-fast bacilli are
difficult to find in these lesions and may be demonstrated at the margins of
recent necrotic foci and in the walls of the cavities.
21. HYPERSENSITIVITY IN TUBERCULOSIS
● Hypersensitivity or allergy, and immunity or resistance,play a major role in the
development of lesions in tuberculosis.
● Tissue changes seen in tuberculosis are the result of host response to the
organism which is in the form of development of cell-mediated hypersensitivity
(or type IV hypersensitivity) and immunity.
● It has been known since the time of Robert Koch that the tissue reaction to
tubercle bacilli is different in healthy animal not previously infected (primary
infection) from an animal who is previously infected (secondary infection).
22. 1.In the primary infection:-
● Intradermal injection of tubercle bacilli into the skin of a healthy guinea pig
evokes, no visible reaction for 10-14 days.
● After this period, a nodule develops at the inoculation site which subsequently
ulcerates and heals poorly as the guinea pig, unlike human beings, does not
possess any natural resistance.
● The regional lymph nodes also develop tubercles. This process is a
manifestation of delayed type of hypersensitivity (type IV reaction) and is
comparable to primary tuberculosis in children although healing invariably
occurs in children.
23. 2. In the secondary infection:-
● The tubercle bacilli are injected into the skin of the guinea pig who has been
infected with tuberculosis 4-6 weeks earlier. In 1-2 days, the site of inoculation
is indurated and dark, attaining a diameter of about 1 cm.
● The skin lesion ulcerates which heals quickly and the regional lymph nodes
are not affected. This is called Koch’s phenomenon and is indicative of
hypersensitivity and immunity in the host.
● Tuberculin (Mantoux) skin test
○ This test is done by intradermal injection of 0.1 ml of tuberculoprotein, purified protein
derivative (PPD).
○ A positive test is indicative of cell-mediated hypersensitivity to tubercular antigens.
25. IMMUNISATION AGAINST TUBERCULOSIS
● Protective immunisation against
tuberculosis is induced by injection of
attenuated strains of bovine type of
tubercle bacilli, Bacille
Calmette-Guérin (BCG).
● Cell-mediated immunity with
consequent delayed hypersensitivity
reaction develops with healing of the
lesion, but the cell-mediated immunity
persists, rendering the host
tuberculin-positive and hence immune.
26.
27. PULMONARY TUBERCULOSIS
• Lung is the main organ affected in tuberculosis.Depending upon the
type of tissue response and age, the infection with tubercle bacilli is of 2
main types:-
A. Primary tuberculosis; and
B. Secondary tuberculosis.
A. Primary Tuberculosis-
The infection of an individual who has not been previously infected or
immunised is called primary tuberculosis or Ghon’s complex or childhood
tuberculosis.
Primary complex or Ghon’s complex is the lesion produced in the tissue
of portal of entry with foci in the draining lymphatic vessels and lymph
nodes.
28. The most commonly involved tissues for primary complex are
lungs and hilar lymph nodes.
Other tissues which may show primary complex are tonsils
and cervical lymph nodes.
Primary complex or Ghon’s complex in lungs consists of 3
components:-
1. Pulmonary component- Lesion in the lung is the primary
focus or Ghon’s focus.
It is 1-2 cm solitary area of tuberculous pneumonia located
peripherally under a patch of pleurisy, in any part of the lung but
more often in subpleural focus in the upper part of lower lobe.
Microscopically, the lung lesion consists of tuberculous granulomas with caseation
necrosis.
29. 2. Lymphatic vessel component-
The lymphatics draining the lung lesion contain phagocytes containing
bacilli and may develop beaded, miliary tubercles along the path of hilar
lymph nodes.
3. Lymph node component-
This consists of enlarged hilar and tracheo-bronchial lymph nodes in
the area drained. The affected lymph nodes are matted and show
caseation necrosis.
Microscopically, the lesions are characterised by extensive caseation,
tuberculous granulomas and fibrosis.
30. Fig- Caseating epithelioid cell granulomas with some
Langhans’ giant cells in the cortex of lymph node component.
31. Figure - The primary complex composed of 3 components:
Ghon’s focus, draining lymphatics, and hilar lymph nodes.
32. FATE OF PRIMARY TUBERCULOSIS
• Primary complex may have one of the following sequelae;-
1. The lesions of primary tuberculosis of lung commonly do not progress but instead
heal by fibrosis, and in time undergo calcification and even ossification.
2. In some cases, the primary focus in the lung continues to grow and the caseous
material is disseminated through bronchi to the other parts of the same lung or
the opposite lung. This is called progressive primary tuberculosis.
3. At times, bacilli may enter the circulation through erosion in a blood vessel and
spread to various tissues and organs. This is called primary miliary tuberculosis
and the lesions are seen in organs like the liver, spleen, kidney, brain and bone
marrow.
33. 4. In certain circumstances like in lowered resistance and increased
hypersensitivity of the host, the healed lesions of primary tuberculosis may get
reactivated. The bacilli lying dormant in acellular caseous material are activated
and cause progressive secondary tuberculosis.
Figure - Sequelae of primary complex
34. B. Secondary Tuberculosis-
The infection of an individual who has been previously
Infected or sensitised is called secondary, or post-primary or
reinfection, or chronic tuberculosis.
The infection may be acquired from:-
endogenous source such as reactivation of dormant primary
complex; or
exogenous source such as fresh dose of reinfection by the tubercle
bacilli.
Secondary tuberculosis occurs most commonly in lungs in the region
of apex. Other sites and tissues which can be involved are tonsils,
pharynx, larynx, small intestine and skin.
36. SECONDARY PULMONARY TUBERCULOSIS
• The lesions in secondary pulmonary tuberculosis usually begin as 1-2 cm
apical area of consolidation of the lung,which may in time develop a small
area of central caseation necrosis and peripheral fibrosis.
• It occurs by haematogenous spread of infection from primary complex to the
apex of the affected lung where the oxygen tension is high and favourable
for growth of aerobic tubercle bacilli.
• Microscopically, the appearance is typical of tuberculous granulomas with
caseation necrosis.
• Patients with HIV infection previously exposed to tuberculous infection have
particularly high incidence of reactivation of primary tuberculosis and the
pattern of lesions in such cases is similar to that of primary tuberculosis.
37. FATE OF SECONDARY PULMONARY
TUBERCULOSIS
o The subapical lesions in lungs can have the following courses:-
1. The lesions may heal with fibrous scarring and calcification.
2. The lesions may coalesce together to form larger area of tuberculous
pneumonia and produce progressive secondary pulmonary tuberculosis
with the following pulmonary and extrapulmonary involvements:-
i) Fibrocaseous tuberculosis
ii) Tuberculous caseous pneumonia
iii) Miliary tuberculosis.
38. I. FIBROCASEOUS TUBERCULOSIS
• The original area of tuberculous pneumonia undergoes massive central
caseation necrosis which may:
either break into a bronchus from a cavity(cavitary or open fibrocaseous
tuberculosis); or
remain, as a soft caseous lesion without drainage into a bronchus or
bronchiole to produce a non-cavitary lesion (chronic fibrocaseous TB)
• The cavity provides favourable environment for proliferation of tubercle
bacilli due to high oxygen tension.
The open case of secondary tuberculosis may implant tuberculous lesion
on the mucosal lining of air passages producing endobronchial and
endotracheal tuberculosis. Ingestion of sputum containing tubercle bacilli
from endogenous pulmonary lesions may produce laryngeal and intestinal
tuberculosis.
39. Figure- Fibrocaseous tuberculosis
. A, Non-cavitary fibrocaseous tuberculosis (left) and cavitary/open fibrocaseous
tuberculosis(right) B, Chronic fibrocaseous tuberculosis lung
40. Figure - Microscopic appearance of lesions of secondary fibrocaseous
tuberculosis of the lung showing wall of the cavity.
41. II. TUBERCULOUS CAUSING PNEUMONIA
• The caseous material from a case of secondary tuberculosis in an
individual with high degree of hypersensitivity may spread to rest of
the lung producing caseous pneumonia.
Figure- Bilateral tuberculous caseous pneumonia
42. III. MILIARY TUBERCULOSIS
• This is lympho haematogenous spread of tuberculous infection from
primary focus or later stages of tuberculosis.
• The spread is either by entry of infection into pulmonary vein or
isolated organ lesion in different extra-pulmonary sites (e.g. liver,
spleen, kidney,brain and bone marrow) or into pulmonary artery
restricting the development of miliary lesions within the lung.
• The miliary lesions are millet seed-sized(1 mm diameter), yellowish,
firm areas without grossly visible caseation necrosis.
Microscopically, the lesions show the structure of tubercles with
minute areas of caseation necrosis.
43. Figure- Miliary tuberculosis lung Figure- histological diagram of Miliary tubercles
in lung having minute central caseation necrosis.
44. INTESTINAL TUBERCULOSIS
• Intestinal tuberculosis can occur in 3 forms—
primary,secondary and hyperplastic caecal tuberculosis.
1. Primary Intestinal Tuberculosis-
. primary tuberculosis of the ileocaecal region is quite common in
developing countries including india.
In the pre-pasteurisation era, it used to occur by ingestion of unpasteurised
cow’s milk infected with Mycobacterium bovis. But, now-a-days due to control
of tuberculosis in cattle and pasteurisation of milk, virtually all cases of
intestinal tuberculosis are caused by M.tuberculosis.
45. Grossly, the affected lymph nodes are enlarged, matted and caseous (tabes mesenterica).
Microscopically, in the initial stage, there is primary complex or Ghon’s focus in the
intestinal mucosa as occurs elsewhere in primary tuberculous infection.
46. 2. Secondary Intestinal Tuberculosis:-
Self-swallowing of sputum in patients with active pulmonary
tuberculosis may cause secondary intestinal tuberculosis, most
commonly in the terminal ileum and rarely in the colon.
47. 3. Hyperplastic Caecal Tuberculosis:-
This is a variant of occurring secondary to pulmonary tuberculosis
48. CLINICAL FEATURES OF TUBERCULOSIS
• The clinical manifestations in tuberculosis may be variable depending
upon the location, extent and type of lesions.However, in secondary
pulmonary tuberculosis which is the common type, the usual clinical
features are as under :-
1. Referable to lungs- such as productive cough, may be with
haemoptysis, pleural effusion,dyspnoea,orthopnoea etc.
- Chest X-ray may show typical apical changes like pleural effusion,
nodularity, and miliary or diffuse infiltrates in the lung parenchyma.
2. Systemic features-
-such as fever, night sweats, fatigue, loss of weight and
appetite. Long-standing and untreated cases of tuberculosis
may develop systemic secondary amyloidosis.
49. DIAGONOSIS OF TUBERCULOSIS
• The diagnosis is made by the following tests:-
i) Positive Mantoux skin test.
ii) Positive sputum for AFB (on smear or culture).
iii) Complete haemogram (lymphocytosis and raised ESR).
iv) Chest X-ray (characteristic hilar nodules and
other parenchymal changes).
v) Fine needle aspiration cytology of an enlarged
peripheral lymph node is quite helpful for confirmation
of diagnosis.
Causes of death in pulmonary tuberculosis are usually
pulmonary insufficiency, pulmonary haemorrhage, sepsis
due to disseminated miliary tuberculosis,or pulmonale or
secondary amyloidosis.
50. TREATMENT OF TUBERCULOSIS
Incidence-
• In spite of great advances in chemotherapy and immunology,
tuberculosis still continues to be worldwide in distribution, more
common in developing countries of Africa, Latin America and Asia.
• Other factors contributing to higher incidence of tuberculosis are
malnutrition, inadequate medical care, poverty, crowding, chronic
debilitating conditions like uncontrolled diabetes, alcoholism and
immunocompromised states like AIDS.
• However,the exact incidence of disease cannot be determined,
as all patients infected with M. tuberculosis may not develop the clinical
disease and many cases remain reactive to tuberculin without
developing symptomatic disease.
51. MEDICATIONS FOR TUBERCULOSIS
Tuberculosis is now treated with a combination of 3-4
antitubercular drugs under the ‘directly observed treatment
short course’ (DOTS) protocol formulated by the WHO.
Under this protocol dose of all firstline drugs was
standardized on body weight basis, applicable to both
adults and children.
The goals of antitubercular chemotherapy are:
(a) Kill dividing bacilli
(b) Kill persisting bacilli
(c) Prevent emergence of resistance
Commonly used antitubercular drugs are:-
Isoniazid, Rifampin, Pyrazinamide, Ethambutol, and
Streptomycin.
52. Source of information;-
Textbook of essential pathology by HARSH MOHAN
Textbook of microbiology by C.P BAVEJA
Essential of pharmacology by K.D TRIPATHI
And, image courtesy;- google images