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Tuberculosis

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Tuberculosis is an example of granulomatous inflammation.
The most common pattern of human tuberculosis (TB) is pulmonary.

The tuberculosis organism is inhaled into the alveolar spaces of the lung, but other tissues are also affected.
Once in the lung the mycobacteria excite a transient but marked immune-mediated response, manifest by
sensitization of T-cells to produce cytokines.
Neutrophils are inadequate to deal with the organisms, the cell walls of which are resistant to degradation and, after three weeks or so, once bacteria have been presented to the immune system, the initial acute inflammatory response is replaced by a chronic inflammatory pattern.
This is dominated by aggregates of macrophages, recruited by the cytokines.
The type of immune response caused by TB is termed type IV hypersensitivity.
In the context of TB, aggregates of macrophages, i.e. the granulomas, are often called tubercles.
Each tubercle has an area of caseous tissue necrosis at its centre. This is characterized by its homogeneity, and no ghost pattern of the original tissue structure remains. Viable mycobacteria are present within the necrotic debris. To the naked eye, this necrotic tissue resembles cream cheese, hence its descriptive name caseous necrosis.
The reason for the necrosis at the centre of tubercles is uncertain, as it is not seen in the centre of granulomas caused by other agents.
A tubercle is composed of activated macrophages with surrounding lymphoid cells and fibroblasts
Around the central area of caseous necrosis lies a collection of large, activated macrophages. Histologically, this functional activation is manifest by the presence of bulky pale-staining granular cytoplasm, which is rich in endoplasmic reticulum, with a prominent Golgi.
Because of a minimal resemblance to some epithelial cells, the term epithelioid cells was originally
coined for these macrophages.
Some of the activated macrophages cells fuse to form large multinucleate cells (macrophage polykaryons)
with many nuclei arranged around the periphery, and a large central cytoplasmic mass. In TB these giant
macrophages are called Langhans' cells.
Around the zone of macrophages bordering the central caseous necrosis lies a collar of lymphocytes,
reflecting the immunological response to the presence of mycobacteria.
As the tubercle persists, some fibroblasts appear within the lymphocyte collar and outside it.
These are recruited by secretion of cytokines from the activated macrophages.

The outcome of tubercle formation depends on the adequacy of the host immune response
Because tuberculosis is resistant to destruction, infections tend to be chronic and
persistent, being difficult to eradicate by natural defence mechanisms. The outcome of
tubercle formation depends on the balance between two conflicting sets of factors: those predisposing
to extension of infection, and those predisposing to containment, or healing and eradication of infection.
Factors predisposing to extension of the infection include:

• Ingestion of large numbers of highly virulent organisms.
• Poor immune response, e.g. due to malnutrition, extreme youth, old age, intercurrent disease or
immunosuppressive therapy.

Factors predisposing to containment or eradication include:

• Ingestion of small numbers of poorly virulent organisms.
• Good immune response, e.g. robust health, heightened immune status due to immunization.
• Administration of appropriate antibiotics.

TB is most severe in patients with poor natural immunity, such as the malnourished, the poor and, increasingly, the underprivileged in the Western World. Those immunosuppressed
by AIDS or treatment for organ transplantation are also greatly at risk. Worryingly, new strains of tuberculosis, resistant to formerly successful anti-tuberculous chemotherapy, are now emerging, so the disease is becoming important once again.
Pulmonary tuberculosis exhibits different tissue patterns according to the level of host immunity.
• If there has been no previous exposure to the organism, a pattern of disease termed primary tuberculosis develops.
• If a person has previously been exposed and is sensitized to the organism, a pattern called
secondary tuberculosis develops.
• If exposure has occurred, but immune responses become abnormal (e.g. by immunosuppression),
the pattern of primary TB develops.

In primary TB the initial lung lesion remains small, but infection spreads to peribronchial lymph nodes
When infection with TB first occurs (e.g. in childhood), the organisms are inhaled and come to proliferate in alveoli at the periphery of the lung, often just beneath the pleura.
Although organisms are of low intrinsic pathogenicity, they cause cell death in adjacent lung. An ineffective acute inflammatory response occurs, which fails to destroy bacteria. Bacteria are then conveyed to local nodes at the lung hilum, where they also proliferate.
After about 3 weeks, an immune response develops, and activated T-cells recruit
macrophages to the lung and nodes, with resulting granulomatous inflammation
and caseation. These early changes may produce no significant symptoms, and the
outcome of the infection will depend on the balance between the host response to disease,
and the virulence and number of organisms.
The peripheral Ghon focus and enlarged peribronchial lymph nodes constitute the primary
complex. The usual outcome is healing by progressive fibrosis surrounding the caseous necrosis.

The primary complex will heal in most cases, with development of immunity to TB
In the vast majority of cases the Ghon focus and caseating granulomas in the lymph nodes
heal by the deposition of collagen around the tubercles. The healed lesion comprises
an area of central caseation surrounded by a wall of dense collagen.
Calcium salts are frequently deposited in the collagen and are sometimes found in the caseous material.
Once the immune system has been exposed to tuberculosis the patient is sensitized
to the organism. The disease does not progress,because the organisms are confined within
the shell of collagen. Importantly, viable bacteria may remain walled off within the
healed primary complex (latent tuberculosis).
Rarely, the primary complex will progress in patients with poor natural immunity
In patients who are unable to mount a vigorous immune and reparative response, further spread
of mycobacteria occurs, with continuing enlargement of the caseating granulomas in the lymph nodes
Known as progressive primary tuberculosis, spread occurs by the enlarging nodes eroding
either through the wall of a bronchus or into a thin-walled blood vessel.
The Ghon focus usually remains small although, rarely, it may rupture through the visceral pleura,
discharging organisms into the pleural cavity to produce tuberculous pleurisy.

Bronchial spread of organisms produces tuberculous bronchopneumonia
If an infected lymph node erodes into a bronchus, tuberculous caseous material
containing living tubercle bacilli passes down bronchi and bronchioles
under the influence of gravity, spreading the infection to the furthest reaches
of the lungs,where extensive, confluent caseating granulomatous lesions develop. Known
as 'galloping consumption', this is usually rapidly fatal.
Bloodstream spread of organisms produces miliary TB
If the enlarging caseating infected lymph node erodes a vessel wall,
tubercle bacilli are carried in the bloodstream to many parts of the body,
including the remainder of the lung, causing miliary tuberculosis.
In secondary TB initial tuberculous infection is at the apex of the upper
lobe of a lung, with little lymph node involvement In secondary TB, organisms may be
acquired exogenously or from healed primary complexes.
An apical lesion (often called an Assmann focus)begins as a small caseating tuberculous granuloma.
Histologically similar to the Ghon focus, it has a central area of caseous necrosis
that is surrounded by a granulomatous inflammatory response. In most cases,
destruction of lung leads to cavitation.
There is little involvement of lymph nodes, as spread of organisms to regional nodes is
prevented by a vigorous tissue-based hypersensitivity response. The outcome of the
infection depends entirely on what happens to the Assmann focus.
In adults, secondary TB heals by fibrosis around the caseating granulomatous mass.
In adults, with vigorous immune responses, healing of the apical lesion occurs through
precisely the same process as that for the Ghon focus. Thus, the lesion contains
a central area of caseous necrotic material, surrounded by a thick dense collagenous wall
in which calcium salts are frequently deposited.
This achieves containment of the infection and there is no further spread of the organism.
Nevertheless, if the fibrous wall breaks down, this latent tuberculosis can lead to spreading
infection at a much later stage (re-activated fibrocaseous tuberculosis).
In adults with poor immune responses, secondary TB progresses locally, with risk of spread to other sites
In adults with poor immune responses, progressive enlargement of the apical lesion
occurs, with caseous necrosis destroying lung tissue.
A large caseous mass is formed as a result, which is surrounded by a thin cellular reaction,
inducing little collagen to wall off the lesion (progressive pulmonary tuberculosis).
As the lesion grows, so too does the risk of erosion into blood vessels or airways.
The release of tubercle bacilli into the main bronchi allows them to be coughed into the
atmosphere in droplets, transmitting the infection to other people (so-called open tuberculosis),
as well as producing TB bronchopneumonia by passage down bronchi to lower lobes.
Bloodstream spread of organisms can lead to single organ infections
Sometimes, only small numbers of tubercle bacilli escape into the blood and, if host defences
are effective, most of the organisms die. However,for reasons that are not yet certain, some bacilli
settle in specific organs and may remain dormant for many years, only proliferating and producing
overt disease at a later date, often after the initial lung and lymph node lesions have healed.
Known as metastatic tuberculosis or isolated organ tuberculosis, those organs
particularly involved in this pattern of disease include: adrenal glands, kidney,fallopian tube, epididymis, brain and meninges, and bones and joints.
A cavitating tuberculous abscess at the lung apex has led to bronchial spread and confluent
tuberculous bronchopneumonia in the lower lobe.
Old Ghon foci from a previous childhood infection persist.
The dilated pelvis and calyces are lined by white caseous necrotic material, the result
of blood stream spread of TB from a lung lesion.
A cavitating tuberculous abscess at the lung apex has led to bronchial spread and confluent tuberculous
bronchopneumonia in the lower lobe. Old Ghon foci from a previous childhood infection persist.

Tuberculous lesions may become re-activated long after apparent healing
In some patients, after collagenous walling-off of a primary or secondary focus, immune defences
wane (often due to immunosuppression or malnutrition), and mycobacteria escape into adjacent lung.
There the mycobacteria are able to proliferate rapidly, producing tissue necrosis, with new
caseation and granulomatous inflammatory reaction.
In the patient's debilitated state, the infection may progress rapidly, and is commonly fatal.
Called re-activated pulmonary TB, it may, like other types, progress to miliary TB or
tuberculous bronchopneumonia.
This illustrates that maintenance of adequate immune and reparative processes is needed to
suppress a persisting damaging stimulus, in this instance a latent mycobacterial infection.

Mycobacteria of other types cause different patterns of infection
Like pulmonary TB, other mycobacterial diseases are characterized by a chronic
inflammatory granulomatous response, with little induction of acute inflammatory response. These include:
• Leprosy (M. leprae), a chronic indolent lesion, mainly of skin. If immunity is high, it may
cause a reaction similar to granulomas in TB. If immunity is low, generalized intracellular proliferation of organisms in phagocytic cells results.
• Bovine TB (M. bovis) is manifest as tuberculous infection of cervical lymph nodes, due to
drinking infected cows' milk.
• M. marinum causes chronic skin lesions, usually on the hands ('fish tank granuloma' or 'swimming pool
granuloma').
• M. scrofulaceum produces enlarged lymph nodes in the neck similar to those in bovine TB,
particularly in children.
M. avium-intracellulare is increasingly being seen in AIDS patients,
in whom it is characterized not so much by a granulomatous reaction (as the immune
system is inactivated), but by vast numbers of organisms proliferating within macrophages
in many organs, resembling lepromatous leprosy.
This organism may also produce a classic caseating granulomatous disease of the lung,
similar to that seen in pulmonary TB due to M. tuberculosis.
Myobacteria are 'acid & alcohol fast', in other words, once a dye or stain gains
entry into the organism, (here a red stain), it cannot easily be rinsed out by dilute acid
or alcohol which removes the red stain from other structures, (here stained blue).
This characteristic staining reaction is due to the same protective coat which renders
the myobacteria relatively impervious to neutrophil killing, and hence initiates
macrophagic granulomatous inflammatory response.

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