PATHOLOGY OF

TUBERCULOSIS

Dr. Maha Arafah and Prof. Ammar Rikabi

Department of Pathology
KSU, Riyadh
2015
TUBERCULOSIS
TB is a chronic communicable granulomatous disease in
which the lungs are the prime target, although any other
organ may be infected.
This disease is mainly caused by Mycobacterium tuberculosis
hominis (Koch bacillus) but also occasionally by
Mycobacterium tuberculosis bovis.
Objectives from Microbiology
lec
Recognize that tuberculosis as a chronic
disease mainly affecting the respiratory
system.
Know the epidemiology of tuberculosis world
wide and in the kingdom of Saudi Arabia
Understand the methods of transmission of
tuberculosis and the people at risk.
 Know the causative agents and their
characteristic and classification and methods
of detection.
Understand the pathogenesis of tuberculosis.
Differentiate between primary and secondary
tuberculosis and the clinical features of each.
 Understand the method of tuberculin skin test
and result interpretation ..
Know the laboratory and radiological
diagnostic methods.
Know the chemotherapeutic and other
methods of management of tuberculosis cases.
Describe the methods of prevention and
control of tuberculosis.

My objectives
Discuss Pathogenesis and different
pathologic features seen in TB
Diseases caused by Mycobacterium
The important species are
Mycobacterium tuberculosis is the etiologic
agent of tuberculosis in humans. Humans are the
only reservoir for the bacterium.
Mycobacterium bovis is the etiologic agent of TB
in cows and rarely in humans. Both cows and
humans can serve as reservoirs. Humans can also
be infected by the consumption of unpasteurized
milk. This route of transmission can lead to the
development of extrapulmonary TB.
M. leprae : causes leprosy
Diseases caused by Mycobacterium
Others:
More than 50 species of the genus Mycobacterium are now
recognized as potential human pathogens. Species other than M.
tuberculosis and M. leprae have been designated as non-
tuberculous mycobacteria
M. kansasii, M. avium, M. intracellulare cause atypical
mycobacterial infections in humans esp in AIDS. They cause
respiratory and gastrointestinal symptoms and can involve
other organs too.
They cause atypical TB.

M. ulcerans causes buruli ulcers of skin.

TUBERCULOSIS: Increase risk

Flourishes wherever there is

Poverty

crowding

malnutrion

chronic debilitating illness e.g.chronic lung disease (particularly

silicosis), chronic renal failure etc.
a disease of the elderly,
people with AIDS,
Diabetes mellitus,
Hodgkin's lymphoma,
Alcoholism,
Immunosuppression e.g. with glucocorticoids
TB is a Granulomatous disease.
What is Granuloma?
A granuloma is a microscopic aggregation of macrophages that are
transformed into epithelium-like cells surrounded by a collar of
mononuclear leukocytes, principally lymphocytes and occasionally plasma
cells.
Epithelioid cells fuse to form giant cells containing 20 or more nuclei.
The nuclei arranged either peripherally (Langhans-type giant cell) or
haphazardly (foreign body-type giant cell). Both Langhans ("classic TB")
and foreign-body giant cells are common.
These giant cells can be found either at the periphery or the center of the
granuloma.
Fibrous connective tissue often surrounds granulomas (remodeling of
tissue)
In TB Areas within the granuloma can undergo necrosis (caseous
necrosis). Necrosis can lead to calcification
TB granulomas are called tubercles, and if they are caseating in the center,
they are called soft tubercles.
Granuloma: the predominant cell type is an activated macrophage with a
modified epithelial-like (epithelioid) appearance. Also seen are lymphocytes,
multinucealted giant cells and occasional plasma cells.
 Langhans Giant Cell

Lymphocytic Rim

Caseous Necrosis

Epithelioid Macrophage
 Ziehl-Neelsen
stain is an acid-
fast staining
method to stain M.
tuberculosis. The
Acid-fast bacilli
appear pink in a
contrasting
background.
Pathogenesis
The steps in M. tuberculosis infection are:
1. Entry into macrophages phagocytosis mediated by several
receptors expressed on the phagocyte, including mannose
binding lectin and other receptors

2. Replication in macrophages. M. tuberculosis inhibits maturation

of the phagosome and blocks formation of the phagolysosome,
allowing the bacterium to replicate unchecked within the
vesicle, protected from the microbicidal mechanisms of
lysosomes.

The bacterium blocks phagolysosome formation by inhibiting

Ca2+ signals and the recruitment and assembly of the
proteins that mediate phagosome-lysosome fusion.
Pathogenesis of granuloma

During the earliest stage of primary tuberculosis (<3

weeks) in the nonsensitized individual, bacteria proliferate
in the pulmonary alveolar macrophages and air spaces,
resulting in bacteremia and seeding of multiple sites.
Despite the bacteremia, most people at this stage are
asymptomatic or have a mild flu-like illness
 Pathogenesis of granuloma

3. The TH1 response. About 3 weeks after infection, a T-helper 1

(TH1) response is mounted that activates macrophages, enabling
them to become bactericidal.

Differentiation of TH1 Macrophages activated

TH1-mediated
cells depends on IL-12, by IFN- differentiate
which is produced by macrophage
into the epithelioid
antigen-presenting cells activation and
histiocytes that
that have encountered killing of bacteria by aggregate to form
the bacilli produce IFN- granulomas
Pathogenesis of granuloma
IFN-
4. TH1-mediated macrophage activation and killing of
bacteria.
IFN- is the critical mediator that enables
macrophages to contain the M.
tuberculosis infection. How?
I. IFN- stimulates maturation of the phagolysosome in
infected macrophages, exposing the bacteria to a lethal
acidic, oxidizing environment.
II. IFN- stimulates expression of inducible nitric oxide
synthase, which produces nitric oxide (NO
III. IFN- mobilizes antimicrobial peptides (defensins)
against the bacteria
IV. IFN- stimulates autophagy, a process that sequesters
and then destroys damaged organelles and intracellular
bacteria such as M. tuberculosis.
Pathogenesis of granuloma

5. Granulomatous inflammation and tissue damage.

Macrophages activated by IFN- differentiate into

the epithelioid histiocytes that aggregate to
form granulomas; some epithelioid cells may fuse
to form giant cells

Activated macrophages also secrete TNF and

chemokines, which promote recruitment of more
monocytes
Pathogenesis of granuloma
Role of other immune cells. In addition to the TH1
response, NKT cells that recognize
mycobacterial lipid antigens bound to CD1 on
antigen-presenting cells, or T cells that express
a T-cell receptor, also make IFN-.
However, it is clear that TH1 cells have a
central role in this process, since defects in any
of the steps in generating a TH1 response result
in absence of resistance and disease
progression.
Pathogenesis of granuloma
Host susceptibility to disease. People with genetic
deficiencies in the IL-12 pathway and the IFN-
pathway, including STAT1 a signal transducer
for IFN-, are vulnerable to severe mycobacterial
infections.
Polymorphisms in a large number of genes,
including HLA, IFN-, IFN- receptor, and TLR2
have been found to be associated with
susceptibility to tuberculosis, but the contribution
of these associations to disease development is
still under investigation.
 Summary of Pathogensis
Immunity to M. tuberculosis is primarily mediated by TH1
cells, which stimulate macrophages to kill the bacteria

This immune response, while largely effective, comes at

the cost of accompanying tissue destruction

Reactivation of the infection or re-exposure to the bacilli

in a previously sensitized host results in rapid
mobilization of a defensive reaction but also increased
tissue necrosis

loss of T-cell immunity (indicated by tuberculin

negativity in a previously tuberculin-positive individual)
may be an ominous sign that resistance to the organism
has faded
Route of transmission of TB
Route of transmission of TB

M. bovis infections, acquired through drinking

infected milk, usually start in the tonsils or
Peyer's patches.
Pathogenesis of TB:

Infection - Immunity

Infection with M. tuberculosis typically

leads to the development of delayed
hypersensitivity, which can be detected by
the tuberculin (Mantoux) test.
When the bacilli enter the body

The bacilli have 4 potential fates upon entering the human body:

1. They may be killed by the immune system,

2. they may multiply and cause primary TB,

3. they may become dormant and remain asymptomatic,

4. they may proliferate after a latency period (reactivation disease).

Reactivation TB may occur following either (2) or (3) above.

5. if immunosuppressed ---- Primary Progressive TB or Miliary TB

The clinical course or presentation of TB

The course of TB depends on the age and the immunity of the

patient and the total burden of organism.
Some patients have only an indolent, asymptomatic infection
while in others TB is a destructive disseminated disease.
There is a difference between infection and active TB. Not
everyone who is infected develops clinical symptoms.
1. Primary TB occurs on first exposure to the organism and
can pursue either an indolent or aggressive course (primary
progressive TB).
2. Secondary TB develops long after a primary infection,
mostly as a result of reactivation of a primary infection. It
can also be produced by exposure to exogenous organisms.
Secondary TB is always an active disease.
3. Miliary TB
 PRIMARY TB
Primary TB is a first exposure to tubercle bacilli. The inhaled organism is
deposited in the alveoli. It is the form of disease that develops in a
previously unexposed and unsensitized person.
They are ingested by macrophages and they ellicit a type IV delayed
hypersensitivity response to the tuberculous bacillus which elicit a cell-
mediated immune response which will resists the growth and spread of
the mycobacterium.
In a immunologically competent person a granulomatous response in
produced. It takes 5-6 days invoke granuloma formation which are usually
formed by 3 to 4weeks. In immunocompromised persons granulomas
are poorly formed or not formed at all.
 PRIMARY TB

The lung lesion of primary TB is known as Ghon

focus.
It is commonly found in the sub-pleural area.
It drains into the hilar lymph nodes.
The combination of the Ghon focus and the
involved medistinal or hilar lymph nodes is called
as Ghon complex.
Most of the time this Ghon complex heals
undergoing shrinkage fibrous scarring and
calcification. It takes 2 to 8 weeks for healing.
 PRIMARY TUBERCULOSIS: Ghon
Focus & Ghon complex

Ghon Focus: lung lesion of primary TB, involves upper segments of the lower lobes
or lower segment of the upper lobe.
Ghon complex: combination of a peripheral ghon focus and involved mediastinal
or hilar lymphnode.
Microscopically the classic lesion of TB is a caseous granuloma
Caseating granulomas
 progressive primary
Possible sequalae of tuberculosis
primary tuberculosis

1. No problems.
2. The disease may advance into
progressive primary tuberculosis in
immunocompromised patients such as
AIDS patients, elderly, and
malnourished children. The infection
progresses and spreads to other areas
of lung, lymph nodes or other multiple
sites.
3. The foci of scarring may harbor a small
number of organisms that remain
viable for years and later if immune
mechanisms wane or fail, these bacilli
may multiply and cause reactivation of
TB (secondary TB).
SECONDARY TUBERCULOSIS

It is post primary infection in an immunized individual.

The mycobacteria in secondary TB may be either coming
from:
1. A reactivation of dormant organisms from old granulomas
(dormant primary lesion) many decades after initial
infection when the host resistance is weakened (in a
previously sensitized host). This is more common. Various
conditions including cancer, chemotherapy, AIDS and old
age predispose to the re-emergence of endogenous
dormant M. Tuberculosis. It may develop even decades
after primary infection.
2. Or exogenous re-infection (newly acquired bacilli) by a
high dose of virulent bacilli. Seen more in endemic areas.
Pathologic features of secondary
tuberculosis:

Secondary pulmonary tuberculosis can involve any organ but

the lungs are the most common site. In the lungs it is classically
localized to the apex of the upper lobes of one or both lungs.
(M.tuberculosis bacilli love oxygen and prefer to grow where it
is most abundant so it starts at the apical and subapical regions
of the lungs).
Appear grossly as sharply circumscribed firm areas with central
caseation and cavitation surrounded by fibrous wall. The
cavitation is loaded with the mycobacteria.
It becomes an important source of infection because the patient
now coughs sputum that contains bacilli.
Histologically: epithelioid granulomas with central caseation
and Langhans type And foreign body type giant cells.
Scondary TB lung

Cavitatory tuberculosis with

intracavitary hemorrhage.
Extensive necrosis with
cavitation, usually occurring in
the upper lung lobe .
Complications of TB

Scarring: It can heal by fibrosis leaving a residual apical

scar.
Calcification (dystrophic)
Local spread e.g. implantation of bacteria in the larynx
leading to hoarseness or bronchial spread leads to
bronchopneumonia
Systemic spread/milary TB, via:
Vein via left ventricle to whole body
Artery miliary spread within the lung

Pleural fibrosis & adhesions

Rupture of caseous lesion
 Miliary Tuberculosis:

when bacteria in the lungs enters

the pulmonary venous return to
the heart; the organisms
subsequently disseminate through
the systemic arterial system and
the lymphatic channels
Systemic miliary
tuberculosis
It produces multiple small yellow
nodular lesions in several organs.
Almost every organ in the body
may be seeded. Lesions resemble
those in the lung.
In the lungs there multiple lesions
either microscopic or small, visible
(2-mm) foci of yellow-white
consolidation scattered through the
lung parenchyma.
Miliary TB
Millet like grain.

Low immunity

blood or bronchial spread

 extrapulmonary tuberculosis
May appear in any of the organs or tissues seeded hematogenously (as
in milary TB) and may be the presenting manifestation of tuberculosis.
Lymph nodes/ tuberculous lymphadenitis : are the most frequent
form of extrapulmonary tuberculosis esp. in the cervical region
("scrofula").
Liver and spleen
adrenals
fallopian tube and endometrium
Epididymis and prostate
kidneys
meninges around the base of the brain (tuberculous meningitis),
Bone marrow
Vertebrae (Pott's disease). It collapses the spine and leads to paraspinal
"cold" abscesses in these patients may track along the tissue planes to
present as an abdominal or pelvic mass
Intestinal tuberculosis contracted by the drinking of contaminated
milk. In developed countries today, intestinal tuberculosis is more often
a complication of protracted advanced secondary tuberculosis,
secondary to the swallowing of coughed-up infective material.
TB adrenal gland TB epididymis
 Renal TB
Tuberculoma

TB Vertebra
(Potts
Spine)
Potts disease

Psoas abscess
TB Prostate gland TB intestine
Prognosis
The prognosis is generally good if infections
are localized to the lungs, except when they
are caused by drug-resistant strains or occur in
aged debilitated, or immunosuppressed
persons, who are at high risk for developing
miliary TB.
 TAKE HOME MESSAGES:
1. Mycobacterium tuberculosis is the causative organism of
tuberculosis (TB) in the lungs and elsewhere.
2. Mycobacterium tuberculosis gains access to the lung by
inhalation and causes pulmonary TB.
3. A granuloma in TB, termed a 'tubercle', is composed of activated
macrophages, Langhans giant cells with surrounding lymphoid
cells and fibroblasts with central caseation necrosis.
4. Primary tuberculosis is the form of disease that develops in a
previously unexposed, and therefore unsensitized, person.
5. Secondary (reactivation) tuberculosis arises in previously
exposed individuals when host immune defenses are
compromised, and usually manifests as cavitary lesions in the
lung apices.
6. Both progressive primary tuberculosis and secondary
tuberculosis can result in systemic seeding, causing life-
threatening forms such as miliary tuberculosis and tuberculous
meningitis.
7. The outcome of tuberculosis depends on the adequacy of the
host immune response.