Pathology of Tuberculosis

Presented by - Batch A
ETIOLOGY AND PATHOGENESIS
 TB

● Tuberculosis is a chronic pulmonary and systemic disease caused

most often by Mycobacterium tuberculosis and is the leading
cause of infectious death worldwide.
● Mycobacteria are slender gram positive aerobic rods that grow in
straight and branching chain.
● Have mycolic acid in their cell wall imparting them acid fastness.
 Mode of Transmission
● Humans with active Tuberculosis who release Mycobacteria into
sputum.
● Drinking of unpasteurised milk.
● Innoculation of strains
● Transplacental
 Burden

● In 2018, about 10 million people developed TB worldwide.

● 1.3 Million deaths without HIV and 300,000 in people with HIV.
● Mortality rate is falling by 3% per year.
● India is the highest TB burden country in terms of absolute
number of incident cases.
● One-fourth of total global burden
 ● Poverty
● Overcrowding
● Chronic debilitating
illness
● Tobacco Consumption
RISK FACTORS ● Malnutrition
● Alcoholism
● Immunosuppression
● Crowded areas like
prison, shelters
● Lack of awareness
● Female gender
● Unpasteurised milk
 TYPES

ACTIVE TUBERCULOSIS LATENT TUBERCULOSIS

● Most infections are acquired by ● Viable organism may remain

person to person transmission of dormant in such lesions for decades,
airborne organism from an active ase rendering person asymptomatic.
to a susceptible host. ● May have fever, pleural effusion or
● Presence of bacteria with syptomatic small lung nodule.
presentation is active TB. ● If immune defenses are lowered, the
infection may be reactivated,
producing communicable and
potentially life threatening disease.
 TYPES

PRIMARY TUBERCULOSIS SECONDARY TUBERCULOSIS

● Usually always Pulmonary type. ● Pattern of disease that arises in

● Inhaled bacilli invade distal lung previously sensitized hosts.
● Progressive pulmonary tuberculosis
airspaces to cause parenchymal
● Milliary lung TB
infection.
● Characteristic chronic granulomatous EXTRAPULMONARY TUBERCULOSIS
infection with both caseating and
● Endobronchial, laryngeal, Endotracheal
non- caseating type of granulomas. TB
● Laghans giant cells are characteristic ● Systemic Milliary Tuberculosis
findings. ● Pott Disease
● Intestinal Tuberculosis
NATURAL HISTORY OF DISEASE
PATHOGENESIS
 PATHOGENESIS

● Infection by M. tuberculosis proceeds in steps, from initial

infection of macrophages to a subsequent Th1 response that both
contains and causes tissue damage.
● Early in infection, M. tuberculosis replicates unchecked in
macrophages and later the cell response stimulates macrophages
to contain the proliferation of bacteria.
Entry into macrophages

● Entry occurs via

mannose binding
lectin and the type 3
complement receptor
(CR3) on the surface
of the phagocyte.
Replication in macrophages

● Inhibits the maturation of

phagosome
● Blocks formation of
phagolysosome by recruiting
Coronin protein to the
membrane of phagosome.
● Coronin activates the
phosphatase calcineurin,
leading to inhibition of
phagosome-lysosome fusion.
● Allows bacterium to
proliferate unchecked within
the vesicle
● In <3 weeks, bacteria
proliferates resulting in
bacteremia and seeding at
multiple sites.
Innate Immunity
● Multiple Pathogen
associated molecular
patterns (PAMPs)
generated by M.
tuberculosis are
recognised by innate
immune system.
● Mycobacterial
lipoarabinomannan bins
to TLR2
● Unmethylated CpG
nucleotides binds to
TLR9.
● Initiate innate and
adaptive immune
response.
Th-1 Response
● 3 weeks after infection,
Th1 response mounts.
● Mycobacterial antigen
drained into lymphatics
are displayed to T-cells.
● Differentiated is mediated
by IL-12 and IL-18,
produced by antigen
presenting cells.
● Stimulation of TLR2 by
mycobacterial ligand
stimulates IL12 release by
dendritic cerlls.
Th1 mediated
macrophage activation
and killing of bacteria
● Th1 cells in lymph nodes
and lungs produce IFN-
gamma, which crritically
activates macrophages.
● IFN-gamma stimulates
fusion of phagolysosome in T
infected macrophages and
exposes bacteria to lethal
acidic, oxidizing
environment.
● It stimulates experssion of
inducible NO synthase
which produces NO, causing
free radical damage.
● Thirdly, IFN-gamma
mobilises defensins against
bacteria.
Granulomatous Inflammation
and tissue damage

● Th1 response orchestrates

formation of granuloma and
caseous necrosis.
● Macrophages activated by IFN-
gamma differentiate into
epitheloid histiocytes that
aggregate to form granuloma.
● Some epitheloid cells fuse to
form Langhans type Giant cells.
● Progression of disease,
immunocompromised state,
ageing promotes necrosis.
● Secreted TNF and chemokines
recruit monocytes.
● Patients of Rheumatoid arthritis
treated with TNF antagonist
have increased risk of TB
infection.
Granuloma
 Fate of Granuloma

The fate of a granuloma is variable:

i) The caseous material may undergo liquefaction and extend into surrounding soft tissues,
discharging the contents on the surface. This is called cold abscess although there are no pus cells
in it.

ii) In tuberculosis of tissues like bones, joints, lymph nodes and epididymis, sinuses are formed and
the sinus tracts are lined by tuberculous granulation tissue.

iii) The adjacent granulomas may coalesce together enlarging the lesion which is surrounded by
progressive fibrosis.

iv) In the granuloma enclosed by fibrous tissue, calcium salts may get deposited in the caseous
material (dystrophic calcification) and sometimes the lesion may even get ossified over the years.
 Host Susceptibility to the disease

● AIDS is the greatest risk for progression to active cases.

● Immunosuppresion due to Glucocorticoids therapy, TNF
inhibitors, transplant carry risk as do malnutrition and renal
failure.
● Inherited mutations in Th1 response, loss of IL12 receptors Beta-1
protein etc
● Atypical infection due to avirulent Mycobacterium avium complex
post attenuated BCG vaccination.
Tuberculosis: Morphology
 • Inhaled bacilli implant in the distal airspaces

Primary of the lower part of the upper lobe or the

upper part of the lower lobe
• A 1- to 1.5-cm area of gray-white
Tuberculosis inflammation with consolidation emerges,
known as the Ghon focus
• Center of this focus undergoes caseous
necrosis.
• Tubercle bacilli, either free or within
phagocytes, drain to the regional nodes,
which also often caseate. This combination
of parenchymal lung lesion and nodal
involvement is referred to as the Ghon
complex
• Ghon complex undergoes progressive fibrosis,
often followed by radiologically detectable
calcification
• Granulomas are usually enclosed within a
fibroblastic rim punctuated by lymphocytes.
 Secondary
Tuberculosis • Initial lesion is usually a small focus of
consolidation, less than 2 cm in diameter

• Sharply circumscribed, firm and gray-white to

yellow in color, and have variable degrees of
central caseation and peripheral fibrosis

• The active lesions show characteristic

coalescent tubercles with central caseation

• Localized, apical, secondary pulmonary

tuberculosis may heal with fibrosis either
spontaneously or after therapy
 Characteristic tubercle at low
magnification (A) and high magnification
(B) shows central granular caseation
surrounded by epithelioid and
multinucleate giant cells. This is the
usual response in people who have
developed cell-mediated immunity to the
organism.
(C) Occasionally, even in
immunocompetent patients, tubercular
granulomas may not show central
caseation; hence regardless of the
presence or absence of caseous
necrosis, use of special stain for acid-fast
organisms is indicated when granulomas
are present.
(D) In this specimen from an
immunocompromised patient,
macrophages with large numbers of
mycobacteria are seen (acid-fast stain).

The morphologic spectrum of tuberculosis

 Progressive pulmonary tuberculosis

● apical lesion expands into adjacent lung and eventually erodes

into bronchi and vessels
● evacuates the caseous center, creating a ragged, irregular cavity
that is poorly walled off by fibrous tissue. Erosion of blood vessels
results in hemoptysis.
● cavities, now free of inflammation, may persist or become fibrotic
Miliary pulmonary disease
● organisms draining through lymphatics enter the
venous blood and circulate back to the lung
● Individual lesions are either microscopic or small,
visible (2-mm) foci of yellow-white consolidation
scattered through the lung parenchyma
● Miliary lesions may expand and coalesce, resulting
in consolidation of large regions
● With progressive pulmonary tuberculosis, the
pleural cavity is invariably involved, and serous
pleural effusions, tuberculous empyema, or
obliterative fibrous pleuritis may develop.
Endobronchial, endotracheal and laryngeal tuberculosis

● develop by spread through lymphatic channels or from

expectorated infectious material.The mucosal lining may be
studded with minute granulomatous lesions
Systemic military tuberculosis and intestinal tuberculosis

● bacteria disseminate through the systemic arterial system. Miliary tuberculosis is most
prominent in the liver, bone marrow, spleen, adrenals, meninges, kidneys, fallopian
tubes, and epididymis
● intestinal tuberculosis contracted by the drinking of contaminated milk is common in
countries where bovine tuberculosis is present and milk is not pasteurized.
● intestinal tuberculosis is more often caused by the swallowing of coughed-up infective
material in patients with advanced pulmonary disease.
● organisms are seeded to mucosal lymphoid aggregates of the small and large bowel,
which then undergo granulomatous inflammation that can lead to ulceration of the
overlying mucosa, particularly in the ileum. Healing creates strictures.
TUBERCULOSIS
CLINICAL FEATURES
CLINICAL TUBERCULOSIS
PRIMARY TUBERCULOSIS SECONDARY TUBERCULOSIS

● This occurs in non-immune ● This occurs in host who is

host. immune to M.tuberculosis.
● Primary TB is a form of ● Secondary TB is the pattern
disease that develops in of disease that arises in a
previously unexposed & previously sensitised host
therefore unsensitized person.
CLINICAL TUBERCULOSIS
PRIMARY TUBERCULOSIS SECONDARY TUBERCULOSIS

● Source of organism is ● It appears many years after

exogenous the initial infection, usually
when host resistance is
weakened.
● It most commonly stems from
reactivation of latent infection.
SYMPTOMS
CONSTITUTIONAL SYMPTOMS

● Malaise
● Anorexia
● Weight loss
● Fever-low grade and remittent(appear late each afternoon and
then subside)
● Night sweats
● Fatigue
PULMONARY SYMPTOMS

● Dyspnea
● Chest tightness
● Non-productive cough
● Mucopurulent sputum with Hemoptysis
● Chest pain
 Extrapulmonary symptoms

CARDIAC
Pericarditis and pericardial effusion

EYES
Choroiditis

GENITOURINARY
Pyuria and hematuria, frequency, flank pain, dysuria, nocturia
Extrapulmonary symptoms

GIT
Abdominal pain and GI upset(peritoneal TB)

SKIN
Jelly-like nodular rash(lupus vulgaris) and possible erythema
nodosum due to hypersensitivity reaction to infection.
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