2.

Tuberculosis

Pathogenesis
Pathology
Prof. Dr. Gabriela Jimborean

TB infection == TB disease
Infection is associated with TB disease - in 10%
Risk Factors who det. progression of infection
to active disease are multiple and depend on:
Abundance in BK of the source
Virulence ()
Intimacy and duration of the contact ()
Dicrease in immunological defense of the host

BK exposure

Events in naive host ( not

immunised)

Non immune defence

of the host
Superior Resp tract. (nose)
retains particles of sputum from
10 to 500 microni
Bronchi mucociliary clearance
Alveoli - BK phagocytosis by
alveolar macrophages
BK are trasported to the large
bronchi, trachea - cough elimination

Donaldson et al 2007, Bennett et al 2010

In-Vivo Measurements of Mucociliary and Cough Clearance

Natural Immunisation
BK

Nonimune defense

In 70% No Infection

Suitable

BK

Unsuitable defense or
repeted close contacts

Non specific
Immune
response

Ag BK

30% Primary TB infection

Specific immune
response

Unsuitable
Specific Immune response
5% Primary TB disease

Cellular immunity
development
+/- treatment

Specific
immune response
= Normal 95%
Latent infection
Recovery +

Latent infection
Variable interval

infection
Decreased immunity +/- overOver
BKBK
infection

Late secondary TB disease reactivation 5%

90%

Pathogenesis
BK multiplicate after deep penetration in the lung

1. Nonspecific inflammation (Congestion, edema, exudate fibrin

neutrophils, Eo, Ly)
(BK cannot be destroied)
2. Ag-presenting cells +LyT deliver chemotactic factors for Mo,
Mf, ly
3. Mf take the BK and transport them in the lymph vessels

and lymph nodes

3. Specific inflammation - primary TB Complex
Will be installed:

Delayed hypersensitivity type IV cell-mediated response Ly-Mf

(= Ag recognition + Reaction)
Protective cellular immunity Ly-Mf
(= Defense capability through effective BK
lysis and granuloma formation)

Primary TB Complex
1. Primary Afect

+ passing of the BK in the lymph

vessels and nodes
2. Hilar limph node
3. Spontaneous healing + fibrous
sequeles +Ca++ sleeping germs
Newly acquired reactivity stop the
germs multiplication + positive PPD
4. +/- Vascular Dissemination to other
organs (in immunocompromised
hosts) miliary TB
exprarespiratory TB

Sensibilisation and immune reaction

Under the Ag, TLy are activated, they sensitize +
blastic transformation -- more subsets of Ly

1. T Ly +immune memory+ longevity (LyT CD4)

2. T Ly secreting lymphokines (LyT CD4) (mediators that modulate IR)
CD4 T Ly several roles
- trigger the delayed hypersensitivity
- Mf activation and protective immunity
- Chemotactic factors
- INF- secretion - Tumor Necrosis Factor
secretion by the Mf

CD4 Ly

- T helper 1 cytokine-producer - INF- (role in

cell immunity for intracellular germs ex. BK)
- T helper 2 - IL 4, IL 5 cooperation with Ly B
and Ig production
CD8 T Ly - lymphotoxine - role in immunological
cytolysis = Ag cell recognition and target
destruction

Ag.
Presenting
cell

LyT

Ag BK
small
amount

Sensibilisation
Transforming

Memory Ly

Lymphokine producerLy
LyB
IL6

FTB
Blastic
transforming
of other
Ly

Increase Ag
information
Ly
Lymphokine releaser

AMf.F

INF FIMMf

Activation of Mf
Chemotactic F.
Mf, Ly, Mo

TNF
Activation of Mf, phagocytosis,
necrosis production

Granuloma
TB

Tissue lesions are the "price" to pay for

BK intracellular presence and
multiplication (Mf Ly produce BK
invaded cell destruction)
Immune response magnitude depends on:
- number BK
- intensity of awareness
- genetic control of immune response

Activated Mf (by lymphokines or by stimulating Ag)

become epithelioid and Langhans multinucleated giant
cells (rich in lysosomes, mitochondria, lytic enzymes)

Secrete cytokines that activated Mf:

TNF - has a protective role in infection by the activation of the
Mf cells, phagocytic necrosis and granuloma formation
If infection is large a great TNF- release -- hight toxic
effects (fever, fatigue, consumption, demineralization,

cachexia)
Interleukins - role in Ly activation, T, B, NK "Natural Killer"

Caseous Necrosis = Immunological mediated

cytolysis = Ly + Mf and Ac-dependent cell (N
killer) destroy target cell ( infected with BK)
Inside the granuloma
Anoxia
Acidosis
Toxic products of granuloma
Macrophages in cooperation with Ly
inhibits proliferation and make BK lysis

Liquefaction of caseation necrosis forms

cavities containing enormous numbers of TB
bacilli
Isolation of the germs inside the granuloma
prevents dissemination

If the Imun Response is modest

Bk

can survive in sleeping mode long time

inside granuloma
BK may be circulated to other sites with Mf
BK multiply and destroy tissue and make
extended necrosis

TB Granuloma
Granulomatous inflammatory
process

- Caseous necrosis (white yellow, acidic pH )

- 1-2 Langhans giant cells

(activated Mf)
- Epithelioid cell (activated Mf)

Around the periphery of the

granuloma
- T Ly

- Fibroblasts

- Collagen fibers
- some PMN

Inflammatory reactions can be very pronounced:

- perifocale pleuro-pulmonary congestion
(epituberculosis)
- extensive caseous necrosis by
Delayed Cell-mediated hypersensitivity
(PPD test shows the presence of cell hypersensibility)

Their moderation occurs when:

- effectively germs are destroied (with in Ag
stimulus)
- fibrogenetic reactions ( Ca +)
Healing = expression of installation of the

Protective cellular immunity

Primary TB Hilar and

paratraheal Adenopaty

Primary TB
Child with HIVinf./AIDS

Langhans giant cell

M. Tuberculosis colonies
Lwenstein Jensen

BK Microscopy
AFB - Ziehl Neelsen

Multinucleated
Langhans cell

Tb Granuloma

Right Hilar Adenopaty

Epituberculosis +
atelectasis by
compresion

Limph nodes perforation

and bronchial spread
Extended Necrosis with
primary cavitation

Cellular immunity in TB

Is protective:

Is relatively:

Prevents passage of the primary infection to manifest

disease
Prevents complications and dissemination
Provides resistance to other breakthrough BK
It does not fully exclude the disease when exist immunosupresive factors (repeated massive infection, risk F.)

Is a "superinfection"

conditioned by the persistence of infection in the body or

new "boosters" (to keep infection active by Ag stimulus)
Sterilization infection (rare in humans) leads to extinction
HSI, immunity and previous positive PPD test negativity

Cellular immunity in TB (2 components)

1). Natural immunity - by factors of resistance (LyT
and Mf native qualities) selected and genetically
transmitted, derived from the experience of previous
generations in contact with TB
2). Acquired Immunity - in the current generation
experience by:
- Recent contact with TB patients

- BCG vaccination
- Cross Immunization by infection with MNT (spread
in the external environment)

Tests of the cellular immunity

Tuberculinic skin test migration of the
activated cells
Quantiferon TB GOLD delivery in serrum
of the INF gama produced by the
activated TLy

Humoral immunity in TB
Development of Ig versus various bacillary Ag
Lack of protective role of humoral immunity in TB
But.....There is cooperation with cell immunity
Highlighting some Ab - humoral "markers" we
can see active disease in the early stages
Ex. TB meningitis

Pathology TB

Specific TB Inflammation and lesions

3 Components (exudative, necrotic, proliferative)

which importance depends on:

- size and virulence of infection

- location of the injury (serous, parenchyma)

- risk factors

- eficiency of the installed immunity

- treatment

1. Exudative processe
Serum extravasation (fibrin) + cells
The exudation

At the level of pleura, peritoneum, pericardum

Big amount even in the presence of a small no. of BK

Build during the maximum DHS periode = epituberculosis (congestion,

pleurisy, peritoneal reaction )

It may initially resolve when no necrosis occurred

By chronic evolution - Fibrin will be organized in connective fibrous tissue scars

2. Dystrophic lesions
1.

Simple dystrophy

2.

Tissue Necrosis + inflammatory cells

necrosis + BK necrosis
specific caseous necrosis

3. Proliferative lesions
Proliferation in

mesenchymal tissue

migrated cells from blood - Ly, Mo (Mf)

connective fibers

Proliferative granulative - fibrous

reaction and caseous necrosis are always associated

Confer specificity to the TB inflammation

-

Try to limit the extension of the lesions

TB granuloma(1)
-

Caseous necrosis (white - yellow, acidic pH )

1-2 Langhans giant cells (activated Mf)

- Epithelioid cell (activated Mf)
-

Around the periphery of the granuloma

- T Ly
- Fibroblasts

- Collagen fibers
- some PMN

TB granuloma (2)
Granuloma are avascular structures
In development:
They extend, confluence with neighboring nodes
tubers " follicles and produce extended lesions:
nodules, infiltrates, cavities
+ / - Dissemination

+ Sleeping bacilli persist in fibrous sequelae (with

reactivation potential)

TB Granuloma

TB granuloma in
lung

Normal lung

Differential diagnosis of TB granuloma

Leprae

Aspergillus

Sarcoidosis (without necrosis, no

confluence)

Foreign body Granuloma - silicon

Vegetal foreign body Granuloma

Bone necrosis + cazeum+ fibrous reactions

Spinal TB

Extended Necrosis with

infiltrates, noduli and
secondary cavitation, (left
uper lobe)

Extended Necrosis ( right uper lobe)

with infiltrates noduli and
(left uper lobe)

Cavitary TB , antracosis

Healed, with epitelium cavity after TB

Cavity with blood clot

Aspergiloma

Miliary TB

Miliary TB

Peritoneal miliary TB

Limph nodeTB

TB Orhiepididimitis

TB Orhiepididimitis

Renal cavitary TB

Subpleural Tuberculoma

TB Sequelaes + Calcium
deposition, emphysema

Necrosis, cavities

Pneumothorax in bilateral
cavitary TB

Primary right TB + gigant primary

tuberculoma

Primary right TB + hylar adenopaty + pleuritis

Primary right TB + hylar adenopaty +

pleuritis and epituberculosis

TB adenopathy compression on
bronchial spur

Bronchial fistula
Lymph node perforation in bronchus

Ganglio bronchial fistulae after primar TB

Pulmonary miliary TB

Peritoneal TB

The main features of primary TB

Predilection for younger ages

Strong hypersensitivity reactions associated

Always important involvement of the lymphatic

system

High potential for dissemination (even occult )

Spontaneous healing, except complicated shapes

BK persistence in post primary sequelaes with

possible secondary endogenous reactivation

Secondary TB

5% of the latent infected people (after the I episode)

By reactivating endogenous or exogenous overinfection

Occurs at different time after I TB (continuing the I TB

or after years / decades)

Predilection for adults

Satellite adenopathy missing

Lymphatic and hematogenous dissemination (possible

but not frequent)

Main organ involved - LUNG "pulmonary phthisis"

Extension by contiguity or canalicular

dissemination

Lesions have caseous necrotic aspect

Trend to cavitation
+ Limitation by fibrosis
(missing in immunosuppressed)

Progressive, chronic,evolution

with relapses and remissions

with worsening in every spurt

without spontaneous healing

with multiple complications

high fatality

Healing
does
In

not include sterilisation

most cases

Clinical

cure

Radiological
Bacteriological
Bioumoral

with persistence of sleep bacilli in sequelae

= Persistent infection (documented by PPD + +
after cured disease)

Extensive bilateral secondary cavitary

TB - extensive necrosis - caverns,
nodules of bronchogenic spread

Bilateral secondary cavitary TB

- Extensive necrosis

Chronic cavitary TB
right fibrothorax

Drained pneumothorax
+ subcutaneus emphysema

Bronchial infiltrative lesions in TB

Scar stenosis

Fistula (lymphnode
and bronchus)
anthracosis

Fistulae
TB granuloma
Membranes with KB

Scar stenosis

Classification of TB
Depending on the time of TB evolutionary cycle:
Primary TB

SecondaryTB

Depending on the location:

Respiratory

TB - pulmonary TB, pleuresy

Extrarespiratory TB - Joint TB, genital, digestive, etc
Respiratory and extrarespiratory

Extrarespiratory TB

Scapulohumeral TB

Limph nodes TB

Rib TB

Potts Disease
Necrosis +
paravertebral abscess

Potts disease
Lytic destruction of anterior
portion of vertebral body

TB Pericarditis
Skin TB

Renal TB

Hydroureter
+ multistage
stenosis

Tuberculous Orhiepididimitis

Intestinal TB

Addison s Diseases
Adrenal gland TB