Tuberculosis

Dr. T. Prasad
Contents
1 Pathogenesis and clinical features of
tuberculosis.
2. Classification of tuberculosis and atypical
mycobacterial infections.
4. Pathological features: both macroscopic and
microscopic
5. Association of tuberculosis with HIV infection.
6. Complications of tuberculosis
 Tuberculosis
• Introduction:
 Is the most important communicable disease in the world.
 It is important to differentiate between infection with
M. tuberculosis & the disease.
 Infection with M. tuberculosis – development of delayed
hypersensitivity to M.tuberculosis antigens.
 Can be detected by tuberculin (Mantoux) test.
- Test does not differentiate between infection and disease.
- False- negative reaction seen in certain viral infections,
sarcoidosis, Hodgkin disease, malnutrition, immunosuppressive
conditions, & in overwhelming active tuberculosis.
- False – positive reaction may be seen in infection by atypical
mycobacterium.
• The hall mark of tuberculosis :
- tubercle( small nodule) formation
- also called hard tubercle - nature of “Progressive
inflammation” (granulomatous inflammation).
- response to low bacillary mass( low dose x high virulence) in
a pt. with good resistance.
• Another type of response “Exudative inflammation”-
- response to large bacillary mass ( high dose x high virulence) in
a pt. with poor resistance.
• Other conditions – hard tubercle seen
- Mycotic inf, Tuberculoid leprosy, Syphilis, Brucellosis, Silicosis,
Foreign body granuloma & sarcoidosis.
• Diagnosis of TB :
- demonstration of TB bacilli in histopathology section & in
culture.
 Evolution of Tubercle
• After ingestion of bacilli :-
• At the end of 24hrs. --- Neutrophils are dominant cells.
• At the end of 48 hrs --- Macrophages digest all the bacilli which
has escaped neutrophils. as well as neutrophils.
• At the end of 2– 3 wks. – focus grown to form a tiny seed—like
nodule, greyish-white in colour &
0.5—2mm in diameter (Miliary tubercle), compact & avascular.
• Microscopy : Langhan’s type of giant cell at the centre,
surrounded by epitheloid cell macrophages, & around epitheloid
cells, is a mantle(Cuff/collar) of lymphocytes.
– Bacilli can be seen in the cytoplasm of epitheloid cells.
– Later caseation, then healing.
• Healing : by Resolution, Fibrosis( takes wks.), Calcification (yrs.), &
ossification.
Langhan’s giant cell lymphocytes Epitheloid cell
 Lympocytes
epitheloid cell

Langhans giant cell

Granuloma
Langhan’s Giant ce

caseation
necrosis
 PATHOGENESIS OF TUBERCLE

Infection acquired by inhalation of tubercle

bacilli.

A. EXOGENOUS
INFECTION
 Mechanism of evolution of a granuloma
Injury by M.tuberculosis
• Failure to digest the bacilli

• Weak acute inflammatory response

• Persistence of injurious agent

• T cell mediated immune Poorly digestible agent

Response

• Activation
• Of CD4+ T cells (release of Lymphokines IL-1 & 2,
Growth factors, IFN—γ, & IFN—α ),Monocyte chemotactic factor.

• Accumulation of tissue macrophages (increased recruitment

from circulation, local proliferation) .
 Macrophages activated by IFN-y

• Transformed to epitheloid cells, giant cells

•
• Granuloma formation.
Pathogenesis :
– Macrophages are the primary cells infected by M.tuberculosis.

 Early in infection - bacilli replicate, unchecked,

 Late in infection - T- helper cells response stimulates

macrophages to contain the proliferation of the bacteria.
Primary Pulmonary TB (0—3wks):--
 Bacteria enters macrophages by endocytosis, mediated
by mannose- receptors:

 mannose capped glycolipid present in the bacterial cell

wall- opsonized bacteria

 macrophages bind opsonized bacteria through

complement receptors .

 N-RAMP1(natural resistance associated macrophage

protein)- a gene, present in small population.
“ In this population”, disease may progress from this point
without development of immune response
 Pathogenesis – contd.
•Bacilli replicates within the phagosome by blocking fusion of phagosome with lysosome.
•Proliferation of bacteria in the pulmonary alveolar macrophages – bacteraemia --- seeding
of multiple sites.
•Despite bacteraemia, most pts. at this stage (< 3wks.) are asymptomatic

• Mannose-capped glycolipids

macrophage mannose receptor

• N-RAMP 1

M.bact.
endosomal manipulation: Bacteraemia

• maturation arrest, lack of acid pH. With multiple

I ineffective phago- lysosome formation. Sites seeding

 Pathogenesis– contd.
 3weeks– after:
• About 3 wks.after infection, T-helper1 cells –activate
macrophage to become bactericidal.
• T helper1 cells- activated with the help of MHC class ii (major
histocompatibility protein class ii) & in the presence of IL-12.
• TH1 cells –in LN & lung produce IFNy– critical mediator.
• INFy- stimulates iNOS (inducible nitric oxide synthetase), which
produces nitric oxide & free radicals.
• Activated macrophgaes produce TNF which recruit monocytes.
• Monocytes differentiate – epitheloid cells– granuloma
formation.
• Epitheloid cells – pale, pink cytoplasm & elongated ,vesicular
nucleus.
 .

• Morphoogy :
 Primary Tuberculosis : most affected organ:
- lung.
- Site – lower part of the upper lobe or upper part of
the lower lobe, usually close to pleura.
 Ghon’s focus – 1 -1.5cmm.gray-white, inflammatory,
consodilated area.
Micro: lesion consists of tuberculous granuloma
with caseous necrosis.
- In most cases center undergoes caseous necrosis.
 Ghon’s complex : consists of 3 components:
i)Pulmonary component: Ghon’s focus located
peripherally under a patch of pleurisy.
 Ghon’s complex(ctd)
• Ii) Lymphatic vessel component : lymphatics draining the lung
lesion – bacilli – develop beaded, miliary tubercle along the path
of hilar nodes.
• Iii) LN component : enlarged hilar & tracheo-broncheal LN.
Involved LN are matted & show caseation necrosis.
- Micro: extensive caseation, tuberculous granuloma & fibrosis.
 Nodal lesions are potential source of re- infection later.
 Radiologically detectable calcification (Ranke complex).
• Fate of Primary tuberculosis :
 Healing by fibrosis ,& in time undergo calcification &
ossification.
 In some cases, caseous material disseminated through bronchi
to other parts of same lung or the opposite lung, called
Progressive primary tuberculosis.
 Hematogenous spread – Primary Miliary tuberculosis.
 Fate of primary tuberculosis –contd.
 Spread along mucous & serous surfaces :
• from lung bacilli larynx during expectoration, or through
swallowed sputum to small intestine – tuberculous ulcers.
• Spread to pleura – tuberculous pleurisy with or without effusion,
pneumothorax or pyo-pneumothorax.

 Progressive primary tuberculosis can be arrested at any stage.

- Healing by fibrosis with or without calcification & seldom by
resolution.
 In lowered resistance & increased hypersensitivity of the host - the
healed lesion may get reactivated – bacilli lying dormant in acellular
caseous material
- activated & cause Progressive secondary tuberculosis.
- affects children more commonly.
Sequelae of primary complex
 Secondary tuberculosis
Reactivation of an old dormant infection is called
Secondary or Post-primary, or reinfection ,or chronic tuberculosis.
Infection may be acquired from :
 Endogenous source :reactivation of an existent healed primary
complex, or progressive primary tuberculosis.
 Exogenous source : reinfection from M. bacilli from outside.
:Lesion :
initial lesion :
-a small area of consolidation- <2cmm in diameter within 1 -2cmm
of the apical pleura
-sharply circumscribed, firm, gray-white to yellow in color with
variable amount of central caseation, & peripheral fibrosis.

Microscopy : coalescent tubercle with central caseation, Fibroblasts

at the periphery.
 Progressive secondary TB
Endogenous reactivation Exogenous fresh infection
 Fate of Secondary Tuberculosis
• 1.the lesion may heal with fibrous scarring & calcification.
• 2.lesion may coalesce together to form tubercular pneumonia &
produce Progressive Secondary tuberculosis, with pulmonary &
extra pulmonary involvements :
– i) Fibrocaseous TB: in elderly & immunosuppressed pt–
expansion of apical lesion – evacuation of caseous material into
bronchus.
 Grossly: cavity is spherical with thick fibrous wall, lined by
yellowish, caseous, necrotic material & the lumen is traversed
by thrombosed blood vessels. Around the wall of cavity is seen
foci of consolidation. The overlying pleura may be thickened.
 Micro : cavity wall shows eosinophilic, granular, caseous
material, which may show foci of calcification. Widespread
coalesced tuberculous granulomas are seen. Outer wall of
cavity shows fibrosis.
 Secondary tuberculosis:
A. Fibrocaseous tuberculosis

• Epithelioid cells

Firoblastic Langhan’s
proliferation giant cell
Lympho cytes
Caseation
necrosis

Fibrocaseous tuberculosis showing wall of cavity

 Fate of secondary TB
• Erosion of blood vessels result in hemoptysis.
• ii) inadequate T/t--- dissemination through airways, lymphatics,
or vascular system – Miliary TB .
• Lesions are either microscopic, or small, visible (2mm) foci
of yellow – white consolidation scattered through the lung
parenchyma.
• Milary lesions coalesce – total consolidation of large area
or even whole of lobe of lung --- progressive disease ---
- pleural effusion,
- tuberculous empyema, or
- obliterative fibrous pleuritis develop.
• Micro : lesions show the structure of granuloma with
minute areas of caseation necrosis.
•
• .
 Fate of secondary TB
• Iii) Endobronchial, endotracheal, & laryngeal TB :
develops when infective material is spread either through lymphatic
channels or from expectorated Infected material.
• Micro : lesions show exudative reaction with oedema, fibrin deposit,
polymorphs, & monocytes.
- Numerous tubercle bacilli can be demonstrated in the exudates.
• The secondary progressive TB possess the following
morphological peculiarities :
– 1) the initial lesion is subapical,
– 2) fibrosis is a prominent feature & the lesion tends to be
chronic,
– 3) the involvement of hilar LN is not conspicuous & spread
of infection occurs from the focus in the lung & not from
that in LN,
– 4) Miliary TB & tuberculous meningitis are infrequent.
 Exudative inflammation
• The infection resolves quickly & has some features of acute
inflammation.

• Characterized by oedema fluid, fibrin, neutrophils ,&

macrophages.

• Quick & well marked caseation , with large number of bacilli.

• At the margins of large caseous area a few well- formed

tubercles may be found.

• Such lesions are seen in serous membranes, particularly in

tuberculous meningitis, & HIV infection; acute caseous
pneumonia & tberculous bronchopneumonia.
Sputum: AFB positive
 Diagrammatic
representation of the
many patterns of
secondary
tuberculosis, ranging
from initial apical
localization to miliary
dissemination to
isolated involvement
of an organ (Kidney)
Mycobacterium Avium-Intracellulare Complex (MAC):
separate species, but the infections they cause are so similar.
common in soil, water, dust, and domestic animals.
Clinically significant infection with MAC is uncommon except among people
with AIDS and low levels of CD4+ lymphocytes (<60 cells/mm3).
 Extrapulmonary manifestations of
tuberculosis
Site Clinical manifestations
Central nervous system
Meninges Acute or chronic meningitis (basal
infiltrate)
Cerebral cortex Tuberculoma- headache, seizures
Pericardium Acute pericarditis (fever, chest pain);
chronic pericarditis (cardiovascular
compromise)
Site Clinical manifestations
Skeletal Osteomyellitis, arthritis
Genitourinary tract
Renal Dysuria, flank pain

Male genital Tender scrotal mass, draining

sinus
Female genital Menstrual disorders, abdominal
pain
Site Clinical manifestations
Gastrointestinal tract
Oral cavity Nonhealing ulcer of tongue or
oropharynx
Esophagus Stricture, tracheoesophageal
fistula
Stomach Ulcer, diffuse thickening
Small intestine Perforation, obstruction,
enteroenteric or entrocutaneous
fistula, hemorrhage,
malabsorption
Large intestine Abdominal pain, anorexia,
diarrhea, obstruction, hemorrhage
Anus Ulcer, fistula, abscess
Site Clinical manifestations
Liver Granulomatous hepatitis
Peritoneal cavity Peritonitis (insidious or acute
onset)
Lymph nodes Lymphadenitis (draining cervical
or supraclavicular nodes)
Skin Ulcers, nodules, abscesses
Larynx Erythema, ulcers, exophytic
masses
Tuberculous bronchopneumonia: Lung
 Pott’s spine
(one Vertebra has been detroyed and replaced by large caseous
mass which extends into the soft tissues).
Desired Learning Outcomes
On completing this lecture, the students should be able to:
1. classify tuberculosis.
2. describe the differences between the primary and secondary
tuberculosis.
3. describe the pathogenesis and clinical features of
tuberculosis and atypical mycobacterial
infections.
4. describe the macroscopic and microscopic features of
tuberculosis of the lungs.
5. discuss its association with HIV and other emerging
infections.
6. describe the process of healing in primary and secondary
tuberculosis.
7. describe the complications of tuberculosis.