2. Objectives
1. Study causative agent of TB and route of spread/infection
2. Classify TB into primary and secondary subtypes and study their
pathogenesis and clinico-morphological pattern
3. List complications of secondary TB and Miliary tuberculosis
4. Identify the relation between TB and immunocompromised like
patients with HIV/AIDS
3. Tuberculosis (TB)
Epidemiology
• Communicable disease
• Any age occurs in both sexes
• Pulmonary tuberculosis is commonest and a leading cause of death
globally
• Extra pulmonary tuberculosis sites; includes, intestine, lymph node, bone,
skin, kidney and genital organs
• Most are infected but do not develop the disease depending upon host
immune response
4. Causative Agents of Tuberculosis
Mycobacterium tuberculosis
Common human pathogenic strains are;
M. tuberculosis hominis
M. tuberculosis bovis (acquire from unpasteurized milk)
Atypical mycobacteria
Mycobacterial species other than mycobacterium tuberculosis
M. avium-intracellulare in immunocompromised hosts
M. scrofulaceum causes cervical lymphadenopathy
5. Mode of Transmission
Inhalation
Inhalation of fresh cough droplets or dried sputum of patient suffering from
pulmonary TB
Ingestion
results from self swallowing of infected sputum or bovine TB bacilli in
infected cows milk, leads to tonsillar or intestinal TB
Inoculation
of organism into the skin, rarely from infected autopsy specimen
Trans-placental route
rarely, from infected mother to fetus
6. Spread of Tuberculosis
Local spread
macrophages carrying M. bacilli into surrounding tissues
Lymphatic spread
into the regional lymph nodes
Haematogenous spread
tuberculous bacteremia producing miliary tuberculosis involving multiple organs
By natural passages
from lung lesions into pleura, transbronchial spread to adjacent lung segments,
tuberculous salpingitis into peritoneal cavity and swallowing of infected sputum into
intestinal tract
8. Primary Pulmonary Tuberculosis
Primary/Ghon Complex
Initial focus of infection a small subpleural granuloma about 10 mm in
diameter with caseous granulomas in draining hilar lymph nodes
Fibrocalcific nodule
Primary lesion get organized, leaving a fibrocalcific nodule, however,
TB bacilli may persist as viable organism for years
Miliary TB
In immunocomprised patient primary pulmonary TB would leads to
miliary TB
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9. Secondary Pulmonary Tuberculosis
Reactivation of old primary infection or by reinfection
Lesions nearly always located in the lung apices, sometimes
bilaterally, and are about 30 mm in diameter, cavitation can
occur at clinical presentation.
Histologically
Chronic caseous granulomatous inflammation
Progression of disease
Depends on the balance between host sensitivity and organism
virulence
Most lesions, converted to fibrocalcific scars
11. Pathogenesis of Granuloma Formation
• Type IV hypersensitivity or delayed type hypersensitivity as the
reaction takes several days to develop. Unlike the other types, it is
not antibody-mediated but rather is a type of cell-mediated response.
• The term delayed is used to differentiate a secondary cellular response,
which appears 48-72 hours after antigen exposure, from an immediate
hypersensitivity response, which generally appears within 12 minutes of
an antigen challenge. These reactions are mediated by T cells and
monocytes/macrophages rather than by antibodies. They are also
termed type IV hypersensitivity reactions.
• CD4+ Th1 helper T cells recognize antigen in a complex with the MHC
class II major histocompatibility complex on the surface of antigen-
presenting cells. These can be macrophages that secrete IL-12, which
stimulates the proliferation of further CD4+ Th1 cells. CD4+ T cells
secrete IL-2 and interferon gamma, inducing the further release of other
Th1 cytokines, thus mediating the immune response. Activated CD8+ T
cells destroy target cells on contact, whereas activated macrophages
produce hydrolytic enzymes and, on presentation with certain
intracellular pathogens, transform into multinucleated giant cells.
Delayed hypersensitivity reactions are inflammatory reactions initiated
by mononuclear leukocytes.
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12.
13. Extrapulmonary or Isolated Organ Secondary Tuberculosis
• Dissemination of TB outside of lungs can lead to TB of tonsils, intestine,
CNS, Kidney, bone , skin and genital organs
Miliary Tuberculosis:
• May be a consequence of either primary or secondary TB when resistance
to infection is particularly poor, a "miliary" pattern of spread can occur in
which small millet seed (1-3 mm) sized granulomas develops either in lung
or in other organs
• Mantoux test is frequently negative
14. Cut surface of spleen shows numerous gray-
white granulomas in Miliary tuberculosis
15. Primary Pulmonary TB
Gross morphology
• Involved area swollen, grey white,
foci of cheesy white caseous
necrotic material
• Lymph node enlarged, cut surface
gray white, shows cheesy white
caseous necrotic material
Ghon complex:
• Gray-white focus under the pleura
in lower part of upper lobe
• Hilar lymph nodes with caseation
3/1/2018
17. Microscopic Features in Tuberculosis
At active sites both caseating and non-caseating granulomas
present comprising of:
- Central caseation necrosis
- Surrounding by epithelioid cells
- Circumferential collar of lymphocytes
- Enclosing rim of fibroblasts ( in old lesions)
- Langhans type of Giant cells, with multiple
nuclei arranged in a horse-shoe pattern
Healed lesion fibrocalcifed
20. Staining Tuberculous Bacilli
Acid Fast : Complex lipid in
bacterial cell wall binds with
Ziehl-Neelsen stain but resists
decolraization by Sulfuric Acid
thus bacilli appear red
21. Tuberculosis and HIV infection
• In the absence of appropriate
T cell-mediated immunity
granulomatous host
response does not occur
• The intracellular bacteria
persist and even proliferate
within the macrophages
Mycobacterium avium infection
in a patient with AIDS, showing
clumps of acid-fast organisms
22. Clinical Manifestations
Pathogenesis
Systemic manifestations are produced by TNF- alpha and IL -1 released
from activated macrophages
Clinical Features
• Fever (low grade, remittent, appear late each afternoon and then subside)
• Night sweats
• Malaise
• Anorexia
• Cough, first mucoid, later purulent and bloody sputum
• Pleuritic chest pain
23. Mantoux Test (Tuberculin Skin Testing)
• 0.1ml of tuberculin purified protein derivative (PPD) is injected
intracutaneously on the forearm
• In 48 to 72 hours, a positive reaction, marked by an area of red induration
over 10 mm in size in non-immunocompromised persons
• Basis of test, type VI hypersensitivity reaction(If a person had previous TB
infection, then sensitized lymphocytes react to another encounter with TB
antigens)
• Anergy, or negative mantoux test in persons infected with TB, can occur in
immunocompromised persons, or it may even occur in persons newly
infected with TB, or in persons with miliary TB
24. Lab Diagnosis
Blood Complete Picture ; ESR is increased
Sputum Examination: Smears stained with Z-N examined, under oil immersion lens,
bacilli appear as red rods
Fluorescence microscopy; auramine stained bacilli, easier to screen
Sputum Culture: on L.J medium after 4-6 weeks grey, rough and raised colonies
Bectec technique: Radioactive techniques, detect Mycobacteria in a shorter period
Polymerase Chain Reaction: mycobacterial DNA detection
Serological tests: By Enzyme Linked Immunosorbent Assay (ELISA)
FNA and Biopsies of Pleura, Lymph nodes, Lung and other tissues
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26. Learning Outcomes
1. Identify the causative agents of TB and their routes of
infection
2. Explain the pathogenesis of Tuberculosis
3. Classify TB into primary and secondary subtypes
4. Describe primary complex of TB and know sites and
morphology of secondary TB and its complications
5. Correlate pathogenesis to clinical presentation of T.B.
6. Identify the relation between TB and HIV infection
The sequence of events in primary pulmonary tuberculosis, commencing with inhalation of virulent M. tuberculosis and culminating with the development of cell-mediated
immunity to the organism. A, Events occurring in the first 3 weeks after exposure. B, events thereafter. The development of resistance to the organism is accompanied by the appearance of
a positive tuberculin test. Cells and bacteria are not drawn to scale. iNOS, inducible nitric oxide synthase; MHC, major histocompatibility complex; MTB, M. tuberculosis; NRAMP1,
natural resistance-associated macrophage protein
Is useful in countries where the incidence of tuberculosis is low but not helpful in BCG vaccinated persons who have a positive skin test.
The TB skin test is based upon the type 4 hypersensitivity reaction. If a previous TB infection has occurred, then sensitized lymphocytes can react to another encounter with TB organism antigens
For the TB skin test, 0.1ml of tuberculin purified protein derivative (PPD) is injected intracutaneously to form a small wheal, typically on the forearm. In 48 to 72 hours, a positive reaction is marked by an area of red induration over 10 mm in size in non-immunocompromised persons.
Anergy, or absence of PPD reactivity in persons infected with TB, can occur in immunocompromised persons, or it may even occur in persons newly infected with TB, or in persons with miliary TB.
