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Tuberculosis: Pathophysiology and Diagnosis

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Title: Tuberculosis: Pathophysiology and Diagnosis


1
TuberculosisPathophysiology and diagnosis
Dr. Aditya Jindal Interventional Pulmonologist
Intensivist Jindal Clinics SCO 21, Sec 20D,
Chandigarh DM Pulmonary and Critical Care
Medicine (PGI Chandigarh), FCCP
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Course of TB infection
4
Types of TB
  • Primary tuberculosis
  • is a form of disease that develops in a
    previously unexposed and therefore unsensitized
    person
  • Secondary tuberculosis
  • is the pattern of disease that arises in
    previously sensitized or infected host.

5
Primary TB
  • Infection of an individual who has not been
    previously infected or immunized.
  • The inhaled bacilli implant in the distal
    airspaces of lower part of upper lobe or upper
    part of lower lobe close to the pleura
  • As sensitization develops, a gray-white
    inflammatory consolidation is formed? Ghon focus

6
Sites of Primary TB
  • Most common - Lungs
  • Other sites Tonsils, adenoids
  • Site of BCG
    vaccination
  • GIT ileum, colon etc
  • GUT

7
Ghons complex
  • Consists of 2 components
  • Pulmonary component
  • lesion in the lung (Ghon focus or primary focus)
  • 1-2cm solitary area located peripherally in the
    subpleural focus in the lower part of upper lobe
    or upper part of lower lobe
  • Micro the lung lesion show tuberculous granuloma
    with caseous necrosis
  • Lymphatic component
  • lymphatics draining lung lesion containing
    phagocytes with M. tuberculosis bacilli

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Ghon complex
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Fate of Primary complex
  • Heal by fibrosis? calcification
  • Progressive primary tuberculosis
  • Primary miliary tuberculosis

10
Secondary TB
  • The infection of an individual who has been
    previously infected or sensitized
  • The infection may be acquired from
  • Endogenous source ? reactivation of dormant
    primary complex
  • Exogenous source

11
Pathological lesions of Secondary TB
  • The initial lesion is a small focus of
    consolidation of lt2cm in diameter within 1 to 2cm
    of apical pleura
  • Gross sharply circumscribed, firm, gray white to
    yellow with variable amount of central caseation
    necrosis
  • Micro coalescent tuberculous granulomas with
    central caseation necrosis.

12
Fate of secondary TB
  • The lesion may heal with fibrous scarring and
    calcification
  • Fibrocaseous tuberculosis (progressive pulmonary
    TB )
  • Tuberculous caseous pneumonia
  • Miliary tuberculosis

13
Pathology of TB
  • Granuloma formation is the hall-mark of pathology
    of TB
  • Granuloma is a
  • i. Rounded tight collection of chronic
    inflammatory cells
  • ii. Central Caseous necrosis
  • iii. Active macrophages - epithelioid
    cells
  • iv. Outer layer of lymphocytes
    fibroblasts
  • v. Langhans giant cells joined
    epithelioid cells

14
TB Pathology
  • Bacterial entry
  • T Lymphocytes.
  • Macrophages.
  • Epithelioid cells.
  • Proliferation.
  • Central Necrosis.
  • Giant cell formation.
  • Fibrosis.

15
Granuloma Histopathology
16
Caseation necrosis
17
Causes of granuloma formation
  • Tuberculosis
  • Other mycobacterial infections, Leprosy
  • Bacterial infections Brucellosis
  • Other infections Fungal, viral, protozoal
  • Non-infectious causes
  • - Sarcoidosis
  • - Foreign bodies
  • - Lymphomas

18
Miliary TB
  • Occurs when organisms drain through lymphatics
    into? lymphatic ducts? venous return on the right
    side of heart? pulmonary arteries
  • Individual lesions are either microscopic or
    small, visible (2mm) foci of yellow-white
    consolidation scattered through the lung
    parenchyma (resembling millet seeds)
  • Micro the lesion shows structure of granuloma
    with minute areas of caseous necrosis.

19
Miliary TB
20
Course of TB infection
21
Tuberculosis
  • Diagnosis

22
  • Clinical Features
  • Sputum Examination
  • Chest Radiology
  • Bronchoscopy
  • Mantoux test
  • Indirect laboratory tests

23
Clinical Symptoms
  • Prolonged fever, malaise, weakness, wt. loss etc.
  • Pulmonary Cough, sputum, haemoptysis
    persistent
  • Lymphadenopathy, organ enlargement, others

24
  • Clinical Features
  • Sputum Examination
  • Mantoux test
  • Chest Radiology
  • Bronchoscopy
  • Indirect laboratory tests

25
Sputum examination
  • Smear examination (Sputum, other secretions)
  • Auramine- Rhodamine staining
  • Culture of material/ tissues

26
Myco-bacteria
  • Myco (fungus like) Bacterium (bacteria)
  • Ability to resist decolourization by a weak
    mineral acid after staining with an aryl-methane
    dyes (acid-fastness)
  • Slender, straight or slightly curved, rod shaped
  • Length 2-4 u, Breadth 0.2-0.8 u
  • Occur singly, in pairs or small groups
  • Long, filamentous, club-shaped (rarely branching)

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MYCOBACTERIAL DEMONSTRATION
  • Smear Easiest, quickest
  • Requires gt 10000 AFB/ml
  • Sensitivity 50-60
    Specificity High
  • Culture More sensitive 10 AFB/ml
  • Traditional 6-8 wks
  • Septi Chek Biphasic High
    yield
  • Radiometric BACTEC
  • Others
  • Animal pathogenicity
  • Antimicrobial sensitivity

28
M tb in sputum smear
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  • Rapid culture methods
  • BACTEC system
  • MycobactGrowth Indicator Tube(MGIT)
  • MB/BacT system
  • Septi-chek
  • ESP culture system
  • Microscopic observation of broth/slide cultures

31
M tb Colonies on culture (LJ medium)
32
  • BACTEC System
  • Radiometric method
  • 14C labelled palmitic acid added to liquid 7H12
    medium
  • Detects MTB by metabolism rather than growth
  • 14CO2 produced detected
  • Growth index(GI) measured
  • Results available in 7-14 days (87-96)

33
  • MGIT
  • Automated system
  • Capable of analyzing 960 specimens
  • Metabolism of MTB produces O2
  • Fluorescence of dye with oxygen measured
  • Results available in 7-14 days
  • Cost effective for high load micro labs

34
  • Clinical Features
  • Sputum Examination
  • Chest Radiology
  • Bronchoscopy
  • Mantoux test
  • Indirect laboratory tests

35
Chest radiology
  • I. Chest Upper Lobes/Diffuse miliary
  • Infiltrates/Exudates/Fibrosis
  • Multiple, thin walled cavities
  • Lymphadenopathy,
    Pl.effusion
  • II. Others Enlargement of organs
  • Erosions/Effusions
  • Caseations/collections

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Role of Chest X-ray
  • No chest X-ray pattern is absolutely typical of
    TB
  • 10-15 of culture-positive TB patients not
    diagnosed by X-ray
  • 40 of patients diagnosed as having TB on the
    basis of x-ray alone do not have active TB

X-ray is unreliable for diagnosing and monitoring
treatment of tuberculosis
41
  • Clinical Features
  • Sputum Examination
  • Chest Radiology
  • Bronchoscopy
  • Mantoux test
  • Indirect laboratory tests

42
Role of bronchoscopy
  • Valuable in early diagnosis of strongly suspected
    sputum-negative TB
  • Diagnosis of endobronchial TB/miliary TB
  • TBLB yield is greater (82) than BAL (26)
  • TBNA has a role in mediastinal lymph nodal
    tuberculosis with negative sputum smears

43
ESR?
  • NO ROLE IN DIAGNOSIS

44
  • Clinical Features
  • Sputum Examination
  • Chest Radiology
  • Bronchoscopy
  • Mantoux test
  • Indirect laboratory tests

45
Tuberculin (Mantoux) Test
  • Infection with mycobacterium tuberculosis leads
    to delayed hypersensitivity reaction which can be
    detected by Mantoux test
  • About 2 to 4 weeks after infection
  • Intracutaneous injection of purified protein
    derivative (PPD) of M.tuberculosis
  • Induces a visible and palpable induration that
    peaks in 48 to 72 hours

46
How to do the test?
  • Sub cutaneous
  • Weal formation
  • Itching no scratch
  • Read after 72 hours
  • Induration size.
  • 5-10-15mm

47
Positive test
48
Interpretation
  • Induration less than 5 mm gt no exposure to
    tubercular bacilli
  • Induration between 5-9 mm gt this can be due to
    atypical mycobacteria or BCG vaccination. It may
    suggest infection in immunocompromised children
    such as HIV infection or other immunosuppression
  • Induation 10 mm or more gt in a child with
    symptoms of tuberculosis should be interpreted as
    tubercular disease

49
Clinical significance
  • Denotes infection
  • Does not differentiate infection from active
    disease
  • A strongly positive Mantoux can support a
    clinical diagnosis
  • Better negative than positive predictive value
  • Cut-off for a positive test?

50
  • Clinical Features
  • Sputum Examination
  • Chest Radiology
  • Bronchoscopy
  • Mantoux test
  • Indirect laboratory tests

51
Indirect Tests
  • Biochemical tests
  • LDH, Proteins
  • Adenosine Deaminase
  • Bromide Partition Test
  • Gas Chromatography Fatty acids, alcohols etc
  • Immuno-diagnosis tests
  • Skin test (Mantoux)
  • Detection of Antibodies (Tests banned)
  • Genetic/ molecular studies
  • Antigen detection
  • Lipo arabinomannan
  • Nucleic Acid Probes
  • Ligase Chain Reaction
  • Polymerase Chain Reaction
  • Gene Xpert

52
Serological Tests
  • Low turn around time
  • Limitation
  • Low sensitivity in
  • smear negative patients
  • HIV positive cases,
  • In disease -endemic countries with a
    high infection rate
  • Poor standardization
  • Banned in 2012.

53
  • Interferon-? release assays
  • An alternative to the TST in the form of a new
    type of in-vitro T-cell-based assay
  • (Test-tube TST)
  • Gold IGRA
  • Elispot T test
  • T cells of individuals sensitized with
    tuberculosis antigens produce interferon-? when
    they re-encounter mycobacterial antigens
  • High level of interferon-? production -
    presumptive of tuberculosis infection

54
  • IGRA in LTBI
  • In the absence of a gold standard for diagnosis
    of Latent TBI, the sensitivity and specificity
    cannot be directly estimated
  • IGRA have higher specificity than TST
  • Better correlation with surrogate markers of
    exposure to M tuberculosis (in low-incidence
    setting countries)
  • Less cross reactivity as a result of BCG
    vaccination than TST

55
  • PCR
  • Synthesis of dsDNA by hybridization of
    oligonucleotides to targets s-DNA
  • Uses thermal cycler to denature the target DNA
  • Thermostable polymerase for DNA amplification
  • Repeated cycles by varying temp for primer
    annealing (70-72 C) and denaturation (94-96 C)
  • Amplified product are then detected by southern
    blotting and fluorescent/radiolabelled probes
    hybridization

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  • Gene X-pert Test
  • Detection and identification of
    mycobacteriadirectly from clinical samples
  • Uses real-time polymerase-chain reaction (PCR)
    assay to amplify an MTB-specific sequence of the
    rpoB gene
  • Cartridge based, PCR test for detection of
    mycobacteria and Rifampicin resistance
  • Rapid test. Results within hours.
  • Costly
  • Continuous electric supply and temperature
    maintenance
  • ? Field feasibility, sensitivity and specificity
    in India

60
  • Integrates sample processing and PCR
  • Reagents required for bacterial lysis, nucleic
    acid extraction, amplification and amplicon
    detection are present in a disposable plastic
    cartridge
  • Only manual step -- addition of a bactericidal
    buffer to sputum before transferring a defined
    volume to the cartridge
  • MTB/RIF cartridge is then inserted into the
    GeneXpert device
  • Results within 2 hours

61
Diagnosis of Extra Pulmonary TB
  • Sputum or other smears are often Negative
  • These are difficult to use for diagnosis and
    start of treatment
  • Follow up
  • Monitoring
  • End point
  • Recurrence / Relapse
  • Mostly clinico-radio-histo/cytological
  • Invasive procedures frequently required to obtain
    tissue, fluids, etc. to look for T.b. and/or
    histo-cytological criteria.

62
Difficulties of specimens testing for EPTB
  • Specimen
  • Relevance of a particular sample
  • Method of collection
  • Contamination/ inappropriate site
  • Processing
  • Technique, Standardization and calibration of
    Instrument/procedure
  • Clinical interpretation
  • Disease ?

63
How to confirm the Diagnosis? LEVELS OF
DIAGNOSIS OF TB
  • Suggestive
  • Clinical/Epidemiological
  • Radiological
  • Presumptive/Possible
  • Therapeutic response
  • Immunological
  • Markers
  • Definitive
  • Demonstration of Myco tuberculosis
    (smear/ culture)
  • Histo/Cytological criteria

64
EPT DIAGNOSIS
Site Site Empirical/ Suggestive Possible Definitive
1 Lymph Nodes Clinical FNAC (Granuloma) AFB on FNAC
2. Pl. Effusion Clinico-radiological Exudative A.D.A. Pl. biopsy AFB positivity P.C.R.
3. Pericarditis As above As above As above
4. Peritoneal As above As above As above
5. Intestinal Clinical Radiological Biopsy Granuloma AFB positivity
6. Genitourinary Endoscopy As above Biopsy Granuloma AFB positivity
7. Bones Joints Clinical Radiology FNAC Biopsy As above
8. Meningeal As above CSF (Biochem.) CSF PCR AFB
65
Comparison of Various Diagnostic Tests for
Diagnosis of TB
Microscopy LED Microscopy GeneXpert MTB/RIF LAMP Solid Culture Liquid Culture
Threshold (CFU/ml) 10,000 - 131 (106-176) - 100 10-50
Turnaround time 1-2 days 1day 90 min - 4-8 week Days - 2 week
Sensitivity 50-60 10 gtthan ZN staining 90 88 Reference Reference
Specificity 98 94 Reference Reference
Technical expertise Required Required Minimal Required Required Required
Biosafety Better than Microscopy
Other Prone to contamination
  • Boehme CC et al. Semin Respir Crit Care Med
    20133417 31.
  • Lawn SD et al. Lancet Infect Dis 2013 13 34961.

66
  • Absence of evidence is not the
    evidence of absence
  • Carl Sagan

67
  • THANK YOU
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