Overview of Tuberculosis

Question 1

Describe the global burden of TB

Answer 1

Over 2 billion infected
Approx. 1.2-1.4 million deaths annually - 98% in low-income countries

Question 2

What is mycobacterium tuberculosis?

Answer 2

Slow-growing rod-like bacteria
Gram positive
Acid fast stainable - lab test for TB

Question 3

Where doe M. tb infect and survive?

Answer 3

In lung macrophages

Question 4

How is TB transmitted?

Answer 4

Aerosol - coughing, sneezing etc.
Prolonged contact needed for transmission

Question 5

What are risk factors of TB?

Answer 5

Household sharing and crowding

Question 6

Why is it that not everyone exposed to TB becomes infected?

Answer 6

Probability of transmission depends on infectiousness, type of environment and length of exposure
10% of infected persons will develop TB at some point in their lives - 5% within 1-2 years, 5% at some point in their lives

Question 7

What are LTBI bacteria?

Answer 7

Latent tuberculosis infection bacteria
May consist of multiple bacillary populations - grow rapidly and metabolically inactive

Question 8

Where do LTBI bacteria reside?

Answer 8

No clear-cut evidence to where they reside
Conventional view is that the bacteria reside in the lung macrophages
Alternative view - extracellular localisation within lung tissue, similar to persister bacilli during drug treatment
Some evidence suggests bronchial lymph nodes and tonsils

Question 9

What are risk factors for reactivation of TB?

Answer 9

Malnutrition
Poverty
Immunosuppression
Diabetes
Old age
Poor health
HIV

Question 10

Describe latent TB infection

Answer 10

No symptoms
Cannot spread TB to others
Usually has positive skin test or QuantiFERON-TB Gold test
Normal chest X-ray and negative sputum test
1/3 world’s population infected
BCG largely ineffective for adult pulmonary disease
Preventative drug treatment possible but not practical
Reactivation many years later

Question 11

Describe active TB disease

Answer 11

Has symptoms:
- bad cough lasting 3 weeks or longer
- chest pain
- coughing up blood or sputum
- weakness or fatigue
- weight loss
- no appetite
- chills
- fever
- sweating at night
Can spread TB to others
Positive skin test
Abnormal chest X-ray or positive sputum smear or culture
1.4 million deaths annually

Question 12

What are the sites of TB disease?

Answer 12

Pulmonary TB occurs in the lungs
Extrapulmonary TB occurs in places other than the lungs including - larynx, lymph nodes, brain, spine, kidneys, bones and joints
Miliary TB occurs when tubercle bacilli enter the bloodstream and are carried to all parts of the body

Question 13

What is a Ghon focus?

Answer 13

Lesion produced when infection with M. tb occurs in an immunocompetent individual in the upper region of the lower lobe of the lung

Question 14

What is the Ghon complex?

Answer 14

Early Ghon focus together with the lymph node lesion

Question 15

What causes lymph node lesions?

Answer 15

Lymphangitic spread from Ghon focus
Causes granulomatous involvement of peribronchial and/or hilar lymph nodes

Question 16

What happens to the lesions?

Answer 16

Undergo healing and over time usually evolve to fibrocalcific nodules

Question 17

When does miliary TB occur?

Answer 17

When resistance to mycobacterial infection is poor
Often in children as a consequence of primary disease

Question 18

What does TB do to the brain and meninges?

Answer 18

Thickened and opaque meninges
Small tubercles present within the brain

Question 19

What is a TB disease of the spine?

Answer 19

Potts disease - haematogenous spread (through blood) of M. tb to the the spine
Most dangerous form of musculoskeletal TB - can cause bone destruction, deformity and paraplegia
Most commonly involves the thoracic and lumbosacral spine

Question 20

What is lymph node TB?

Answer 20

Scrofula
Infection of M. tb from inhalation of contaminated air then spread to lymph nodes in the neck

Question 21

Describe immuno-pathogenesis of MTB infection

Answer 21

Inhalation
Alveolar macrophages
Lymph nodes
Haematogenous spread to other parts of lung via lymphatics and capillaries
Brief acute inflammatory response
Recruitment of CD4, CD8 and NK cells
Down regulation of acute inflammation, leading to chronic inflammation
Formation of granuloma - immune containment of MTB
Caseation
Liquefaction, cavitation and release
Transmission

Question 22

What is good about the immune response in TB?

Answer 22

Innate immunity - alveolar macrophages kill ingested bacilli
Th1 adoptive immune response - CD8 and CD4 T cells, IFN-g release (essential for controlling infection)

Question 23

What is bad about the immune response in TB?

Answer 23

Excessive immune response leads to overproduction of TNF-a and healthy tissue damage and fibrosis (immunopathology of TB)

Question 24

What determines the outcome of infection with TB?

Answer 24

Immune response

Question 25

What is the outcome of infection with innate immune response to TB?

Answer 25

Macrophages Granuloma formation

Question 26

What is the outcome of infection with adaptive immune response to TB?

Answer 26

Develops typically from 2 weeks onwards Requires presentation of mycobacterial antigen peptides to T cells DCs are the most important APCs (others being macrophages and memory B cells)

Question 27

Describe macrophages in TB

Answer 27

Most efficient phagocyte for killing MTB but also shelter for bacteria because MTB evolved strategies for avoiding intracellular kill Kill by phagocytosis and phago-lysosome fusion

Question 28

What do tuberculous granulomas do?

Answer 28

Containment of infection but also leads to tissue damage Can be intact granuloma or caseating/necrotising granuloma

Question 29

What are granulomas composed of?

Answer 29

Macrophages Persistent mycobacteria Bacterial and macrophage fragments Killed macrophages Lymphocytes

Question 30

What leads to TB transmission?

Answer 30

Liquefaction of granuloma and cavitation

Question 31

What do CD8+ T cells do in TB?

Answer 31

Kill MT infected cells

Question 32

What do Th1 CD4+ cells do in TB?

Answer 32

Activate macrophages by production of IFN-g to aggressively ingest antigen and kill ingested MTB

Question 33

What do Th2 CD4+ cells do in TB?

Answer 33

Stimulate B cells via production of cytokines such as IL-4 and IL-13, and also by cell-cell contact to differentiate into Ab-producing plasma cells

Question 34

What is the purpose of Ab responses in TB?

Answer 34

May contribute to protection (but insufficient on their own) May also exacerbate infection

Question 35

How can we test for TB and LTBI?

Answer 35

Chest x-ray Sputum cultures Tuberculin skin test IFN-g blood test - looks for an immune response to proteins produced by MTB Biopsy of affected tissue (rare) - typically lungs, pleura or lymph nodes GeneXpert - new

Question 36

What is the Mantoux test?

Answer 36

Cell-mediated delayed hypersensitivity response type 4 Detects exposure to MTB, does not diagnose TB

Question 37

Describe MTB in sputum

Answer 37

Acid fast bacilli found in TB infections in sputum - detected by microscopy using Ziehl-Neelsen stain Auramine stain used for fluorescence microscopy

Question 38

How is GeneXpert used to diagnose TB?

Answer 38

Detects the DNA in TB bacteria using a sputum sample Or can detect genetic mutations associated with resistance to Rifampicin drug via mutations in rpoB by qPCR

Question 39

What are the first line drugs for TB?

Answer 39

Isoniazid (1952) Pyrazinamide (1954) Ethambutol (1962) Rifampicin (1963)

Question 40

Describe drug treatment for TB

Answer 40

Protracted 6-9 months Usually 4-6 drugs Most drugs act on dividing bacilli High relapse rate due to poor compliance Increase in MDR-TB Directly observed treatment short course (DOTS)

Question 41

What drugs are MDR-TB resistant to?

Answer 41

Isoniazid and rifampicin

Question 42

How does treatment of MDR-TB compare to normal TB?

Answer 42

Less effective Longer duration - 6mo vs 2 years More side effects More expensive

Question 43

What is the vaccine for TB?

Answer 43

Attenuated M. bovis Bacillus Calmette-Guerin (BCG) Most heavily used vaccine in medical history

Question 44

Who is the BCG vaccine given to?

Answer 44

Usually to infants or in early childhood

Question 45

What does BCG protect against?

Answer 45

Disseminated primary infection Ineffective against reactivation adult TB

Question 46

What are reasons for BCG failing?

Answer 46

Protection ranges from 80% to zero in different parts of the world Environmental influences Vaccination given to infants but protection only lasts 15years - strong protection against childhood TB but little against adult infectious form Boost with BCG does not work