Overview of Tuberculosis Flashcards
Describe the global burden of TB
Over 2 billion infected
Approx. 1.2-1.4 million deaths annually - 98% in low-income countries
What is mycobacterium tuberculosis?
Slow-growing rod-like bacteria
Gram positive
Acid fast stainable - lab test for TB
Where doe M. tb infect and survive?
In lung macrophages
How is TB transmitted?
Aerosol - coughing, sneezing etc.
Prolonged contact needed for transmission
What are risk factors of TB?
Household sharing and crowding
Why is it that not everyone exposed to TB becomes infected?
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
What are LTBI bacteria?
Latent tuberculosis infection bacteria
May consist of multiple bacillary populations - grow rapidly and metabolically inactive
Where do LTBI bacteria reside?
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
What are risk factors for reactivation of TB?
Malnutrition
Poverty
Immunosuppression
Diabetes
Old age
Poor health
HIV
Describe latent TB infection
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
Describe active TB disease
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
What are the sites of TB disease?
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
What is a Ghon focus?
Lesion produced when infection with M. tb occurs in an immunocompetent individual in the upper region of the lower lobe of the lung
What is the Ghon complex?
Early Ghon focus together with the lymph node lesion
What causes lymph node lesions?
Lymphangitic spread from Ghon focus
Causes granulomatous involvement of peribronchial and/or hilar lymph nodes
What happens to the lesions?
Undergo healing and over time usually evolve to fibrocalcific nodules
When does miliary TB occur?
When resistance to mycobacterial infection is poor
Often in children as a consequence of primary disease
What does TB do to the brain and meninges?
Thickened and opaque meninges
Small tubercles present within the brain
What is a TB disease of the spine?
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
What is lymph node TB?
Scrofula
Infection of M. tb from inhalation of contaminated air then spread to lymph nodes in the neck
Describe immuno-pathogenesis of MTB infection
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
What is good about the immune response in TB?
Innate immunity - alveolar macrophages kill ingested bacilli
Th1 adoptive immune response - CD8 and CD4 T cells, IFN-g release (essential for controlling infection)
What is bad about the immune response in TB?
Excessive immune response leads to overproduction of TNF-a and healthy tissue damage and fibrosis (immunopathology of TB)
What determines the outcome of infection with TB?
Immune response
What is the outcome of infection with innate immune response to TB?
Macrophages
Granuloma formation
What is the outcome of infection with adaptive immune response to TB?
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)
Describe macrophages in TB
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
What do tuberculous granulomas do?
Containment of infection but also leads to tissue damage
Can be intact granuloma or caseating/necrotising granuloma
What are granulomas composed of?
Macrophages
Persistent mycobacteria
Bacterial and macrophage fragments
Killed macrophages
Lymphocytes
What leads to TB transmission?
Liquefaction of granuloma and cavitation
What do CD8+ T cells do in TB?
Kill MT infected cells
What do Th1 CD4+ cells do in TB?
Activate macrophages by production of IFN-g to aggressively ingest antigen and kill ingested MTB
What do Th2 CD4+ cells do in TB?
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
What is the purpose of Ab responses in TB?
May contribute to protection (but insufficient on their own)
May also exacerbate infection
How can we test for TB and LTBI?
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
What is the Mantoux test?
Cell-mediated delayed hypersensitivity response type 4
Detects exposure to MTB, does not diagnose TB
Describe MTB in sputum
Acid fast bacilli found in TB infections in sputum - detected by microscopy using Ziehl-Neelsen stain
Auramine stain used for fluorescence microscopy
How is GeneXpert used to diagnose TB?
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
What are the first line drugs for TB?
Isoniazid (1952)
Pyrazinamide (1954)
Ethambutol (1962)
Rifampicin (1963)
Describe drug treatment for TB
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)
What drugs are MDR-TB resistant to?
Isoniazid and rifampicin
How does treatment of MDR-TB compare to normal TB?
Less effective
Longer duration - 6mo vs 2 years
More side effects
More expensive
What is the vaccine for TB?
Attenuated M. bovis Bacillus Calmette-Guerin (BCG)
Most heavily used vaccine in medical history
Who is the BCG vaccine given to?
Usually to infants or in early childhood
What does BCG protect against?
Disseminated primary infection
Ineffective against reactivation adult TB
What are reasons for BCG failing?
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
