14-11-22 - Tuberculosis: Pathogen, Pathology & Treatment Flashcards
Learning outcomes
- Appreciate the global burden of tuberculosis as a major Public health problem
- Understand how Mycobacterium tuberculosis causes infection and disease
- Consider the strengths and limitations of current diagnostic methods for tuberculosis
- Describe current approaches to treatment of tuberculosis
What were 7 Impacts of COVID-19 on Global TB control?
- 7 Impacts of COVID-19 on Global TB control:
1) Increased stigma to TB symptoms such as cough
2) Resources diverted and focused on managing COVID-19
3) Reduced access to diagnosis and treatment services
4) Reduction in TB notifications to as low as 40% in some countries
5) Loss of employment and livelihoods aggravating poverty, a major risk for TB
6) Shrinking global economy putting a strain on the money available for TB response
7) Excess deaths which would otherwise be prevented.
What were some 2020 WHO TB targets and UN Treatment targets (in picture)?
What are 3 reasons WHO and UN TB treatment targets were not met?
- 3 reasons WHO and UN TB treatment targets were not met
1) Poverty
* Little money, meaning less nutrition and treatment
2) Health systems
* Health systems not funded well enough and up to a high enough standard
3) HIV
* HIV is human immunodeficiency virus
* TB is an opportunistic disease that re-activates in the immunocompromised
What is TB caused by?
What is Mycobacterium tuberculosis (MTB)?
What type of bacteria is it?
What staining does not work for MTB?
What staining is used instead?
What is MTB’s regeneration time?
How can MTB stay in a dormant/latent state?
What is a latent infection?
- TB is caused by Mycobacterium tuberculosis (MTB), which is a tubercle bacillus (rod shaped bacterium – pleural bacilli)
- Mycobacterium tuberculosis is a fungus-like bacterium
- MTB is a gram-positive bacterium
- Acid fastness is a physical property that gives a bacterium the ability to resist decolorization by acids during staining procedures
- MTB has this property, so gram positive staining can’t be used
- Instead, acid-fast staining is used
*. MTB has a slow generation time (around 17 hours) - MTB have complex metabolic responses which allow it to stay in a latent/persistent state for a long time
- A latent infection is an infection by an organism that lies hidden or dormant (inactive) in the body
What are 4 steps in the pathogenesis of TB?
Describe the timeline of tuberculosis (in picture)
- 4 steps in the pathogenesis of TB:
1) Transmission
* TB is known to be transmitted by airborne infectious aerosol in the 1–5 μm range which are small enough to remain airborne and disperse on air currents
* When someone sneezes, they release aerosol into the air
2) Primary infection
* Primary infection occurs when someone inhales MTB
* It goes deep into the lung and into the alveoli, which causes primary infection
3) Latent infection
* A granuloma (small area of inflammation) forms which contains the MTB
* Macrophages and other immune cells surround this granuloma
4) Active disease
* The granuloma breaks up and release MTB, which will spread around the area
* Most people who develop tuberculosis, do so after a long period of latency (usually several years after initial primary infection).
* This is known as secondary tuberculosis
* 5 factors which can influence MTB to go from a latent infection to an active disease:
1) HIV
2) TNFα
3) IFNγ
4) Vitamin D
5) Immune immaturity/ senescence
How infectious is MTB?
What concentration of MTB is needed to cause infection?
How is TB transmitted?
What is the size of aerosol nuclei?
How many bacilli are there per aerosol?
- MTB is not a very infectious organism
- Around 10^8 MTB organisms /mL of sputum is needed to cause infection
- TB is known to be transmitted by airborne infectious aerosol in the 1–5 μm range which are small enough to remain airborne and disperse on air currents
- The aerosol nuclei are <5µm
- There are 6 bacilli per aerosol
How do the following factors affect probability of active TB (in picture):
1) Number of infecting bacilli
2) Duration of exposure
3) Immune system
How do the following factors affect probability of active TB (in picture):
1) Number of infecting bacilli
2) Duration of exposure
3) Immune system
What are 2 ways we can diagnose latent MTB infection?
- 2 ways we can diagnose latent TB infection:
1) Mantoux test (aka Tuberculin Skin Test)
* May not be as accurate, as people can have factors from previous MTB infection
* 3 steps to the Mantoux test:
1) Tuberculin injected intradermally
2) Immune response if individual previously exposed to bacterium
3) Induration (palpable hardened area) measured after 48-72 hours
2) Interferon Gamma Release Assays (IGRA)
How can primary disease TB be diagnosed?
What are 2 ways this can be done in microscopy?
- Primary diagnosis of TB is made from visualising acid-fast bacilli in sputum smears
- 2 ways this can be done in microscopy:
1) Auramine stain
* Positive organisms fluoresce bright yellow,
* More sensitive than Z/N for initial diagnosis because the whole smear can be examined under low power magnification
* Presence or absence
2) Ziehl-Neelsen (Z/N) stain
* Carbol fuchsin stain and methylene blue counter stain.
* 100 fields examined under 100x objective
* Semi-quantification
What % of TB cases are pulmonary TB (PTB)?
What accounts for a majority of PTB transmission?
What are 5 typical PTB symptoms?
- 85% of clinical TB cases are pulmonary TB (PTB)
- Sputum smear positive PTB patients are believed to cause the majority of community transmission
- 5 typical PTB symptoms:
1) Cough of ≥ 2-3 weeks, not responding to antibiotics
2) Sputum production (± haemoptysis – coughing blood)
3) Fever
4) Night sweats
5) Weight loss
How do solid and liquid sputum cultures compare?
What are 2 positives of sputum culture?
What are 3 negatives of sputum culture?
- Solid sputum culture has less sensitivity, and very few bacteria can grow
- Liquid sputum culture has very sensitive, but it is so rich that even other bacteria can grow, leading to false positives
- 2 positives of sputum culture:
1) Additional 20-30% diagnostic yield
2) Susceptibility testing
- 3 negatives of sputum culture:
1) Expensive
2) Slow
3) Biohazard
What are 6 advantages of the Xpert MTB/RIF: Rapid Automated TB Culture System?
What is a disadvantage?
6 advantages of the Xpert MTB/RIF: Rapid Automated TB Culture System:
1) A two-hour test
2) Detects TB bacilli
3) Determines RIF resistance
4) 95% sensitive
5) 95% specific
6) Little technical expertise
- A disadvantage is that it is expensive
What is TB-MBLA?
What is it used for?
How does it do this?
- Tuberculosis Molecular Bacterial Load Assay (TB-MBLA) is a molecular test
- This test can be used to monitor treatment response
- It can measure the number of MTB without growing them in culture and monitor how many remain after treatment
How does Primary TB appear on an x-ray?
What is A Ghon complex?
What 2 things does the Ghon complex consist of?
- Primary TB appears on an x-ray with a Ghon complex
- A Ghon complex is a lesion (area of abnormal tissues) seen on a chest x-ray that is significant for pulmonary infection of tuberculosis.
- The Ghon complex consists of:
1) Small (often calcified) Ghon focus of pulmonary infection
* The location of the Ghon focus is usually subpleural and predominantly in the upper part of the lower lobe and lower part of the middle or upper lobe
2) Associated lymphadenopathy in a nearby pulmonary lymph node
* Swelling of lymph nodes which can be secondary to bacterial, viral, or fungal infections, autoimmune disease, and malignancy
When do most people develop TB?
What is secondary TB?
What is Miliary TB?
When do cavitations occur?
What are cavitations?
- Most people who develop tuberculosis, do so after a long period of latency (usually several years after initial primary infection).
- This is known as secondary tuberculosis
- Miliary TB is a potentially fatal form of disseminated secondary TB
- Miliary tuberculosis occurs when organisms draining through lymphatics enter venous blood and there is consequent dissemination of bacteria via the blood stream to the lungs and other organs (haematogenous)
- Cavitations are a feature of secondary TB
- Cavitation is a dangerous consequence of pulmonary TB associated with poor outcomes, treatment relapse, higher transmission rates, and development of drug resistance.
- However, in the antibiotic era, cavities are often identified as the extreme outcome of treatment failure and are one of the least-studied aspects of TB
How is TB classified?
What is miliary TB classified as?
What is extrapulmonary TB?
- Tuberculosis may be classified according to site of disease as pulmonary or extrapulmonary
- Miliary disease has been classified as both an extrapulmonary and a pulmonary form of TB
- Extrapulmonary TB is TB that occurs anywhere other than the lungs
What was the original treatment of TB?
Why is it not used as much for TB anymore?
- Streptomycin was one of the original medications used for TB
- It isn’t used as much for TB anymore due to Streptomycin resistance being developed in some TB bacilli
What are the 4 drugs used in the intensive phase of TB treatment?
What are the 2 drugs used in the continuation phase of TB treatment?
- 4 drugs (all orals) used in the intensive phase of TB treatment (first 2 months):
1) Rifampicin (R)
2) Isoniazid (H)
3) Pyrazinamide (Z)
4) Ethambutol (E)
- 2 drugs (all orals) used in the continuation phase of TB treatment (4 months)
1) Rifampicin (R)
2) Isoniazid (H)
What is the mechanism of action of Rifampicin?
What does Rifampicin work against?
What else can it be used for outside of TB?
What is the dose used?
What 3 things can it be used to increase the clearance of?
How is this done?
What are 3 toxicities caused by Rifampicin?
- Rifampicin is highly bactericidal against rapidly replicating and non-replicating bacteria
- It works by Inhibiting bacterial DNA-dependent RNA polymerase
- Rifampicin is also crucial to short courses of chemotherapy
- Rifampicin has a current single daily oral dose (10mg/kg)
- Rifampicin Induces liver enzymes (CYP450) increasing clearance of other drugs:
1) Warfarin
2) OCP (oral contraceptive pills)
3) Anti-retroviral therapy interactions
- 3 toxicities caused by Rifampicin:
1) Hepatitis
2) Itch, rash, GI upset
3) Discolouration of urine, tears, sweat,
What is the mechanism of action of Isoniazid?
What does Isoniazid work against?
What type of drug is Isoniazid?
What dose of Isozianid used?
What are 3 toxicities of Isoniazid?
- Isoniazid is highly bactericidal against rapidly replicating bacteria
- It Inhibits mycolic acid biosynthesis in cell wall (amongst others)
- Isoniazid is a pro drug activated by KatG enzyme
- Isoniazid has an easily tolerated orally in single daily dose (5mg/kg)
- 3 toxicities of Isoniazid:
1) Hepatitis
2) Peripheral neuropathy – minimized by using pyridoxine (vitamin B6)
3) Resistance – overall 10%, varies by population
What is the mechanism of action of Pyrazinamide?
What does Pyrazinamide work against?
How does it affect other drugs in combination therapy?
What is the dose for pyrazinamide?
What are 2 toxicities of Pyrazinamide?
- Pyrazinamide is bacteriostatic (prevents bacterial growth), but bactericidal at acid pH (e.g. inside cells)
- It inhibits fatty acid synthetase I
- In combination therapy, Pyrazinamide accelerates sterilizing effects of isoniazid and rifampicin, allowing 6-month treatment
- The dose for pyrazinamide is once daily dose (15-35 mg/kg/day)
- 2 toxicities of Pyrazinamide:
1) Hepatitis
2) Hyperuricemia (lab test); can exacerbate gout
* Hyperuricaemia is an abnormally high level of uric acid in the blood, associated especially with the disease gout
What is the mechanism of action of Ethambutol?
What Ethambutol work against?
What is the dose of Ethambutol?
Why is it added to drug regimens?
What is a toxicity of Ethambutol?
- Ethambutol is bacteriostatic (prevents bacterial growth)
- Ethambutol inhibits Arabinosyltransferase
- The dose of Ethambutol is a usually well tolerated Single daily dose (15mg/kg)
- Ethambutol is mainly added to regimen to help prevent resistance to other drugs
- A toxicity of Ethambutol is Optic neuritis (uncommon at < 15 mg/kg)
What did 3 clinical trials try to use to reduce treatment duration of TB?
Why did they not work?
- There were 3 major clinical trials published on 2014
- All attempted to use 8-methoxyfluoroquinolones to reduce treatment duration
- All failed because of high rates of post-treatment relapse in experimental arms
What are 2 mutations that cause Isoniazid resistant TB strains?
What mutation causes Rifampicin resistant TB strains?
Which resistance usually comes first?
- 2 mutations that cause Isoniazid resistant TB strains:
1) katG mutations account for 50-90% of ISONIAZID RESISTANT TB strains
2) inhA mutations account for ~31% of ISONIAZID RESISTANT TB strains
- rpoB mutations account for 96% of RIFAMPICIN RESISTANT TB strains
- Resistance to Isoniazid usually precedes resistance to Rifampicin
Global distribution of MDR-TB
- Global distribution of MDR-TB:
- 30 high burden countries defined in 2015
- 45% of global total of MDR-TB cases originate in India, China & Russian Federation
- Highest incidence per 100,000 in Eastern Europe & Central Asia
- UK MDR-TB data:
- ~50-90 per year
- 1.6% of total TB cases
- ~90% acquired overseas
Describe the Second-line treatment for ”multi-drug resistant” TB?
What are 3 negatives of second-line drugs?
- Second-line treatment for” multi-drug resistant” TB:
1) Intensive phase
* 8 months
* At least 5 drugs (May include injectable)
2) Continuation phase
* 12 months
* At least 4 drugs All oral
- 3 negatives of second-line drugs:
1) Less effective – patients are infectious for longer, and cured more slowly
2) More toxic – patients have more side-effects and may require several regimen changes during therapy
3) Not well studied - the best doses and combinations are incompletely understood
What studies are under investigation of multi-drug resistant TB?
Studies are currently underway to reduce the treatment of multi-drug resistant TB from 20 months to 9 – 12 months
What is Nix-TB?
- Nix-TB is a pivotal TB trial that tests the three-drug BPaL regimen, consisting of bedaquiline, pretomanid and linezolid – collectively referred to as the BPaL regimen
