TB - 1-4 Flashcards
What is the incidence of TB worldwide?
10 million new cases worldwide in 2017 (WHO)
How many cases of the incidence of global TB have HIV?
1.2 million - high incidence in SSA as linked with HIV
Which is more prevalent: latent TB or active TB?
More people with latent TB than active
1 in 7 people have latent TB
Which 6 countries account for 60% of TB cases worldwide?
India, Pakistan, Indonesia, China, Nigeria, South Africa
Half of cases are rifampicin resistant
What is the trend in TB incidence compared to mortality?
TB deaths falling faster than TB incidence but people still getting latent TB in LMICs
Decline in incidence rates since 2010 exceeded 4% per year in several high TB burden countries
What is the definition of elimination in a TB setting?
< 1 case per million/year
What is the definition of pre-elimination in a TB setting?
< 10 cases per million/year
Why is there a high incidence of TB in former Soviet Union countries?
Collapse of the healthcare system + therefore poor access to healthcare
Civil unrest, inequality + poverty
What is the definition of Multi-Drug Resistance TB?
Resistant to rifampicin + isoniazid
How many people have MDR-TB?
Roughly 460 000
Where is MDR-TB significantly prevalent in?
Russia, China + India
What HIC country is TB still prevalent in?
UK!
8.9 new cases per 100 000
In 2017, lowest number of new TB cases for past 30 years
What % of migrants have MDR-TB in the UK?
70%; 30% Native - marginated or economically suffering
What are the 5 outcomes of an exposed person to TB?
1) Uninfected - insufficient infecting dose + mucosal barriers
2) Cleared - Innate response but no B cell response
3) Contained - local immune response but not detectable systematically
4) Latent TB infection - Innate + adaptive immunity
5) Active TB infection - 5% of all people exposed
What is the natural course of Mtb infection?
Disease most likely occurs in the first few years of infection + then declines e.g. S Korea + Taiwan have an increased prevalence in the elderly as they were exposed when they were young + now reactivated when their immune systems are weak
What are the predisposing factors to TB?
HIV Malnutrition Diabetes Alcoholism Deficiency of TNF-a --> encourages pro/anti-inflammatory balance
What is the innate immune response to TB?
TB recognised by PRRs on macrophages in the lung
Macrophage activated and causes a local response
Cytokines released to induce adaptive response
What is the adaptive response to TB?
TB travels to lymph nodes + activates dendritic cells
Dendritic cells activate T cells - T cell priming
T cells go to the lung and activate IFN-gamma which increases macrophage response and all gather to the lung
There a protective granuloma forms - causes symptoms - If any present, this is latent TB
This then turns into transmissive granuloma whereby it bursts if immune system can’t handle it - active TB
When does the first immune response to TB occur?
Usually 8 -12 days post infection
Describe why there is a symbiosis between TB and immune response
If there is an impaired immune response e.g. from HIV, malnutrition, diabetes, alcoholism - disease
If tissue damage e.g. pro inflammatory > anti-inflammatory - disease, transmission (problem with forming TNF-alpha so no granuloma forms
If balance between pro-inflammatory = anti-inflammatory - equilibrium so no disease
What are the 2 diagnostic tests for TB?
TST (Tuberculin skin test) + IGRA (Interferon gamma release assay)
How does a TST work?
If antibodies produced before will produce a positive TST result + cause an inflammatory response
What are the weaknesses of TST?
Can’t differentiate between latent or active TB
False +ve if exposed to other mycobacterium e.g. in the soil (cross-reactivity)
False +ve for BCG as it contains tuberculin
What are the strengths of IGRA?
Strong specificity for antigens in Mtb that are not in BCG - Less likely to get false positives
However, more costly + require work in the lab
What is the WHO Tb strategy?
END TB 2015-2030
What is in the END TB 2015-2030 strategy?
WHO Tb strategy Vision: world free of TB Goal: reduce TB epidemic 95% reduction in deaths 90% reduction in incidence 0% to suffer catastrophic costs = >40% of total income
Who should be tested following the WHO End TB strategy?
Should systematic test for LTBI and treat
Definitely test and treat: HIV, Exposed, Healthcare workers
Does the WHO use IGRA/TBT?
Yes, if no IGRA still use TBT
High incidence, high burden
What is the PHE strategy for TB?
Collaborative TB Strategy for England 2015-2020
What does the Collaborative TB Strategy for England 2015-2020 entail?
Voluntary screening:
Migrants from countries of incidence > 50/100 000 year
What is the problem with the Collaborative TB Strategy for England 2015-2020?
GP registration? Undocumented migrants Adherence Language Accessibility Loss to follow up - refer to cascade of care
What does PHE say in terms of screening for TB?
IGRA + TST
Low incidence, high burden
What type of vaccine is the BCG?
Live attenuated
What is the gold standard vaccine for TB?
BCG
When was BCG made?
In 1921, cultured from Mycobacterium. bovis and took 11 years
How available is the BCG?
Widely available - different countries have different stocks due to controversial efficacy
When should people be vaccinated?
Before 1 year old as more efficacious in infants due to immunological maturation
What are the strengths of the BCG?
Safe
Widely available
Works in kids and provides immunity against TB meningitis
Cures bladder cancer and improves outcomes in leprosy
Cheap
What are the weaknesses of BCG?
Doesn’t work in high-incidence countries but works in HICs - tragedy of BCG
Too many different strains of vaccine - variable efficacy: 0-80%
Fridge storage
Doesn’t work in lifelong immunity
Injectable
Don’t have anything for LTBI/ATBI
Can’t be used in immunocompromised patients
Why is there a variability in efficacy of the BCG?
Cross-reactivity with previous mycobacterium exposure e.g. in the soil
Strain variation - no horizontal transmission so lost genes of Mtb
Nutritional
Other infections
Population genetics
What are the 5 new TB candidates?
MTBVAC M72/AS01 MVA85A VPM1002 H4:IC31
What are the characteristics of MTBVAC?
Live attenuated - first and only Mtb live vaccine
Safe
TB + HIV -ve
What are the characteristics of M72/AS01?
Conjugate/subunit - most promising candidate
Safe
High efficacy (54%) in adults
Can be used in TB or HIV +ve
What is the most promising TB Vaccine candidate?
M72/AS01
Broom (2018) - Very good and worth investing in vaccines as vaccines cost less than the burden of TB
Needs more funding
What are the characteristics of MVA85A?
Used as a BCG booster but failed
Large Phase III RCT w/ 3000 people in S. Africa but failed - lots of money was invested
What are the characteristics of VPM1002?
Recombinant protein based on BCG, Used in kids/adolescents
Ongoing trials since 2012/2015
TB + HIV - ve
What are the characteristics of H4: IC31?
BCG re-vaccination
Nemes et al did 3 armed RCT and found BCG was better than H4:IC31 > Placebo
Generally still low efficacy
What did Kaufmann, 2011 say about vaccination?
Vaccines are expensive so need acknowledge this
MDRTB is a huge problem but nothing is being done
Need predictors of how trials are doing e.g. MVA85A
What is a key driver to the problems of HIV + MDR-TB?
HIV epidemic
Young children have similar presentations for TB as HIV Patients due to an immature immune system
What is the incidence of TB in Africa?
High due to also high HIV burden
What are the issues with HIV TB coinfection?
Less likely classical presentation, more likely extra pulmonary (more serious), X ray change variable, tests less sensitive, false -ves
What is the treatment regime for TB?
RIPE Rifampicin Isoniazid Pyrazinamide Ethambutol 6/12 months minimum
What is an extensively drug resistant TB?
Resistant to isonniazid and rifampicin AND any fluoroquinolone + at least one of three injectable second-line drugs
Why is MDRTB more prevalent in the former Soviet Union countries?
Due to collapse of the healthcare system
What are the interventions to control MDR/XDRTB?
Invest in R&D for new vaccines, drugs + diagnostics Optimise MDR + XDRTB management Prioritise infection control Address global workforce crisis Address lab costs Ensure access to high quality drugs Finance - abolish barriers to care Restrict availability of anti-TB drugs for efficacy The Three I's for TB/HIV (WHO) DOTS (End TB Strategy 2015) Patient activism/education
What is the challenge to R&D for new vaccines, drugs + diagnostics?
Dx takes time as TB must be grown
New molecular targets in diagnostics
Costly
Not always easy to detect pathogen - children
What is the challenge to prioritise infection control?
In high prevalence settings, many hospitals have high rates of undiagnosed TB
Natural ventilation proven benefit + UV light
What is the challenge to addressing the global workforce crisis?
Migration of healthcare workers - spread globally (Williams 2015)
What are the 3 I’s for TB/HIV (WHO)?
Intensified case finding
Isoniazid Preventative therapy (IPT) - Treating those with LTBI with isoniazid for 9 months
Infection control for TB
What is causing the TB burden in the migrant population?
Reactivation of remotely-acquired latent TB infection following migration from high TB burden, LICs + migrated to HICs, low TB burden countries
Historically, what have HICs focused on combating TB control?
Focused on combating active TB but with an increasing migrant population where TB burden lies in LTBI, new mechanisms to tackle this burden are needed
What does evidence suggest HICs do to control TB?
LTBI screening post-arrival and Rx to certain migrant groups
Barriers to access + implementation + sub-optimal Rx must still be overcome to achieve elimination
What is the most effective mechanism to screen?
Pre-arrival screening for active TB
Targeted post arrival screening for LTBI in migrants from intermediate/high burden settings
Single step IGRA
What are the challenges to post-arrival screening for LTBI?
Limited uptake - loss in the cascade of care
Acceptance
Completion of therapy
How do foreign-born individuals bear the TB burden in HICs?
Disproportionate
Reactivation of LTBI is important in migrants
