Comprehensive lecture notes for the tuberculosis module covered in MCB3024S. These notes cover all content taught in lectures as well as additional materials (powerpoints, textbooks) required to succeed. These notes were created by a student who achieved a distinction in this course.
TB: host-pathogen interactions and molecular and cellular mechanisms
Introduction to Tuberculosis
TB is a national health crisis in South Africa
- South Africa is one the countries that has the highest number of cases of d rug susceptible TB
- is also one of the countries with the highest multiple-drug resistant TB (resistant to two of the major frontline drugs used
to treat TB)
- we are also a country on the list with the highest rates of TB HIV co-endemic
- the national TB prevalence survey is important because it involves going out into communities and setting up sampling
sites and testing a lot of samples so that the confidence on the data and statistics is much higher
- In this survey, they only called people “having TB” is they could confirm the presence of the Mycobacterium in samples
taken from those individuals (not based on an immunological test)
Statistics
- South Africa’s TBV prevalence survey revealed that the bacterium was present in 000 (1% of the people
sampled in sputum)
- what is much more likely is that between 30-100% of people in a room are carrying the organism in an undetectable way
(not able to produce sputum and ti is not able to be detected)
- statistics of TB is about 2:1 for males: females, has been speculated due to social factors and work-related factors but these
are not adequate to explain
- 1% is maintained between most age groups and TB is not associated with any particular preferential age group
TB is under-diagnosed in SA
- the survey also looked at the P:N ratio (prevalence: notification)
- when the P:N ratio is greater than 1, it means that there is more disease being detected in a prevalence survey than is
actually being diagnosed and reporter in clinical facilities
- the P:N ratio was found to be >1 for all age categories
- this means that there is more TB out there than is being detected and diagnosed clinically and the burden of TB is greater
than the statistics are suggesting
- in some categories, the P:N ratio gets as high as about 3
- in the 15-24s and over 65 age groups, there is about 3 times more TB than is being detected and diagnose clinically
Implications
- the implications of these TB cases that are not being detected and diagnosed is that people are walking around with the
organism who are not on treatment, this results in transmission of the organism
- people may be asymptomatic of have low-level symptoms therefore are not on treatment and presenting to clinics and
have severe implications being that there will be continued transmission
- is a challenge to eliminate TB if only people who are presenting symptoms are being treated
Tuberculosis: number 1 infectious killer globally
- estimated that one-fifth to one-quarter of the worlds’ population is infected with Mycobacterium tuberculosis (MTB) ~ 1.7
billion people (20-25%)
- approximately 10 million new cases per annum; 5.6 million men, 3.2 million women and 1.2 million children
- 0.8 million (~8%) in HIV positive individuals
- 8 countries contribute to 66% of new cases: India (26%), Indonesia (8.5%), China (8.4%), the Philippines (6.0%) Pakistan
(5.7%), Nigeria (4.4%), Bangladesh (3.6%) and South Africa (3.6%)
- 1.41 million people died of TB in 2019, this is equal to 3858 deaths per day or a death around every second
- TB is primarily a disease of the poor and mostly affects young adults
- TB is the most common opportunistic infection and cause of death among HIV-infected patients in resource-limited
settings (0.21 million deaths in 2019)
,TB is associated with HIV
- the darker the colour, the higher the
prevalence
- the dark colour indicates that more than 50%
of TB cases are HIV associated in South
Africa
- a challenge in SA is the stigma of being
diagnosed with TB and that being associated
with having a simultaneous HIV diagnoses,
which is not the case
- HIV is a major driver to high TB
Age and gender inequality in TB
- there is a 2:1 ratio of gender TB incidence that is maintained globally and across age category
- many people have speculated that this is due to work or social factors, but the real cause is still
unclear
What about a vaccine?
- there is a vaccine, the BCG vaccine which is given to a child at birth
- this is a live, attenuated vaccine
- this vaccine is derived from Mycobacterium bovis (this bacterium causes disease in cattle) and is
a very closely related mycobacterium
- about 100 million people are vaccinated each year, some regions it is compulsory such as South Africa
- >5 billion people globally have received the BCG vaccine
- it protects against childhood forms of the disease
- the limitation: no reliable protection against adult TB
- a study released last week concluded that “our results suggest that the BGC vaccination at birth is effective at preventing
tuberculosis in young children but is ineffective in adolescence and adults. Immunoprotection therefore needs to be boosted
in older populations.”
- there are external factors that increase susceptibility to the disease, including having HIV
- similarly, if you are on a medication such as immune suppressants, this will also increase the chance of developing TB
- age is also a risk factor for TB and co-morbidities such as diabetes are also risk factors for TB
The problem of the “one in four”
- the 1.4 million deaths per annum and the 10 million new cases annually are “the tip of the
iceberg”
- below that is the estimate of 1.7 billion are characterized as being TST positive (TST stands for
tuberculin skin test in which the skin will have a reaction when ground up TB is injected under
the skin because they have immunological memory either due to having the vaccine or having had TB previously) and this
test is used as an estimate of how many people have been exposed to the bacterium
- a complication with the TST is that if a person has been vaccinated, they will produce a positive response to this test
- below that is that 5-6 billion TST-negative people and they are assumed to not carry the organism at all
- the problem with the “one in four” is that the people who are being diagnosed and treated for TB alone is not going to
eliminate TB
- to eliminate TB, need to find a way to prevent transmission from the massive reservoir of individuals who are carrying the
organism and could go on to become active TB cases and potentially transmitters of the organism, and it is difficult to find
these carriers as they are asymptomatic and thus are not presenting at clinics
How is TB diagnosed?
Bacteriological/microbiological:
- this is the first and oldest method where you look to see if you can find the organism in the individual, this is done via
being able to culture the organism in the lab however the bacterium takes 4-6 weeks to grow so this is very long
- can also do a sputum smear and stain and visualize under the microscope to identity the bacterium
- limitations: for people who are unable to produce sputum in large amounts, such as those that are HIV positive or
pediatrics, it is difficult to get sample; TB is also not only a lung disease, it is most commonly a pulmonary disease but there
is extra-pulmonary TB and only invasive surgical procedures can access sites where the TB is
Immunologic:
- Tuberculin skin test (TST) which looks to see if someone has evidence of their immune system having seen the organism
before or potentially seeing this organism currently
, - TST is taking purified or derivative protein components from TB and injecting them into an individual and looking for an
immunological reaction to that antigen
- IGRA (IFN-y release assay) is similar and looks for the production of immune cytokines in response to exposure to TB
antigens
- limitations: cannot differentiate latent versus active disease, based on immune read-out not pathology or presence of Mtb
organisms as it is based on a memory response
Molecular
- is a modern method such as NAATS (Nucleic acid amplification techniques) which are basically variations of PCR which
is a molecular method to find a DNA sequence that conforms that it is TB
- limitations: limited sensitivity in HIV positive and pediatric TB because you need a sample that you can extract DNA
from; requires sputum sample
The spectrum of TB
- TB disease can be viewed as a dynamic continuum from infection to active infectious disease
- Patients are characterized as having either latent TB infection or active TB disease for simplicity in clinical and public
health settings
- patients can advance or reverse positions, depending on changes in host immunity and comorbidities
- exposure to M. tuberculosis can result in the elimination of the pathogen, either because of innate immune responses or
because of acquired T cell immunity
- individuals who have eliminated the infection via innate immune responses or acquired immune response without T cell
priming or memory can have negative tuberculin skin test or interferon-y release assay results
- some individuals will eliminate the pathogen but retain a strong memory T cell response and will be positive on the TST
or the IGRA, these individuals will not benefit from LTBI treatment
- if the pathogen is not eliminated, bacteria persist in a quiescent or latent state that can be detected as positive TST or
IGRA results; these tests elicit T cell responses against M. tuberculosis antigens
- these patients would benefit from receiving one of the recommended LTBI preventive therapy regimens
- patients with subclinical TB might not report symptoms but will be culture-positive (generally smear-negative because of
the low bacillary load)
- patients with active TB disease experience symptoms such as a cough, fever and weight loss and the diagnosis can usually
be confirmed with sputum smear, culture and molecular tests
- patients with active TB disease might sometimes be negative on the TST or the IGRA because of anergy that is induced by
the disease itself or immune suppression caused by comorbid conditions such as HIV infection or malnutrition
- individuals with subclinical or active TB disease should receive one of the recommended treatment regimens for active TB
disease, which consist of an intensive drug phase with 4 drugs followed by a longer continuation phase with 2 drugs
What about drugs?
Directly Observed Therapy Short Course (DOTS)
- 2 months Intensive phase of at least 4 drugs: Isoniazid, Rifampicin, Ethambutol, Pyrazinamide and Streptomycin
- 4 months Continuation phase of Isoniazid and Rifampicin
- MDR (multidrug resistance): is defined as resistance to Isoniazid and Rifampicin, the two major front-line anti-TB drugs
- Isoniazid and Rifampicin are the two major front-line drugs because they occur in both the intensive and continuation
phases
- if someone has multidrug resistant TB, need to look at second line drugs to eliminate the infection
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