27: Tuberculosis

Question 1

originally called…

Answer 1

consumption because patients appeared as if being consumed from within

weight loss, gaunt appearance, etc.

Question 2

symptoms

Answer 2

bloody cough

weight loss (wasting)

fever, nausea

progresses slowly but almost always leads to death if untreated

Question 3

industrial revolution

Answer 3

causing disease for at leat 50,000 years but increased during the industrial revolution

responsible for 1/7 of deaths during the 19th century

Question 4

cases and deaths in present day

Answer 4

10M new symptomatic (active) TB cases annually

~1.6M deaths annually
- more than any other infection disease until COVID

Question 5

TB comparison with COVID

Answer 5

basically causing a COVID-scale pandemic annually for more than 200 years

Question 6

where do TB deaths occur?

Answer 6

> 90% occur in the developing world

Question 7

lethal synergy between HIV-AIDS and TB

Answer 7

co-infection with HIV is a huge problem
- of 1.6M deaths, 200K in HIV-infected people

AIDS characterised by a decrease in CD4 T cells which are critical to control TB

Question 8

mycobacterium tuberculosis discovery

Answer 8

1882 by Robert Koch

second bacterium discovered and showed to cause an infectious disease

Question 9

Koch’s postulates

Answer 9

scientific methodology to prove that it was caused by bacteria

1. suspected microbe must be identified in infected patients, but not healthy individuals
2. suspected microbe must be grown in pure culture
3. when introduced in a healthy host, the suspected microbe must cause disease similar to human disease
4. same microbe must be isolated from diseased host

Question 10

characteristics of mycobacterium tuberculosis

Answer 10

non-motile
- no flagellum

humans are the only natural reservoir
- since coughing is the main way for transmission

stained and visualised with acid fast stain

intracellular bacterial pathogen
- can hide within host cells, allowing it to avoid extracellular immune defenses

thick waxy coat
- intrinsic resistance to immune responses/antibiotics

Question 11

mycobacterium tuberculosis grows very slowly

Answer 11

divides every 20 hours
- very slow-growing

takes 2-3 weeks to form a colony

hard to work on/diagnose/perform rapid antibiotic susceptibility testing/treat

Question 12

waxy coat of mtb

Answer 12

made up of mycolic acids and other lipids

normal bacteria only have the membrane and peptidoglycan which make up the cell wall

Question 13

mtb is aerosol transmissible

Answer 13

after inhalation, replication in alveolar macrophages
- typically, when breathing in harmless bacteria, it goes into air sacs and macrophages kill it

infectious dose is very low

alveolar macrophages are unable to kill mtb
- waxy protective coat
- disruption of phagosome maturation

Question 14

most bacteria engulfed by alveolar macrophages are killed in lysosomes

Answer 14

engulfed, goes into an early endosome (membrane-bond compartment), fusion with lysosomes which then degrade and destroy bacterium

killing of bacterium in lysosomes depends on acidification of the phagosome

Question 15

mtb avoids being killed by stopping phagosome maturation

Answer 15

phagosome never fully acidifies because of the block, so pH stays neutral and not enough fusion with lysosomes

Question 16

tuberculosis life cycle

Answer 16

breathed in, taken into lungs, get taken up by alveolar macrophages and bacteria starts to grow

bacteria continues to grow and forms granulomas
- then divergence in outcomes

if bacteria still grows, large lesions in lungs and patients develop symptoms

another outcome where bacteria aren’t killed but also don’t grow
- stalled stage and standoff between immune system and bacteria

Question 17

active disease is associated with

Answer 17

uncontrolled lung inflammation in about 10% of infected individuals

Question 18

granulomas

Answer 18

organised aggregates of immune cells and bacteria

immune response that helps contain but not eliminate mtb
- without elimination, always susceptible to reactivation

Question 19

conversion from latent to active TB

Answer 19

normally, 5% chance of conversion within a year of being infected and total 5-15% chance in remaining lifetime

for someone with AIDS, 8% chance of conversion annually and 80% change within 10 years

patients on anti-TNF also have an increased risk of reactivation

Question 20

diagnosis of active TB

Answer 20

chest x-rays

smear test

culture test

Question 21

diagnosing active TB: chest x-ray

Answer 21

lots of abnormalities so not always super obvious

cloudiness and central cavitative park

Question 22

diagnosing active TB: smear test

Answer 22

patients cough up sputum and bacteria can be visualised with acid-fast tain

inexpensive, rapid and specific (low rate of false positives)

but test is not sensitive enough (high rate of false negatives)

only gives positive if >10k bacilli/mm of sputum
- cannot detect latently infected patients

Question 23

diagnosing active TB: culture test

Answer 23

more sensitive than sputum test, so gold standard
- but very very slow and more difficult

Question 24

diagnosis of latent TB

Answer 24

tuberculin skin test

interferon gamma release assay (IGRA)

no method of diagnosis to detect viable bacteria so it is diagnosed indirectly by looking for the presence of an immune response

Question 25

diagnosing latent TB: tuberculin skin test (TST) - mantoux test

Answer 25

purified protein derivative injected into skin

bump forms due to an immune response which indicates previous exposure to mtb

anyone given the BCG vaccine also gives a positive TST even without infection

Question 26

diagnosing latent TB: interferon gamma release assay

Answer 26

detection of a cytokine called interferon gamma produced by T cells in response to mtb

detects antigens unique to mtb and not found in BCG so can be used to detect mtb in BCG-vaccinated individuals

Question 27

antibiotic treatments for TB

Answer 27

in general, can cure someone with TB as long as the bacteria is susceptible to antibiotics

first-line antibiotics for simple cases
- isoniazid
- rifampin

second-line antibiotics
- fluoroquinolones

Question 28

antibiotics for drug-sensitive TB

Answer 28

6 months of first-line treatment is standard

for multiple drug-resistant TB, often requires 1-2 years of treatment with second-line antibiotics