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Clinical Micro > Lecture 5 Mycobacteria > Flashcards

Lecture 5 Mycobacteria Flashcards

1
Q

How much of the worlds population is affected by TB

A

1/3

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2
Q

How many million deaths are caused by TB every year

A

2.5 million deaths

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3
Q

Which city has the highest incidence of TB

A

Mumbai

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4
Q

TB has been classed as a DDW, what does this mean

A

Disease of the developing world

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5
Q

What was the number of infections of tb in 2013 in the UK

A

7892

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6
Q

M tuberculosis accounts for what percentage of all TB infections in the U.K.

A

98%

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7
Q

Who are at risk of catching TB

A

Travellers to endemic countries/regions, close contact with infected, immunosuppressed, elderly, homeless, drug abusers and alcoholics

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8
Q

Which bacterium uses humans as reservoir and causes TB (high virulence)

A

Mycobacterium tuberculosis

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9
Q

Name two species of microorganisms that can use animal reservoirs and their virulence for humans

A 
M canetti (unsure of animal) and high virulence 
M bovis (cows) high virulence get bovine TB
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10
Q

Which microorganism uses armadillos (alongside humans) as a reservoir, and what is the condition called?

A

M leprae, causes leprosy with high virulence

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11
Q

M avium-intracellulare and M. Abscessus both have low virulence for humans. What is their reservoir and in what conditions do they cause human disease

A

Reservoir in environment or birds. As environmental hard to kill for resistance reasons, but cause. A TB-like lung infection or disseminated infection in AIDS patients

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12
Q

Describe major characteristics of the mycobacterial cell

A

Acid fast: cell envelope is 60% long chain branched hydrocarbons (waxy)

Mycolic acid - most abundant and big virulence factor

Trehalose dimycolate (TDM) or cord factor - two mycolic acids with trehalose sugar head group.

Cell wall prevent dessication - essential for intracellular survival

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13
Q

What is the normal growth duration for mycobacterium to divide once

A

15-20 hrs

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14
Q

State the structure of the mycobacterial cell wall from inner to outer

A

Inner membrane
Periplasm
Peptidoglycan with arabinogalactan overlay
Bound mycolic acids
Outer membrane
Characteristic free lipids
Running vertically through whole cell wall and linked to cytoplasmic membrane is lipoarabinomannan

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15
Q

What is does the overlay of arabinogalactin linked to

A

(overlay is covalently linked to outer layer composed of mycolic acid, glycophospholipids and cord Factor)

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16
Q

What is the complex between the mycolic acid, arabinogalactan and peptidoglycan called

A

Mycolatearabinogalactan-peptidoglycan-complex (MAPc)

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17
Q

Describe stage 1 of m tuberculosis pathogenesis

A

Inhalation of infectious particles as DROPLET NUCLEI, approx 3 bacilli needed

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18
Q

Describe stage 2 of m tuberculosis (MTB) pathogenesis including a rough timeline

A

7-21 days
MTB multiplies in macs due to inhibition of phagolysosome fusion by cord factor
Macrophages secrete IL-12 and present MTB antigen on surface
Eventually bursting with high TB levels and release the microorganisms

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19
Q

Describe stage 3 of m tuberculosis pathogenesis

A

IL-12 stimulates CD4 and CD8 T cells to infiltrate and recognise MTB antigen and are activated.

CD4 release inflammatory factors - Gamma interferon resulting in tubercule formation (primary lesion)

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20
Q

Describe stage 4 of m tuberculosis pathogenesis

A

MTB continues to multiply within inactivated/poorly activated macrophages and tubercule expands into granuloma

This is a fully encapsulated, immune maintained vessel to prevent wider dissemination

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21
Q

Describe stage 5 of m tuberculosis pathogenesis

A

Primary lesion heals: GHON FOCUS - type of granuloma

Dormant lesion, contains MTB, may reactivate

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22
Q

What does a ghon focus look like an an X-ray?

A

White bunches of grapes within he lung

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23
Q

What receptors on alveolar macrophages allow for entry of MTB

A

Surface complement receptors, scavenger receptors and Fcg receptors

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24
Q

What cell other than alveolar macrophages can take up mycobacteria

A

DC cells which travel to the draining lymph nodes to activate t cells which contribute to tubercule and granuloma formation.

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25
Q

Spread of MTB by which arteries can lead to miliary tuberculosis

A

Pulmonary

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26
Q

Which patients often will obtain miliary tuberculosis

A

Immunocompromised or small children

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27
Q 
FILL IN THE GAPS. 
Although MTB often inhibits phagolysosome fusion, some are degraded and presented to T cells by MHC class II. In the presence of _/_ produced by macrophages and _, the T cells will differentiate into _. These _ cells produce pro inflammatory cytokines _ and _ which in combination with IFNgamma and _ produced by macrophages themselves, further activate bactericidal effectors of macrophages such as _, _ and autophagy induction.
A 
1- IL-12
2-IL-18
3- Dendritic cells 
4- Th1 cells.
5 - th1 cells 
6- IFNgamma 
7- TNFalpha
8- IL-1
9- defensins
10- nitric oxide production
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28
Q

After inhalation of droplet nuclei, what are the three pathways of disease that can occur and the percentage of people in each

A

No infection = 50%

Latent TB infection/ active infection = 25-50%

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29
Q

When does a tb infeciton become latent

A

At the granulomatous lesion form and bacteria cease to grow and the lesion calsifies (90% of infection cases)

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30
Q

In an active tb infection what happens after a granulomatous lesion is formed.

A

The lesion liquifies and spread bacteria to blood and organs and the bacteria can be coughed up in sputum.

The end result is often death if left untreated. A latent infeciton can become active upon immunosuppression

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31
Q

What is the predicted outcome for primary tuberculosis (primary exposure) in an immunoCOMPETENT host

A

Cell mediated immunity prevent spread of MTB, minimal or no symptoms (90% of people)
MTB remain LATENT
REACTIVATION MAY OCCUR

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32
Q

What is the predicted outcome for primary tuberculosis (primary exposure) in an immunocompromised host

A

Primary focus worsens, pneumonia develops (LRTI link here)
Systematic dissemination (lymph nodes, meninges, upper parts of the lung)
Symptoms result from host Cell mediated immunity response and get chronic inflammation.

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33
Q

Does M tuberculosis have an endotoxin or exotoxin

A

NO

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34
Q

Non replicating persistence is a term applicable to which type of tb

A

LATENT INFECTION

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35
Q

When does resactivation of an initial infection occur within (years) of tb

A

Within 2 years but may occur at any time after

36
Q

Why does secondary TB (reactivatin of latent tb) occur

A

Associated with impairment of cell mediated immunity such as steroid therapy, immunosuppressive drugs, cancer or HIV

Also local disturbance of dormant tubercules

37
Q

What is involved in secondary TB

A

Breakdown of latent tubercules, and immune system can’t maintain it and keep the bacteria encased. As break down bacteria can access nutrients and oxygen and burst out of granuloma. At break down get CASEOUS NECROTIC LESION - good for bacteria to disseminate.

38
Q

The switch from hypoxic core to oxygen environment of lungs is essential to reactivation of tb in secondary tb

A

true

39
Q

Why does tb occur in HIV patients

A

Immunocompromised as depleted cd4+ helper cells so impairs cell mediated immunity.

40
Q

How many AIDS patients in sub saharan Africa have developed TB

A

2/3q

41
Q

In developed nations what are we recently seeing regarding aids and tb

A

Prone to rapid primary infection and rapid reactivation

Advanced AIDS patients very susceptible to M avium-intracellulare which is environmental and hard to kill

Disseminated complex (MAC) infection: chronic, fever, M Adium wasting, multiple organ involvement and death

42
Q

What percentage of tb patients are symptomatic in form of primary tuberculosis and what percent are asymptomatic

A

10% symptomatic with primary

90% asymptomatic

43
Q

What are the symptoms of lower respiratory tract TB

A 
Cough sputum with blood
Tissue destruction in lungs result in cavitation and can lead to loss of lung volume and erosion of bronchial arteries 
Significant weight loss
Night sweats
Fatigue 
Fever
44
Q

What are the symptoms of TB spread to other body parts (miliary TB)

A

Meningitis
Septicaemia
Kidney infection
Joint infections; pott disease (curvature of the spine)

45
Q

What is PPD used in mantoux text

A

Purified protein derivative - from mycobacteria

46
Q

What clinical diagnosis tools can be used to identify TB (NOT LAB)

A

Symptoms
Radiological changes on chest x ray
Tuberculin skin test (TST) or Mantoux - inject with PPD

47
Q

How does the mantoux test work

A

Inject a patient with PPD and if previously exposed to TB get very strong immune response - length of induration can tell you if exposed to TB before (room for false positive)

48
Q

What laboratory diagnosis can be used for TB

A

Non culture: Interferon gamma release assay
Nucleic acid amplification and PCR - molecular detection
Microscopy

Culture - LJ slopes

49
Q

What is pcr useful for in tb diagnosis

A

Detect presence of multi drug resistant tuberculosis (drug resistance correlated with characteristic mutations in specific genes)

50
Q

What are the clinical samples used to establish a lab diagnosis for pulmonary, renal, mengitis from TB and checks to see if it has disseminated

A 
Pulmonary - early morning sputum 
Renal - Complete early morning urine 
Meningitis - CSF aspirate
Dissemination check - lymph node biopsy, blood/bone marrow aspirate
IGRA test - whole blood
51
Q

What category is m tuberculosis

A

Category 3 bacteria

52
Q

What is the theory of IGRA test

A

A persons t cells previously exposed to tb infection produce high levels of IFN gamma when re-exposed to same antigen (memory)

False positive if had BcG vaccine - as ‘previous exposure’

53
Q

What patients have IGRA test performed

A

Blood sample from patient with possible or latent TB re exposed to same mycobacterial antigen

54
Q

What genomic seq are the antigens encoded for the IGRA test

A

Antigens used rate encoded in region of difference (RD)1 - genomic sequence absent from most MOTT (e.g BcG, environmental mycobacteria)

55
Q

Name some RD1 encoded antigens for IGRA

A

Early secretary antigenic target (ESAT-6)

Culture filtrate protein (CFP-10)

56
Q

Name 2 commercial kits available for IGRA

A

T-SPOT. TB = ENUMERATE IFNgamma secreting t cells (more sensitive)

QuantiFERON-TB Gold - INF gamma secretion measured (less sensitive as not enumerate cells)

57
Q

What stain is used to detect TB

A

Ziehl-Neelson stain

58
Q

What is the lower limit of detection of ZN stain

A

5 x 10^3 organisms/ml

59
Q

When would a fluorescent auramine stain be used for TB non culture

A

Using fluorescent microscopy to get results within an hour

60
Q

Why do negative smears from microscopy not rule out a tb infection

A

Because low numbers of microorganisms in samples

61
Q

What is the overal sensitivity of microscopy for tb detection

A

<50%

62
Q

What can ZN stain not detect

A

Not differentiate between mycobacteria species, just know the genus with red staining.

63
Q

Describe the principle of TB-REaD

A

Using a flourescent substrate, the device targets BlaC (beta lactamase) produced by the bacteria. Beta lactamase breaks open the fluorescent substrate to see fluorescence and light up sample quickly if MTB is present

64
Q

How quickly can TB-REaD get results

A

20 minutes

65
Q

What is the sensitivity and specificity of TB-REaD

A

Sensitivity is 86%

Specificity is 73%

66
Q

What preparation is required for sputum samples of TB

A

Liquefaction of sputum using Sputasol
Concentration by centrifugation
Decontamination with 4% NaOH (sputum sample is non sterile)

67
Q

What two types of culture media can be used for TB

A

Solid culture - Lowenstein Jensen slopes

Broth culture e.g. Bactec mycobacterial broth, or newer quicker method MGIT

68
Q

What is the benefit of MGIT

A

MGIT - mycobacterial growth indicator test - use low volumes of growth media and high inoculum to force rapid positive/negative result in just over 2 weeks

69
Q

How long can culture of TB take to grow and what components are in LJ slopes

A

37 degrees for up to 8 weeks for M tuberculosis

Eggs, salt, glycerol, potato flour and inhibitory agents such as malachite green and PENICILLIN, nalidixic acid

70
Q

What does full biochemical ID of MTB involve

A

Biochemical characteristics: things MTB + for but other mycobacteria arent
Niacin
Nitrate reductase

Can take 4 weeks

71
Q

What does full ID molecular of TB involve

A

PCR
Rapid ID molecular probes (result in 1-2 days) - species specific DNA probes or ribosomal rRNA based probes (10-100x more sensitive than DNA probes)

72
Q

Which guidelines are followed for treatment of TB

A

British thoracic society

National institute for health and care excellence (NICE)

73
Q

What is the management of active TB

A

2 phases
First two months have ISONIAZID, RIFAMPICIN, PYRAZINAMIDE & ETHAMBUTOL.

Next four months only have ISONIAZID AND RIFAMPICIN

74
Q

What changes have been made to improve patient compliance over the long 6 month period

A

Directly observed therapy (DOT) following a patient risk assessment. DOT considered for patients having adverse factors on risk assessment such as homeless, or alcohols.

75
Q

Why has DOT been introduced for TB treatment

A

To eliminate the infection properly and prevent drug resistance amongst tb strains

76
Q

What percentage of tb strains in uk are resistant to one or more of the antibiotics

A

6-8%

77
Q

What is MDR-TB and what are they resistant to

A

Multidrug resistant TB - resistant to isoniazid and rifampicin - best tb drugs.

78
Q

Why has drug resistance in tb risen

A

Administration of improper treatment regimens by healthcare workers )solved by trained tb physicians)

Failure to complete treatment (solved using DOT)

79
Q

When would the drug SHREZ be used and what does it contain

A

Multi drug resistant TB BASED ON SENSITIVITY TESTING

(Streptomycin + isonicotinyl hydrazine + rifampicin + ethambutol + pyrazinamide) wth moxifloxacin and cycloserine

80
Q

Does does XDR-TB AND TDR-TB stand for

A

extensively drug resistant TB and totally drug resistant TB

81
Q

What combination drug preparations have been developed to improve patient compliance

A

Rifater: initial phase isoniazid/RIFAMPICIN/pyrazinamide

Rifinah 300 or Rimactazid 300: continuous phase ISONIAZID/rifampicin

82
Q

Describe Isoniazid target, MOA and side effects

A

Inhibit cell wall formation, (stop mycolic acid formation)
Pro-drug converted to isonictonic acid-NADH complex, bind to InhAat NADH inning site which facilitates mycolic acid synthesis

Hepatitis, peripheral neuropathy

83
Q

Describe RIFAMPICIN target, MOA and side effects

A

Inhibit nucleic acid synthesis
Bind to RNA polymerase (block mRNA synthesis and subsequent nucleic acid synthesis)

Hepatitis (stains body fluids orange) and make cornea change colour

84
Q

Describe pyrazinamide target, MOA and side effects

A

Cell acidification
Converted to pyrazinoic acid by pyrazinamidase which decreases pH and inhibits ribosomes

Hepatitis

85
Q

Describe ethambutol target, MOA and side effects

A

Inhibit cell wall formation

Bund to arabinosyl transferases dirstupting cell wall component formation

Ocular toxicity which is reversible

Clinical Micro (9 decks)

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