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Respiratory/Musculoskeletal > M- Tuberculosis > Flashcards

M- Tuberculosis Flashcards

1
Q

What fraction of the worlds population is infected with MTb?
How many people die yearly of TB?
In the US what are the “high risk subgroups”?

A

1/3 of the worlds population (2 billion ppl)
3 million people die yearly

  1. HIV/AIDS
  2. homeless
  3. immigrants
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2
Q

In the hospital setting, droplet precaution masks are for particles of what size?
What does this mean for Tb?

A

> 5microns. Tb is only 2 microns so you need a special mask to protect from the smaller particles.

If MTb where on larger particles, it wouldn’t infect as well because they would impact bronchial walls instead of alveoli and would be removed by mucocilliary clearance

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3
Q

How is MTb transmitted?

A

Transmission occurs when an infected person with active pulmonary diseas coughs.

1-3 bacteria carried in a 2 micron droplet is sufficient to infect someone.

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4
Q

How is MTb able to maintain dormancy in the human body for years?

A

It reaches alveoli, proliferates, enters metabolically quiescent alveolar macrophages and remains there walled up in a granuloma.

This hides the pathogen from effective immune response allowing it to persist for decades.

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5
Q

Although the disease is actually a continuum, what are the four general phases it can be divided into?

A
  1. Early phase
  2. Cell mediated immune response
  3. Latent phase
  4. reactivation
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6
Q

What occurs during the “early stage” of MTb infection?
How long does it last?
What organs are generally involved?

A

Early stage lasts from inhalation of infectious droplet to onset of cell-mediated immunity.

4 weeks

Hematogenous dissemination occurs during the early phase and the bacteria likes to go to well-oxygenated areas so it is found in:

  1. apex of lungs
  2. renal cortices
  3. growth plate of long bone
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7
Q

What occurs during cell-mediated immunity phase of MTb infection?
What happens to the number of viable bacteria?
What clinically can be measured in this phase?

A

TH1- type response forms granulomas (giant cells, multiple macrophages, surrounded by T cells) with central caseation.

The number of viable bacteria decreases, dissemination is curtailed and the infection is controlled.

Clinically, the patient will now have a positive PPD test

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8
Q

What phase are over 90% of MTb infections in? What occurs during this phase?

A

Most infections are in the latent phase.

Bacterial replication within the granuloma is balanced by immune-mediated killing and bacterial cell death.

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9
Q

What percent of MTb infected patients will have reactivation? What causes it?
What are the changes that occur during reactivation?

A

10% will have reactivation due to waning cell-mediated immunity (age, illness, immunosuppressive drugs).

The bacterial growth increases and the granulomas become necrotic and enlarge. They rupture into the bronchi spilling large number of bacteria.
The patient coughs and infects another person.

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10
Q

What is the preferred niche of MTb?
What are the two receptor mediated pathways it uses to get there?
Why is this strategy advantageous for the bacteria ?

A

The preferred niche is the alveolar macrophage.
MTb:
1. Virulent strains add mannose group to the end of the lipoarabinomannan (LAM) on the mycobacterial cell wall. This is recognized by mannose receptor on macrophage.

  1. Cell wall C3 convertase activity forming C3b on its surface which is recognized by CR4 on macrophages triggering phagocytosis.

Good strategy for the bacteria bc it triggers less TNFa release.

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11
Q

Phagolysosome formation helps prevent infection by intracellular pathogens. How does MTb avoid this fate and proliferate in the phagosome?

A
  1. decreasing acidification of the phagosome–> mgtC gene of MTb encodes a protein which blocks proton-pumping ATPase which normally brings the phagosome to pH 6.5
  2. maturation arrest of the phagosome
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12
Q

How does MTb decrease acidification of the phagosome?

What are the 2 main reasons maintaining neutral pH is this important for the bacteria?

A

MTb has a mgtC gene that encodes a protein that blocks the proton-pumping ATPase which usually acidifies the phagosome.

  1. Neutral pH of the phagosome decreases killing by NO and lysosomal proteases which are only active in acidic environments
  2. acidic pH is needed to process and present mycobacterial glycolipid antigens on MHCII so rapid immune response doesn’t occur.
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13
Q

What are the two types of local immune responses? How do they keep each other in check?
Which is more important for controlling MTb infections?

A
  1. Cell-mediated TH1
  2. Humoral TH2

TH1 is critical for controlling MTb infections.

IL10 from TH2 suppresses TH1
IFNg from TH1 suppresses TH2

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14
Q

What are the key TH1 cytokines for controlling TB?

A

IFNg, IL12, TNFa

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15
Q

What is the key TH1 effector molecule for efficient MTb killing?

A

NO which is produced by the inducible nitric oxide synthase (iNOS) in macrophages

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16
Q

What is the function of IFNg released by TH1?

A
  1. inhibits TH2 (which suppresses macrophages)

2. activates macrophages directly to overcome phagolysosome arrest and acidify the phagolysosome

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17
Q

What is the function of IL12 released from activated macrophages?

A
  1. initiates TH1 by driving uncommitted T cells to TH1
  2. upregulates IFNg which feeds back to stimulate more IL12 production by activating macrophages
  3. NRAMP1 - early killing
  4. acid proteases- lysosomal digestion
  5. MHCII- antigen presentation
  6. MCP- monocyte recruitment
  7. IL12- TH1 response
  8. iNOS - late killing
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18
Q

Why are HIV infected patients more likely to be infected by mycobacterial infections?

A

They have predominantly TH2 which makes IL10 and IL4 to inhibit macrophage release of IL12 and TH1 release of IFNg

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19
Q

How does TNFa promote MTb killing?

A
  1. upregulates iNOS gene to increase NO production at the infection site
  2. upregulates leukocyte adhesion molecules (selectin, integrins) on pulmonary endothelial cells to recruit monocytes to the lung

*necessary for granuloma formation

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20
Q

What drug used for rheumatoid arthritis might cause reactivation of latent TB?

A

TNFa inhibitors –> they can cause reactivation because TNFa is necessary for granuloma formation to wall off TB infections

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21
Q

Which two cytokines are MOST important for upregulating iNOS?

A

IL12 and TNFa

IFNg is more indirect by upregulating IL12

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22
Q

What is the histologic hallmark of TB?

What does it reflect the intensity of?

A

caseating granulomas–> reflects the intensity of the TH1 response

Granuloma with small areas of central necrosis, few bacteria, large quantities of local IFNg, TNFa, IL12, and NO

23
Q

MTb adapts to the ______ rich environment within the granulomas necrotic center by using ___________ to form _____ from fatty acids.

A

MTb adapts to the LIPID rich environment within the granulomas necrotic center but using ISOCITRATE LYASE to form glucose from fatty acids.

24
Q

What is an average bacterial titer inside the granuloma during latent phase TB?
What happens to the granuloma and the titer in reactivation?

A

In latent phase there is a small bacterial titer:
10^3 CFU

Reactivation-> TH1 response wanes, granuloma breaks down due to enlargement of nectrotic center and larger bacterial titer (10^9)

25
Q

What is the most common form of TB infection?

What will the PPD, CXR and symptoms be?

A

Latent phase:

  1. PPD is positive
  2. CXR is normal
  3. patient is asymptomatic
26
Q

How is PPD performed?
What are common causes for false positives?
What are potential causes for false negatives?

A

Inject 10 units of PPD intradermally and recording the diameter of induration 48 hours later

> 10mm induration is considered positive

False-positive would show for:
people infected with non-TB mycobacteria but the induration would be >20mm

False negatives would show for:

  1. malnourished/immunosuppressed individuals
  2. overwhelming disease
  3. early infection
27
Q

What is a “recent converter”?

What is their annual risk of developing active TB?

A

A person that goes from a negative to postive PPD within a year

In the first 2 years there is an annual risk of 4% of developing ACTIVE TB.
After 2 years there is only a 0.3% chance

28
Q

What is the BCG vaccination? What does it do to the PPD test? For how many years?

A

Common vaccine in TB prevalent areas.
It will give a false positive on the PPD in RECENTLY vaccinated people

Skin test reactivity wanes in 3-5 years and becomes negative

29
Q

What is the incidence of medical students/residents/interns getting converted to a positive PPD during training?

A

1% will convert to positive PPD

30
Q

What is “boosting”?

A

PPD reactivity wanes with time, so adults that were infected as children will have a negative PPD when first tested.
PPD boosts TH1 response so if subsequent PPDs are positive they can be falsely called a recent converter.

Detect boosting by doing a second PPD 2 wks later. If the second test is positive, boosting has occurred.

31
Q

What are the symptoms of active TB?
Is the onset of symptoms indolent or acute?
What causes the symptoms?

A

fever, malaise, night sweats, weight loss, fatigue.
These symptoms are chronic and take weeks to months to develop.
symptoms are caused by systemic release of TNFa

32
Q

What are the major risk factors for developing ACTIVE TB in the US?

A
  1. household contact of active case
  2. jails or nursing homes
  3. HIV
  4. recent immigration from endemic areas
  5. immunosupression or malnutrition
33
Q

How would TB appear in the lung in someone with HIV?

A

There would be lower lobe infiltrates
No cavities- because no T cells to wall off
Adenopathy
60% extrapulmonary

34
Q

What is progressive primary TB?
What lobes are usually involved?
What is shown on the PPD?

A

It is when the TH1 response cannot contain the initial infection which is often in the lower lobes.

  • lower lobe infiltrates
  • ipsilateral hilar adenopathy
  • pleural effusion

PPD will initially be negative, but will become + in a month

35
Q

Describe REactivation TB.
What lobes are usually involved?
What is the clinical presentation?

A

The patient had previously controlled TB (with caseating granulomas)
The bacteria were in latent foci in the upper lobes and when they became reactive, they cause cavitary upper lobe infiltrates. (posterior and apical)

Clinical presentation:

  1. sputum and culture smears are +
  2. cavitation empties matter into bronchi
  3. coughing with hemoptysis
36
Q

In disseminated or miliary TB, what are the 3 major tissues where small granulomas form?
Why?

A

Bone marrow
Liver
Lungs

TB is present inside macrophage derived cells which helps explain the distribution.

37
Q

What is the clinical presentation of someone with disseminated TB?
What does the CXR look like?

A

They will have:

  1. high fever
  2. night sweats
  3. weight loss
  4. severe malaise/prostration
  5. pancytopenia - due to BM involvement
  6. high alkaline phosphatase due to hepatic granulomas

CXR has thousands of 1-2mm nodules

38
Q

Tuberculous meningitis involes the ________ meninges and thus is often complicated by _______________ and ___________.

Describe the lymphocyte count, glucose level and protein level of the CSF in a TB meningitis.

Why will the AFB smear be negative for TB meningitis?

A

basilar meninges so is complicated by obstructive hydroencephalus and CN palsies

Lymphocytes: high
Glucose: low
Protein: high

AFB will be negative because bacteria is in gramulomata not free within CSF.

39
Q

What is Potts disease?

A

Skeletal TB manifest as osteomyelitis of the vertebral column

40
Q

What is the classic laboratory finding for a TB caused GU infection?

A

Sterile pyuria- urine sample has many leukocytes but routine bacteria cultures are negative

41
Q

TB should ALWAYS be considered in patients with __________ of undetermined origin that lasts over 2 wks with negative routine testing.

A

Fever

42
Q

A patient comes to you with a negative PPD. Does this always rule out TB?

A

No. A test can be falsely negative in immunocomrpomised/malnourished, severe disease, early disease

43
Q

What is a + skin test?
What should it be for non-tuberculous mycobacteria?
What is a + skin test in someone with HIV?

A

+ test = 10mm
HIV with +test = 5mm

NonTB mycobacteria = 20mm

44
Q

What test has been developed as a replacement for PPD?

A

IFNg Release Assay/Quantiferon Gold

  • more sensitive, more specific
  • don’t have to come back to check skin
  • PPd in a test tube
45
Q

What is the Zeihl-Neelson stain?

What is required for it to come up positive?

A

AFB sputum stain in which MTb will appear as long rod-shaped red bacilli.

+ = high titer of bacteria (>10^4) which will detect patients with upper lobe reactivation disease

  • = no TB or non-cavitary pulmonary TB, non-pulmonary TB
46
Q

What is the “gold standard” for TB diagnosis?

What is the drawback?

A

Gold Standard is Culturing but it requires 4-6 weeks due to the slow growth rate in vitro

47
Q

What test is more sensitive than AFB staining but less sensitive than culturing? Why would it be used?

A

PCR- use it while you wait for culture to be growing

48
Q

What four factors determine drug selection for TB?

A
  1. number of MTb present
  2. prior anti-TB drug administration
  3. HIV
  4. geographic origin (predictor or resistance)
49
Q

What are the 4 commonly used “first line” TB drugs?

What 5th drug was added to first line?

A
  1. Rifampin
  2. Isoniazid
  3. Pyrazinamide
  4. Ethambutol

Moxifloxacin was recently added

50
Q

Resistance of TB drugs occurs due to chromosomal mutations that arise at a rate of:
10^6 for which 3 drug?
10^8 for what drug?

A

10^6 for isoniazid, pyrazinamide, ethambutol

10^8 for rifampin

51
Q

What is the bacteria titer for patients with latent TB?

What does this mean for drug therapy?

A

They have <10,000 so this means it can be treated with a single drug usually (INH) but for a long time (9months)

52
Q

What is the number and duration of drugs needed for extrapulmonary TB?

A

Rifampin and Isoniazid for 1 year

53
Q

What are the 2 major strategies utilized for minimizing the development of resistance to TB drugs?

A
  1. start with 4 drugs, then work down to 2 when susceptibility tests are in
  2. DOT
54
Q

What is the requirement for something to be classified as:

  1. MDR TB
  2. XDR TB

How long must treatment be given for each?

A
  1. resistance to 2 front line agents (usually rifampin/isoniazid). Treatment must be given for 2 years.
  2. resistance to isoniazid, rifampin, fluoroquinolones (moxifloxacin) and atleast one injectable 2nd line drug (amikacin, capreomycin, kanamycin). Treatment for minimum 2 years

Respiratory/Musculoskeletal (36 decks)

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