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Flashcards in Mycobacterium Tuberculosis Deck (32)
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1
Q

What causes TB? Symptoms?

A
  • Mycobacterium Tuberculosis
  • presents as chronic pneumonia, other organs can be infected
  • insidious onset: creep up
  • fatigue, cough, weight loss, weakness, night sweats and fever, not distinct or specific
  • sputum may be scant, or bloody and purulent
  • need TB test and chest X-ray to diagnose disease
2
Q

Places with highest incidence of TB?

A
  • sub saharan Africa, Eastern Europe, South East Asia
  • 9 million developed active disease in 2013
3
Q

In the US, who is mostly affected by TB?

A
  • elderly malnourished men
  • African americans, native americans, native alaskans
  • HIV+, malnourished, alcoholics, patients with diabetes mellitus, Hodgkin Lymphoma, chronic lung disease, renal failure, immunosuppressed
4
Q

Properties of TB?

A
  • humans are only natural reservoir- causes more deaths than any single microbe
  • obligate aerobe- predilection for growing in highly oxygenated tissues
  • can grow inside and outside macrophages (facultative intracellular pathogen)
  • slow growth rate- generation 18 hours, clinical specimens held for 6-8 weeks before recorded as negative
  • growth pattern showing cording, strings
5
Q

Stain of TB?

A
  • Acid fast bacillus, stains weakly Gram+
  • acid fast retains stains even when treated with a mix of acid and alcohol
  • hard to stain, hard to decolorize
6
Q

Cell wall characteristics of TB? (slide 14)

A
  • cell wall unique to proks, very complex
  • thick wall of peptidoglycan, have LTA like molecule
  • rich in waxes and lipids (60%):
  • mycolic acid (C78-C90, long chain fatty acids)
  • pthiocerol dimycocerosate required for lung pathogenesis
  • cell wall accounts for:
  • acid fastness
  • slow growth
  • resistance to drying, disinfectants, acids and alkalis
  • resistance to antibiotics- trouble getting through wax coat
  • resistance to phagocytic killing
  • Purified Protein Derivatives (PPD):
  • transport and porin proteins throughout cell wall
  • when combined with waxes stimulate patients cell immune response (delayed hypersensitivity)
  • TB test
7
Q

TB resistance to antibiotics?

A
  • multi drug resistant (MDR) strains:
  • resistant to Isoniazid (isonicotinic acid hydrazine, INH) and other anti TB drugs
  • INH resistance is due to mutation in a gene for mycolic acid synthesis and a gene for catalase peroxidase (enzyme required to activate INH)
  • extensively drug resistant (XDR) strains:
  • MDR TB are resistant to fluoroquinolone and at least one second line drug
  • potentially untreatable
  • HIV+ patients often are at risk
8
Q

Transmission of TB? (slide 18)

A
  • person to person by respiratory aerosols produced by coughing (3 bacilli/droplet)
  • if person is around a person infected, they will most likely become infected by a cough
  • when bacilli reach lungs they are ingested and grow inside and outside of non activated or activated macrophages and dendritic cells (inhibit phagosome fusing with lysosome)
9
Q

Process of TB bacteria proliferating in macrophage? (slide 19)

A
  1. mycobacteria infect non activated macrophage
  2. proliferate unchecked
  3. macrophage presents antigen to T cell in lymph nodes
  4. macrophage secretes IL-12
  5. T cell differentiates into TH-1 cells and secrete IFN-gamma (T helper cells in lymph node and lung)
  6. Macrophage is activated (TNF alpha)
  7. Granuloma in some cases see pic
10
Q

Where does Mtb grow? (slide 20)

A

inside and outside of inactive and active macrophages

  • cells fuse together
  • apoptosis can help spread the bacteria
11
Q

Anatomy of a TB granuloma? (slide 20)

A
  • middle: alveolar macrophages, epithelioid cells, giant cells with intracellular Mtb
  • periphery: macrophages, CD4 and CD8 T cells, B cells, NK cells
12
Q

What conditions can Mtb survive while in the macrophage? (slide 22)

A

-survives NO, decrease in pH and H2O2

13
Q

What initiates the immune response to Mtb?

A

-initiated by recognition of Mtb MAMPs (microbe associated molecular patterns) by PRRs (TLR2, TLR4)

14
Q

What cytokines are important to pathogenesis of Mtb?

A
  • IL-12
  • IFN-gamma
  • TNF-alpha
15
Q

What happens during the earliest stages of infection of Mtb?

A
  • less than 3 weeks
  • Mtb inhibit maturation of phagosome and formation of phagolysosome and replicate in the vesicles and cytoplasm of inactive alveolar macrophages and dendritic cells
16
Q

IFN-gamma effects?

A
  • activates macrophages, leads to maturation and activation of phagolysosomes
  • stimulates production of of nitric oxide (NO), which combined with other ROS limits Mtb growth
  • stimulates autophagy destruction of damaged organelles and some intracellular Mtb (may facilitate spread of bacteria)
17
Q

What leads to granuloma and caseous necrosis?

A
  • the immune response is trying to fight the bacteria, which leads to destruction of tissue and granulomas
  • IFN-gamma activates macrophages to differentiate into epithelioid histiocytes that aggregate to form granulomas, some may fuse to form giant cells
  • activated macrophages secrete TNF alpha and chemokine to recruit more monocytes
  • infection is halted in some, progresses in older or immunosuppressed patients
  • ongoing immune response leads to caseating necrosis
18
Q

What could prevent further spread?

A

formation of nodular inflammation

19
Q

What defects lead patients to increased risk of Mtb infections?

A
  • patients with defects in TNF-alpha or IFN-gamma
  • if patient is undergoing therapy that inhibits these things
20
Q

What mediates immunity?

A
  • mediated by T helper cells which stimulate macrophages to kill bacteria
  • immune response leads to tissue destruction
  • reactivation of infection or re-exposure (secondary response) leads to a rapid immune response but increased tissue necrosis
21
Q

Primary TB? outcomes?

A
  • infection of a non immune host (initial exposure to Mtb)
  • possible outcomes:
  • healing by fibrosis (asymptomatic)
  • progressive lung disease (within 2 years), lesion in lower part of lung
  • Bacteremia (bacteria in blood) and Miliary TB (small, many granulomas in different tissues)
  • Hematogenous dissemination with no immediate disease but risk of reactivation later in life (LTBI) when immunosuppressed
  • granulomas may contain viable Mtb for years
  • associated with lymphohematogenous spread through body and lung apices
  • prior to development of immune response, organisms grow uninhibited in lungs and other sites
22
Q

Primary infection? chest X-ray?

A
  • Ghon complex- lung inflammation (granuloma) associated with a granuloma in a draining hilar lymph node
  • xray shows some fibrosis (in children)
23
Q

Progressive Primary TB?

A
  • caseuous material released into bronchioles with cavitation
  • tissue destruction and erosion of bronchiole arteries coughing up blood
  • seeding of TB into lymphatics and blood stream granulomas in liver, spell, kidneys, bones, meninges, skin (Miliary TB)
  • young children (5 years old) are at risk for Miliary TB
24
Q

Complications of Progressive TB?

A
  • overall granulomas have space occupying effects and cause tissue destruction
  • Miliary TB- seeding of Mtb to distant organs with development of foci in the meninge, urogenital tract, peritoneum, skin, bone, usually occurs in immune compromised individuals (HIV)
  • lung- chronic pneumonitis
  • brain- meningitis, seizures
  • adrenal gland- adrenal failure (Addisons disease)
  • bone- bone fractures (Potts disease)
25
Q

Secondary TB?

A
  • occurs in a host who has developed immunity to Mtb
  • cavity usually in upper lobes of lungs, later on
  • reactivation of a latent primary infection usually when host resistance is weakened
  • patient re-infected in an area endemic for TB
  • granulomas cavitation occurs more readily -> decay into structure-less mass of cell debris that spill thousands of viable Mtb -> extra pulmonary manifestations (other tissues)
26
Q

Summary of clinical infection? (slide 36)

A

see pic

27
Q

Do circulating antibodies play a role in resistance to TB?

A
  • no
  • resistance is mediated by cell mediated immunity mainly CD4+ T cells and macrophages
  • patients with aids or mutations in IFN receptor gene are at increased risk for severe TB
28
Q

Tuberculin skin test? (slide 40)

A
  • useful for diagnosis and control of TB
  • based on fact that individuals infected with TB have T cells that mediate a Type IV hypersensitivity response to the proteins of the organism (PPD, purified protein derivative)
  • positive reaction is indicated by a red, indurated area at site of inoculation (cell mediated immunity), depends on clinical picture
  • positive test identifies a recent or past TB infection but not an active disease
  • diameter indicates positive result varies depending on status of individual (small diameter is positive for HIV patients), large diameter for young and healthy needed for positive result
29
Q

In vitro IFN-gamma Release Assay (IGRA)?

A
  • patients previously infected with Mtb will have sensitized T cells in their blood that will make IFN-gamma when exposed to Mtb antigen
  • patients don’t have to return to office for analysis of results
  • Mtb specific antigen used, so result not affected by BCG immunization
  • used to make sure not a false positive
30
Q

Treatment of active TB? (slide 43)

A
  • mutation frequency to drug resistance among mycobacteria is relatively high
  • must treat with multiple drugs simultaneously and for extended periods (6-9 months) to limit the multiplication of drug resistant mutants, depends on clinical picture, treatment is complex
  • different treatment regimens exist for infections with drug susceptible, multi drug resistant (MDR TB) or extensively drug resistant (XDR TB) strains
31
Q

Prevention of TB?

A
  • better housing and nutrition
  • prompt identification, prophylactic and therapeutic intervention and careful case monitoring (latent disease- especially patients that converted to PPD+)
  • Vaccination:
  • BCG (live, attenuated M. Bovis) vaccine used in areas of high incidence, where disease is endemic
  • variable effectiveness, significantly reduces incidence when administered when people are young (not effective in adults)
  • effective in preventing appearance of disease but not infection with Mtb
  • cannot be used in immunocompromised patients- it is a live organism
  • In US, BCG vaccine is used for young children in close contact with individuals with active disease and military
32
Q

TB xray?

A

pic