Mycobacterium Tuberculosis Flashcards
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
- mycobacteria infect non activated macrophage
- proliferate unchecked
- macrophage presents antigen to T cell in lymph nodes
- macrophage secretes IL-12
- T cell differentiates into TH-1 cells and secrete IFN-gamma (T helper cells in lymph node and lung)
- Macrophage is activated (TNF alpha)
- 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
