Mycobacterial Diseases I & II Flashcards Preview

Infectious Disease: Unit 2 > Mycobacterial Diseases I & II > Flashcards

Flashcards in Mycobacterial Diseases I & II Deck (23):
1

Unique properties of mycobacteria 

  • Slow-growing: 3-6 weeks for isolation
  • 60% of their cell wall is lipid, largely composed of mycolic acids
  • Very difficult to gram stain
    • Resist de-staining once stained = acid-fast
  • Resistant to dessication --> viable after 6-8 months in dried sputum
  • Resistant to many disinfectants, but you can kill them with UV light

2

Transmission of M. tuberculosis & odds of developing disease

  • Respiratory droplets from active infection via cough, sneeze, or speaking
  • Only need 1 bug to catch it
    • 5% w/ infected contacts will progress from positive PPD to active TB within first 2 years
    • 5% chance will develop active TB in their lifetime beyond that 2 years
  • HIV-infected person with latent TB have a 7-10% chance of developing active TB each year
  • Other conditions (diabetes, ESRD, immunosuppression) also have increased chance of developing active TB

3

Development of immunity to M. tuberculosis

  • Initial infection: no symptoms or mild flu-like disease
  • Cell-mediated immunity develops at 2-6 weeks, dominated by Th1s
    • Control of infection is via cell-mediate immunity
    • Abs do not play a major role in recovery or prevention
  • Antigen-specific CD4+ Th cells secrete IFN-gamma which attracts/activates macrophages
  • Macrophages kill intracellular bacteria (TB) or at least slow growth

4

Immune factors known to control M. tuberculosis

  • IFN-gamma and TNF-a (released by macrophages)
    • If inhibited with drugs for other conditions, you risk reactivation of latent infection
  • When macrophages die, bacilli released - travel through lymph to bloodstream and can get to rest of body --> liver, spleen, kidney, bone, brain, meninges, and lung again
  • Granulomas: 
    • Site of confined bacteria
    • Made up of epithelioid cells, giant cells, and lymphocytes
    • Centers become necrotic as they grow (caseous necrosis)
  • Ghon complex: 
    • Combination of single lesion in lung + draining bronchial lymph node
  • In healthy people, lesions heal & calcify --> seen on CXR
  • Sometimes bacilli persist in granuloma for decades --> latent TB infection

5

Primary TB infection

  • Occurs in about 5-10% of cases within first 2 years post-infection in otherwise healthy individuals
  • In immunocompromised:
    • Cell-mediated immunity inadequate
    • Macrophages unable to contain primary infection
    • Possible consequence = bacterial spread to virtually all organs --> potentially fatal miliary (disseminated) tuberculosis 
      • Contagious bacterial infection spread from lungs to other parts of body through blood/lymph system

6

Latent TB infection

  • In healthy individuals exposed to TB, lesions heal and become fibrotic or calcified 
    • Can be seen on CXR as evidence of primary infection
  • Actiated macrophages successfully able to kill or inhibit bacterial growth
  • Mycobacteria are difficult to kill --> some organisms may persist within granuloma for decades 
  • Results in continued antigenic stimulation, possible reactivation of disease later in life
  • Infection is controlled, cannot be spread to other people, shows no signs of active disease, considered clinically latent TB

7

Secondary TB infection

  • May occur by reactivation of mycobacteria that have been carried in body in latent form for any # of years
  • Most common site of reactivation = apex of lung
    • Most likely due to high oxygenation levels
  • Reactivation can occur in any tissue harboring latent bacteria from primary infection
  • Lesions slowly become necrotic --> caseous --> liquefactive
  • Adjacent lesions can coalesce to form larger lesions, eventually penetrate bronchi
  • Organisms grow intra- and extra-cellularly --> may reach very high densities 
  • Organisms discharged into bronchi can result in coughing, ultimately spread of bacteria to other humans

8

M. tuberculosis survival within phagosome

  • Infected bacilli that reach alveoli are ingested by phagocytosis, multiply unimpeded in resident alveolar macrophages
  • Virulence of bacilli depends on ability to survive in activated & unactivated macrophages
  • Interferes with membrane-controlled trafficking, arrests phagosome maturation at stage when no harm can be done to pathogen by host acidification, while delivery of nutrients by membrane bound vesicles is unimpeded

9

Key players in phagosome maturation arrest

  • PIM and ManLAM
    • Resemble mammalian phosphatidylinositols (involved in vesicular trafficking)
  • PIM 
    • Stimulates fusion between phagosomes & early endosomes 
    • Ensures continual nutrient supply to phagosomal compartment
  • Man-LAM
    • Inhibits phagosomal maturation
  • SapM
    • Protein produced by M. tuberculosis 
    • Cleaves late endosomal vesicular marker PIP-3-phosphate in phagosome membrane, preventing fusion with lysosomes

10

Primary goal of tuberculosis control

  • To identify active infectious cases, treat to stop transmission
  • Next step: identify contacts with latent infections
  • Then identify high-risk individuals with latent infections
  • BCG vaccination helps prevent disseminated forms in kids in high prevalence areas

11

Symptoms of active TB: pulmonary and systemic

  • Active pulmonary TB
    • Cough
    • Chest pain
    • Hemoptysis
  • Active systemic TB
    • Fever
    • Chills
    • Night sweats
    • Appetite loss
    • Weight loss
    • Fatigue

12

Frequency of extrapulmonary sx in active TB

  • Most commonly affects lungs = 70% of cases
  • Extrapulmonary symptoms = 20% of cases
  • Pulmonary + extrapulmonary = 8% of cases
  • Most common forms of extrapulmonary disease:
    • Lymphatic 42%
    • Pleural disease 18%
    • Miliary 2-3%

13

Detection of latent TB infection

  • Mantoux tuberculin skin test (TST/PPD)
    • 20% of pulmonary TB, 50% of disseminated will be negative
  • Interferon gamma release assays (IGRAs) 
    • Measure release of IFN-gamma in whole blood in response to stimulation by various antigens
    • More sensitive than TST

14

Typical treatment for drug-sensitive TB

  • "4 for 2 and 2 for 4" pattern
  • 2 months of:
    • Rifampin
    • Isoniazid
    • Pyrazinamide
    • Ethambutol
  • After 2 months, discontinue pyrazinamide
  • As soon as drug-susceptibility is confirmed, stop ethambutol
  • For another 4 months:
    • Rifampin
    • INH
  •  6 months total of treatment

15

Treatment regimen for latent TB

  • 600mg rifampin daily x 4 months
  • 900mg rifapentine 1x/week + 900mg INH 1x/week for 3 months

16

Treatment for non-TB mycobacterial illnesses

  • MAC
    • Macrolide, ethambutol, rifamycin, + aminoglycoside 
  • M. kansasii
    • INH, rifampin, ethambutol > 12 months
  • M. abscessus
    • Macrolide, cefoxitin/impinem, amikacin (very resistant)
  • M. ulcerans/Buruli ulcer
    • Surgery for early disease
    • Rifampin + streptomycin/amikacin x 8 weeks
    • Local application of heat
  • M. leprae
    • Rifampin, dapsone, clofazimine

17

BCG vaccination: pros and cons

  • Pros
    • Prevents or minimizes severity of meningeal and disseminated TB, especially in young kids
  • Cons
    • Little (if any) protection against adult pulmonary TB
    • Causes immunized individual to be TST/PPD positive (unlikely if given in infancy though)

18

Non-tuberculosis mycobacterial infections & presentations

  • Over 100 species - environmental mycobacteria, atypical TB, mycobacteria other than TB (MOTT)
  • Lower respiratory disease similar to TB
    • M. kansasii
    • M. avium-intracellulare (MAC)
    • M. abscessus
  • Cervical lymphadenitis 
    • M. avium-intracellulare (MAC)
  • Skin & soft tissue infections - rapid growers
    • M. ulcerans
    • M. marinum

19

Disease caused by MAC

  • Mycobacterium avium & Mycobacterium intracellulare
  • Immunocompetent patients:
    • Pulmonary disease
  • Kids:
    • Cervical lymphadenitis (scrofula)
  • HIV-infected patients:
    • Disseminated infection

20

Definitive treatment for Buruli ulcer in early disease

  • Surgery

21

Transmission of M. leprae

  • Shed from nasal septa, person to person
  • Many bugs in lesions of lepromatous
  • Incubation 3-5 years

22

Tuberculoid leprosy

  • High cell-mediated immunity
  • Non-progressing disease
  • Papular, hypopigmented, anesthetic skin lesions with few or no bacilli in lesions
  • Hardened, thickened peripheral nerves --> completely lost sensation in extremities
  • CD4+ Th, IL-2, IFN-a, IL-12 promote healing
  • Strongly positive lepromin skin test
  • Single skin lesion with absent hair growth

23

Lepromatous leprosy

  • Low cell-mediated immunity
  • Progressive disease
  • Nodular skin lesions w/ abundant bacilli in lesions
  • Leonine facies, skin deformity, blindness, infertility, stocking glove loss of sensation, contraction and resorption of fingers and toes 
  • Eventually leads to death
  • CD8+ T-cells, IL-4, & IL-10 suppress healing
  • Lepromin skin test negative