Mycobacterial Diseases I & II Flashcards Preview

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

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

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


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


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


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


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


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


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


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


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


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


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


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%


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


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


Treatment regimen for latent TB

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


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


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)


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


Disease caused by MAC

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


Definitive treatment for Buruli ulcer in early disease

  • Surgery


Transmission of M. leprae

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


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


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