Chagas (cont.) - diagnosis, treatment and prevention

Diagnosis
1. Suspected in patients:
  1. With a matching history (lived in latin america for extended period of time in sub-standard housing / recipient of unscreened blood/organ)
  2. Exhibiting symptoms (early: general fever, malaise, mild cardiac involvement(?) and chagoma/romana's sign; late: cardiac +/- GI symptoms)
  3. Imaging: (e.g. Xray) revealing enlarged organs (heart/colon etc.)
    1. In chronic stage only
2. Lab testing
  1. Direct methods
    1. Microscopy of fresh blood smear (coupled with Giemsa stain)
    2. Concentration technique (like with HAT)
      1. E.g. - quantitiative buffy coat (QBC) test
        Blood sample pllced in anticoagulant capillary tube andncentrifuged to separate into its components (e.g. RBC's, buffy coat and plasma)
        T. cruzi replicates in WBCs so an analysis of the buffy coat will confirm their presence - stained with fluorescent acridine orange (binds DNA/RNA)
    3. Xenodiagnosis
      1. Allowing sterile insect vectors to take a blood meal from the patient, allow the insect to incubate, then examine the vector's faeces
  2. Indirect meods
    1. PCR (only conducted in research labs)
    2. Serological tests
      1. Indirect fluorescence assay (IFA)
        Use of two Ab's - the primary Ab binds to the organism, the second binds the first and carries a fluorescent tag
        I this case the primary Ab comes from the patient (i.e. theyre producing anti-T. cruzi Ab's)
      2. Indirect haemagglutination
      3. Enzyme linked immunodluorescent assay (ELISA)
Treatment
1. Nifurtimox
  1. 5-nitrofuran prodrug
  2. Introduced in 1964
  3. Absorption/dose
    1. 8-10mg/kg daily - for 90-120days (Orally administered)
  4. Distribution
    1. Crosses BBB
    2. Readily taken up by cells
  5. Elimination
    1. Not excreted in urine, half life is about 3hrs
    2. Metabolised by liver cytochrome P450 reductase
  6. Side effects
    1. Mutagenic -> carcinogenic
    2. May not clear parasitaemia (limited efficacy - acute phase only)
  7. MOA
    1. Nifurtimox = pro-drug of 5-nitrofuran
      1. Uptake into parasite by passive diffusion
        Activated by parasite enzyme type 1 nitroreductase (only found in certain protozoa and bacteria)
        Therefore doesnt become active in host cells
        Type 1 nitroreductase converts nitro (NO2+) group to hydroxyl amine (NH(OH))
        Furan ring (aromatic structure with 4 carbons and 1 oxygen) spontaneously breaks forming an open chain nitrile
        Hydroxylamine reduced fully during break to nitrile (C triple bonded to N)
        This unsaturated bond is highly reactive and toxic to pathogens (and host)
        Reacts with proteins, nucleic acids and thiols
        Selective toxicity due to hosts lacking the type 1 nitroreductase
2. Benznidazole
  1. 2-nitroimidazole pro-drug
  2. Itroduced in 1970's
  3. Absorption/dose
    1. 5-7mg/kg daily (for 30-60 days) - given orally
  4. Distribution
    1. Found equally in plasma and cells
  5. Elimination
    1. 70% excreted in urine, metabolised in liver by unknown mechanism
    2. Half life is about 12hrs
  6. Side effects
    1. Same as nifurtimox
      1. Mutagenic -> carcinogen
  7. MOA
    1. Uptake into the parasite is by passive diffusion (same for host cells too)
      1. Again it is activated (because its a pro-drug) by the type 1 nitroreductase (only found in the parasite)
        Nitrate group (NO2+) is converted to the hydroxylamine (NH(OH))
        This hydroxylamine is unstable - and the incorporated imidazole ring becomes hydroxylated instead
        This causes the imidazole ring to break releasing glyoxal (O=CH-CH-O)
        Glyoxal
        All form adducts with proteins, nucleic acids and thiols
        Reaction intermediate is nitrenium
        Hydroxylamine
Prevention
1. Msquito nets (to reduce exposure to triatomid bugs during sleep)
2. Insecticide sprays and paints
3. Iproved housing and sanitation conditions in rural areas
4. Southern cone initiative (1991) - argentina, brazil, chile, uraguay, paraguay and bolivia
  1. Active elimination of Triatoma infestans in domestic and rral areas as well as mass screening of donated organs and blood
    1. 72% reduction of cases
5. In 2010: chile, uruguay, 10 brazilian provinces and 12 argentinian provinces were declared free of disease
6. Other programmes (All 1997)
  1. Central American initiative
  2. Andean countries initiative
  3. Amazon countries initiative

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Chagas (cont.) - diagnosis, treatment and prevention

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	Created by maisie_oj about 11 years ago