Parasites

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    General Principles

    • Definitive Host: The host in which sexual reproduction takes place.
    • Intermediate Host: The host in which asexual reproduction takes place
    • Divided into:
      • Blood Protozoa
        • Malaria (Plasmodium)
        • Babesiosis (Babesia)
      • Tissue Protozoa
        • Leishmaniasis (Leishmania)
        • Trypanosoma cruzi
      • Intestinal Helminths
        • Intestinal Nematodes (Roundworms)
          • Acquired by Ingestion
            • Trichuris trichiura (Whip Worm)
            • Ascaris
            • Enterobius (Pinworm)
          • Acquired by Skin Penetration
            • Strongyloides
            • Hookworm
      • Tissue and Blood Helminths
        • Trichinella
        • Echinococcosis
        • Cysticercosis
        • Schistosomiasis
        • Filariasis (Wuchereria Bancrofti and Brugia Malayi)
        • Dirofilariasis (Dog Heartworm)
        • Onchocerciasis
        • Loiasis

    Malaria

    Introduction

    • Plasmodium species!
    • Areas with significant malaria:
      • Africa, Middle East, India, Southeast Asia, South America, Central America, parts of Caribbean.
    • Transmitted to humans via anophiline female mosquito.  (requires blood to lay eggs)
    • Prevent by:
      • Bed nets
      • Insect repellant (DEET)
      • Adherence to chemoprophylaxis
    • Life cycles:
      • Humans: Intermediate Host
      • Mosquitoes: Definitive Host
      • Sporozoite enters human via mosquito bite.  Migrates to liver --> invate hepatocytes (via receptor) --> within hepatocyte, sporozoites mature to merozites (some dormant as hypnozoite - 6-11mo to activate) --> hepatic cell lysis --> merozites invade single RBC--> asexually replicate 5 times in 48-72hrs --> RBC lysis --> invasion of additional RBC

     

    Species

    (red-bold kill)

    Type of cell

    Risk of 

    Parasitemia

    (Disease

    severity)

    Dormant

    Phase?

    Features

    P. falciparum

    (Inc: 8-25d)

    Hepatocytes

    RBC any age

    HIGH None!

    - Most common, most dangerous.

    - Can invade RBC of any age!

    - RBC membrane forms knobs that adhere to vascular endothelium

       knobs bind CR-1 receptor on other RBC causes clumping "Rosetting".

       These clumps block flow-->hypoxic damage to brain + kidneys.

        - Results in hemolysis, renal failure, CNS damage, pulmonary edema

    - VERY HIGH Chloroquine resistance

    P. vivax

    (Inc: 10-30d)

    Hepatocytes

    Young RBC

     (mostly retics)

    LOW

    Dormant

    In Liver 

    - 2nd most common

    - Can remain dormant in liver (relapse after tx)

    - Low level parasitemia

    - Some chloroquine resistance

    P. ovale

    (Inc: 10-20d)

    West-African

    SE Asia

    Hepatocytes

    Young RBC

    (mostly retics)

    LOW

    Dormant

    In Liver

    - VERY RARE

    - Can remain dormant in liver (relapse after tx)

    - Low level parasitemia.

    - NO chloroquine resistance described

    P. malariae

    (Inc: 15-35d)

     

    Hepatocytes

    ? RBC

    LOW  

    - Uncommon

    - No dormant phase, but can persist low-level for 30yrs.

    - Very low level parasitemia

    - RARE chloroquine resistance

    P. knowlesi

    (Inc: unknown)

    S/SE Asia

    Hepatocytes 

    ? RBC

    HIGH

     

    - Isolated only in Malaysia

    - Known to infect only monkeys, now infects humans.

    - Looks like P. malariae, but kills like P. falciparum

    - No relapse reported

    - NO chloroquine resistance


     

     

    • Protective genetic factors that interfere with Plasmodium invasion:
      • Surface Proteins
        • Absence of "Duffy" group protein on surface --> resistant to P. vivax
        • Reduced CR-1 expression --> less rosetting in P. falciparum (less cerebral involement)
      • Cytoskeleton (interfere with entry and release of parasite)
        • Hereditary ovalocytosis
        • Hereditary elliptocytosis
        • Hereditary spherocytosis
      • Hemoglobin
        • Sickle cell disease or trait (HbS) --> resistance to P. falciparum (slows growth with abnormal hemoglobin)
          • When P. falciparum forms "knobs" to aggregate RBC's --> traps RBCs in small vessels --> decrease O2 tension --> HbS polymerizes --> kills P. falciparum
          • People with Sickle cell are resistant to SEVERE P. falciparum infection
          • Other types of malaria P. vivax/ovale/malariae do not form knobs --> HbS has no effect.
        • Other hemoglobinopathies (Hb C, Hb E, a-thalassemia, and (lesser extent) B-thalassemia) reduce severity of P. falciparum infection.
        • Neonatal hemoglobin Hb F --> interferes with P. falciparum growth, neonates are protected form severe malaria.
    • Highest risk:
      • Tourists with no previous malaria exposure
      • Pregnant women + fetuses.  (P. falciparum binds chondroitin sulfate A in intervillous space of placenta causing hemolytic anemia --> low birth weight infants).

     

    Symptoms

    • FEVER, FEVER, FEVER!!!! (the only reliable symptom)
      • Characteristic paroxysms of fever every 48-72hrs.
      • Others: headache, myalgia, nausea, vomiting, abdo pain, diarrhea.
      • Fever often fluctuating, but three stages:
        • 1. "Cold stage" feeling code + chills for 15-60min.
        • 2. "Hot stage" body temp rises 39-41°.  Lassitude, loss of appetite, vague pains in bones/joints.  Influenza-like.  (many other sx: diarrhea, unwell, back pain, nausea etc....)
        • 3. "Sweating stage": diaphoresis, and resolution of fever at 2-6hrs.  --> then fatigue and desire to sleep.
      • Fever in a patient returning from an endemic country is MALARIA UNTIL PROVEN

        OTHERWISE!

        (Also look out for Jaundice or Confusion/Obtundation)

    • Hemolysis markers
      • Unconjugated bilirubin
      • Hemoglobinuria (dark coke-colored urine)
      • Jaundice  (jaundice + hemoglobuinuria --> blackwater fever).
    • CNS confusion
      • P. falciparum --> RBCs form knobs --> aggregate in small vessels --> hypoxic damage.

     

     

    falciparum: 9-14d very rarely >6mo

    P.vivax (10-30 days) 

    ovale 12-18d

    P vivax up to 6-12mo

    P. malariae 18-40d

    P knowlesi 9 days to 4 weeks (limited data)

     

    Diagnosis/Workup

    • Three Questions:
      • 1. Is there malaria?
      • 2. MUST differentiate falciparum vs. non-falciparum.
      • 3. Is there chloroquine resistance?
      • 4. Where is parasitemia?

     

    • Define level of parasitemia
      •  >1% ok,
      • >5% get nervous,
      • >10% very dangerous!!!
      • (NOTE: parasitized RBCs adhere to small blood vessels.)
    • Associated with:
      • Alteration in mentation
      • Liver failure
      • DIC
      • Hemolysis
      • Metabolic acidosis
      • Renal Failure
      • Hypoglycemia
    • Long-standing Infection:
      • Anemia
      • Splenomegaly

     

    • Blood smear x 3  (primary dx method!)
      • Giemsa-stained blood
      • Best collected after fever spike (otherwise parasites clogged in peripheral capillaries and parasites not seen).
      • MUST take blood for 3-4 successive days before rule out malaria.
      • Thick films: Used for diagnosis (higher yield)
      • Thin film: 1000X with oil objective microscope. --> speciation
    • Differentiate falciparum from non-falciparum
      • ELISA for histidine-rich P. falciparum antigen.
      • Immunoassay for lactate dehydrogenase enzyme
      • PCR for DNA or mRNA
    • Other bloods:
      • Anemia
      • WBC (Decreased or Normal) [90%]
      • Platelets [60-83%]
      • LDH (high) [70-83%]
      • Liver Enzymes [50%]
      • Other:
        • Increased Retics
        • Elevated reatinine, proteinuria, hemoglobinuria. 

     

    Treatment

    • Aminoquinolones, chloroquine, quinine, mefloquine, primaquine, and halofantrine
      • 1. Inhibit proteolysis of hemoglobin in food vacuole
      • 2. Inhibit heme polymerase required for malaria pigment production.
      • --> kills organism.
    • Pyrimethamine, fulfonamides, dapsone 
      • Folate antagonists
    • Atovaquone
      • Inhibits mitochondrial transport
    • Artemisinin
      • Binds iron --> produces free radicals --> damages proteins.
         
    • All derivatives are faster acting than quinine.
    • Africa, northern South America, India, Southeast Asia --> chloroquine resistant P. falciparum.
      • Energy depdent chloroquine efflux pump.
    • Mefloquiine and halofantrine also found resistance (Southeast asia).
    • Prophylaxis:
      • Chloroquine susceptible areas: chloroquine. (weekly)
        • If areas of resistance:
          •  Mefloquine 250mg PO /week.
          • Doxycycline 100mg PO /day
          • Primaquine 0.5 mg/kg/day
          • Atovaquone 250mg + Proguanil 100mg PO/day (called Malarone)
      • No vaccine! Immune response is poorly understood.. makes vaccine development difficult.
    • Treatment:
      • Refer to websites
        • UK health protection agency
        • US CDC
        • WHO Malaria Programme.
      • General principles:
        • For chloroquine-sensitive strains: use chloroquine
        • For chloroquine-resistant strains: use qunine or equivalent. (Artemisinin very effective for severe disease, but manufacturing quality unreliable???).  If too ill use IV quinidine.

     

    Drug Advantage Disadvantage
    Chloroquine Short Course Limited efficacy (resistance)
    Atovaquone/prog. Short Course Vomiting
    Mefloquine Short Course Neuropsych
    Quinine + doxy Long Course Cinchonism
    Quinine + clinda Long Course Cinch + C. diff.
    Artemisinin Short Course Availability

     

    Babesia

    • Disease of cattle and wild animals, but can infect humans.
    • Similar to malaria --> blood protozoan, but no hepatic phase. (lifecycle similar to Plasmodium)
    • Transmitted by deer tick Ixodes scapularis.
      • Babesia does not infect deer (curiously).
      • White-footed deer moouse is primarily infected.
      • Nymph (tick) can leave mouse and attach to human.
    • Replicates by binary fission inside RBC. (Hemolysis never massive).
    • Symptoms:
      • Presents with intermittent fever "summer flu" 1-3 weeks post-exposure.
      • Often hiking hx in tick infested areas.
        • Often no hx of tick bite. Ixodes scapularis nymph too small - mistaken for small freckle.
    • Often resolves, but serious in splenectomized patients and elderly.
    • Pts with babesiosis can have Lyme disease b/c same tick transmits both.

     

    Echinococcosis

    • Two species:
      • Echinococcus multilocularis:
        • usually symptomatic, and progresses to symptoms.
        • Found: Northern Europe, Asia, Northern US, and Arctic
      • Echinococcus granulosus:
        • usually asymptomatic (90%), rarely progressive.
        • Found worldwide (incl. Africa, Middle East, Southern Europe, Latin America, southwestern US)
    • Member of the cestode (tapeworm) family.
    • Humans --> Intermediate host
    • Transmission: Food infected with parasite eggs.
      • Carried in: feces of sheep, goats, camels, horses, and domestic dogs that live around lifestock.
      • Eggs resistant to drying - viable for many weeks (can contaminate food indirectly)

    Echinococcus_granulosus_distribution_map.png

    Lifecycle:

    • Infected eggs hatch --> oncospheres --> penetrate bowel wall to bloodstream --> deposited in organs
      • Commonly: Lung, liver
      • Less common: Brain, heart, and bones.
    • Re resulting Hydatid cysts consist of germinal membrane with multiple tapeworm heads --> buds to form daughter cysts within primary.
    • Cysts survive in hosts for decades.
    • LifeCycle.jpgEchinococcusLifeCycle.gif

    Clinical Presentation

    • Most asymptomatic, often detected incidentally on imaging.
    • Can become asymptomatic when reaches large size >8-10cm compessing vital structures. and erode into biliary tract or bronchus (if in lung).
      • Cysts can become superinfected, resulting in bacterial abscess.
      • Cysts can rupture producing anaphylactic-type reaction (Fever, Hypotension)

     

    Investigations

    • U/S, CT, MRI:
      • Show hydatid cyst with distinct septated structure (daughter cysts).
      • Sometimes tapeworm heads can be visualized
      •  Hydatid Cyst CT.png
    • Laboratory:
      • ELISA - highly sensitive for liver cysts, less sensitive for extra-hepatic.

     

    Treatment

    • Surgical resection if symptomatic.
      • Must be removed INTACT, to avoid rupture that can spread infection.
      • Procedure involves removing fraction of contents, and injecting hypertonic saline (30% NaCl), iodophore, or 95% ethanol.  -> kills germinal layer and daughter cysts.
      • Instil solution 30min before surgery.
      • Peri-operative treatment 3-4 cycles of:
        • albendazole 400mg BID for 4 weeks followed by 2-week rest period.
      • (Some studies do 1 week pre-op and 1-3 months post-op).
    • Medical treatment:
      • If small cyst and/or asymptomatic, can do medical treatment only:
      • Same as peri-operative treatment.
      • Can also percutaneously aspirate with needle to drain and instill of cidal agent (hypertonic saline or ethanol). Followed by re-aspiration in 15min to remove cidal agent. (Called PAIR treatment).
        • PAIR treatment is often curative, but no randomized trials comparing to surgery.

    Other

    Leishmaniasis

    TODO

     

    Trypanosoma Cruzi

    TODO

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