Malaria Module Flashcards
In what areas of the world is malaria endemic?
AFRICA
but also part of Asia and Latin America
The few cases that occur annually in the US are generally from what source?
contaminated blood transfusions - malaria is a disease we don’t screen for
What causes malaria?
a protozoa called plasmodium
What is hemozoin?
It’s a crystallized pigment that the plasmodium creates as a byproduct when it eats hemoglobin
WHY does the parasite form hemozoin?
the first break down product of eating hemoglobin is hematin, which is toxic. So it turns hematin to hemazoin which is nontoxic.
How is malaria spread?
the anopheles mosquito
What’s the stereotypical histology picture of malaria?
A RBC with ring strucutres = trophozoites
What are the four species of plasmodium we’re concerned about for humans?
- plasmodium vivax
- plasmodium ovale
- plasmodium malariae
- plasmodium falciparum
Which species causes the worst disease/is most deadly? Why?
falciparum - it causes the highest parasite burden because it doesn’t care what stage the RBCs are in. Leads to severe anemia - it’s capable of entering the brain and has multi-organ symptoms
very high fatality rate
Why are the three other species less deadly?
they don’t cause as high a parasite load, so the anemia is much milder
Which two species can cause relapse? How?
vivax and ovale
They form hypnozoite forms that lay dormant in the liver for years
What two species are most common? Where?
vivax = everywhere but africa falciparum = africa
What form is the parasite in when the mosquito injects it into the human?
sporozoites
What’s the first cell the sporozoites infect?
hepatocytes
What does the parasite do in the hepatoctes?
proliferates and forms a schizont
What eventually happens to the schizont?
When it’s large enough, it will rupture, releasing the “babies” as merozoites
Merozoites re-enter the blood and infect what cells?
RBCs
What do the merozoites form in the RBCs?
trophozoites = the ring structures
What does the trophozoite develop into?
Another schizont with merozoites inside
Some of the merozoites that are released from the schizont will then go to infect other RBCs, but others will do what?
Form gametocytes, which will be picked up in the blood by another anopheles mosquito that comes along - then they will undergo sexual reproduction in the mosquito
How can you differentiate the falciparum species from the others?
In the gametocyte stage, they aren’t round like the others - they’re shaped more like a banana
How can you differentiate vivax and ovale from the other two?
vivax and ovale have dark schuffner’s dots in the cytoplasm
What two red cell pathologies are caused by a falciparum that leads to blocked capillaries?
- they form rosettes - an infected RBC surrounded by three healthy RBCs - these clump together and block capillaries
- Proteins secreted by the parasite make the outside of the cell all “bumpy” and they exhibit abnormal binding tot he endothelial walls, causing blockage as well
What’s the main cause of death with falciparum infection in children?
cerebral ischemia
What three cytokines are produced in high amounts by infected RBCs?
TNF, INF-gamma and IL-1
What receptor in particular does the parasite use to enter the RBC?
glycophorin
What two organs become enlarged in a malarial infection?
spleen and liver
What color will the liver and spleen turn? Why?
gray - because of the hemozoin
What are the classic symptoms of malaria?
1-2 week incubation
then flu-like illness
focus on the fever! It will relapse and remit at different rates depending on the species
Describe the fevers for the following:
falciparum
vivax or ovale
malariae
falciparum = quotidian = daily
vivax or ovale - tertian = every 48 hours
malariae = quartan = every 72 hours
What are some traits that will lend resistance against malaria to the host?
inherited red cell alterations - sickle cell trait, HbC, or different red blood cell antigens (O infected less severely than A and B)
People who live in endemic areas often develop partial immune-mediated resistance over time, but how does falciparum evade this?
It alters it’s PFEMP protein (the one that makes it bulgy) so the T and B memory cells can’t recognize it
How is the diagnosis of malaria made?
- clinical symptoms plus history of exposure
- identificaiton of plasmodia in red cells on a regularly stained blood smear
- rapid immunochromatographic tests sometimes used (quicker, but less accurate)
WHat are the main considerations in choosing treatments for malaria?
- which area was visited - chloroquine resistance?
- Probability of persistent hepatic forms?
- Clinical status of disease?
What two species readily develop resistance?
vivax and falciparum
What drug is always first-line unless you’re in a resistance area?
chloroquine
Do we have any drugs that work on the sporozoite form?
Unfortunately not - most treatment is focused on the asexual RBC stages
How does chloroquine work?
As the parasite eats hemoglobin, they produces ferriprotoporphyrin (hematin) in the vacuole, which is toxic to the parasite
chloroquine binds to hematin and prevents its conversion to hemozoin, so the plasmodium dies
How does chloroquine get its selective toxicity>
It reaches MUCH higher concentrations in infected RBCs than in uninfected RBCs
What major side effects do you need to consider with acute attack doses of chloroquine?
the worst is severe eye damage leading to blindness
also dizzines, HA, itching, vomiting, skin rashes
When do we use quinine? Is it more or less toxic than chloroquine?
It’s more toxic than chloroquine, but resistance has nor eadily developed, so we use it against chloroquin-resistant falciparum
What’s the mechanism of quinine?
probalby the same as chloroquine
What’s the main side effect of quinine?
again - you have to be concerned about vision, but it also causes damage to balance and hearing as well - also tinnitus, nausea, and headache
constellation of symptoms = cinchonism
When do we use quinidine?
we use it in severe malaria because it can be given IV
What’s the main side effect of quinidine?
cardiac problems - it’s also used as an anti-arrythmic
Mefloquine probably works like chloroquine, but what’s the main side effect that limits its use?
neuropsychiatric reactions - hallucinations, depression, disorientation, etc.
What drug combo works through depolarizing the parasite’s mitochondria and blocking their DHFR?
Atovaquone (the mitochondria) and Proguanil (the DHFR)
Why don’t you use the atovaquone-proguanil combo alone in severe malaria?
Because the effect onset is slow
What’s the limiting side effect in the atovaquone-proguanil combo?
GI distress
What’s the mechanism of the artemisinins?
Hemozoin will interact with the artemisinins and produce ROS that damage the parasite proteins
(may also inhibit a calcium ion ATPase in falciparum)
Why don’t we use the artemisinins alone?
Because they’re the newest ones and we don’t want bugs to develop resistance to them
What drug should you use for vivax or ovale to deal with the hypnozoites in the liver?
primaquine - the “radical cure”
What’s the mechanism of action of primaquine?
We’re not sure - but likely generating ROS or interfering with electron transport
What’s the main worrisome side effect you have to watch for with primaquine?
hemolytic anemia in people with G6PD deficiency
