Malaria Module Dr. Krafts/Regal 5/8/14

Question 1

Distribution of malaria

Answer 1

Africa, Latin America, Central America, and Asia

Question 2

Epidemiology

Answer 2

• 216 million affected, 655,000 die each year
• 90% of deaths occur in sub-Saharan Africa
• 1500 case in US each year (mostly from transfusions in which they don’t test for malaria. The Anopheles mosquito is not endemic to US)

Question 3

Infected cell

Answer 3

The infected cell contains parasite forms and hemozoin (non-toxic). Hematin is made as the parasite eats up Hb. Hematin is toxic to even the organism as it oxidizes everything. The organism turns hematin into hemozoin

Question 4

Mosquitoes

Answer 4

Culex is common in the US and is harmless while Anopheles carries the plasmodia. The female anopheles is the only sex than can transmit the disease.

Question 5

Normal places that protozoa act?

Answer 5

Favorite places are the gut and blood although they can act in the CNS and also some are multi-organ.

Question 6

Describe the prototypical blood smear slide

Answer 6

Ring form is the prototypical presentation with intraerythrocytic plasmodium trophozoites.

Question 7

Plasmodium vivax, P. ovale, P. malariae

Answer 7

• low parasite burden
• mild anemia
• relapses (P. vivax and P. ovale) because of hypnozoite forms

Question 8

Plasmodium falciparum

Answer 8

• high parasite burden
• severe anemia
• cerebral and multi-organ symptoms
• high fatality rate

Question 9

1. Most common
2. Most deadly
3. Relapses

Answer 9

1. P. vivax (rest of the world) P. falciparum (Africa)
2. P. falciparum
3. P. vivax and P. ovale

Question 10

Life cycle of Plasmodium falciparum

Answer 10

Sporozoites is the infected form released from the mosquito. It first goes to the liver and hepatic cells. It then starts to divide and forms the schizont form. Eventually it will burst and the merozoites are what infect the RBC and begin the erythrocyte cycle. In the erythrocyte cycle it first is the ring form then the trophozoite, next the schizont then to the merozoites which burst. Up until this point it is in the human and part of the asexual process. When the merzoites of the erythrocyte cycle burst it forms a male micro-gametocyte and a female macro-gametocyte. The male micro-gametocyte goes onto exflagellation and eventually meets up w/ the macro-gametocyte.

Question 11

General appearance from trophozite–>gametocyte

Answer 11

Trophozyte starts w/ ring then goes to a funnier looking ring to a schizont that looks like it has a bunch of baby organisms in it to a gametocyte.

Question 12

Distinguishing characteristics of P. falciparum, P. ovale, and P. vivax gametocytes

Answer 12

P. falciparum gametocytes look like a banana. P. ovale and P. vivax have schiffners dots in the cytoplasm as a result of the way the organism develops.

Question 13

P. faciparum

Answer 13

-It is the worse and is able to infect RBC at any age.
-It forms “rosettes” (infected cell surrounded by normal cells) which can impede blood flow, abnormal binding to the endothelium, and the main cause of death in children is cerebral ischemia.
-Stimulates high production of cytokines:
=TNF, INF-Y, IL-1
=Suppress RBC production, causes fever, tissue damage, and RBC binding to endothelium.

Question 14

How does merozoite enter RBC?

Answer 14

Different proteins are used to get in. Glycophorin is the main one used. pfrmp are “knobs” that bind to ligands on vascular wall such as ICAM-1 and CD36

Question 15

Clinical Sx

Answer 15

-Spleen becomes enlarged. Parasites in red cells. Super active macrophages and if chronic can turn it fibrosis, grayish color.
-Liver becomes enlarged and pigmented
-Brain vessels get plugged. Red cells rosettes–>hypoxia around vessels–>eventually ischemia.
-Heart and lungs may also be involved.
-Incubation is 1-2 weeks
-Pro-drome is flu-like illness
-Paroxysms fever/chills, sweating, myalgia
=Quotidian (daily) - P. falciparum
=Tertian (every 48 hours)-P. vivax or ovale
=Quartan (every 72 hours)-P. malaria

Question 16

Diagnosis

Answer 16

• Clinical Sx + appropriate history (travel, contact w/ infected, etc)
• Gold standard is identification of plasmodia in red cells on regular-stained blood smear
• Rapid immunochromatographic test sometimes used (quicker but less accurate)

Question 17

Consideration in Tx

Answer 17

Which Area is visited? Resistance or not? Previous use of antimalarials?
With or without Chloroquine resistant P. falciparum or Chloroquine resistant P. vivax

What is the probability of persistent hepatic forms of the organism
P. vivax and P. ovale
You need the ‘radical’ cure

Clinical status of the disease?
Severity of the disease and necessity to achieve therapeutic levels quickly with parenteral therapy.

Which Area is visited? Resistance or not? Previous use of antimalarials?
With or without Chloroquine resistant P. falciparum or Chloroquine resistant P. vivax
Determine the infecting species
Severity of disease dictates how aggressive the therapy will be (P. falciparum)
Possibility of relapse (P. vivax and P. ovale)

**What is the probability of persistent hepatic forms of the organism
P. vivax and P. ovale
You need the ‘radical’ cure

**Clinical status of the disease?
Uncomplicated disease
Severe disease: Most deaths from severe malaria occur within the first 24-48 hours
Need parenteral therapy

Question 18

What types does resistance readily occur and which have persistent hepatic forms?

Answer 18

Resistance readily occurs in Vivax and Falciparum.

Hepatic forms persist in vivax and ovale.

Question 19

Suppressive prophylaxis malarial drugs

Answer 19

Chloroquine (2. atovaquone/proguanil) is the first line prophylaxis in prevention of malaria. In choloquine resistant areas the drug of choice is atovaquone/proguanil (2. doxycycline or mefloquine).

Question 20

Treatment of acute attack malarial drugs

Answer 20

Chloroquine. In Chloroquine resistant P. falciparum use quinine plus doxycycline. In Chloroquine resistant P. vivax use quinine plus doxycycline. In severe disease use parental quinidine plus doxycycline (alternative is artesunate). Radical cure or prevention of relapse use primaquine.

Question 21

Drugs that work in the different stage of the life cycle

Answer 21

• No drugs work in the sporozoite life stage
• Primaquine works in the primary and hypnozoite liver stages (possibly also atovaquone/proguanil)
• Most of the drugs work in the asexual RBC stage.

Question 22

Chloroquine

Answer 22

• selectivity is based on the fact that the parasitized RBC concentrates chloroquine at least 25 fold more than unparasitized RBC. Chloroquine accumulates in the acid pH of the food vacuole.
• Mechanism is it interferes w/ heme handling. The parasite digests host hemoglobin within the acid food vacuole. This results in the production of ferriprotoporphyrin IX (FPIX)(Hematin) inside the food vacuole which is toxic to the parasite so the parasite uses the enzyme heme polymerase to convert it to hemozoin which accumulates in the vacuole. Chloroquine binds to FPIX and prevents its conversion to hemozoin.
• Disrupts sequestration of heme as hemozoin
• Low doses are used for prophylaxis w/ no significant toxicity
• Acute attack doses can cause vision problems and large doses for prolonged periods can cause severe eye damage and even blindness (this may also be true for accumulation doses)

Question 23

Quinine

Answer 23

More toxic than chloroquine. Used in chlroquine resistant P. falciparum. Mechanism is probably the same as chloroquine. Acute attack doses can cause blurred or permanent damage to vision. (also tinnitus/balance problems).

Question 24

Quinidine

Answer 24

More toxic than quinine. It is used as an anti-arrhthymic drug that blocks Na and K. It is used IV for severe malaria and can have side effects of cardiac issues.

Question 25

Mefloquine

Answer 25

Mechanism most likely the same as chloroquine. It is indicated only for the treatment and prevention of Chlorquine resistant P. falciparum. Can cause neuropsychiatric reactions.

Question 26

Atovaquone-Proguanil

Answer 26

• Atovaquone mechanism is it depolarizes parasitic mitochondria and inhibits their electron transport.
• Proguanil mechanism is a metabolite of proguanil inhibits dihydrofolate reductase. Concentrated in the erythrocyte. Using the combination of these drugs reduces resistance.
• Slow onset so wouldn’t want to give this for severe malaria.
• Expensive and needs to be taken daily.
• GI disturbances can be a problem.

Question 27

Artemisinins and combinations

• Artesunate plus mefloquine
• Artemether plus lumefantrine

Answer 27

Mechanism is that heme iron in the malarial pigment acts on the drug to produce free radicals that damage parasite proteins. It is rapid (and potent even against MDR) so can be used for severe anemia but not used alone to avoid selection of resistant organisms.

Question 28

Primaquine ‘radical cure’

Answer 28

Drug of choice for P. vivax and P. ovale. It eradicate hypnozoite forms dormant in the liver by a mechanism that is unknown (possibly by generating ROS). Can cause hemolytic anemia in people w/ glucose-6-phosphate dehydrogenase deficiency.

Question 29

Doxycycline

Answer 29

A protein synthesis inhibitor that can result in sun sensitivity and yellow teeth in children.