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Malaria is the most important of all tropical and parasitic diseases.
41% of the worlds population lives in an area where malaria is endemic.
WHO estimates for 2015:
--- ~200, 000, 000 cases
--- ~500,000 deaths
--- ~2/3 of deaths occur in children under 5.


Malaria and Anemia

Some level of anemia seen with most clinical cases of malaria.
--- Severe anemia (hematocrit< 15 % ) most commonly observed in young children and pregnant women.


Five species of Plasmodium cause malaria in humans.

P. falciparum – world-wide distribution
P. vivax – less common in sub-Saharan Africa
P. malariae - world-wide distribution
P. ovale – Africa, parts of Asia, Pacific Islands
P. knowlesi – Malaysia, parts of Southeast Asia

*Most cases are caused by P. falciparum and then P. vivax*


Location of Acquisition of infections

Most (~90%) P. falciparum infections were acquired in Africa.
Most P. vivax infections were acquired in Asia (~50%) or Africa (~25%).


Which forms of plasmodium can go into the dormant (Hypnozoite) form?

- vivax and ovale


malarial paroxysm

- characteristic clinical feature of malaria
- associated with the synchronous release of merozoites, and the lysis of RBCs
- presents with flu-like symptoms, most notably fever, chills, headache, and muscle ache
- Stages:
Cold Stage (15-60 min)
Hot Stage (2-6 hrs)
Sweat Stage (8-12 hrs)


Stages of malarial paroxysm

Cold Stage (15-60 min)
--- rigors, cold dry skin, high core temperature, rapid pulse, nausea, vomiting

Hot Stage (2-6 hrs)
--- severe headache, palpitations, confusion, delirium.

Sweat Stage (8-12 hrs)
--- perspiration, exhaustion, sleep


Symptoms and severity of disease are dictated by

the species of Plasmodium involved.


Duration and Pattern of paroxysm by species:

P. vivax / ovale: recur every 48 hrs
P. malariae: recur every 72 hrs
P. falciparum: recur ~48 hrs
--- In some cases of P. falciparum infection the hot (fever) stage is prolonged, allowing little time for the patient to recover between paroxysms.
P. knowlesi: recur every 24hrs


P. falciparum Malaria: presentation

Rapidly progressing.
Less than synchronous paroxysms.
Incubation 1-2 weeks.
--- “flu-like” symptoms, chills
--- jaundice (misdiagnosis as viral hepatitis)


P. falciparum Malaria: most severe complication

Cerebral malaria
--- Coma and seizures follow 4-5 days with fever.
--- 15-20 % mortality even with treatment.


P. falciparum Malaria: other complications

anemia, hypoglycemia, lactic acidosis, renal failure, etc.


P. vivax and P. ovale Malaria: presentation

- Incubation 2-3 weeks.
--- Parasite may remain dormant (hypnozoite) for years !
- “Flu-like” symptoms for 2-3 days followed by the onset of paroxysms.
- Relapse (hypnozoite) have been reported to occur at intervals of 8-40 weeks.
--- Untreated or inadequately treated cases


P. vivax and P. ovale Malaria: most serious complication

splenic rupture


P. malariae Malaria: presentation

- Incubation 3-6 weeks.
- Clinical picture similar to P. vivax / ovale except paroxysm occur every 72 hrs.
- Symptomatic recrudescence occur due to persistent low level (undetectable) parasitemia.
--- Has been reported to occur up to 52 years after initial infection.
--- can be difficult to diagnose



is a common complication of malaria. The asexual stage of the parasite destroys RBCs each time it completes a cycle of replication.


Three mechanisms involved in the pathogenesis of anemia:

1. RBC lysis by mature asexual intra-erythrocytic parasites.
2. Suppression of erythropoiesis by cytokines (TNF-a, IL-1).
3. Destruction of RBCs by the spleen.


severity of anemia is dictated by ...

the species involved and the population of RBCs it infects.


Which species infect both mature and young erythrocytes?

P. falciparum and P. knowlesi


Which species infect only young RBCs (reticulocytes)?

P.vivax and P.ovale

- (reticulocytes), which comprise only a small population of peripheral cells.
- P.vivax can only infect reticulocytes bearing Duffy blood group determinants.
- P.ovale can infect Duffy negative or positive reticulocytes.


Which species infects older erythrocytes?



Severe anemia is most commonly seen in ....

P.falciparum infections because this causes the highest parasitemia.
--- More than 20% of circulating RBCs can become infected !


Other symptoms / complications of malaria

Splenomegaly-clearance of infected RBCs
Hypoglycemia / lactic acidosis-P. falciparum
--- Depress CNS function, coma, seizures
Microvascular sequestration-P. falciparum
--- Cerebral malaria
-----> coma , seizures


Causes of Hypoglycemia in Malaria

- Decreased oral intake
--- Decreased appetite, no production of liver glycogen
- Depletion of liver glycogen
--- Attempt to maintain normal blood glucose level
- Parasite consumption of glucose
--- Anaerobic glycolysis by asexual parasites
- Inhibition of gluconeogenesis
--- Elevated TNF-a and IL-1



Recognize clinical syndrome (high grade fever, cycling)
Travel history
Blood smear positive for parasites


P. falciparum infection on PBS

highest parasitemia
only rings and gametocytes
multiple infection
no dots or stippling
normal RBC shape

*See purple banana outside of the RBC (gametocyte)


P. vivax on PBS

large pale RBCs (oval)
Schuffner dots
all stages present


P. ovale on PBS

large, pale, oval RBCs
Schuffner dots
all stages present


P. malariae on PBS

normal RBC shape / size
no dots or stippling
all stages present
band forms


Malaria - Immunodiagnosis

Dipstick method.
Detects circulating antigen.
FDA approved
Differentiate P. falciparum from other species.


Natural Resistance to Plasmodium spp.

Several genetic polymorphisms that affect the properties or functions of RBCs appear to provide some level of resistance:
Sickle Cell Anemia
Glucose-6-phosphate dehydrogenase
Southeast Asian Ovalocytosis
Absence of Duffy Blood Group Antigen



Eradicate insect vector / breeding grounds
Prophylaxis for travelers
Vaccine trials have been disappointing
Drug resistance is a major concern


Babesia spp.- Babesiosis: transmission

Transmitted by bite of tick.
--- Rodents (B. microti) and cattle (B. divergens) serve as reservoir


Babesia spp.- Babesiosis: location

In US, most cases reported in Massachusetts, New York, and Rhode Island
--- Also reported in CT, WI, MN, MO, CA, WA


Babesia spp.- Babesiosis: symptoms

Symptoms develop 1-8 weeks after bite.
fever, chills, myalgia
Hemolytic anemia-replication of parasites in RBCs

- Many infections are asymptomatic.


Babesia spp.- Babesiosis: high risk groups

The elderly, asplenic, and immunosuppressed are at highest risk of symptomatic infection.


Babesia spp.- Babesiosis: diagnosis

History of tick bite
Blood smear
--- Maltese Cross


Babesia spp.- Babesiosis: treatment

quinine and clindamycin


Malaria Therapy in Relation to Life Cycle (and species)

- Different drugs kill different forms of bugs.
--- Most are effective against asexual blood forms (merozoites, trophozoites).
--- Few are effective against liver forms (hypnozoites of P. vivax and P. ovale).


Prevention of relapse and prophylaxis for hepatic stages



Prophylaxis for blood stages (drug sensitivity)



Prophylaxis for blood stages (drug resistance)

atovaquone - proguanil


Drugs - Chloroquine

- kill intra-erythrocytic forms.
- interfere with the ability to detoxify compounds generated during the degradation of hemoglobin (?).
- administered orally, is well tolerated, half-life in the body of ~4 days. Once-weekly regimen of prophylaxis.
- rapid and widespread emergence of chloroquine-RESISTANCE limits its usefulness in many parts of the world.
*--- OK to use West of the Panama Canal !!! (central america, mexico)


Drugs - Quinine ( and quinidine)

- kill intra-erythrocytic forms (digestive vacuole)

- Replaced by chloroquine due to poor therapeutic-to–toxic ratio. (Use increasing due to chloroquine resistance)
- still use it for treatment, but not really prophylaxis


Drugs - Quinine ( and quinidine): side effects

CINCHONISM: tinnitus, temporary hearing loss, headache, nausea, vomiting, and visual disturbances.


Drugs - Quinine ( and quinidine): major adverse effect

--- induced release of insulin from the pancreas.
--- Problematic for patients with severe P. falciparum malaria, who may already be suffering from hypoglycemia as a result of the parasites consumption of blood glucose.


Drugs - Mefloquine

- derivative of quinine (less toxic).
- Widely used in areas where chloroquine resistance exists.
- targets merozoites and trophozoites.
- may induce neuropsychiatric reactions (less than 1%).
--- hallucinations, vivid dreams
--- usually when being treated for malaria with high doses, not prophylaxis
- half-life of 14 days, allowing for weekly dosing for prophylaxis.



- Doxycycline (and other tetracyclines) can be used for both malaria prophylaxis and treatment.
- Thought to inhibit the growth of Plasmodium by disrupting protein synthesis
--- primarily used in prophylaxis
--- in combination with other drugs for the treatment for malaria
- Major side effects include photosensitivity dermatitis (increased sensitivity to sunburn) and the staining of teeth in children.
--- contraindicated in children and pregnant women.


*Drugs - Primaquine

*only drug available that has activity against the liver (hypnozoite) forms of P. vivax and P. ovale.
- interfere with mitochondrial electron transport as well as pyrimidine synthesis (?)
- administered after treatment of acute P. vivax or P. ovale infection (clinical cure then radical cure)
- Used for terminal prophylaxis (get rid of the rest hiding out) with chloroquine (or other drugs) in individuals who have had substantial risk of exposure to P. vivax or P. ovale.


*Drugs - Primaquine: major toxicity

*RBC lysis in persons with glucose-6-phosphate dehydrogenase (G6PD) deficiency.
*--- screen for G6PD deficiency before administering primaquine



- Combination of two drugs:

Atovaquone: Mechanism of action unknown. Highly lipophilic (take with fatty meal). Activity against all species of Plasmodium. Well tolerated, half-life of 2-3 days.

Proguanil: Inhibits dihydrofolate reductase (DHFR). Rarely used alone due to the development of resistance. Has been used with chloroquine for prophylaxis.


Malaria Prophylaxis

Review travel itinerary for:
Risk of exposure (What species ?)
Presence of drug resistance
Previous history with antimalarials
Access to medical care


Prophylaxis in Travel to areas WITHOUT chloroquine-resistant Plasmodium

Chloroquine (once weekly)
--- begin 1 to 2 weeks before travel; continue weekly during travel in malarious areas, and for 4 weeks after return.
--- safe for infants, children, and pregnant women.


Prophylaxis in Travel to areas WITH chloroquine-resistant Plasmodium.

Mefloquine, Malarone, doxycycline
--- The same regimen as for chloroquine. (warn of neuropsychiatric side effects).
--- Daily starting 1-2 days before travel and continue for 7 days following return from malarious area.
--- Similar to Malarone, but need to continue for 4-weeks following return


Prophylaxis in Travel to areas where P. vivax and P. ovale are endemic.

- “Terminal prophylaxis” with primaquine.
--- when they're getting ready to return
--- CHECK G6PD status !
- indicated only for people who have had prolonged exposure in malaria-endemic areas.
- begin within the last 2 weeks of prophylaxis and continue with daily doses for 2 weeks, or weekly doses for 8 weeks.


Self Treatment

- Advise individuals to take presumptive self-treatment promptly if they have a febrile illness during their travel and if professional medical care is not available within 24 hours; prompt medical evaluation is imperative.
- Drugs with potentially severe side effects or toxicities (Quinine, Mefloquine) are not recommended for presumptive self-treatment.


Clinical cure vs. Radical cure

- Clinical:
--- Clinical symptoms no longer present.
--- Parasites no longer detected in blood.
- Radical:
--- Necessary following clinical cure of P. vivax , P.ovale
--- Parasites no longer present in liver (hypnozoites)


Prevention of relapse (P. vivax and P. ovale).

- radical cure
*- treated with primaquine after laboratory confirmation of G6PD status
- daily doses for 2 weeks, or weekly doses for 8 weeks


Response to Therapy

- patients generally become afebrile and show signs of clinical improvement within 48-72 hrs.

- by 48 hours after initiation of therapy, parasitemia should have been reduced by 75%.


What to consider if there's no improvement after therapy

inappropriate therapy
poor absorption
drug resistance
development of a complication
--- such as hypoglycemia, renal failure, splenic rupture, aspiration, pneumonia, pulmonary edema, gram-negative sepsis, or anemia.



inappropriate radical cure (P. vivax and P. ovale)
--- re-treat for clinical cure and radical cure (primaquine)



- reappearance of detectable bloodstream forms
- re-treatment with the appropriate drug