Definition
- Mosquito-borne protozoal infection caused by Plasmodium species
Microbiology
- Intracellular protozoal parasite of red blood cells
- Species that cause human disease are: P. falciparum, P. vivax, P. ovale, P. malariae, and P. knowlesi (from the macaque monkey)
- P. knowlesi looks like P. malariae microscopically, but has a higher (>1%) parasitemia with a clinical course more like P. falciparum
- Identified on thick-and-thin Giemsa-stained blood films
Life Cycle
Malaria lifecycle
- Infected mosquito injects sporozoites into human
- Sporozoites infect the hepatocytes, which develop intracellular schizonts
- P. vivax and P. ovale can have prolonged (months to years) liver stages during which the patient is asymptomatic
- The hepatocytes rupture and release trophozoites, which infect erythrocytes
- Schizonts develop in the erythrocytes, then rupture
Pathogenesis
- Infected red blood cells adhere to endothelial cells, and clump, causing rosetting
- This causes microvascular obstruction and ischemia, which causes cerebral malaria and metabolic acidosis
- Can cause marrow suppression
- P. falciparum manages to avoid splenic sequestration
- Hypoglycemia
- In children, hypermetabolic and consumes glucose
- In adults, hyperinsulin state and quinine also contributes
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Epidemiology
- Transmitted by female Anopheles mosquitoes, but can also be transmitted through blood transfusions
- Distribution is that of the Anopheles mosquito: tropical and subtropical regions worldwide with the exception of North America, Europe, and Australia
Distribution of Anopheles
- Distribution varies by species
- P. falciparum in tropical and subtropical Americas, Africa, and Southeast Asia
- P. vivax in the Americas, India, and Southeast Asia
- P. malariae in tropical and subtropical Americas, Africa, and Southeast Asia
- P. ovale in sub-Saharan Africa
- P. knowlesi in Southeast Asia
- Resistance varies geographically
- Chloroquine-resistant P. falciparum is widespread in sub-Saharan Africa, Asia, and the Americas (except Mexico, regions west of the Panama Canal, Haiti, and the Dominican Republic)
- Chloroquine-resistant P. vivax is in Papua New Guinea and Indonesia, with case reports in many other countries
- Chloroquine-resistant P. malariae is found in Sumatra and Indonesia
- Amodiaquine-resistant P. falciparum can be found in Africa and Asia
- Mefloquine-resistant P. falciparum is in Thailand, Cambodia, Myanmar, and Vietnam, with case reports in Brazil and Africa
- Sulfadoxine-pyrimethamine resistance is widespread in Southeast Asia, the Amazon Basin, and Africa
- Atovaquone-proguanil resistance is increasing but still rare
- Reduced quinine susceptibility is reported in Southeast Asia, sub-Saharan Africa, and South America
- Reduced artemisinin susceptibility is reported in Cambodia, Thailand, Vietnam, and Myanmar
- Doxycycline has no known resistance
Presentation
- History of travel to an endemic country
- Non-specific febrile illness with headaches, myalgias, and malaise
- Fevers are often periodic, appearing based on rupture of schizonts (tertian and quartan fever)
- q24h: P. falciparum
- q48h: P. vivax or P. ovale
- q72h: P. malariae
Severe malaria
- Mostly caused by P. falciparum, though can also be caused by P. vivax
WHO Criteria (2010)
- Clinical
- Prostration / impaired consciousness
- Respiratory distress
- Multiple convulsions, which can be from cerebral malaria, hypoglycemia, severe metabolic acidosis, etc
- Circulatory collapse
- Pulmonary edema
- Abnormal bleeding
- Jaundice
- Hemoglobinuria
- Laboratory
- Severe anemia (Hb ≤ 50)
- Hypoglycemia (< 2.2)
- Acidosis (pH < 7.25 or bicarb < 15)
- Renal impairment (creatinine > 265)
- Hyperlactatemia
- Hyperparasitemia (≥ 2%)
Cerebral malaria
- Erythrocytes sequester in the cerebral microvessels
Malaria in pregnancy
- Accumulation of infected erythrocytes in the placenta, causing IUGR, prematurity, and neonatal mortality
Late or relapsing malaria
- P. vivax and P. ovale can have liver stages that lie latent for months to years before causing relapses
- P. malariae can have a low-level asymptomatic parasitemia lasting for years before presentation
Diagnosis
- Thick and thin peripheral blood films
- Thick for detecting parasites
- Thin for parasitemia and species
- P. knowlesi looks similar to P. malariae but presents like P. falciparum
- Rapid diagnostic test (RDT) for antigens
- BinaxNow is the only test in Canada
- T1 band: histidine-rich protein-2 (HRP-2) of P. falciparum
- T2 band: aldolase, a common antigen of four species of human malaria parasites
- C+ / T1+ / T2+: P. falciparum or mixed
- C+ / T1+ / T2–: P. falciparum
- C+ / T1– / T2+: non-falciparum
- C+ / T1– / T2–: no malaria
- Can remain positive for up to 4 weeks due to detection of dead organisms
- PCR is available
- Done reflexively in Ontario to confirm species and detect a mixed infection
Management
- All returned travellers with fever should have thick and thin smears to rule out malaria
- Management depends on severity, including the level of parasitemia, and country of acquisition, which predicts susceptibilities
- Most of the world is resistant; when in doubt, treat all P. falciparum malaria as chloroquine-resistant
- All patients with P. falciparum malaria should be considered for hospital admission
- If severe, advocate for ICU-level care
Uncomplicated malaria
- Chloroquine-sensitive P. falciparum (Mexico, Central America west of the Panama Canal, Haiti, the Dominican Republic, and most of the Middle East), P. vivax, P. ovale, P. malariae, and P. knowlesi
- Oral chloroquine 600 mg base po once, followed by 300 mg base po at 6, 24, and 48 hours
- The dose for salt is 1000 mg and 500 mg
- Chloroquine-resistant P. falciparum (most of the world) or chloroquine-resistant P. vivax (Papua New Guinea and Indonesia)
- Atovaquone-proguanil 1000/400 mg (4 tablets) po daily for 3 days
- Alternative: quinine 542 mg base (650 mg salt) po q8h for 3 to 7 days, plus doxycycline 100 mg po bid for 7 days
- Prevention of relapsing P. vivax and P. ovale
- Indicated for patients with prolonged exposure
- Primaquine 30 mg base daily for 14 days following chloroquine
- First rule out G6PD deficiency and pregnancy
- If pregnant, just treat intermittently until after delivery
Severe malaria
- Usually due to P. falciparum, though can also be caused by P. vivax or P. knowlesi
- Admit to hospital, ideally ICU
- Frequent vitals & urine output
- Capillary glucose at least q4h
- Antimalarials
- Artesunate 2.4 mg/kg IV bolus over 1-2 minutes at 0, 12, 24, and 48 hours
- Four hours after the last dose, add one of the following
- Atovaquone-proguanil 1000/400 mg po daily for 3 days
- Doxycycline 100 mg po BID for 7 days
- Clindamycin 10 mg/kg IV followed by 5 mg/kg IV q8h for 7 days
- Quinine 5.8 mg/kg IV loading dose over 30 min followed by 8.3 mg/kg IV infused over 4 hours q8h for 7 days
- Dose of quinine dihydrochloride would be 7 mg/kg and 10 mg/kg
- Do not use loading dose if they had quinine within 24 hours or mefloquine within 2 weeks
- Switch to oral tablets as soon as able to swallow
- If no infusion pump, run the loading dose as quinine 16.7 mg/kg IV over 4 hours
- Concurrent to last dose of quinine
- Atovaquone-proguanil 1000/400 mg po daily for 3 days
- Doxycycline 100 mg po BID for 7 days
- Clindamycin 10mg/kg IV load followed by 5 mg/kg q8h for 7 days
- Clindamycin is the preferred treatment in pregnant women and children under 8 years
- Treat seizures with benzos; No role for seizure prophylaxis
- Avoid steroids in cerebral malaria (worse outcomes)
- Exchange transfusion has been investigated; it reduces parasitemia but has no clinically-important benefits
- CATMAT still recommends considering it if parasitemia ≥10%
- Usually 5 to 10 units of pRBC
Pregnancy
- Clindamycin, not doxycycline or atovaquone-proguanil, should be added to artesunate or quinine
- Quinine and chloroquine is safe in pregnancy; artesunate safe after first trimester
- So for chloroquine-resistant malaria in pregnancy is treated with quinine and clindamycin
Prevention and Chemoprophylaxis
Behavioural interventions
- Mosquito avoidance (Anopheles mosquitoes are evening biters)
- Long sleeves & pants
- Insecticide-treated clothing
- Bed nets, screens on doors & windows
Chemoprophylaxis
- Chemoprophylaxis is recommended for travelers to endemic areas
- Agent chosen based on the local drug-resistance, patient age, and pregnancy status
Chloroquine-sensitive regions
- Regions include Haiti, the Dominican Republic, Central America north of the Panama Canal, parts of Mexico, parts of South America, north Africa, parts of the Middle East, and west/central China
- Drugs of choice
- Chloroquine (Aralen) preferred, though hydroxychloroquine (Plaquenil) is also acceptable
- Chloroquine or hydroxychloroquine once a week, from 1 week before to 4 weeks after exposure
- Alternatives: atovaquone-proguanil, doxycycline or mefloquine
Chloroquine-resistant regions
- Regions include most of sub-Saharan Africa, South America, Oceania and Asia
- See the CATMAT list for specific countries
- Some areas of Thailand, Myanmar (Burma), Laos and Cambodia, and southern Vietnam are both chloroquine-resistant and mefloquine-resistant
- Drugs of choice
- Atovaquone-proguanil daily, from 1 day before to 1 week after exposure (because it treats the liver phase)
- Doxycycline daily, from 1 day before to 4 weeks after exposure (does not treat the liver phase)
- Mefloquine weekly, from 1 week before to 4 weeks after exposure
- Alternatives: primaquine daily, from 1 day before to 7 days after exposure
- Primaquine contraindicated in G6PD deficiency and pregnancy
Chloroquine-and mefloquine-resistant regions
- Regions include Asia, Africa and the Amazon basin, specifically in rural, wooded regions on the Thai borders with Myanmar, Cambodia, and Laos, as well as in southern Vietnam
- Drugs of choice
- Atovaquone-proguanil daily, from 1 day before to 1 week after exposure
- Doxycycline daily, from 1 day before to 4 weeks after exposure
- No approved drugs for pregnancy or children less than 5 kg, though atovaquone-proguanil may be considered after the first trimester
Pregnancy
- Mefloquine can be used, if they cannot avoid travelling to malaria-endemic areas
- Can cause neuropsychiatric symptoms
Bases and Salts
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Further Reading
