Plasmodium

• Mosquito-borne protozoon that causes malaria

Background

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

• 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 and mature into trophozoites
• Trophozoites develop into schizonts, then rupture the erythrocyte to release more merozoites
  • These cycles of merozoite to trophoziote to schizont to merozoite explain the periodic fevers
• Trophozoites can also develop into gametocytes (micro- or macro-gametocytes), which are taken up by the mosquito
• In the mosquito, the micro- and macro-gametocytes join to form a zygote, which matures into an ookinete then oocyst, which releases infective sporozoites

Pathophysiology

• 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

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 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

Clinical 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
• Usually done three times for improved sensitivity

Rapid diagnostic antigen test (RDT)

• Good sensitivity and specificity for falciparum malaria, but lower sensitivity (66-88%) for non-falciparum or at low levels of parasitemia
• May cross-react with ANA and RF, and with dengue, hepatitis C, leishmaniasis, trypanosomiasis, schistosomiasis, tuberculosis, and toxoplasmosis
• May be positive up to 4 weeks after treatment from persistent gamecotyes and slow antigen clearance, so are not used to document treatment success
• 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

Molecular

• 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
  • See the CATMAT list for specific countries
• 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

Further Reading

• Boggild A, et al. Summary of recommendations for the diagnosis and treatment of malaria by the Committee to Advise on Tropical Medicine and Travel (CATMAT). CCDR 2014;40(7).