Plasmodium

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Plasmodium / (Redirected from Malaria)
  • 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)
    • Most common cause of disease in humans is Plasmodium falciparum
    • 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
      • Chloroquine-resistant P. falciparum is widespread in sub-Saharan Africa, Asia, and the Americas
        • Chloroquine-susceptible is in Mexico, regions west/north of the Panama Canal, Haiti, and the Dominican Republic, and parts of Middle East
      • 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 Manifestations

  • History of travel to an endemic country
  • Non-specific febrile illness with headache, myalgias, and malaise
  • Incubation period can vary, but is generally 9 to 14 days for P. falciparum, 12 to 18 days P. vivax and P. ovale, and longer for others
  • Fevers are often periodic, appearing based on rupture of schizonts (tertian and quartan fever)
    • q24h: P. falciparum, but wide variation
    • q48h: P. vivax or P. ovale
    • q72h: P. malariae
    • May vary by timepoint in infection, with early infection having daily or more frequent fevers from shedding from the liver stage
  • Leukopenia more common
  • May have concurrent bacterial or other infections

Severe Malaria

  • Mostly caused by P. falciparum, though can also be caused by P. vivax

CATMAT Criteria (2019)

  • Severe disease is defined as the presence of any one of criteria below
  • Clinical
    • Prostration (unable to walk to sit up without assistance) or impaired consciousness
    • Respiratory distress
    • Multiple convulsions (>2 in 24 hours), which can be from cerebral malaria, hypoglycemia, severe metabolic acidosis, etc
    • Circulatory collapse (SBP <80 in adults, <50 in children)
    • Pulmonary edema
    • Abnormal bleeding
    • Jaundice (clinical or total bilirubin >25)
    • Hemoglobinuria (macroscopic)
  • Laboratory
    • Severe anemia (Hb ≤70 or Hct <20%)
    • Hypoglycemia (<2.2)
    • Acidosis (pH <7.25 or bicarb <15)
    • Renal impairment (creatinine >265)
    • Hyperlactatemia (>5 mmol/L)
    • Hyperparasitemia
      • ≥2% for children <5 years
      • ≥5% for non-immune adults and children ≥5 years
      • ≥10% for semi-immune adults and children ≥5 years
  • Non-immune: born in non-endemic or low-transmission areas (e.g. as travellers), and those who are more than 6 to 12 months away from malaria exposure
  • Semi-immune: birth and long-term residence in an endemic country and prior episodes of malaria

Cerebral Malaria

  • Classically defined as coma not attributable to other cause such as post-ictal state, hypoglycemia, or another disease altogether2014se
  • Seizures are common
  • Most suggestive physical examination finding that helps to rule in malaria and rule out other causes of fever and coma is malarial retinopathy, which can include:
    • Patchy retinal whitening in the macula (especially peri-foveal) and/or in the peripheral retina
    • White or orange discolouration of retinal vessels
    • White-centred haemorrhages
    • Papilloedema
  • Pathophysiology is the sequestration of erythrocytes in the cerebral microvessels

Blackwater Fever

Malaria in Pregnancy

  • Accumulation of infected erythrocytes in the placenta, causing IUGR, prematurity, and neonatal mortality
  • P. falciparum has a tropism for the placenta, and can form a reservoir for recurrence even after appropriate treatment

Late or Relapsing Malaria

  • P. vivax and P. ovale can have liver stages (hypnozoites) that lie latent for months to years before causing relapses
  • P. malariae can have a low-level asymptomatic parasitemia lasting for years before presentation

Differential Diagnosis

Diagnosis

Thick and Thin Peripheral Blood Films

  • Thick for detecting parasites, thin for parasitemia and species
  • Usually done three times over three days for improved sensitivity
  • Clues on microscopy:
    • Banana or crescent-shaped gametocytes: P. falciparum
    • Only ring forms, without trophozoites: P. falciparum more likely
    • Amoeboid trophozoite: P. vivax
    • Ring form in an enlarged erythrocyte: P. vivax
    • Band-shaped trophozoite: P. malariae
    • Ring form in an oval-shaped erythrocytes: P. ovale
    • Looks like P. malariae but clinically severe: P. knowlesi

Rapid Diagnostic Antigen Test (RDT)

  • Detects Plasmodium antigen in circulating blood
  • Good sensitivity and specificity for falciparum malaria, but lower sensitivity (66-88%) for non-falciparum or at low levels of parasitemia
  • BinaxNOW is the only test in Canada
    • T1 band: histidine-rich protein-2 (HRP-2) of P. falciparum, which is fairly specific and sensitive
    • 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, persistent gamecotyes, and slow antigen clearance, so are not used to document treatment success
  • Because of the low specificity, every patient with a positive RDT must have a peripheral blood film

Molecular Testing

  • 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 species and susceptibility (predicted by country of acquisition), and severity (including the level of parasitemia)
    • Most of the world has chloroquine-resistant P. falciparum, so when in doubt, treat all P. falciparum malaria as resistant
  • All patients with P. falciparum malaria should be considered for hospital admission
    • If severe, advocate for ICU-level care
    • If severe, monitor for hypoglycemia
    • Monitor with daily peripheral blood films until they are negative

Concurrent Supportive Care

  • Fluid resuscitation as needed (too much may be harmful in children)
  • Rule out hypoglycemia if sudden change in clinical status (worsened with quinine)
  • Avoid steroids, which are associated with worse outcomes in cerebral malaria
  • Correct coagulopathy and bleeding with blood products and vitamin K
  • If shock develops, treat empirically with antibiotics while getting blood cultures to rule out intercurrent bacteremia

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
    • If from Papua New Guinea or Indonesia adjacent to Papua New Guinea, treat with atovaquone-proguanil
  • Chloroquine-resistant P. falciparum (most of the world) or chloroquine-resistant P. vivax (Papua New Guinea and Indonesia)
  • Prevention of relapsing P. vivax and P. ovale with radical cure

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 and urine output
    • Capillary glucose at least q4h
    • Follow peripheral blood films q12-24h until cleared, and longer if pregnant
      • With P. falciparum, can have some fluctuations due to irregular releasing from sequestration
      • Parasitemia and clinical status should both improve by 48 to 72 hours
  • Antimalarials
    • Artesunate 2.4 mg/kg IV bolus over 1-2 minutes at 0, 12, 24, and 48 hours
      • Artesunate is held in specific centres in Canada
      • Should be followed by weekly CBC x4 to monitor for post-artesunate delayed hemolysis
      • Four hours after the last dose, add one of the following:
    • 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
      • Monitor for cardiovascular toxicity (hypotension and QTc prolongation), ototoxicity (tinnitus and hearing loss), and hypoglycemia (which is exacerbated by quinine)
      • Concurrent to last dose of quinine
  • Treat seizures with benzodiazepines; 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

  • Uncomplicated chloroquine-susceptible malaria:
  • Uncomplicated chloroquine-resistant P. falciparum or P. vivax:
  • Prevention of relapsing P. vivax and P. ovale:
    • Maintained chloroquine prophylaxis 300 mg base (500 mg salt) PO weekly for the duration of their pregnancy
    • Reassess for terminal with primaquine or tafenoquine prophylaxis after delivery
  • Severe malaria:
    • Preferred is artesunate followed by clindamycin
    • Alternative is quinine followed by clindamycin
    • There are few data on artesunate in first trimester, but it appears safe, and the overall risk-benefit assessment favours treatment
    • Monitor peripheral blood films q12-24h until cleared, and then for a few more days, to confirm clearance and no relapse from parasites sequestered in the placenta
  • Other antimalarials

Prevention

Behavioural Interventions

  • Mosquito avoidance (Anopheles mosquitoes are evening biters)
    • Long sleeves & pants
    • Insecticide-treated clothing
    • Bed nets, screens on doors & windows

Chemoprophylaxis

Further Reading