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
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 altogether1
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
Caused by massive hemolysis leading to hemoglobinuria, usually in the context of severe malaria but with low or undetectable parasitemia
Increasing pfhrp2/3 mutations leading to false negatives (higher in South America and Africa)[1]
BinaxNOW is the only test in Canada
3 bands
C band: control
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
Interpretation
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 and LAMP are available
PCR is done reflexively in Ontario to confirm species and detect a mixed infection
LAMP may need to replace RDT due to increasing falciparum false-negatives
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
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)
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
Atovaquone-proguanil is likely safe and can be used after the first trimester for any of the above regimens
↑Jejaw Zeleke, A., Hailu, A., Bayih, A.G. et al.Plasmodium falciparum histidine-rich protein 2 and 3 genes deletion in global settings (2010–2021): a systematic review and meta-analysis. Malar J21, 26 (2022). https://doi.org/10.1186/s12936-022-04051-7
References
^ Severe Malaria. Tropical Medicine & International Health. 2014;19:7-131. doi:10.1111/tmi.12313_2.
