Mosquito-borne Plasmodium infection; P. falciparum causes most morbidity and severe disease — empiric treatment guided by species and severity.
Also known as: malaria, Plasmodium falciparum, Plasmodium vivax, P. ovale, P. malariae, P. knowlesi
Overview
Parasitic illness caused by Plasmodium protozoa transmitted by female Anopheles mosquitoes. Five species infect humans: P. falciparum, P. vivax, P. ovale, P. malariae, and P. knowlesi (Southeast Asia, zoonotic). P. falciparum and P. knowlesi cause the most severe disease.
Epidemiology
Worldwide ~240 million cases and ~600,000 deaths annually (WHO 2022), predominantly children under 5 in sub-Saharan Africa. ~2,000 imported US cases yearly. Sub-Saharan Africa: P. falciparum dominant. Asia/Americas: P. vivax common.
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Inadequate vector avoidance (no bed nets, no DEET, dawn/dusk exposure)
Pregnancy (severe malaria more common; placental sequestration)
Asplenia (poor parasite clearance)
Sickle cell trait protects against severe P. falciparum
Pathophysiology
Sporozoites injected by mosquito infect hepatocytes (exoerythrocytic stage). After 1-2 weeks, merozoites release into the bloodstream and invade RBCs (erythrocytic stage). Repeated cycles of RBC rupture cause cyclic fever paroxysms. P. falciparum infects RBCs of all ages and causes cytoadherence to endothelium → microvascular sequestration → cerebral malaria, ARDS, AKI, severe anemia. P. vivax and P. ovale form dormant liver hypnozoites that can reactivate months to years later.
Clinical presentation
Symptoms
Incubation: P. falciparum 7-30 days; P. vivax/ovale weeks to months (or years for relapse)
Cyclic fever paroxysms (cold stage → hot stage → diaphoretic stage); classic 48-hour cycle (vivax, ovale) or 72-hour (malariae); P. falciparum often continuous or irregular
Severe malaria (P. falciparum): impaired consciousness, seizures (cerebral malaria), respiratory distress, jaundice, oliguria, severe anemia, hypoglycemia, shock
Signs / physical exam
Fever (may be high), pallor, hepatosplenomegaly, jaundice
Tachypnea (compensatory for metabolic acidosis)
Petechiae rare (unlike dengue)
Coma, decerebrate posturing in cerebral malaria
Classic findings
A returning traveler from sub-Saharan Africa with cyclic fevers, thrombocytopenia, and elevated LDH — malaria until proven otherwise. Severe disease in non-immune travelers can present with shock, AKI, and ARDS.
Acute HIV — Recent high-risk exposure; RNA viral load
Babesiosis — Tick exposure (Ixodes), hemolytic anemia, intra-erythrocytic ring forms similar to P. falciparum; co-endemic in Northeast US
Influenza, other viral illnesses — Common; presents similarly early — always ask about travel
Diagnostic workup
Diagnostic criteria
Positive blood smear or RDT in a patient with consistent clinical syndrome. Severe malaria per WHO: impaired consciousness, prostration, multiple convulsions, acidosis, hypoglycemia, severe anemia (Hgb <7 adults), AKI, jaundice, pulmonary edema, abnormal bleeding, shock, hyperparasitemia (≥5% in non-immune).
Labs
Thick and thin blood smears (Giemsa) — thick for sensitivity, thin for species and parasitemia quantitation; obtain 3 sets over 12-24 hours before excluding diagnosis
Rapid diagnostic test (RDT, BinaxNOW Malaria) for antigen detection — useful in emergency settings
PCR for species confirmation (especially mixed infections)
G6PD activity before primaquine/tafenoquine (hemolysis risk)
CBC (hemolytic anemia, thrombocytopenia), CMP (AKI, transaminitis), bilirubin (indirect hyperbilirubinemia), glucose (hypoglycemia in severe disease), lactate, coagulation
Imaging
CXR if pulmonary symptoms (rule out ARDS)
CT/MRI brain if cerebral malaria features
Diagnostic algorithm
Species
Periodicity
Hypnozoite?
Severe Disease?
First-line Therapy
P. falciparum
Irregular / 36-48 h
No
Yes (most severe)
Artemether-lumefantrine; IV artesunate if severe
P. vivax
48 h (tertian)
Yes
Rare
Chloroquine + primaquine (or tafenoquine)
P. ovale
48 h (tertian)
Yes
Rare
Chloroquine + primaquine
P. malariae
72 h (quartan)
No
Rare
Chloroquine
P. knowlesi
24 h
No
Yes
Artemisinin-based therapy
Plasmodium species comparison: clinical features and first-line treatment.
Treatment
First-line
Uncomplicated P. falciparum (or unidentified species, chloroquine-resistant areas):
• Artemether-lumefantrine (Coartem) PO × 3 days — first-line in US for uncomplicated falciparum
• Atovaquone-proguanil (Malarone) PO × 3 days
• Quinine sulfate + doxycycline (or tetracycline/clindamycin) × 7 days
Severe malaria:
• IV artesunate (CDC stocks, available emergently 24/7) — initial dose 2.4 mg/kg, repeat at 12 and 24 h, then daily; transition to oral once stable
• Followed by full course of oral artemether-lumefantrine or atovaquone-proguanil
Chloroquine-sensitive infections (P. malariae, P. ovale, P. vivax from chloroquine-sensitive areas):
• Chloroquine phosphate PO × 3 days
Hypnozoite eradication (P. vivax, P. ovale):
• Primaquine 30 mg base daily × 14 days (after G6PD testing); single-dose tafenoquine 300 mg alternative
Second-line / adjunct
Chemoprophylaxis options for travelers:
• Atovaquone-proguanil daily (starting 1-2 days before travel, continuing 7 days after return)
• Doxycycline daily (1-2 days before, continuing 4 weeks after — also covers leptospirosis, rickettsial illness)
• Tafenoquine weekly (3 days before, weekly during, single dose after; requires G6PD testing)
Exchange transfusion historically considered for hyperparasitemia (>10%) — no longer routinely recommended with IV artesunate
Complications
Cerebral malaria (impaired consciousness, seizures, death) — leading cause of mortality
Severe hemolytic anemia, blackwater fever (massive intravascular hemolysis with hemoglobinuria)
ARDS, AKI requiring dialysis
Hypoglycemia (especially in pregnancy, children, quinine-treated patients)
Splenic rupture (especially P. vivax)
Relapse months to years later (P. vivax, P. ovale)
Adverse fetal outcomes in pregnancy (low birth weight, prematurity, stillbirth)
PANCE pearls
Fever in a returned traveler is malaria until proven otherwise — obtain smears within hours, not days.
Always check G6PD before primaquine or tafenoquine (severe hemolysis if deficient).
IV artesunate is now standard for severe malaria worldwide and is available emergently from the CDC for US clinicians.
Pregnant patients with malaria are at extreme risk — early specialist involvement; quinine + clindamycin historically used in first trimester though artemether-lumefantrine increasingly used.
P. vivax and P. ovale hypnozoites require primaquine/tafenoquine for radical cure to prevent relapse months later.
References
WHO 2023 — Guidelines for the treatment of malaria, third edition
CDC 2023 — Treatment of Malaria: Guidelines for Clinicians (United States) — CDC Yellow Book/Malaria branch
AQUAMAT — Dondorp et al., Artesunate versus quinine in the treatment of severe falciparum malaria in African children (Lancet 2010)
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