Plasmodium spp.

**Life cycle:** (1) Infected female Anopheles bite injects sporozoites, which travel to hepatocytes. (2) Exoerythrocytic (liver) stage: sporozoites become schizonts, which release merozoites. In P. vivax and P. ovale, some sporozoites become dormant hypnozoites that cause relapse months to years later. P. falciparum and P. malariae have no hypnozoites. (3) Erythrocytic stage: merozoites invade RBCs and form ring-form trophozoites, then schizonts. RBCs rupture and release more merozoites, causing the periodic fever. (4) Some merozoites become gametocytes, which a mosquito ingests. Sexual reproduction occurs in the mosquito gut. Humans are the intermediate host, and the mosquito is the definitive host.

**RBC invasion receptors:** P. vivax uses the Duffy antigen (Fy), so Duffy-negative individuals, mostly of West African descent, are resistant. P. falciparum uses multiple receptors, including glycophorins, and infects RBCs of all ages. P. vivax and P. ovale prefer reticulocytes. P. malariae prefers old RBCs.

**Clinical features:** Cyclic fever, chills and rigors, and sweats; headache and myalgias; anemia from hemolysis; splenomegaly; jaundice; and hemoglobinuria. Fever timing: P. vivax and P. ovale are tertian (48 h), P. malariae is quartan (72 h), and P. falciparum is irregular or continuous. P. knowlesi is quotidian (24 h).

**P. falciparum complications:** Infected RBCs express PfEMP1 on knobs, which causes cytoadherence and sequestration in microvasculature. This leads to: - Cerebral malaria (altered mental status, seizures, coma) - Severe anemia - Acute kidney injury and blackwater fever (massive hemolysis with hemoglobinuria) - ARDS and pulmonary edema - Hypoglycemia (also worsened by quinine) - Lactic acidosis - Thrombocytopenia and DIC Severe disease is defined by parasitemia >5% (or >10% in some references) plus end-organ dysfunction. It is a medical emergency treated with IV artesunate.

**Other associations:** P. malariae causes immune complex nephrotic syndrome (membranous or FSGS pattern). Tropical splenomegaly (hyperreactive malarial splenomegaly) is another association. Protection against severe malaria comes from sickle cell trait (HbAS), HbC, thalassemia, G6PD deficiency, and Duffy-negativity (P. vivax only). Hypnozoites are the reason P. vivax and P. ovale need a second drug.

**Diagnosis:** Thick and thin Giemsa-stained peripheral blood smears are the gold standard. The thick smear detects the parasite and the thin smear identifies the species and quantifies parasitemia. Repeat smears every 12-24 h x3 if the first is negative and suspicion is high. Rapid antigen tests (HRP2 for P. falciparum, pLDH) and PCR are also used. Findings by species: - P. falciparum: Banana-shaped gametocytes, multiple ring forms per RBC, and accole (applique) forms. Mature trophozoites and schizonts are generally not seen on the peripheral smear because of sequestration. - P. vivax and P. ovale: Enlarged RBCs with Schüffner stippling. P. ovale RBCs appear oval and fimbriated. - P. malariae: Band forms and "basket-shaped" or rosette schizonts. RBCs are normal size.

**Treatment:** - Uncomplicated chloroquine-sensitive disease (P. vivax, P. ovale, P. malariae, and sensitive P. falciparum): chloroquine, or hydroxychloroquine. - Chloroquine-resistant P. falciparum (most areas) and P. vivax in some regions: artemisinin-based combination therapy (e.g., artemether-lumefantrine), atovaquone-proguanil, or mefloquine. - Severe or complicated malaria: IV artesunate (followed by an oral regimen). Quinidine is no longer available in the US. - Radical cure for P. vivax and P. ovale: primaquine or tafenoquine to kill hypnozoites. Check G6PD first because of the risk of hemolysis. - Pregnancy: avoid primaquine, tafenoquine, and doxycycline. Mefloquine is an option for prophylaxis.

**Prophylaxis:** Choose by destination resistance patterns. Options include atovaquone-proguanil, doxycycline, mefloquine, chloroquine or hydroxychloroquine (only in chloroquine-sensitive areas), and primaquine or tafenoquine. Also use bed nets (insecticide-treated), DEET, and protective clothing. Vaccines (RTS,S and R21/Matrix-M) are recommended by the WHO for children in endemic areas.

**Pathophysiology of resistance:** Chloroquine normally accumulates in the parasite's food vacuole and blocks heme polymerization, so toxic free heme builds up. Resistance results from PfCRT mutations that efflux the drug. Artemisinins generate free radicals through activation by heme iron. Partial artemisinin resistance is linked to PfKelch13 mutations, which are emerging in Southeast Asia and Africa.

**Board pearls:** Fever after travel to an endemic area means getting a blood smear immediately. Cyclic fever with hemolytic anemia and splenomegaly suggests malaria. Relapse months after leaving an endemic area points to P. vivax or P. ovale. Coma plus a high parasitemia points to P. falciparum. Differential diagnosis includes babesiosis (Maltese cross tetrads, Ixodes tick, no liver stage). Hemolysis from primaquine in G6PD deficiency is a classic drug-adverse-effect question.