Malaria and Plasmodium Protozoa

• Malaria is caused by Plasmodium, an obligate intracellular protozoa.
• Plasmodium reproduces asexually in humans and sexually in mosquitos.
• The five species of Plasmodium are P. falciparum, P. vivax, P. malariae, P. ovale, and P. knowlesi.
• Annually, 1-3 million malaria-related deaths occur in Africa.
• Approximately 800 travelers in the USA are diagnosed with malaria each year.
• 300-500 million infections develop worldwide each year.
• P. vivax is the most common type in temperate regions.
• P. falciparum is most often found in tropical regions.
• P. ovale is most often found in Africa.
• Malaria is transmitted via the bite of an infected anopheline mosquito and inoculation of infected blood.
• The infective stage of the malaria parasite is called sporozoites.
• Sporozoites are injected from the mosquito's salivary glands.
• Sporozoites circulate to the liver, invade hepatic parenchymal cells, and multiply into exoerythrocytic forms.
• Exoerythrocytic forms become become hepatic schizonts.
• Schizonts rupture after 1-2 weeks of development.
• Each ruptured schizont releases thousands of merozoites.
• Merozoites then enter circulation and invade erythrocytes, but never invade the liver.
• Ring forms develop when erythrocytes are invaded.
• Trophozoites develop next, where cytoplasm increases.
• Schizonts then develop, during which nuclear division occurs.

P. vivax- P. ovale

• These forms result in primary exoerythrocytic forms and rupture resulting in parasitemia.
• Some parasites can remain in the liver for months or years.
• These latent forms are called hypnozoites.
• Relapses may occur when hypnozoites rupture.

Schizogony

• The asexual cycle lasts 48-72 hours and occurs in humans.
• Intracellular maturation leads to the development of a schizont and its ultimate rupture.
• P. malariae has a 72 hour schizogony cycle.
• Other strains have a 48 hour cycle.

Sporogony

• Sporogony is the sexual cycle which lasts 10 days.
• The cycle begins with gametocytes from merozoites.
• Female anopheline mosquitos ingest gametocytes.
• Exflagellation of male gametes occurs within the mosquito's gut.
• Microgametes fertilize macrogametes and form a zygote.
• Ookinetes from the zygote invades the gut epithelium.
• Oocysts are formed in the gut wall; then sporozoites develop.
• The sporozoites then migrate to the salivary glands.
• Only the asexual intraerythrocytic parasite can cause the disease.

Pathogenic mechanisms

• Fever
• Anemia
• Tissue hypoxia
• Immunopathologic events
• Fever is a direct result of schizont rupture, and the parasite releases pyrogen
• Endogenous pyrogen is secreted by tissue macrophages.
• Fever is also caused by tumor necrosis factor-cachectin.
• These result in periodic fevers.
• Hemolysis is caused by infected erythrocytes and rupture, resulting in anemia.
• Anemia may also occur as a result of splenic sequestration of erythrocytes and potentially and autoimmune basis.
• Tissue hypoxia can result from anemia and alterations to microcirculation, which can cause pulmonary edema, acute renal failure, cerebral dysfunction, and malabsorption.
• Tissue hypoxia can also cause gram negative sepsis.
• Immunopathologic events can lead to an increase in circulating immunoglobulins, thrombocytopenia via antibody-mediated splenic sequestration, and glomerulonephritis via the deposition of immune complexes.
• Glomerulonephritis occurs mainly with P. malariae infections

Clinical Manifestations

• Periodic fevers and chills
• Splenomagaly
• Anemia
• Non-specific symptoms may also occur days before parasitemia, including general malaise, headache, myalgia, fatigue, chest pain, abdominal pain, and arthralgias.
• During the cold period, patients can present with cold pale skin, cyanosis of the lips, cyanosis of nail beds, and peripheral vasoconstriction.
• During the hot period, temperature rises up to 40°C, with warm dry skin, tachycardia, tachypnea, dry cough, severe headache, backache, abdominal pain, nausea, vomiting, and delirium.

Physical examination findings

• Splenomegaly, which may rupture
• Tender hepatomegaly
• Jaundice
• Urticaria
• Petechial rash
• Conjunctiva suffusion
• Hemorrhage
• Pulmonary edema

Complications

• Observed with P. falciparum: hypoglycemia, pulmonary edema, bleeding, severe hemolysis, lactic acidosis, hypoxic tissues, and renal failure
• Cerebral malaria is the most serious complication, with potential death up to 50%.
• Sequestration of parasitized erythrocytes occurs in cerebral capillaries.
• Disturbances of consciousness include somnolence and coma.
• Acute organic brain syndromes may occur.
• Potential seizures
• Focal neurologic deficits

Selective Advantages Against Malaria

• G-6-PD deficiency is essential for parasite metabolism.
• HbS results in premature death of erythrocyte forms, especially with P. falciparum.

Diagnosis

• Diagnosis includes blood smears, using Giemsa stains on thin and thick smears.
• Indirect hemagglutination test
• Indirect fluorescent antibody test
• PCR test
• Rapid tests that are dipstick tests

Therapy

• Therapy is directed at prompt control of acute clinical attack by rapid elimination of asexual erythrocyte parasites.
• Prevention of relapses results from destroying hypnozoites of vivax and ovale.
• Transmission is prevented by mosquito insect repellent DEET (diethyltoluamide).