Malaria: Plasmodium Parasite Life Cycle

• Malaria is caused by Plasmodium, an obligate intracellular protozoan.
• Plasmodium undergoes asexual reproduction in humans.
• Plasmodium undergoes sexual reproduction in mosquitoes.
• Species include P. falciparum, P. vivax, P. malariae, P. ovale, and P. knowlesi.

Epidemiology

• Malaria causes 1-3 million deaths per year in Africa.
• About 800 travelers are diagnosed with malaria in the USA.
• Worldwide, 300-500 million malaria infections occur each year.

Distribution

• P. vivax is the most common type of malaria in temperate regions.
• P. falciparum is common in the tropics.
• P. ovale is common in Africa.
• Malaria transmission happens through the bite of infected anopheline mosquitoes.
• Malaria transmission can also occur through inoculation of infected blood.

Infective Stage - Sporozoites

• Sporozoites are injected from mosquito salivary glands.
• Sporozoites circulate to the liver.
• Sporozoites invade hepatic parenchymal cells.
• Sporozoites multiply in stages called exoerythrocytic forms.
• Sporozoites become hepatic schizonts.
• Schizonts rupture after 1-2 weeks of development.
• Each schizont releases thousands of merozoites.

Erythrocyte Invasion

• Merozoites enter circulation and invade erythrocytes, never invading the liver.
• After invasion, ring forms appear.
• Trophozoites emerge with increased cytoplasm.
• Schizonts appear when nuclear division occurs.
• P. vivax and P. ovale primary exoerythrocytic forms.
• Rupture of forms results in parasitemia.
• Some remain in liver for months or years.
• Hypnozoites are latent forms of malaria that may cause relapses when rupture occurs

Schizogony

• Schizogony refers to the asexual cycle that takes 48-72 hours.
• It involves intracellular maturation, which leads to schizont development and rupture and occurs in humans.
• P. malariae schizogony takes 72 hours whereas other species take 48 hours.

Sporogony

• Sporogony refers to the sexual cycle taking around 10 days.
• Sporogony begins with gametocytes from merozoites.
• Female anopheline mosquitoes ingest gametocytes.
• Exflagellation happens within the mosquito's gut to produce male gametes.
• Microgametes fertilize macrogametes, forming a zygote.
• Ookinetes from zygote invade the gut epithelium.
• Oocysts are formed in the gut wall where sporozoites develop and migrate to the salivary glands.

Pathogenesis

• Only the asexual intraerythrocytic parasite can cause disease.
• Fever is directly associated with schizont rupture and pyrogen liberation.
• Tissue macrophages secrete endogenous pyrogens.
• Tumor necrosis factor-cachectin is also produced, resulting in periodic fevers.
• Anemia can be caused by Hemolysis of infected erythrocytes upon rupture.
• Splenic sequestration of erythrocytes can result in anemia.
• Possibly an autoimmune basis.
• Tissue hypoxia can cause pulmonary edema, acute renal failure, cerebral dysfunction, and malabsorption due to anemia and alterations in microcirculation.
• Immunopathologic events involve increased circulating immunoglobulins.
• Thrombocytopenia happens due to antibody-mediated splenic sequestration.
• Glomerulonephritis is related to deposition of immune complexes mainly on P. malariae

Clinical Manifestations

• Patients may experience periodic fevers and chills.
• Patients may experience Splenomegaly and anemia.
• Non-specific malaria symptoms appear days before parasitemia, including general malaise, headache, myalgia, fatigue, chest pain, abdominal pain, and arthralgias.
• The cold period involves cold pale skin and cyanosis of lips and nail beds, lasting minutes to 2 hours.
• Hot period symptoms include temperature up to 40°C, warm and dry skin, tachycardia, tachypnea, dry cough, severe headache, backache, abdominal pain, nausea, vomiting, and delirium.
• Physical examination findings include splenomegaly (which may rupture), tender hepatomegaly, jaundice, urticaria, petechial rash, conjunctiva suffusion, hemorrhage, and pulmonary edema.

Complications of P. falciparum

• Hypoglycemia is due to impaired glycogenolysis.
• Pulmonary edema.
• Bleeding and severe hemolysis.
• Lactic acidosis is due to increased anaerobic glycolysis.
• Hypoxic tissues.
• Renal failure.

Cerebral Malaria

• Cerebral malaria is the most serious complication where death can occur in up to 50% of cases.
• Sequestration of parasitized erythrocytes in cerebral capillaries.
• Disturbance of consciousness from somnolence to coma.
• Acute organic brain syndromes.
• Seizures.
• Focal neurologic deficit.
• G-6-PD deficiency is essential for parasite metabolism.
• HbS results in premature death of erythrocyte forms of P. falciparum.

Diagnosis

• Malaria can be diagnosed in patients with Blood smears (Giemsa stains thin and thick smears).
• Indirect hemagglutination can be used.
• An indirect fluorescent antibody test may be used.
• PCR testing.
• Rapid tests (dipstick tests).

Therapy for Malaria

• Therapy is focused on prompt control of acute clinical attacks through rapid elimination of asexual erythrocyte parasites.
• Therapy aims to prevent relapses of vivax and ovale by destruction of hypnozoites.
• Therapy involves prevention of transmission by mosquito using insect repellent DEET.