Microbiology and Epidemiology

Six major species of Plasmodium cause nearly all cases of human disease: P. falciparum, P. vivax, two morphologically identical sympatric species of P. ovale, P. malariae, and P. knowlesi.

• P. falciparum, the cause of most cases of severe disease and most deaths, predominates in Africa, New Guinea, and Hispaniola.
• P. vivax is more common in Central America.
• P. falciparum and P. vivax are equally prevalent in South America, the Indian subcontinent, eastern Asia, and Oceania.
• P. ovale makes up <1% of isolates outside Africa.
• P. malariae is found in most areas (especially throughout sub-Saharan Africa) but is less common.
• P. knowlesi (the monkey malaria parasite) can reliably be identified only by molecular techniques and is present in Borneo and Southeast Asia.
• Malaria is the most important parasitic disease in humans, causing ∼1200 deaths each day.

Pathogenesis

After introduction of sporozoites into the bloodstream by female anopheline mosquitoes, the parasite travels to the liver and reproduces asexually to form merozoites that infect RBCs. The merozoites transform into trophozoites, feed on intracellular proteins (principally hemoglobin), multiply 6- to 20-fold every 48 h (P. knowlesi, 24 h; P. malariae, 72 h), and cause the RBCs to rupture, releasing daughter merozoites. The process then repeats.

• Some parasites develop into long-lived sexual forms called gametocytes, whose uptake by another female anopheline mosquito allows transmission.
• In P. vivax or P. ovale infection, dormant forms called hypnozoites remain in liver cells and may cause disease 2 weeks to >1 year later.
• RBCs infected with P. falciparum may exhibit cytoadherence (attachment to venular and capillary endothelium), rosetting (adherence to uninfected RBCs), and agglutination (adherence to other infected RBCs). The result is sequestration of P. falciparum in vital organs, with consequent underestimation (through parasitemia determinations) of parasite numbers in the body. Sequestration is central to the pathogenesis of falciparum malaria but is not evident in the other human malarias.
• In nonimmune individuals, infection triggers nonspecific host defense mechanisms such as increased splenic filtration.
  • With repeated exposure to malaria, pts develop resistance to high-level parasitemia and disease but not to infection.
  • Hemoglobinopathies (e.g., sickle cell disease, ovalocytosis, thalassemia) and G6PD deficiency are more common in endemic areas and protect against death from malaria.

Clinical Manifestations

Pts initially develop nonspecific symptoms (e.g., headache, fatigue, myalgias) that are followed by fever.

• Febrile paroxysms at regular intervals are unusual and suggest infection with P. vivax or P. ovale.
• Splenomegaly, hepatomegaly, mild anemia, and jaundice may develop.
• The diagnosis of severe falciparum malaria requires one or more of the following: impaired consciousness/coma, severe normocytic anemia, renal failure, pulmonary edema, ARDS, circulatory shock, DIC, spontaneous bleeding, acidosis, hemoglobinuria, jaundice, repeated generalized convulsions, and a parasitemia level of >5%.
  • Cerebral malaria manifests as diffuse symmetric encephalopathy, typically without focal neurologic signs.
  • Coma is an ominous sign associated with mortality rates of ∼20%.
• Pregnant women have unusually severe illness. Premature labor, fetal distress, stillbirth, and delivery of low-birth-weight infants are common.
• Tropical splenomegaly (hyperreactive malarial splenomegaly) may result as a chronic complication of malaria and is characterized by massive splenomegaly, hepatomegaly, and an abnormal immunologic response to infection.

Diagnosis

Although antibody-based diagnostic tests are being used with increasing frequency, demonstration of asexual forms of the parasite on peripheral-blood smears is required for diagnosis.

• Thick and thin smears should be examined; thick smears offer higher diagnostic sensitivity, and thin smears enable identification of the specific Plasmodium species.
• If the level of clinical suspicion is high and smears are initially negative, smear examination should be repeated daily for 2 days.
• Other laboratory findings generally include normochromic, normocytic anemia; elevated inflammatory markers; and thrombocytopenia (∼10⁵ /µL).

Personal Protection Measures

Measures that can protect persons against infection include avoidance of mosquito exposure, with particular caution at peak feeding times (dusk to dawn); use of insect repellents containing DEET (10-35%) or (if DEET is unacceptable) picaridin (7%); suitable clothing; and insecticide-impregnated bed nets.

Chemoprophylaxis

See Table 110-2 Drugs Used in the Prophylaxis of Malaria for prophylaxis options.

• Mefloquine is the only drug advised for pregnant women traveling to areas with drug-resistant malaria and is generally considered safe in the second and third trimesters; data regarding use in the first trimester, although limited, are reassuring.