Etiology

Malaria is caused by intracellular Plasmodium protozoa transmitted to humans by female Anopheles mosquitoes. Prior to 2004, only 4 species of Plasmodium were known to cause malaria in humans: P. falciparum, P. malariae, P. ovale, and P. vivax. In 2004 P. knowlesi (a primate malaria species) was also shown to cause human malaria, and cases of P. knowlesi infection have been documented in Malaysia, Indonesia, Singapore, and the Philippines. Malaria also can be transmitted through blood transfusion, use of contaminated needles, and from a pregnant woman to her fetus. The risk for blood transmission is small and decreasing in the USA but may occur by way of whole blood, packed red blood cells, platelets, leukocytes, and organ transplantation.

Epidemiology

Malaria is a major worldwide problem, occurring in more than 100 countries with a combined population of over 1.6 billion people (Fig. 280-1). The principal areas of transmission are Africa, Asia, and South America. P. falciparum and P. malariae are found in most malarious areas. P. falciparum is the predominant species in Africa, Haiti, and New Guinea. P. vivax predominates in Bangladesh, Central America, India, Pakistan, and Sri Lanka. P. vivax and P. falciparum predominate in Southeast Asia, South America, and Oceania. P. ovale is the least common species and is transmitted primarily in Africa. Transmission of malaria has been eliminated in most of North America (including the USA), Europe, and the Caribbean, as well as Australia, Chile, Israel, Japan, Korea, Lebanon, and Taiwan.

Figure 280-1 Global spatial distribution of Plasmodium falciparum malaria in 2007 and preliminary global distribution of Plasmodium vivax malaria.

(From Crawley J, Chu C, Mtove G, et al: Malaria in children, Lancet 375:1468–1478, 2010, Fig 1, p 1469.)

Most cases of malaria in the USA occur among previously infected visitors to the USA from endemic areas and among U.S. citizens who travel to endemic areas without appropriate chemoprophylaxis. The most common regions of acquisition of the 10,100 cases of malaria reported to the Centers for Disease Control and Prevention (CDC) among U.S. citizens between 1985 and 2001 were sub-Saharan Africa (58%), Asia (18%), and the Caribbean and Central or South America (16%). Most of the fatal cases were caused by P. falciparum (94% or 66 of the 70 cases), of which 47 (71%) were acquired in sub-Saharan Africa. Rare cases of apparent locally transmitted malaria have been reported since the 1950s. These cases are likely due to transmission from untreated and often asymptomatic infected individuals from malaria endemic countries who travel to the USA and infect local mosquitoes or to infected mosquitoes from malaria endemic areas that are transported to the USA on airplanes.

Pathogenesis

Plasmodium species exist in a variety of forms and have a complex life cycle that enables them to survive in different cellular environments in the human host (asexual phase) and the mosquito (sexual phase) (Fig. 280-2). A marked amplification of Plasmodium, from approximately 10² to as many as 10¹⁴ organisms, occurs during a 2-step process in humans, with the 1st phase in hepatic cells (exoerythrocytic phase) and the 2nd phase in the red cells (erythrocytic phase). The exoerythrocytic phase begins with inoculation of sporozoites into the bloodstream by a female Anopheles mosquito. Within minutes, the sporozoites enter the hepatocytes of the liver, where they develop and multiply asexually as a schizont. After 1-2 wk, the hepatocytes rupture and release thousands of merozoites into the circulation. The tissue schizonts of P. falciparum, P. malariae, and apparently P. knowlesi rupture once and do not persist in the liver. There are 2 types of tissue schizonts for P. ovale and P. vivax. The primary type ruptures in 6-9 days, and the secondary type remains dormant in the liver cell for weeks, months, or as long as 5 yr before releasing merozoites and causing relapse of infection. The erythrocytic phase of Plasmodium asexual development begins when the merozoites from the liver penetrate erythrocytes. Once inside the erythrocyte, the parasite transforms into the ring form, which then enlarges to become a trophozoite. These latter 2 forms can be identified with Giemsa stain on blood smear, the primary means of confirming the diagnosis of malaria (Fig. 280-3). The trophozoite multiplies asexually to produce a number of small erythrocytic merozoites that are released into the bloodstream when the erythrocyte membrane ruptures, which is associated with fever. Over time, some of the merozoites develop into male and female gametocytes that complete the Plasmodium life cycle when they are ingested during a blood meal by the female anopheline mosquito. The male and female gametocytes fuse to form a zygote in the stomach cavity of the mosquito. After a series of further transformations, sporozoites enter the salivary gland of the mosquito and are inoculated into a new host with the next blood meal.

Figure 280-2 Life cycle of Plasmodium spp.

(From Centers for Disease Control and Prevention: Laboratory diagnosis of malaria: Plasmodium spp. [pdf]. www.dpd.cdc.gov/dpdx/HTML/PDF_Files/Parasitemia_and_LifeCycle.pdf. Accessed September 20, 2010.)

Figure 280-3 Giemsa-stained thick (A) and thin (B-H) smears used for the diagnosis of malaria and the speciation of Plasmodium parasites. A, Multiple signet-ring Plasmodium falciparum trophozoites, which are visualized outside erythrocytes. B, A multiply infected erythrocyte containing signet-ring P. falciparum trophozoites, including an accolade form positioned up against the inner surface of the erythrocyte membrane. C, Banana-shaped gametocyte unique to P. falciparum. D, Ameboid trophozoite characteristic of Plasmodium vivax. Both P. vivax– and Plasmodium ovale–infected erythrocytes exhibit Schuffner dots and tend to be enlarged compared with uninfected erythrocytes. E, P. vivax schizont. Mature P. falciparum parasites, by contrast, are rarely seen on blood smears because they sequester in the systemic microvasculature. F, P. vivax spherical gametocyte. G, P. ovale trophozoite. Note Schuffner dots and ovoid shapes of the infected erythrocyte. H, Characteristic band form trophozoite of Plasmodium malariae, containing intracellular pigment hemozoin.

(A, B, and F from Centers for Disease Control and Prevention: DPDx: laboratory identification of parasites of public health concern. www.dpd.cdc.gov/dpdx/. C, D, E, G, and H courtesy of David Wyler, Newton Centre, MA.)

Four important pathologic processes have been identified in patients with malaria: fever, anemia, immunopathologic events, and tissue anoxia. Fever occurs when erythrocytes rupture and release merozoites into the circulation. Anemia is caused by hemolysis, sequestration of erythrocytes in the spleen and other organs, and bone marrow suppression. Immunopathologic events that have been documented in patients with malaria include excessive production of proinflammatory cytokines, such as tumor necrosis factor, that may be responsible for most of the pathology of the disease, including tissue anoxia; polyclonal activation resulting in both hypergammaglobulinemia and the formation of immune complexes; and immunosuppression. Cytoadherence of infected erythrocytes to vascular endothelium occurs in P. falciparum malaria and may lead to obstruction of blood flow and capillary damage, with resultant vascular leakage of blood, protein, and fluid and tissue anoxia. In addition, hypoglycemia and lactic acidemia are caused by anaerobic metabolism of glucose. The cumulative effects of these pathologic processes may lead to cerebral, cardiac, pulmonary, intestinal, renal, and hepatic failure.

Immunity after Plasmodium species infection is incomplete, preventing severe disease but still allowing future infection. In some cases, parasites circulate in small numbers for a long time but are prevented from rapidly multiplying and causing severe illness. Repeated episodes of infection occur because the parasite has developed a number of immune evasive strategies, such as intracellular replication, vascular cytoadherence that prevents infected erythrocytes from circulating through the spleen, rapid antigenic variation, and alteration of the host immune system resulting in partial immune suppression. The human host response to Plasmodium infection includes natural immune mechanisms that prevent infection by other Plasmodium species, such as those of birds or rodents, as well as several alterations in erythrocyte physiology that prevent or modify malarial infection. Erythrocytes containing hemoglobin S (sickle erythrocytes) resist malaria parasite growth, erythrocytes lacking Duffy blood group antigen are resistant to P. vivax, and erythrocytes containing hemoglobin F (fetal hemoglobin) and ovalocytes are resistant to P. falciparum. In hyperendemic areas, newborns rarely become ill with malaria, in part because of passive maternal antibody and high levels of fetal hemoglobin. Children 3 mo to 2-5 yr of age have little specific immunity to malaria species and therefore suffer yearly attacks of debilitating and potentially fatal disease. Immunity is subsequently acquired, and severe cases of malaria become less common. Severe disease may occur during pregnancy, particularly 1st pregnancies or after extended residence outside the endemic region. In general, extracellular Plasmodium organisms are targeted by antibody, whereas intracellular organisms are targeted by cellular defenses such as T lymphocytes, macrophages, polymorphonuclear leukocytes, and the spleen.

Clinical Manifestations

Children and adults are asymptomatic during the initial phase of infection, the incubation period of malaria infection. The usual incubation periods are 9-14 days for P. falciparum, 12-17 days for P. vivax, 16-18 days for P. ovale, and 18-40 days for P. malariae. The incubation period can be as long as 6-12 mo for P. vivax and can also be prolonged for patients with partial immunity or incomplete chemoprophylaxis. A prodrome lasting 2-3 days is noted in some patients before parasites are detected in the blood. Prodromal symptoms include headache, fatigue, anorexia, myalgia, slight fever, and pain in the chest, abdomen, and joints.

The classic presentation of malaria is seldom noted with other infectious diseases and consists of paroxysms of fever alternating with periods of fatigue but otherwise relative wellness. Febrile paroxysms are characterized by high fever, sweats, and headache, as well as myalgia, back pain, abdominal pain, nausea, vomiting, diarrhea, pallor, and jaundice. Paroxysms coincide with the rupture of schizonts that occurs every 48 hr with P. vivax and P. ovale, resulting in fever spikes every other day. Rupture of schizonts occurs every 72 hr with P. malariae, resulting in fever spikes every 3rd or 4th day. Periodicity is less apparent with P. falciparum and mixed infections and may not be apparent early on in infection, when parasite broods have not yet synchronized. Patients with primary infection, such as travelers from nonendemic regions, also may have irregular symptomatic episodes for 2-3 days before regular paroxysms begin. Children with malaria often lack typical paroxysms and have nonspecific symptoms, including fever (may be low-grade but is often greater than 104°F), headache, drowsiness, anorexia, nausea, vomiting, and diarrhea. Distinctive physical signs may include splenomegaly (common), hepatomegaly, and pallor due to anemia. Typical laboratory findings include anemia, thrombocytopenia, and a normal or low leukocyte count. The erythrocyte sedimentation rate (ESR) is often elevated.

P. falciparum is the most severe form of malaria and is associated with higher density parasitemia and a number of complications. The most common serious complication is severe anemia, which also is associated with other malaria species. Serious complications that appear unique to P. falciparum include cerebral malaria, acute renal failure, respiratory distress from metabolic acidosis, algid malaria and bleeding diatheses (see later section on complications, and Table 280-1). The diagnosis of P. falciparum malaria in a nonimmune individual constitutes a medical emergency. Severe complications and death can occur if appropriate therapy is not instituted promptly. In contrast to malaria caused by P. ovale, P. vivax, and P. malariae, which usually results in parasitemias of less than 2%, malaria caused by P. falciparum can be associated with parasitemia levels as high as 60%. The differences in parasitemia reflect the fact that P. falciparum infects both immature and mature erythrocytes, while P. ovale and P. vivax primarily infect immature erythrocytes and P. malariae infects only mature erythrocytes. Like P. falciparum, P. knowlesi has a 24 hr replication cycle and can also lead to very high density parasitemia.

P. vivax malaria has long been considered less severe than P. falciparum malaria, but recent reports suggest that in some areas of Indonesia it is as frequent a cause of severe disease and death as P. falciparum. Severe disease and death from P. vivax are usually due to severe anemia and sometimes to splenic rupture. P. ovale malaria is the least common type of malaria. It is similar to P. vivax malaria and commonly is found in conjunction with P. falciparum malaria. P. malariae is the mildest and most chronic of all malaria infections. Nephrotic syndrome is a rare complication of P. malariae infection that is not observed with any other human malaria species. Nephrotic syndrome associated with P. malariae infection is poorly responsive to steroids. Low-level, undetected P. malariae

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