Malaria

The Pathogen

P. falciparum, which is responsible for most episodes of severe malaria, is endemic in most malarious areas and is by far the predominant species in Africa. Plasmodium vivax is about as common as P. falciparum , except in Africa, but it causes severe disease much less commonly. Plasmodium ovale and Plasmodium malariae are much less common causes of disease and generally do not cause severe illness. Plasmodium knowlesi , which is a parasite of macaque monkeys, is a fairly common zoonosis in parts of Southeast Asia and has been responsible for malarial illnesses, including severe disease, in individuals exposed to macaque-biting vectors in forested areas. Other zoonotic plasmodia, including Plasmodium cynomolgi in southeast Asia and Plasmodium simium and Plasmodium brasilianum (which may be zoonotic forms of P. vivax and P. malariae, respectively, in Brazil), occasionally cause human disease.

Malaria in Endemic Countries

Malaria, which is the most important parasitic disease of humans, is endemic in most of the tropics, including many parts of Africa, South and Central America, the Middle East, the Indian subcontinent, Southeast Asia, and Oceania. Transmission, morbidity, and mortality are greatest in Africa, where infection with P. falciparum predominates. In most other endemic areas, disease caused by both P. falciparum and P. vivax is common. In highly endemic areas, the group at greatest risk is young children, who experience the most episodes of disease and the most deaths. A second high-risk group is pregnant women, with high risks of maternal and fetal morbidity from P. falciparum malaria, including many deaths secondary to low birthweight. In highly endemic areas, in addition to extensive mortality, malaria exerts a massive toll through its adverse effects on child development; contributions to school and work absenteeism; and, overall, billions of dollars in lost income among the poorest citizens of the poorest countries of the world. In areas of developing countries with lower levels of malaria transmission, malaria can be epidemic, with intermittent increases in transmission that cause major morbidity in relatively nonimmune populations. Increased control activities worldwide reduced malaria deaths by almost 60% from 2000 to 2015, but morbidity and mortality appear to have stabilized since 2015. Currently, malaria is estimated to cause nearly 250 million clinical cases and over 600,000 deaths annually worldwide.

Malaria in Travelers

Malaria is also common when travelers of any age travel from nonendemic areas to the tropics, with symptoms sometimes not manifesting until many months after travel ( Chapter 265 ). Malaria is the most common documented cause of febrile illness in travelers returning from the tropics to developed countries. Malaria is also occasionally transmitted in areas considered nonendemic, including the United States, when imported parasites are transmitted by local anopheline mosquitoes, by blood products, or by congenital spread.

Malaria Transmission

Malaria is transmitted by multiple species of mosquitoes of the genus Anopheles, which vary in geographic distribution, ecologic preferences, and susceptibility to mosquito control measures. Anopheline mosquitoes bite at night, so personal mosquito control measures focus on avoidance of mosquito bites during sleep. Levels of malaria transmission in endemic areas vary greatly, from areas where residents experience only rare infectious bites to regions of Africa where individuals may receive hundreds of infectious bites each year.

Parasite Life Cycle

Malaria is transmitted by the bite of infected female anopheline mosquitoes. During feeding, mosquitoes inject sporozoites, which circulate to the liver and infect hepatocytes, thereby causing asymptomatic liver infection ( Fig. 316-1 ). Merozoites are subsequently released from the liver, and they rapidly infect erythrocytes to begin the asexual erythrocytic stage of infection that is responsible for human disease. Multiple rounds of erythrocytic development, with production of merozoites that invade additional erythrocytes, lead to large numbers of circulating parasites and clinical illness. Each erythrocytic cycle lasts approximately 24 hours for P. knowlesi ; 48 hours for P. falciparum , P. vivax , and P. ovale; and 72 hours for P. malariae . Some erythrocytic parasites also develop into sexual gametocytes, which are taken up by mosquitoes. In the mosquito, gametocytes mature to gametes, and after fusion of male and female gametes to produce zygotes, parasites develop into ookinetes, oocysts, and then salivary gland sporozoites that are infectious for humans, thereby allowing completion of the life cycle and infection of others. P. vivax and P. ovale also cause a chronic liver infection, in which hypnozoites persist in hepatocytes in a dormant state not eradicated by most therapies for acute disease and subsequently can progress to erythrocytic infection and a relapse of clinical illness.

Pathogenic Features of Malaria Parasites

The most common clinical feature of malaria is fever. Fever coincides with rupture of large numbers of schizont-infected erythrocytes at the completion of the erythrocytic cycle and with high circulating levels of tumor necrosis factor (TNF). Severe falciparum malaria is associated with very high levels of TNF and other inflammatory cytokines, but the specific roles of cytokines in pathogenesis are not well understood. P. falciparum infects erythrocytes of all ages, so it is capable of routinely causing high parasitemias, with infection of more than 1% of erythrocytes and more than 10 ⁵ infected erythrocytes per microliter of blood. Non– P. falciparum parasites infect smaller numbers of erythrocytes, thereby limiting the extent of infection and morbidity. Non– P. falciparum parasites are more likely to cause highly synchronous infections, so untreated infected patients can have regular cycles of fever every 48 ( P. vivax and P. ovale ) or 72 ( P. malariae ) hours, often with minimal symptoms between fever episodes.

The contribution of parasitic virulence determinants to the severity of malaria is poorly understood. A key biologic feature of P. falciparum infection is the ability of parasites to mediate the adherence of infected erythrocytes to a number of ligands on endothelial cells. By this mechanism, erythrocytes infected with the more mature stages of erythrocytic parasites do not circulate but rather adhere within small blood vessels in the brain and other organs. This phenomenon, termed cytoadherence, allows parasites to avoid passing through the spleen, where abnormal erythrocytes would be cleared. Cytoadherence is also likely to play a major role in mediating severe manifestations of P. falciparum malaria, with local inflammatory changes mediated by large numbers of adherent parasites leading to organ dysfunction. Pregnancy selects for a subset of P. falciparum strains that specifically bind to ligands in the placenta.

P. falciparum parasites use antigenic variation to evade the host immune response. The principal protein that mediates the cytoadherence of infected erythrocytes to endothelial cells, P. falciparum erythrocyte membrane protein-1 (PfEMP-1), is transported to the erythrocyte surface and is a target of host immune responses that limit infection. The PfEMP-1 family comprises about 60 proteins, but only one PfEMP-1 variant is expressed on the surface of an infected erythrocyte at a time. During the course of an infection, parasites frequently vary the expression of PfEMP-1s to stymie host responses. This factor and the high variability in sequence of many PfEMP-1 molecules present a broad repertoire of antigens and probably help explain the slow acquisition of protective antimalarial immunity. Antigenic variation and other aspects of immunologic diversity are not clearly understood for non– P. falciparum malaria parasites, but each species appears capable of repeated infections.

Host Immunity and Genetics

The nature of human immune responses to malaria is not well characterized, but protective responses require multiple infections and apparently humoral and cell-mediated responses. Where P. falciparum malaria is common, disease occurs primarily in children. After some protection during the first few months of life, probably because of protective effects of maternal antiplasmodial antibodies and fetal hemoglobin, young children are infected frequently, experience repeated febrile malaria illnesses, and are at high risk of severe disease. With repeated episodes of malaria, children develop partial immunity. Immunity develops gradually, with some protection against severe malaria after only a few infections, increasing protection against symptomatic illness, and eventually strong protection against infection. However, antimalarial immunity is not complete; malaria can occur in individuals of any age. In addition, immunity requires boosting by repeated infections, so adults are at increased risk of disease if they return to a highly endemic site after an extended stay in a nonendemic area.

A number of human genetic polymorphisms offer protection against malaria. The best characterized is sickle hemoglobin ( Chapter 149 ). Hemoglobin S heterozygotes are partially protected against severe P. falciparum malaria, leading to a balanced polymorphism in which the survival advantage of the polymorphism allows persistence of sickle cell disease in homozygotes. Other erythrocyte polymorphisms that also are likely to offer protection against malaria include hemoglobin C and E, thalassemias ( Chapter 148 ), glucose-6-phosphate dehydrogenase deficiency ( Chapter 147 ), and ovalocytosis ( Chapter 147 ). The Duffy antigen, an erythrocyte chemokine receptor of uncertain function, is the principal receptor on human erythrocytes for attachment and subsequent invasion of P. vivax . Most Africans lack the erythrocyte Duffy antigen, explaining the uncommon prevalence of P. vivax in most of Africa.