Plasmodium Species (Malaria)

Description of The Pathogen

Five species of malarial parasites can naturally infect humans. Humans are the natural hosts for four: Plasmodium falciparum , P. vivax , P. ovale , and P. malariae , whereas the fifth, P. knowlesi , typically infects macaques . Although all species of malaria can cause severe infections, P. falciparum is the most lethal and the most drug resistant. Of the human species, P. vivax was previously the most widely distributed geographically and the best adapted to survive in temperate climates. However, successful malaria control programs in the US and Europe essentially eliminated P. vivax from these regions. P. falciparum is the most prevalent species in sub-Saharan Africa. P. ovale mainly occurs in the western areas of sub-Saharan Africa . P. knowlesi normally infects macaques in Southeast Asia; however, human cases have been detected throughout Southeast Asia and it is responsible for approximately 50% of cases in Malaysia. Different stages of P. knowlesi closely resemble P. malariae , thus making it difficult to diagnose by microscopy. In contrast to the usually benign infections with P. malariae , infection with P. knowlesi can be rapidly fatal, so considering this possibility when treating patients who could have acquired malaria in this region is important to minimize severe morbidity and mortality.

The life cycles of all human malarial parasites are illustrated in Fig. 271.1 . Sporozoites are inoculated into humans by the bite of a female Anopheles species mosquito and invade hepatic parenchymal cells within minutes. The parasites undergo asexual multiplication, or schizogony, in this tissue phase of their life cycle, also called exoerythrocytic schizogony. After a period of development and multiplication (7–10 days for P. falciparum , P. ovale , and P. vivax ; and 10–14 days for P. malariae and P. knowlesi ), merozoites emerge to invade erythrocytes and begin what will become the symptomatic phase of the illness. Parasites of the two relapsing species , P. ovale and P. vivax, also can differentiate into a quiescent stage, the hypnozoite, which can later enter into schizogony and reemerge to invade erythrocytes. P. malariae has the potential to persist at very low levels in the circulation for decades if it is not recognized and treated.

Each species has developed an efficient strategy for erythrocyte invasion that relies on a specific, complex interaction of certain surface proteins or glycoproteins on the erythrocyte and a specific ligand of the parasite. For example, P. vivax preferentially invades erythrocytes bearing the Duffy blood group antigen, an antigen that is rarely found on erythrocytes in people from West and central Africa; consequently P. vivax malaria is uncommon throughout most of West Africa. P. falciparum invades erythrocytes of all ages, allowing it to reach high levels of parasitemia, while P. vivax and P. ovale preferentially invade reticulocytes, and P. malariae and P. knowlesi preferentially invade mature erythrocytes. Once inside the erythrocyte, parasites can undergo either asexual schizogony or sexual differentiation (gametocytogenesis) to produce gametocytes.

During asexual schizogony, the parasites are known as trophozoites once they are established inside the erythrocyte; the early trophozoite forms often are called rings because of their apparent lack of central cytoplasmic staining, causing them to appear like rings in stained smears. Parasites in this stage ferment homolactate and actively digest the host cell hemoglobin, which they use as a source of amino acids and energy. This activity is accomplished through a set of highly adapted proteinases in a singularly adapted organelle, the food vacuole. The residue of hemoglobin degradation is an intact tetrapyrrole ring, ferriprotoporphyrin IX, which the parasites detoxify through polymerization and can be seen microscopically as malarial pigment, hemozoin. This polymerization step is thought to be the site of action of quinoline-containing antimalarial compounds, including chloroquine. ^,

The actual replicative phase, when the parasite is called a schizont, comprises the last few hours of the erythrocytic stage of the parasite’s life cycle, during which the parasite undergoes mitosis and subdivides and differentiates into merozoites. The subsequent rupture and release of merozoites lead to fever and other malarial symptoms. In synchronized infections, which typically occur only after the infection is well established, the periodicity of symptoms is 48 hours in P. ovale and P. vivax malaria, 72 hours in P. malariae infections, and 24 hours in P. knowlesi infections. Although periodicity can be every 48 hours in P. falciparum infections, it often is irregular. The absence of periodicity does not rule out malaria (any species) as a diagnosis for a febrile illness in a person with an appropriate travel history.

Parasites in the erythrocytic stages also can undergo sexual differentiation, a step that is necessary for transmission. Male and female gametocytes, which are produced by each Plasmodium species, remain inside the erythrocyte until they are ingested by the mosquito. At this point, they undergo further differentiation and join to form a zygote, which differentiates into an ookinete and invades the mosquito midgut to form the reproductive oocyst. Sporozoites emerge from the oocyst and migrate to the salivary gland, where they can infect a human during a subsequent blood meal.

In general, all the erythrocytic asexual and sexual developmental stages of P. ovale , P. vivax , P. malariae , and P. knowlesi occur in circulating blood and can be visualized in the stained peripheral blood smear. The late trophozoite stages of P. falciparum are rarely seen in the peripheral circulation because of the development of “knobs” on infected erythrocytes that lead to adherence of the parasitized erythrocytes to the capillary endothelium. Sequestration of parasites in various organs is believed to be responsible for the clinical manifestations of P. falciparum infections, such as central nervous system and pulmonary complications.

No sterile immunity per se develops to malaria but rather an acquired ability to tolerate Plasmodium spp. infections occurs that is a selective process related to the degree of exposure to a variety of strains. Most deaths caused by malaria in malaria-endemic areas with high transmission of P. falciparum occur in children <5 years of age . Although P. falciparum can cause lethal infection in young children or nonimmune people, asymptomatic parasitemia is common in older age groups in highly endemic areas. In the US, most malaria cases occur among first- and second-generation immigrants returning to their countries of origin to visit friends and relatives and who either do not believe that malaria prophylaxis is necessary or are unaware of the need to take prophylaxis while traveling, despite their loss of immunity. Malaria deaths in the US occur among all age groups.

Epidemiology

The epidemiology of malarial infections is intricately linked to the distribution and habits of the anopheline vectors in that particular region. In highly endemic areas, mosquito breeding can take place nearly year round, and reproductive capacity in the mosquito is maximized by a tropical climate. In areas of seasonal transmission, prevalence is particularly related to rainfall, temperature, or other ecologic events that affect the mosquito population. Malaria also can be related to occupation when only certain segments of the population are exposed to the vectors (e.g., people whose jobs require them to enter the forests where the vectors live). In nonendemic countries, such as the US, the epidemiology of malaria is most closely linked to international travel patterns.

The estimated worldwide incidence of malaria is 229 million (95% confidence interval [CI] 211 million to 252 million) clinical malaria episodes per year, with an estimated 409,000 deaths in 2019, most of which occurred in children <5 years of age. Almost all deaths are caused by P. falciparum , with more than 90% occurring in sub-Saharan Africa. Before the 1950s, malaria was endemic in the US. During the late 1940s, a combination of improved housing and socioeconomic conditions, water management, vector-control efforts, and case management was successful in interrupting malaria transmission. In the US today, an average of 2000 cases and 5-10 deaths occur each year; almost all cases are in people who have traveled to or are emigrating from malarious areas, although transmission occasionally occurs congenitally or through transfusion or transplantation. From 1963 to 2017, 104 cases of malaria acquired through transfusion were reported in the US. ^, From 1966 to 2005, 81 cases of congenital malaria were reported in the US. Anopheline vectors still are present in most areas of the US and infrequent locally acquired mosquito-borne cases of malaria occur after transmission from imported cases.