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Chapter: Medical Microbiology: An Introduction to Infectious Diseases: Sporozoa

Pathogenesis - Malaria

The fever, anemia, circulatory changes, and immunopathologic phenomena characteristic of malaria are all the result of erythrocytic invasion by the plasmodia.

PATHOGENESIS

The fever, anemia, circulatory changes, and immunopathologic phenomena characteristic of malaria are all the result of erythrocytic invasion by the plasmodia.

Fever

Fever, the hallmark of malaria, appears to be initiated by the process of RBC rupture that leads to the liberation of a new generation of merozoites (sporulation). To date, all attempts to detect the factor(s) mediating the fever have been unsuccessful. It is possi-ble that parasite-derived pyrogens are released at the time of sporulation; alternatively, the fever might result from the release of interleukin-1 (IL-1) and/or tumor necrosis factor (TNF) from macrophages involved in the ingestion of parasitic or erythrocytic debris. Early in malaria, RBCs appear to be infected with malarial parasites at several different stages of development, each inducing sporulation at a different time. The resulting fever is irregular and hectic. Because temperatures in excess of 40°C destroy mature parasites, a single population eventually emerges, sporulation is synchronized, and fever occurs in distinct paroxysms at 48-hour or, in the case of P. malariae, 72-hour intervals. Periodicity is seldom seen in patients who are rapidly diagnosed and treated.

Anemia

Parasitized erythrocytes are phagocytosed by a stimulated reticuloendothelial system or are destroyed at the time of sporulation. At times, the anemia is disproportionate to the degree of parasitism. Depression of marrow function, sequestration of erythrocytes within the enlarging spleen, and accelerated clearance of nonparasitized cells all appear to con-tribute to the anemia. The mechanisms responsible for the latter are unclear. Intravascular hemolysis, although uncommon, may occur, particularly in falciparum malaria. When he-molysis is massive, hemoglobinuria develops, resulting in the production of dark urine. This process in conjunction with malaria is known asblackwater fever.

Circulatory Changes

The high fever results in significant vasodilatation. In falciparum malaria, vasodilatation leads to a decrease in the effective circulating blood volume and hypotension, which may be aggravated by other changes in the small vessels and capillaries. The intense para-sitemias P. falciparum is capable of producing and the adhesion of infected RBCs to the endothelium of visceral capillaries can impair the microcirculation and precipitate tissue hypoxia, lactic acidosis, and hypoglycemia. Although all deep tissues are involved, the brain is the most intensely affected.

Cytokines

Elevated levels of IL-1 and TNF are consistently found in patients with malaria. Probably released at the time of sporulation, these proteins are certainly an essential part of the host’s immune response to malaria . By modulating the effects of endothelial cells, macrophages, monocytes, and neutrophils, they may play an important role in the destruction of the invading parasite. However, TNF levels increase with parasite density and high concentrations appear harmful. TNF has been shown to cause upregulation of endothelial adhesion molecules; high concentrations might precipitate cerebral malaria by increasing the sequestration of P. falciparum–parasitized erythrocytes in the cerebral vas-cular endothelium. Alternatively, excessive TNF levels might precipitate cerebral malaria by directly inducing hypoglycemia and lactic acidosis.

Other Pathogenic Phenomena

Thrombocytopenia is common in malaria and appears to be related to both splenic pooling and a shortened platelet lifespan. Both direct parasitic invasion and immune mechanisms may be responsible. There may be an acute transient glomerulonephritis in falciparum malaria and progressive renal disease in chronic P. malariae malaria. These phenomena probably result from the host immune response, with deposition of immune complexes in the glomeruli.

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