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The incubation period may be short (minimum 1 week for P. falciparum) to very long (several years for P. ovale). In falciparum malaria the parasitaemia can be very high: up to 80% of erythrocytes may contain parasites, but even 5% is sufficient to result in severe disease. These situations may be life-threatening. The other malaria parasites produce much lower parasitaemia (maximum 2 %). They do cause severe illness, but are practically never life-threatening.
The rupture of the red blood cells (haemolysis) is accompanied by fever, muscle pain and general malaise. Massive haemolysis may cause kidney failure. Parasitised red blood cells are removed by the spleen. Splenomegaly will result. Anaemia occurs due to the destruction of erythrocytes, suppression of the bone marrow and excess activity of the enlarged spleen (hypersplenism). In falciparum malaria there will often be a drop in glycaemia. The hypoglycaemia can be corrected by administration of glucose.
Erythrocytes which contain schizonts of P. falciparum, develop small knobs on their cell membranes. These consist, among other things, of a histidine-rich protein. With this they cling to the walls of the capillaries and to the vascular endothelium of the post-capillary venules in the brain. The low local O2 pressure and high CO2 pressure are optimal for further maturation of the parasite. Infected red blood cells are less easily distorted and more rigid than normal erythrocytes. This impedes the bloodflow, which can lead to cerebral malaria. Other organs too may be affected, for example the placenta and the intestines (resulting in abdominal pain and diarrhoea). Red blood cells which contain schizonts of P. malariae, also develop knobs on their membranes, but these cells do not adhere to the vascular endothelium.
There are two groups of parasites in P. falciparum infections: (1) the young forms in the peripheral blood which can easily be observed in a thin blood smear, and (2) the mature group which is attached to small blood vessels and which cannot be seen. Falciparum schizonts are rarely found in peripheral blood, but these are important for the development of cerebral malaria. The whole mechanism of cerebral malaria has not to date been fully explained. As well as the attachment of parasitised red blood cells to the vessel walls (cytoadherence) other mechanisms possibly also play a part. Normal red blood cells sometimes atta
ch to parasited cells, which impairs the microcirculation. All kinds of released chemical substances (cytokines, oxygen radicals, etc.) may also play a part. Cytokines such as tumour necrosis factor (TNF-α) increase the expression of receptor molecules on the endothelium and will contribute to the cytoadherence and flow obstruction which characterise falciparum malaria. When the schizont is mature and the red blood cell ruptures, glycosyl-phosphatidyl inositol anchors (GPI-anchors) are released, which stimulates the production of TNF-α from macrophages. This mechanism ("malaria toxin") is similar to the release of TNF-α by endotoxins in Gram-negative septicaemia.
Increased intracranial pressure is found in some patients, but certainly not in all. Increased permeability of the vessel wall may play a part, but oedema of the brain is not the general rule. The role of certain immunological mechanisms is being investigated. The final answer will require further study. There is still no good animal model for cerebral malaria, which makes research difficult.
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Carriers of the sickle cell anaemia gene (heterozygotes for haemoglobin S) have relative protection against severe infection with P. falciparum and thus have a survival advantage (in homozygous patients, malaria may be fatal).
See balanced polymorphism and the Hardy-Weinberg equilibrium. The same advantage probably applies to persons deficient in G6PD (a red blood cell enzyme). This may explain why these two conditions are so common in Africa. In Papua New Guinea ovalocytosis is common. These red blood cells have an oval shape and cannot be penetrated by P. falciparum parasites. Heterozygotes are thus protected against P. falciparum (homozygosity is not compatible with life). Haemoglobin C (chiefly West Africa) and haemoglobin E (chiefly Southeast Asia) do not protect against P. falciparum infections. The data on the influence of thalassemia on the clinical severity of malaria are contradictory (many mutations lead to thalassemia, an important confounding factor).While circulating in human blood Plasmodium falciparum exhibits antigenic variation. On the surface of the infected red blood cell a certain protein is expressed: the P. falciparum-infected erythrocyte membrane protein 1 (PfEMP-1). The parasite is able to make many variants of this protein. By interchanging which variant of PfEMP-1 is present, the parasite can evade the immune response to these immunodominant antigens. PfEMP-1 also inhibits antigen presentation by dendritic cells. The proteins can bind to endothelial receptors [such as
ICAM-1 (intercellular adhesion molecule type 1), VCAM-1 (vascular cell adhesion molecule-1), ELAM-1 (E-selectin), CD36 and thrombospondin]. The PfEMP1 proteins are the gene products of what are called var-genes, of which there are 50 to 150 present in the genome of the parasite. There are also some other variant multigenic families, the products of which can be expressed on the surface of infected red blood cells. Antigenic variation has important implications for the development of vaccines. The repertoire of proteins which are expressed in the Anopheles mosquito is far less pronounced, probably because the vector has no adaptive immune system.*
There seems to be several genetic factors that influence the final clinical outcome of an infection. Persons with a gain-of-function mutation in the promoter-region of "inducible nitric oxide synthase" (NOS2), the enzyme which synthetizes NO, have a 75-85% lower risk of severe malaria. NO is a strong vasodilator. High NO levels may be protective against P. falciparum infection by inhibiting cytoadherence. This suggests that the therapeutic potential of NO in the treatment of severe falciparum malaria should be evaluated. Preliminary data suggest that certain TNF-alpha alleles and certain promoters (DNA regios) confer protection against severe malaria. The mean number of complement receptor 1 (CR1, syn. CD35) molecules on erythrocytes in normal individuals is 100-1000 molecules per cell. There seems to be a direct interaction between PfEMP1 on infected cells and a functional site of CR1 on uninfected erythrocytes. This 'stickiness' between PfEMP1 and CR1 contributes to rosetting, and rosetting probably relates to obstruction of blood vessels. Complement-receptor polymorphism probably influences this interaction and therefore the severity of a malaria attack. Certain blood group antigens (e.g. Knops) are located on CR1. The relationship between malaria severity and Knops blood groups (cfr McCoy, Swain-Langley) is being studied at present. A large case-control study of malaria in West African children showed that a human leukocyte class I antigen (HLA-Bw53) and an HLA class II haplotype (DRB1*1302-DQB1*0501), common in West Africans but rare in other racial groups, are independently associated with protection from severe malaria. In this population they account for as great a reduction in disease incidence as sickle-cell trait. These data support the hypothesis that the extraordinary polymorphism of major histocompatibility complex genes as well as other genes has evolved primarily through natural selection by infectious pathogens.
