All the symptoms of malaria are caused by erythrocytic schizogony - the growth and reproduction in the blood of asexual erythrocyte forms of the parasite. Tissue schizogonia is not clinically apparent.
Malarial attack is associated with the completion of erythrocytic schizogony, the massive disintegration of erythrocytes and the ingress of a large number of merozoites, metabolic products of parasites that have pyrogenic and toxic properties that provoke the development of a febrile reaction. Due to the cyclicity of erythrocytic schizogony, feverish attacks are repeated every 48 hours with three-day, oval and tropical malaria and 72 hours at four days. A heterogeneous population of malarial parasites enters the human body during infection, and schizogony in the initial period proceeds asynchronously, because of this, the type of fever may be wrong. With the formation of immune reactions, the ability to parasitize in erythrocytes is retained in one major generation of plasmodia, which determines the rhythm of fever characteristic of this type. Only with tropical malaria there may be several (2-3) major generations of plasmodium, so fever is often of the wrong nature.
Anemia, characteristic of malaria, is a consequence of the destruction of red blood cells by parasites present in them. It is known that P. Vivax and P. Ovale are mainly introduced into young erythrocytes, P. Malariae - into mature. P. Falciparum infects erythrocytes of varying degrees of maturity, which contributes to their more significant lesion and hemolysis, therefore, in tropical malaria in the genesis of anemia, hemolysis plays a leading role. Additional factors of hemolytic erythrocytes are also autoimmune mechanisms that damage uninfected red blood cells. Developing with malaria, hyperplasia of the reticuloendothelial elements of the spleen depresses hemopoiesis, which increases anemia and thrombocytopenia.
The enlargement of the liver and spleen was initially caused by congestion in the organs, but soon there is a lymphoid and reticuloendothelial hyperplasia in them. As a result of hemolysis of erythrocytes, as well as lesions of hepatocytes, jaundice develops. Reducing the absorption of carbohydrates and inhibition of gluconeogenesis in the liver causes hypoglycemia. Activation of anaerobic glycolysis leads to the accumulation of lactate in the blood, cerebrospinal fluid and the occurrence of lactate acidosis, which is one of the causes of the severe course of tropical malaria.
With tropical malaria, the properties of erythrocytes change, as a result of which microcirculation is disturbed (cytoadhesis, sequestration, rosetting). Cytoadhesion - gluing of infected red blood cells to endothelial cells, the cause of sequestration in capillaries and postcapillary venules. The main role in cytoadhesion is assigned to specific ligand proteins (their expression on the erythrocyte surface is induced by a parasite) and receptors located on the outer surface of endothelial cells. Occlusion of vessels causes ischemia of affected organs. On the membranes of erythrocytes appear prominences (knobs), which contact with outgrowths in the form of pseudopodia formed on endothelial cells. Some varieties of P. Falciparum cause the adhesion of healthy erythrocytes to infected - as a result, "rosettes" are formed. Erythrocytes become rigid, which worsens the rheological properties of the blood and aggravates the disturbance of microcirculation. An important damaging factor is hypoxia, caused by insufficient oxygen-transport function of infected red blood cells. The brain tissue is least resistant to hypoxia, which contributes to the development of cerebral malaria. There are irregularities in the coagulation system of the blood: in severe tropical malaria, signs of an ICE-syndrome of thrombocytopenia and hypophybrinogenemia are observed. A specific role in the pathogenesis of tropical malaria is attributed to a generalized nonspecific inflammatory reaction. Vascular damage is caused mainly by the action of inflammatory mediators. The most active products are lipid peroxidation and protease, released by granulocytes. In the pathogenesis of severe malaria, much attention is paid to cytokines, in particular, TNF and IL (IL-2 and IL-6). The most characteristic changes in severe tropical malaria occur in the brain, where edema, cerebral swelling, perivascular and periganglionic growths of neuroglia (Durk granulomas) are observed. Capillaries are blocked by invaded erythrocytes and parasites; there are extensive hemostasis. Develops a perivascular edema with hemorrhages and focal necrosis. Based on the pathoanatomical picture, it can be concluded that in cases of malarial coma, a specific meningoencephalitis develops.
Malaria infection is capable of disrupting the host's immune response, which triggers a cascade of immunopathological responses. Fixation of immunoglobulins and complement on the basal membranes of the glomeruli causes acute nephropathy. Nephrotic syndrome, which develops in patients with four-day malaria, is referred to as immunocomplex glomerulopathy.
The life cycle of all pathogens of malaria
The life cycle of all pathogens of malaria includes two hosts: a man (schizogony - an asexual development cycle) and mosquitoes of the genus Anopheles (sporogony - the sexual cycle of development).
Traditionally, in the cycle of schizogony, in all types of malarial parasites, three stages are distinguished: exoerythrocytic schizogony (EES), erythrocytic schizogony (ES), and gametocytogony. In addition, in the life cycles of Pl. Vivax and Pl. Ovale isolated a separate stage - hibernation - due to the possible introduction into the human body of a mosquito bite of a morphologically heterogeneous group of sporozoites (tachysporozoites and bradysporozoites or only bradysporozoites). In these cases, bradisporozoites (hypnozoites) persist for a long time in the hepatocytes in the inactive state prior to the onset of EEC.
Introduced with saliva mosquito in the human body sporozoites very quickly (within 15-30 minutes) with the blood flow into the liver, where they actively penetrate into the hepatocytes without damaging them. Sporozoites Pl. Falciparum, Pl. Malariae and tachysporozoites Pl. Vivax and Pl. Ovale immediately begin EES with the formation of a large number of exoerythrocytic merozoites (up to 40 000 from one sporozoite with malaria-falciparum). Hepatocytes are destroyed, and the merozoites again enter the bloodstream followed by a rapid (within 15-30 minutes) introduction into the erythrocytes. Duration of EEC for malaria-falciparum is usually 6 days, for malaria-vivax - 8 days, for malaria-ovafe - 9 days, for malaria-malariae - 15 days.
The stage of hibernation
With malaria-vivax and malaria-ovale, bradysporozoites, implanted in hepatocytes, turn into inactive forms-hypnozoites, which can remain without division for several months or even years before subsequent reactivation (fission and formation of merozoites). Thus, long-term incubation (up to 3-10 months or more) and the development of distant exoerythrocyte relapses are associated with hypnosis with characteristic only for these forms of malaria.
After the introduction of merozoites into erythrocytes, malarial parasites repeatedly (cyclically) consistently pass the stages: trophozoite (feeding, mononuclear cell), schizont (dividing multinucleate cell) and morulae (formed parasites located inside the erythrocyte). Later, after the destruction of red blood cells, merozoites enter the blood plasma. The largest number of daughter merozoites is formed with tropical malaria - up to 40 in one erythrocyte. Stage ES goes strictly a certain time: 48 hours for malaria-falciparum, malaria-viva, malaria-ovale and 72 hours for malaria-malariae.
Features of the cycle of erythrocytic schizogony and the main pathogenetic mechanisms of development of severe and complicated forms of malaria-falciparum:
- accumulation (sequestration) of invasive erythrocytes containing adult trophozoites (from the amoeboid-like trophozoite stage), schizonts in the vessels of the internal organs, mainly the brain, as well as the kidneys, liver, intestines, bone marrow, placenta, etc .;
- formation of so-called rosettes consisting of invasive and unaffected erythrocytes;
- development of microcirculation disorders, tissue hypoxia, metabolic acidosis (significant accumulation of lactic acid);
- activation of MPS (predominantly Th-1 immune response) with increased synthesis of tumor necrosis factor a-factor, y-interferon, interleukin-1 and other cytokines, damaging the vascular endothelium and causing the adhesion of red blood cells to the endothelium of blood vessels.
In recent years, the special role of increased synthesis of nitric oxide (NO) by endothelial cells of cerebral vessels in the development of the cerebral form of malaria-falciparum has been considered.
An important pathophysiological mechanism in the development of severe forms of malaria-falciparum, in comparison with other forms of malaria, is hypoglycemia, aggravating microcirculatory and metabolic disorders (metabolic acidosis) in patients, especially in children and pregnant women. In the development of hypoglycemia in malaria-falciparum, three main factors are distinguished: a decrease in glucose in the liver, utilization of glucose by parasites, and stimulation of insulin secretion. At the same time, hypoglycemia can be a consequence of hyperinsulinemia, which develops after the administration of quinine to relieve the attacks of malaria-falciparum.
As a consequence of the prolonged persistence of the parasite (without adequate therapy) for malaria-malariae, the development of a nephrotic syndrome is possible as a result of the immune mechanism (the deposition of immune complexes containing parasite antigens on the basal membrane of the renal glomeruli).
It should be noted that the main clinical manifestations of all forms of malaria (intoxication, enlargement of the liver and spleen, anemia) are associated precisely with the stage of erythrocytic schizogony (multiple asexual reproduction of parasites in erythrocytes), and the higher parasite content in a patient in 1 μl of blood, microscopy of a thick drop, the more malaria usually takes place. Therefore, in the laboratory diagnosis of malaria it is important not only to establish the type of malarial plasmodium, but also to determine the level of parasitemia. According to the maximum level of parasitemia, the forms of malaria are distributed in descending order: malaria-falciparum (up to 100 thousand in μl and more), malaria-viva (up to 20 thousand in μl, rarely more), malaria-ovale and malaria-malariae (up to 10 -15 thousand in μl). With malaria-falciparum, which proceeds with a high level of parasitemia (100,000 cells per μL and higher), the risk of severe, fatal complications increases significantly, which determines the tactics of intensive (parenteral) antimalarial therapy.
The occurrence of febrile paroxysms in malaria is caused by hemolysis of erythrocytes, the release of merozoites into the plasma, the destruction of a part of them (another part of the merozoites re-enters the erythrocytes), activation of MPS and increased synthesis of interleukin-1, -6, tumor necrosis factor a-factor and other endogenous pyrogens proinflammatory cytokines) that affect the center of thermoregulation of the hypothalamus.
If there is a single generation of plasmodium in the blood, correctly alternating paroxysms appear from the first days of the disease. Often, for malaria-falciparum and malaria-vivax (in hyperendemic regions with intensive transmission of malaria), an initial (initial) fever is observed in non-immune individuals associated with the development in the erythrocytes of patients of several generations of pathogens with different end times of the development cycle, which leads to stratification attacks, smoothing of the period of apirexia, distortion of typical paroxysm.
In the course of the development of the disease, the growth of specific and nonspecific protective factors (by the end of the 1-2 weeks), a part of the generations die, and there remains one (two) leading parasite genera with the development of typical paroxysms every other day (or every day).
The enlargement of the liver and spleen in all forms of malaria is associated with their significant blood filling, edema, hyperplasia of MFS.
Malaria, as a rule, always leads to hemolytic hypochromic anemia, in the pathogenesis of which a number of factors are important:
- intravascular hemolysis of infected erythrocytes;
- phagocytosis by cells of the reticuloendothelium of the spleen of both infected and uninfected erythrocytes;
- sequestration (accumulation) of erythrocytes containing mature parasites, in the bone marrow, oppression of hematopoiesis;
- immune mechanism (destruction of unaffected erythrocytes as a result of adsorption of immune complexes containing the C-3 complement fraction on the erythrocyte membrane).
The stage of gametocytogony is, as it were, a branch from the stage of ES. Part of the merozoites (genetically determined process), instead of repeating the asexual development cycle after introduction into the red blood cell, turns into sexual forms - gametocytes (male and female).
Features of the stage of gametocytogony for malaria-falciparum:
- gametocytes appear in peripheral blood not earlier than 10-12 days of illness;
- gametocytes, accumulating during the course of the disease, can circulate for a long time in the bloodstream (up to 4-6 weeks or more).
In other forms of malaria (vivax, ovale, malariae), gametocytes can be detected in the peripheral blood from the first days of the disease and die quickly (within a few hours - days).