Malaria

Malaria (English malaria, French paludisme) is an acute anthroponotic transmissible protozoal disease with a transmissible mechanism of infection characterized by marked symptoms of intoxication, a cyclic course with alternating fever episodes and periods of apyrexia, an increase in the spleen and liver, the development of hemolytic anemia in the eventual course, relapses disease.

[1], [2], [3], [4], [5], [6]

Epidemiology

The source of the infectious agent is a sick person or a parasite carrier in whose blood the gametocytes are contained. Malaria is a transmissible infection transmitted through a mosquito bite. The gametocytes P. Vivax, P. Ovale and P. Malariae are found in the blood in the early days of the disease; their number increases after several cycles of erythrocytic schizogony. When P. Falciparum is infected a person becomes a source of infection 10-12 days after the beginning of parasitemia and can stay for 2 months or more.

With malaria, different mechanisms for transmission of infection are possible:

Transmissive transfer mechanism (with mosquito bite)

This mechanism is the main one, which ensures the existence of plasmodia as a biological species. The source of the infection is a person (a malaria patient or a parasite carrier), in the blood of which there are mature gametocytes (male and female germ cells of the parasite). The carriers of malaria are only females of the genus Anopheles.

In the stomach of a mosquito, where both male and female gametocytes, which are inside the erythrocytes, get together with the blood, their further maturation (after lysis of red blood cells), fusion and multiple division with the formation of sporozoites, which accumulate in the salivary glands of the mosquito. Sexless forms of the parasite (trophozoites, schizonts), having got into the stomach of a mosquito, perish.

Thus, in the human body there is an asexual path of development of parasites (schizogony) with the formation and accumulation of gametocytes, and in the body of a mosquito - sexual (sporogony), the fusion of male and female gametocytes with their further development and the formation of sporozoites.

[7], [8], [9], [10], [11], [12], [13], [14], [15]

Vertical Transmission Transmission Mechanism

The vertical mechanism of transmission (from the mother to the fetus) or from the mother to the newborn (in the process of delivery, the parenteral mechanism). In vertical transmission, the fetus rarely becomes infected through the placenta. More often, infection occurs in childbirth when a newborn enters the bloodstream of a certain amount of maternal blood, in the red blood cells of which are the asexual forms of the parasite.

The parenteral delivery mechanism

The parenteral mechanism of infection leads to the development of so-called schizon malaria. It is realized with blood transfusions or less with violations of aseptic injections (for example, among drug users using a single syringe). In case of infection with blood transfusion, the source of infection is a parasitic donor, often with sublatent parasitemia (the number of parasites is less than five in one μl of blood). Therefore, in the malaria endemic regions of the world, in addition to parasitological methods (parasite detection in thick drops and blood smears) and serological (immunological) methods for the laboratory diagnosis of malaria (RNIF, ELISA, etc.), it is necessary to use blood parity to control blood donors. Given that parenteral infection usually involves a few parasites (especially with injections), the incubation period can be extended to 3 months (with a massive infection, the incubation period, on the contrary, can be very short - several days), which is important to know when diagnosis of malaria in patients who underwent surgical treatment, drug addicts.

Conditions for the spread of malaria

The following conditions are necessary for the spread of malaria in a certain region (country, province, region):

1. Source of infection (malaria or parasite carrier).
2. The presence of an effective carrier (mosquitoes of the genus Anopheles). Susceptibility to malarial parasites is the main quality of a specific type of mosquito from the genus Anopheles. The number of mosquitoes of the genus Anopheles among the populations of other species is not as high as that of non-malarial mosquitoes, and they rarely seriously bother with their bites. However, small species under other favorable circumstances (proximity of mosquito breeding sites to people's homes) can play quite a serious role. More than 70 species of Anopheles mosquitoes (among more than 200 known species) can be effective carriers of malaria.
3. Favorable climatic conditions: average daily air temperature above 16 ° С and availability of mosquito breeding sites: water reservoirs, water reservoirs, irrigation facilities, etc. The minimum daily mean air temperature required for the development of the mosquito in the body Pl. Vivax, - 16 ° C, for Pl. Falciparum - 18 ° C, at a lower temperature sporogony does not occur. The duration of sporogony is less, the higher the temperature (up to a certain level, since the average daily temperature of 30 ° C and above is unfavorable for sporogony). At the optimal average daily temperature (25-26 ° C), sporogony in Pl. Vivax takes 8-9 days, from Pl. Falciparum - 10-11 days.

The whole area of malaria spreading on the globe (between 45 ° N and 40 ° S to 64 ° N and 45 ° S in different years) is occupied by malaria-vivax. The areas of malaria-falciparum and malaria-malaria are somewhat smaller due to the necessary higher temperature for effective sporogony; The area of malaria-ovale is located in two regions that are not geographically interconnected: tropical Africa and the states of the western Pacific (Indonesia, Vietnam, the Philippines, New Guinea, etc.). In mountainous countries, foci of malaria can form up to heights of 1000 m in the zone of temperate climate and up to 1500-2500 m in the zone of subtropics and tropics, and only foci of malaria-vivax occur at high altitudes (1000-1500 m and above).

Malaria is characterized by pronounced seasonality. In temperate and subtropical climates, the malaria season is divided into periods: effective mosquito infestation, transmission of infection and mass manifestations of the disease. The beginning of the period of effective mosquito infestation (in the presence of a source of infection - patients, parasites) coincides with the moment of a steady increase in the average daily temperature to 16 ° C. The beginning of the transmission period is associated with the completion of sporogony in the mosquito, which depends on the specific daily average temperatures of the given year. In the Moscow region, the transmission of malaria-vivax can reach 1.5-2 months or more, before the first autumn frosts. The boundaries of the period of mass manifestations are less defined. In foci, where only three-day malaria is transmitted, the mass morbidity may begin long before the transmission period begins. The observed cases are primary manifestations of malaria-vivax with prolonged incubation (3-10 months) due to infection in the previous season and the preservation of hypnosis in the liver (without primary manifestations with a short incubation), as well as distant exoerythrocyte relapses (after a series of malaria attacks with a short incubation last season, without adequate anti-relapse therapy).

The susceptibility to malaria is universal. The outcome of infection after the causative agent enters the bloodstream and the clinical course of the disease is determined by individual immunological status, the activity of factors of nonspecific congenital resistance, the intensity of post-infection immunity, and for newborns - by the level of specific antibodies of class G, received from the mother. Exceptions are indigenous people of West Africa and New Guinea, most of them immune to infection Pl. Vivax, which is due to the genetically determined absence of erythrocyte isoantigens of the Daffy group performing the function of receptors for merozoites PI. Vivax. Accordingly, in this region is much less likely than in other regions of tropical Africa, there are cases of infection with malaria-vivax.

Relatively resistant to infection by all types of plasmodia are people who are carriers of abnormal hemoglobin (thalassemia, sickle cell anemia, carriage of hemoglobin E, C, etc.), with disturbances in the structure of the cytoskeleton of erythrocytes (hereditary spherocytosis, southeastern ovalocytosis, hereditary elliptic cytosis) or having a deficiency of the enzyme glucose-6-phosphate dehydrogenase of erythrocytes. In the case of malaria infection, they are easily affected, the number of parasites in the blood is kept at a relatively low level, cases of malignant course (cerebral form of malaria-falciparum) are practically absent. On the other hand, people with glucose-6-phosphate dehydrogenase deficiency risk developing acute hemolysis with a number of antimalarial drugs (primaquine, quinine, etc.). Mechanisms of natural resistance to various types of malaria are largely not yet clear and continue to be studied.

Newborns also have a certain resistance to infection with all forms of malaria. This is due to:

1. the presence of passive immunity due to antibodies of class G, obtained by the newborn from the hyperimmune mother (in foci with a high incidence of malaria);
2. maintenance of specific immunity after birth due to antibodies of class A, obtained by newborns with breast milk;
3. the presence of a fetal hemoglobin in a newborn, a malarial parasite that is not suitable for nutrition.

After the first three to six months of life in newborns, the risk of developing severe, malignant forms of malaria-falciparum (changing red blood cells containing fetal hemoglobin into erythrocytes containing normal hemoglobin, the transfer to mixed nutrition - the ingestion of parahaminobenzoic acid necessary for the development of the parasite , which is absent in human milk).

[16], [17], [18], [19], [20]

Immunity with malaria

Immunity in malaria is non-sterile, species-specific and strain-specific, unstable and short-lived. To maintain a protective level of antibodies, constant antigenic stimulation is required in the form of repeated infections with malaria. Immunity to Pl. Malariae and Pl. Vivax is installed earlier and is maintained longer than to Pl. Falciparum. Antimalarial immunity includes cellular and humoral responses. The beginning of immune processes that stimulate the synthesis of antibodies is the phagocytosis of malarial parasites by macrophages. This is manifested by hyperplasia of the histiophagocytic system of the spleen, liver, bone marrow.

Prevalence of malaria

Of the four types of pathogens of human malaria, the most common in the world is P. Vivax. In the subtropics and tropics in the gene pool of the P. Vivax population, sporozoites predominate. The cause of the disease after a short incubation (10-21 days). On the African continent P. Vivax is constantly found in the countries of East Africa among Arabs, Indians, Ethiopians, Europeans. In West African countries inhabited mainly by representatives of the Negroid race, P. Vivax is not met, which is explained by the genetically conditioned congenital immunity of African negroes to P. Vivax [on the erythrocytes there is no receptor for merozoites P. Vivax - isoantigens Daffy (Fy ^d or Fy ^b )] . The area of P. Ovale is small and consists of two parts. The main African part occupies tropical Africa from the Gambia in the north to the Congo in the south of the continent. The second part of the range is the countries of the Western Pacific and South-East Asia. The geographical area of tropical malaria reaches 40 ° N latitude and 20 ° S latitude P. Falciparum accounts for up to 50% of the incidence of malaria in the world. Four-day malaria is currently found in Africa, parts of Central and South America, the Caribbean. South-East Asia.

Most people are susceptible to malaria. The exception is indigenous to West Africa. For hyperendemic foci of tropical Africa, where P. Falciparum predominates, the relatively stable immune structure of the indigenous population is characteristic:

• children under the age of 6 months do not fall ill due to passive immunity received from the mother:
• most children aged 6-24 months are affected by P. Falciparum; passive immunity is extinct, active is not yet developed; in this group the highest mortality from malaria is observed:
• in children older than 2 years P. Falciparum is less common, the course of malaria is mitigated as a result of acquired immunity, the intensity of parasitemia decreases with age:
• in adults P. Falciparum is rarely found due to high immunity, there are no clinical manifestations when infected.

Tropic malaria is also easily tolerated by carriers of abnormal hemoglobin S (sickle-cell anemia) and faces with some other genetically determined hemoglobin anomalies and erythrocyte enzymes (deficiency of G-6-FDH).

History of the study of malaria

The study of malaria (one of the most ancient human diseases) is inextricably linked with the very history of the development of human civilization. It is assumed that malaria began to spread on Earth (from the African region of the Mediterranean) about 10,000 years ago due to intensive development of agriculture, trade, development of new lands. In ancient Egyptian papyri, Chinese ancient literature and canons ("Charaka" and "Sushrutha") of classical ancient Indian medicine ("Ayurveda"), the descriptions of the clinic and epidemics of malaria have survived to this day; already then there were suggestions of a possible connection between the development of the disease and mosquito bites. Later (5th-6th centuries BC), the ancient physicians of Greece: Hippocrates, Geradot, Empedocles described in detail the malaria clinic. Hippocrates deserves credit for the allocation of malaria from the group of febrile illnesses: he proposed to isolate 3 forms of the disease: "quotidian" (daily bouts), "tertian" (attacks every other day) and "quartan" (attacks after 2 days).

The beginning of the era of scientific discoveries in the study of malaria is associated with 1640, when for the first time the Spanish conquistador Juan del Vego (Nyap del Vego) used the cinchona bark extract, previously used by the Indians of Peru and Ecuador as an antiplatelet agent, for the treatment of malaria. Merit in the name of the disease "malaria" (ital "mal aria" - bad air) belongs to the Italian Lancisi (1717), which linked the infection of people with malaria through "poisonous" fumes from the marshes. In 1880 the French doctor A. Laveran, working in Algiers, described in detail the morphology of the pathogen of malaria. In 1897 the English military doctor Ronald Ross (Ronald Ross) in India had established a transmissible mechanism for the transmission of malaria.

Currently, malaria is one of the most serious health problems for more than 100 countries in Africa, Asia and South America, about half of the world's population lives with the risk of contracting malaria. Almost all countries in Europe and North America annually register hundreds of imported cases of malaria among people who come from the regions where it is spread, the number of cases of so-called airport malaria is increasing. According to the WHO, 200-250 million people worldwide get malaria every year, at least 80% of all malaria cases are registered in sub-Saharan Africa. Every year from 1 to 2 million people die from malaria, mostly children under 5 years old. Social and economic losses in Africa alone are estimated at 2 billion US dollars per year. Since 1998, under the auspices of WHO, the World Bank, UNICEF, the Roll Back Malaria Initiative has been implemented to monitor malaria (mainly in the developing world). The program is valid until 2010-2015. Efforts are actively being made to create an effective antimalarial vaccine, but this will require at least another 10-15 years. The search, development and improvement of drugs for the treatment of malaria are one of WHO's priority programs, various pharmaceutical companies, research institutes around the world. In recent years, as a result of the growth of migration processes, intensive development of international tourism, an increase in imported cases of malaria has been noted in Russia.

Causes of the malaria

The name of the disease "malaria" actually summarizes four separate protozoal diseases, caused respectively by four types of pathogens.

The cause of malaria is parasites, which are classed as Protozoa, the class Sporozoa, the family Plasmodiidae, the genus Plasmodium. Four types of pathogens are parasitized: P. Vivax causes a three-day, P. Malariae - a four-day, P. Falciparum - tropical malaria; P. Ovale is the cause of the three-day oval malaria.

Pathogens of malaria

Causative agent	The form of malaria (in accordance with ICD-10)
Plasmodium (Laverania) falciparum	Malaria caused by Plasmodium falciparum (malaria-falciparum)
Plasmodium (Plasmodium) vivax	Malaria caused by Plasmodium vivax (malaria-vivax)
Plasmodium (Plasmodium) ovale	Malaria caused by Plasmodium ovale (malaria-ovale)
Plasmodium (Plasmodium) malariae	Malaria caused by Plasmodium malariae (malaria-malariae)

In most domestic publications (textbooks, manuals, reference books), the former names of forms of malaria remain: tropical malaria (falciparum malaria), malaria (malaria-vivax), malaria (malaria-ovale) and malaria-malaria (malaria).

Each of the four forms of malaria is characterized by its clinical, pathogenetic and epidemiological features. The most important is malaria-falciparum, accounting for 80-90% of all malaria cases in the world, the causative agent of which belongs to a particular subgenus (Laverania). Only malaria-falciparum can be malignant, leading to death.

The pathogens of malaria in the process of life are the next cycle of development with a change of hosts:

• asexual development (schizogonia) occurs in the body of the intermediate host - the person;
• sexual development (sporogony) takes place in the body of the final host - a female gnat of the genus Anopheles.

In the human body sporozoites get into a bite when infected with a malarial mosquito. After penetration into the blood sporozoites through 15-45 minutes are introduced into the hepatocytes from the sinusoidal vessels of the liver and begin the exoerythrocytic cycle (tissue schizogony). Selectivity and rapidity of infestation are due to the presence of specific receptors on the membranes of hepatocytes. Parasites increase, divide many times and form many small single-nucleated formations - merozoites. The minimum duration of the exerythrocyte cycle is 5-7 days in P. Falciparum, 6-8 days in P. Vivax, 9 days in P. Ovale and 14-16 days in P. Malariae. Then, the merozoites emerge from the hepatocytes into the bloodstream and are introduced into red blood cells, where the erythrocytic schizogony occurs. For the three-day and oval malaria, a special type of exoerythrocyte development is characteristic: all parasites or a part of them are able to remain in the hepatocytes in the "dormant" state (hypnozoites) for a long time (7-14 months and more), and only after the end of this period they begin to turn into Merozoites, capable of infecting erythrocytes. Thus, this causes the possibility of prolonged incubation and the occurrence of distant relapses up to 3 years.

Erythrocytic schizogony is accompanied by cyclic development and multiple division of parasites, while malarial plasmodia undergo the following stages: young trophozoite (has the form of a ring); developing trophozoite; mature trophozoite (has a large nucleus): an evolving schizon; mature schizonont. After the completion of the schizogony process, the erythrocyte is destroyed. Free merozoites actively penetrate into new red blood cells, but most of them die from the influence of the host's protective immune mechanisms. The duration of erythrocytic schizogony is in P. Vivax, P. Ovale, P. Falciparum 48 h, and in P. Malariae 72 h. During the erythrocyte cycle, some of the merozoites are transformed into sexual forms - female (macrogamethocytes) or masculine (microgametocytes).

The gametocytes enter the body of a mosquito carrier when it feeds on the blood of a patient with malaria or a parasite carrier. Containing mature gametocytes. In the stomach of the mosquito, after 9-12 minutes, the male gametocyte throws out eight thin movable bundles. Free bundles (microgamets) penetrate the female cell (macrogamet); after the fusion of nuclei a zygote is formed - a round fertilized cell. Further, ookinets, oocysts with sporozoites develop successively, their ripening proceeds in the salivary glands of the mosquito. At the optimal ambient air temperature (25 ° C) sporogony lasts 10 days in P. Vivax. 12 days in P. Falciparum. 16 days in P. Malariae and P. Ovale; at an air temperature below 15 ° C sporozoites do not develop.

[21], [22], [23], [24], [25], [26], [27]

Pathogenesis

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.

[28], [29], [30], [31], [32], [33], [34], [35], [36], [37], [38]

Exoerythrocytic schizogony

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.

[39], [40], [41], [42], [43], [44], [45], [46], [47], [48], [49]

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.

Erythrocytic schizogony

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).

[50], [51], [52], [53], [54], [55], [56], [57]

Symptoms of the malaria

Given the specific features of malarial parasites and the corresponding symptoms of malaria, four forms of the disease are identified: malaria tartiana, malaria, malaria, malaria).

The course of primary malaria includes the initial period of the disease, the period of high disease and convalescence. Without treatment or with inadequate etiotropic therapy, malaria passes into a period of recurrent course. There are relapses exoerythrocytic and erythrocytic, in time of development - early and late. Erythrocyte relapses are observed when all types of plasmodia are infected. The earliest occur within 2 months after the initial seizures; relapses that develop at a later date are late. Without treatment or with improper treatment of the three-day and oval malaria, there comes a "lull" of 6-11 months with the disappearance of parasites from the blood and clinical well-being. Then there are late relapses (caused by activation of hypnozoites in the liver), without treatment again followed by a latent period, after which the disease recurs again.

P. Falciparum live in the human body (without treatment) to 1.5 years, P. Vivax and P. Ovale - up to 3 years, P. Malariae - many years, sometimes for life.

Forms

On the recommendation of WHO, malaria is divided into uncomplicated, severe and complicated. Malignant forms of malaria and complications are characteristic mainly for the infection of P. Falciparum. The disease caused by P. Vivax, P. Ovale and P. Malariae, as a rule, has a benign course.

Three-day malaria

The incubation period of the three-day malaria is from 10-21 days to 6-14 months. The prodromal symptoms of malaria are rarely seen before the initial malaria attack, but they often precede relapses and are expressed by a feeling of general malaise, weakness, weakness, pain in the lumbar region, limbs, a slight rise in body temperature, a worsening of appetite, and headache. The duration of the prodromal period on average is 1-5 days.

At first, the temperature curve is incorrect (initial fever), which is associated with the inadvertent release of several generations of P. Vivax into the blood. Later, typical malarial seizures begin with intermittent three-day fever, indicating the formation of the main generation of parasites in the blood. In a malarial febrile seizure, three phases are clearly marked, immediately following one after another: the stage of chill, heat and sweat. The malarial attack begins with a chill, its intensity can be different - from easy cognition to a tremendous chill. At this time the patient goes to bed, tries unsuccessfully to warm up, but the chill builds up. The skin becomes dry, to the touch rough or "goose", cold, limbs and visible mucous cyanotic. There are symptoms of malaria, such as: severe headache, sometimes vomiting, pain in the joints and lumbar region. The stage of chills lasts from a few minutes to 1-2 hours, it is replaced by the heat stage. The patient discards his clothes, his underwear, but this does not bring him relief. The body temperature reaches 40-41 ° C, the skin becomes dry and hot, the face turns red. Headache, pain in the lumbar region and joints are amplified, nonsense and confusion are possible. The stage of heat lasts from one to several hours and is followed by a period of sweating. The temperature falls critically, perspiration is often profuse, so the patient has to repeatedly change clothes. Relieved by a seizure, he soon falls asleep. The duration of the attack is 6-10 hours. Characteristic is the onset of attacks of the disease in the morning and afternoon. After the attack, a period of apyrexia begins, lasting about 40 hours. After 2-3 temperature attacks, the liver and spleen are markedly enlarged. Changes in blood: anemia, which develops gradually from the second week of the disease, leukopenia, neutropenia with a stab-shift left, relative lymphocytosis, aneosinophilia and elevated ESR.

In the natural course of the disease without etiotropic treatment after 12-14 attacks (4-6 weeks), fever intensity decreases, attacks gradually fade, liver and spleen sizes are reduced. However, after 2 weeks-2 months, early relapses occur, characterized by a synchronous temperature curve, an increase in the liver and spleen, anemia. In the future, with increasing immunity, parasites disappear from the blood and a latent period sets in. If at this time not treated with histoshysotrophic drugs, then after 6-8 months (and sometimes after 1-3 years) activation of the "dormant" tissue forms of parasites occurs and distant relapses develop. They are characterized by an acute onset, a lighter course, an early increase in the spleen, a short number of seizures (up to 7-8), less intensity and duration of parasitemia, and the presence of gametocytes in the blood.

Oval-malaria

In many clinical and pathogenetic features, the oval-malaria is similar to the three-day vivax-malaria. The incubation period of oval malaria is 11-16 days. With oval malaria, the tendency of the pathogen to primary latency is observed. In this case, the duration of the incubation period can extend for 2 months to 2 years or more. Symptoms of malaria are in intermittent three-day fever, less often it is daily. Feverish attacks often occur in the evening hours, and not in the morning, as is typical of other forms of malaria. Oval malaria is characterized mainly by an easy flow with a small amount of paroxysms, taking place without a pronounced chill and with a lower temperature at the peak of the seizures. It is characteristic that paroxysms during a primary attack very often terminate spontaneously. This is due to the rapid formation of persistent immunity. If treatment with histoshysotropic drugs is not performed, 1-3 relapses with an interrepid interval from 17 days to 7 months are possible.

[58], [59], [60]

Quartan

It usually flows kindly. The incubation period is from 3 to 6 weeks. The prodromal symptoms of malaria are rarely observed. The onset of the disease is acute. From the first attack, intermittent fever is established with a frequency of seizures after 2 days. Paroxysm usually begins at noon, its average duration is about 13 hours. The period of chills is long and pronounced. The period of heat lasts up to 6 hours, it is accompanied by a headache, myalgia, arthralgia, sometimes nausea, vomiting. Sometimes patients are restless and raving. During the interictal period, the condition of the patients is satisfactory. Anemia, hepatosplenomegaly develop slowly - not earlier than 2 weeks after the onset of the disease. In the absence of treatment, there are 8-14 seizures, but the process of erythrocytic schizogony at a low level lasts for many years. Most often, the infection occurs in the form of parasitosis without activating erythrocytic schizogony, which makes these individuals potentially dangerous donors. In endemic foci, four-day malaria causes nephrotic syndrome with poor prognosis in children.

Tropical Malaria

The most severe form of malarial infection. The incubation period is 8-16 days. At the end of it, some prothromal malaria symptoms lasting from several hours to 1-2 days are noted in a part of nonimmune individuals: malaise, weakness, weakness, body aches, myalgia and arthralgia, headache. In most patients, tropical malaria begins acutely, without a prodromal period, with a rise in body temperature to 38-39 ° C. If in an infected organism in several generations of P. Falciparum, the cycles of erythrocytic schizogony do not end concurrently, it is often clinically expressed by the absence of a cyclic periodicity of febrile seizures. Seizures that occur with alternating phase change begin with a fever lasting from 30 minutes to 1 hour. During this period, the skin is pale, cold to the touch, often with a goose-skin roughness. Chills are accompanied by a rise in body temperature to 38-39 ° C. With the cessation of chill comes the second phase of paroxysm - fever. Patients experience a slight sensation of heat, sometimes they experience a feeling of true heat. The skin becomes hot to the touch, the face is hyperemic. The duration of this phase is about 12 hours, it is replaced by mild sweating. Body temperature drops to normal and subnormal digits and after 1-2 hours rises again. In some cases, the onset of tropical malaria is accompanied by nausea, vomiting, diarrhea. Sometimes catarrhal symptoms of malaria from the upper respiratory tract are recorded: cough, runny nose, sore throat. In later periods, there are herpetic eruptions on the lips and wings of the nose. In the acute stage, the patients notice hyperemia of the conjunctiva, in case of severe disease it can be accompanied by petechial or larger subconjunctival hemorrhages.

During the height of tropical malaria, the chill is less pronounced than in the first days of the disease, its duration is 15-30 minutes. Fever lasts for days, periods of apyrexia are rarely recorded. With a mild course of the disease, the body temperature at the peak reaches 38.5 ° C, the duration of the fever is 3-4 days; at an average severity - 39.5 ° C and 6-7 days, respectively. Severe course of the disease is characterized by an increase in body temperature to 40 ° C and above, and its duration is eight or more days. The duration of individual paroxysms (and, in fact, the stratification of several) with tropical malaria reaches 30-40 hours. The wrong type of temperature curve prevails, rarely remittent, occasionally intermittent and permanent types.

Liver enlargement is usually determined on day 3 of the disease, spleen enlargement is also from 3 days, but it is recorded more often only percussion; clear palpation becomes possible only for 5-6 days. With ultrasound of the abdominal cavity, the increase in the size of the liver and spleen is determined already on the 2-3 day after the clinical manifestations of tropical malaria. Disturbances of pigmental metabolism are observed only in patients with severe and less frequently moderate course of tropical malaria. More than threefold increase in aminotransferase activity in serum is regarded as an indicator of unfavorable prognosis. To metabolic disorders in tropical malaria include changes in the system of hemostasis and hypoglycemia. Disorders from the cardiovascular system have a functional character, are expressed by tachycardia, muffled heart tones, hypotension. Occasionally, a transient systolic murmur at the apex of the heart is heard. With severe disease, ECG changes are noted as a deformation of the final part of the ventricular complex: flattening and converse configuration of the T wave, a decrease in the ST segment. At the same time, the voltage of the R teeth in the standard leads is reduced. In patients with a cerebral form, the changes in the P wave are of the P-pulmonale type.

In tropical malaria, CNS abnormalities associated with high fever and intoxication are often observed: headache, vomiting, meningism, seizures, drowsiness, sometimes a delirious syndrome, but the patient's consciousness is preserved.

Characteristic signs of moderate and severe malarial infection are hemolytic anemia and leukopenia, in the leukocyte formula eosin- and neutropenia, relative lymphocytosis, are noted. In severe forms of the disease, neutrophilic leukocytosis is possible; ESR is constantly and significantly enhanced. Thrombocytopenia is a symptom typical of all types of malaria. As with other infectious diseases, transient proteinuria is observed in patients.

The recurring course of tropical malaria is due to either inadequate etiotropic treatment or the presence of P. Falciparum resistance to the chemotherapeutic agents used. The natural course of tropical malaria with a favorable outcome lasts no more than 2 weeks. In the absence of etiotropic therapy, relapses occur after 7-10 days.

Pregnancy is a recognized risk factor for tropical malaria. This is due to a higher incidence of pregnancy, with a tendency to severe clinical forms, a risk to the health and life of the child, with a limited therapeutic arsenal. Tropical malaria in children of the first five years should be considered a potentially fatal disease. In children of younger age groups (up to 3-4 years), especially in infants, malaria is characterized by a peculiar clinical picture: it lacks the most vivid clinical symptom - malarial paroxysm. At the same time, such malaria symptoms as convulsions, vomiting, diarrhea, abdominal pain, with a rapidly progressive deterioration of the child's condition are observed. The appearance of seizures and other brain symptoms does not necessarily mean the development of cerebral malaria - this is often one of the symptoms of neurotoxicosis. Parasitemia in young children is usually high: P. Falciparum can affect up to 20% of red blood cells. The disease can quickly acquire a malignant course and end with the death of the child.

Complications and consequences

Record in all stages of tropical malaria. Prognostically unfavorable symptoms of malaria, indicating the possibility of malignant malaria. - daily fever, absence of apyrexia between seizures, severe headache, generalized convulsions, repeated more than twice in 24 hours, decerebral rigidity, hemodynamic shock (systolic blood pressure below 70 mmHg in adults and less than 50 mmHg at child). This is also evidenced by high parasitemia (more than 100 thousand P. Falciparum in 1 μl of blood), detection of different age stages of the parasite in peripheral blood, presence of gametocytes, increasing leukocytosis (more than 12,0х10 ⁹ / l). Hypoglycemia less than 2.2 mmol / L, decompensated metabolic acidosis, more than threefold increase in aminotransferase activity in serum, as well as a decrease in glucose level in the cerebrospinal fluid and a lactate level of more than 6 μmol / L are also prognostically unfavorable.

Heavy lesions of the central nervous system in tropical malaria are united under the name "cerebral malaria", its main sign is the development of a coma. Malaria coma is a complication of primary, recurrent and recurrent malaria, but more often it is observed in primary malaria, mainly in children, pregnant women and in young and middle-aged people.

The cerebral form is the most frequent complication of the severe course of malaria-falciparum. In modern conditions, the cerebral form develops in 10% of all cases of malaria-falciparum in the world, and 60-80% of all deaths of the disease are associated with this complication. The cerebral form can develop from the first days, but more often it is registered at the 2nd week of the disease against the background of the absence of specific or inadequately conducted therapy. A lethal outcome can occur within 1-2 days. In the clinical picture of cerebral malaria, three periods are distinguished: stunning, sopor and true coma.

The stage of stunning is characterized by mental and physical sluggishness of the patient, rapid exhaustion. He is oriented in time and space, but he enters into contact reluctantly, answers questions monosyllabically, quickly becomes tired. Tendon reflexes are preserved.

The stage of sopor is expressed by deep prostration of the patient with rare glimpses of consciousness. Possible ataxia, amnesia, convulsions, sometimes epileptiform nature. Corneal reflexes are preserved, the pupils are normal. Tendon reflexes are increased, pathological reflexes arise.

At a coma the patient is unconscious, does not react to external stimuli. Observe the violation of convergence, divergent strabismus, floating movements of the eyeballs with open eyelids (as if the patient is examining the ceiling), horizontal and vertical nystagmus, paralysis of the VI pair of cranial nerves; tendon and abdominal reflexes are absent, vegetative functions are sharply broken. Meningeal symptoms of malaria and pathological reflexes of Babinsky, Rossolimo, etc. Are expressed. They note incontinence of urine and feces. With spinal puncture, an increase in intracranial pressure is detected without pronounced disturbances in the protein and cellular composition of the CSF. In a thick drop and a blood smear of patients with coma malaria, a high degree of parasitemia with different age stages of P. Falciparum is determined. At the same time, cases of lethal outcomes of cerebral malaria are known with a very low level of parasitaemia. Cerebral malaria in children is often accompanied by anemia. Anemia aggravates the neurological and somatic state of the child. With effective treatment, consciousness returns usually suddenly.

With cerebral malaria, the development of psychoses as a consequence of dystrophic changes in the parenchyma of the brain is possible. In an acute period, psychoses occur in the form of delirium, amenia, epileptic seizures, manic conditions. For post-malaria psychoses are characterized by depression, mental weakness, hysteria, schizophreniform syndromes, in children - a temporary delay in mental development. Sometimes the remote consequences of cerebral malaria are observed: hemiplegia, ataxia, focal nerves, extrapyramidal disorders, mono- and polyneuritis.

A frequent complication of all forms of malarial infection is hypochromic anemia. Severe anemia is diagnosed in cases where the hematocrit falls below 20%, and the hemoglobin level is less than 50 g / l. The degree of anemia depends on the type of parasite, as well as on the intensity and duration of the infection. The severity of malaria in indigenous people in tropical countries is often exacerbated by iron and folate deficiency in the diet. Already after the first attacks of malaria, the development of anemia is possible, which is more pronounced in tropical malaria than in other forms.

Infectious-toxic shock (ITSH) with the development of DIC-syndrome is a complication typical of malaria-falsiram, which occurs with high parasitemia. Characteristic of the development of acute adrenal insufficiency. The course of infectious-toxic shock in a hot climate is accompanied by hypovolemia.

The development of acute renal failure is usually observed in malignant, complicated course of malaria-falciparum. Characteristic of the development of oliguria and anuria with the increase in the blood of creatinine, urea, urine analysis determined pronounced proteinuria, cylindruria, pyuria, microhematuria.

Nephrotic syndrome - a characteristic complication of malaria-malariae, is characterized by a slow, steadily progressing course, accompanied by edema, arterial hypertension, proteinuria, and development of renal insufficiency.

Hemoglobinuria fever is a consequence of massive intravascular hemolysis both with intensive invasion and as a result of the use of some antimalarial drugs (quinine, primaquine, sulfonamides) in persons with a deficiency of the enzyme glucose-6-phosphate dehydrogenase. In severe its form, intense jaundice, severe hemorrhagic syndrome, anemia and anuria accompanied by chills, fever (40 ° C), pain in the lumbar region, repeated vomiting of bile, myalgia. Arthralgia. Urine acquires a dark brown color, which is due to the presence of oxyhemoglobin. The number of erythrocytes in severe cases is reduced to 1x10 ¹² / l, and the level of hemoglobin - to 20-30 g / l. Parasites in the blood with malarial hemoglobinuria are very few or are not detected at all. With the rapid cancellation of the antimalarial drug that caused hemolysis of red blood cells, the patient's condition improves without serious consequences. In severe cases, due to the development of acute renal failure, the prognosis may be unfavorable. In recent years, the autoimmune nature of the development of acute hemolysis, associated with the long and frequent use of antimalarial drugs - quinine and primaquine - is considered. There is a high fever (with insignificant parasitemia), urine acquires black color, anemia, leukocytosis, acceleration of ESR, fast progression of renal failure, which leads to a lethal outcome in the absence of adequate therapy.

The malarial algid is characterized by clinical manifestations peculiar to infectious-toxic shock: hemodynamic disorders, microcirculation, disorders in the hemostasis system, multiple organ failure and hypothermia. Unlike cerebral malaria, consciousness is preserved, although in the future, the development of coma is possible. Algid can develop against a background of pulmonary edema, metabolic acidosis and severe dehydration. Mark a high level of parasitemia. The prognosis largely depends on timely and correct treatment.

Acute pulmonary edema in patients with tropical malaria often leads to death. The mechanism of this severe complication is not fully understood. Lung edema is provoked by excessive rehydration, but it can develop and against the background of normal pressure in a small circle of circulation. Currently, most researchers consider acute respiratory failure in tropical malaria as a manifestation of adult respiratory distress syndrome.

A rare but formidable complication in any clinical form of malaria with or without hyperreactive splenomegaly is the rupture of the spleen. The rupture can be caused by the twisting of the spleen's leg with acute stagnation of the blood and the development of subcapsular hematoma.

In tropical malaria, lesions of the cornea, iritis, iridocyclitis, vitreous opacity, optic neuritis, chorioretinitis and retinal hemorrhage are possible, there are reports of paralysis of the eye muscles caused by III, IV and VI pairs of cranial nerves, paralysis of accommodation.

Relapses of malaria

The level of parasitemia during relapse is usually lower than with the primary symptoms of malaria. Due to the increased pyrogen threshold in the course of the course of the infection, clinical manifestations during relapse usually occur with a higher parasitaemia. Relapses, as a rule, proceed benignly, with a mildly expressed toxic syndrome and the correct alternation of malarial paroxysms from the onset of relapse; the number of paroxysms is considerably less than in the case of primary manifestations of the disease. By the time of the offensive, the early (development of clinical manifestations within the first 2 months after the initial manifestations of malaria) and late (after 2 months) are isolated. By origin relapses are subdivided into erythrocytic (all forms of malaria) and exoerythrocytic (only for malaria-vivax and ovale).

[61], [62], [63], [64]

Diagnostics of the malaria

The diagnosis of malaria is based on epidemiological data (stay in the malaria focus, lack or lack of chemoprophylaxis). On the clinical picture of the disease (characteristic seizures) and is confirmed by laboratory tests.

Diagnosis of malaria should take into account:

• acute onset of the disease, marked symptoms of intoxication, cyclic course with alternating fever attacks and periods of apyrexia, enlarged liver and spleen, development of progressive hemolytic anemia;
• data of epidemiological history (stay in a malaria-poor area, blood transfusion, drug addiction);

Duration of the course of malaria, taking into account the development of relapses with a single infection and without adequate etiotropic therapy

Form of malaria	Duration of infection
	Usual	Maximum
Malaria-falciparum	Up to 1 year	Up to 3 years
Malaria-malariae	Up to 2-3 years	Possible for life
Malaria-vivax and ovale	Up to 1,5-2 years	Up to 4-5 years

• laboratory test data:
  • hemogram results: reduction of hemoglobin level, leukopenia, lymphomonocytosis, increased ESR;
  • results of microscopy of a thick drop of blood (viewing at least 100 fields of vision in cases of low parasitemia): finding plasmodium and establishing the level of parasitemia in 1 μl of blood (100 fields of vision - 0.2 μl of blood).

It's necessary:

1. To select the degree of intensity of specific antimalarial therapy (with a high level of parasitemia in patients with tropical malaria, parenteral administration is preferred).
2. To control the effectiveness of specific therapy.

The level of parasitemia can be estimated when counting 100 leucocytes in a thick drop of blood, the percentage of infected red blood cells (in this case, to estimate the number of parasites in 1 μl, you need to know the total number of leukocytes and erythrocytes in 1 μl in the patient);

• blood smear microscopy data for determining the species of plasmodia. The color of a thick drop and a blood smear is carried out according to the method of Romanovsky-Giemsa.

As a result of the accumulation of invaded erythrocytes containing adult trophozoites and schizonts in the vessels of the internal organs, only young (young) trophozoites at the ring stage are determined in the investigation of the thick drop drug with mild malaria-falciparum in erythrocytes. Occurrence in the peripheral blood of invasive erythrocytes containing adult stages of parasite development (adults or amoebaids trophozoites, schizonts) is an unfavorable laboratory indication pointing to the severe (complicated) course of malaria-falciparum.

Degrees of parasitemia in malaria

Degrees of parasitemia	Symbol	Number of parasites in the fields of vision	The number of parasites in 1 μl of blood
IV	+	1-20 in 100 fields	5-50
III	+ +	10-100 in 100 fields	50-500
II	+ + +	1-10 in 1 field	500-5000
I	+ + + +	More than 10 in 1 field	More than 5000

In people who first contacted (not immune) with this infection, young children, the first seizures can occur at very low parasitemia, sometimes not detectable by microscopy; this involves the need for a repeat blood test (thick drop) in 6-12 hours, but no later than 24 hours.

Laboratory diagnosis of malaria is a microscopic study of blood products (methods of thick drop and thin smear), painted by Romanovsky-Giemsa.

Malaria patients should be examined for febrile patients with an unidentified diagnosis within 3 days during the epidemic season and 5 days during the rest of the year; patients with continuing periodic body temperature rises, despite ongoing treatment in accordance with the established diagnosis; recipients of blood with an increase in body temperature in the last 3 months after transfusion; people living in an active focus, with any increase in body temperature. It should be borne in mind that at the first attacks of malaria the number of parasites in the peripheral blood is small, so you need the most careful study. With low parasitemia, malaria also occurs in people taking antimalarial medications with a preventive purpose (suppressive therapy) or preparations (tetracycline, sulfonamides) that have a suppressive effect on the plasmodium of malaria before the disease. Blood sampling for research is recommended to be performed both during the fever period and during apyrexia. To identify parasites, a thick drop is examined, since the blood volume in it is 30-40 times greater than in a thin smear. With high parasitemia, the malignant pathogen is also detected in the study of a thin smear. Morphology features and tinctorial properties (staining) of different age stages of asexual forms in erythrocytes are well distinguishable in a thin smear. Determine the type of parasite is necessary: this is especially important for P. Falciparum. In uncomplicated tropical malaria P. Falciparum in peripheral blood is observed only in the stage of young ring-shaped trophozoites. In primary infection, the more mature stages of the parasite in the peripheral blood are detected when the disease has a severe malignant course. Parasitemia grows faster than infection with other types of pathogens. P. Falciparum gametocytes mature slowly, but live long (up to 6 weeks), while gametocytes of other species die several hours after their maturation. Discovered in tropical malaria gametocytes help determine the period of the disease: in the early period (in uncomplicated course) only ring-shaped trophozoites are revealed, during ring-up period - rings and gametocytes (in the case of primary infection in the absence of treatment, this indicates that malaria lasts at least 10-12 days) ; in the period of convalescence, only gametocytes are found. In the process of treatment, the level of parasitemia in peripheral blood is determined in dynamics. A day after the initiation of etiotropic treatment, it should be reduced by 25% or more, and on the third day should not exceed 25% of the initial one. The presence of parasites in the blood preparation on the 4th day after the initiation of treatment, under all the conditions of successful treatment, is a sign of the resistance of the pathogen to the drug used.

In recent years, rapid tests (immunochromatographic methods) based on the detection of a specific protein HRP-2a and the enzyme pLDH P. Falciparum have been used in rapid endoscopy to obtain a preliminary response in endemic foci . The tests of one of the known rapid tests KAT-PF ("CAT MEDICAL", South Africa) showed high efficiency and specificity for P. Falciparum. Comparison of the results of the rapid test, microscopy and PCR showed that its diagnostic efficiency reaches 95-98%. The use of rapid tests allows you to recognize the result after 10 minutes. The laboratory staff can learn how to react in 1-2 hours. Express methods enable self-diagnostics to people living or traveling in endemic regions, they can be conducted in the field setting. In Russia, the rapid diagnosis of malaria is still limited to individual clinical trials.

In modern conditions, especially in mass studies, the PCR method, based on the detection of the DNA of a malarial parasite, is of particular importance. Using the method, it is possible to determine carriage with low parasitemia and mixed infection by different types of plasmodia, and to differentiate the relapse of drug-resistant falciparum malaria from reinfection of P. Falciparum. Currently, it is used mainly in epidemiological studies.

[65], [66], [67], [68], [69], [70], [71], [72]

Differential diagnosis

Differential diagnostic search for malaria is carried out depending on the severity of clinical manifestations of the disease and its duration. First of all, malaria differentiates from diseases that occur with prolonged fever, enlargement of the liver, spleen, possible development of anemia: typhoid fever and paratyphoid, brucellosis, leptospirosis, sepsis, and lymphogranulomatosis. In the first 5 days after the disease, a frequent erroneous diagnosis of malaria in non-endemic regions is influenza (or other ARVI).

In tropical countries of South America, Africa, Southeast Asia, India, a differential diagnosis of malaria with hemorrhagic viral fevers (yellow fever, dengue fever, etc.) is carried out.

In the cerebral form of malaria-falciparum, differential diagnosis of malaria is conducted with encephalopathies (coma) developing with decompensated diabetes mellitus, hepatic and renal insufficiencies, as well as swelling and swelling of the brain with meningitis or meningoencephalitis of bacterial or viral etiology.

Treatment of the malaria

Treatment of malaria includes relief of acute attacks of the disease, prevention of relapses and gamete-carrying, as well as restoration of impaired functions of the body.

Anti-malarial drugs, depending on their effect on one or another stage of parasite development, are divided into the following groups: hematoschotropic agents effective for asexual erythrocyte stages of plasmodia; histoshose -otropic agents effective against asexual tissue stages of plasmodia; Gamotropic drugs that cause the death of gametocytes in the patient's blood or disrupt the maturation of gametes and the formation of sporozoites in the mosquito's body.

Etiotropic treatment

Etiotropic treatment of malaria of patients with malaria should be appointed immediately after the establishment of a clinical and epidemiological diagnosis and taking blood for a parasitological study.

Currently used drugs are classified into six groups of chemical compounds: 4-aminoquinolines (chloroquine-deligil, chloroquine phosphate, nivaxine), quinoline-methanol (quinine-quinine dihydrochloride, quinine sulfate, hinamax, mefloquine), phenanthrenemethanol (halfan, halofantrine), artemisinin derivative (artesunate, artemether, artheater), antimetabolites (proguanil), 8-aminoquinolines (primaquine, tafenohin). In addition, combined antimalarial drugs are used: savarine (chloroquine + proguanil), malarone (atovajon + proguanil), coartemia or riamet (artemether + lumefantrin).

When a patient finds P. Vivax, P. Ovale or P. Malariae, drugs from the group of 4-aminoquinolines, most often chloroquine (delagil), are used. Treatment of malaria is as follows: the first two days the drug is used in a daily dose of 10 mg / kg of the base (four tablets delagila for one dose), on the third day - 5 mg / kg (two tablets delagila) once. There are some reports of resistance of P. Vivax strains to chloroquine in Burma, Indonesia, Papua New Guinea and Vanuatu. In such cases, treatment should be carried out with mefloquine or quinine according to the scheme of treatment of uncomplicated malaria. Attacks cease in 24-48 hours, and parasites disappear from the blood 48-72 hours after the start of chloroquine intake.

For radical cure (prevention of long-term relapses) with malaria caused by P. Vivax or P. Ovale, after the end of the course of chloroquine, a tissue shizontocid-primaquine is used. It is taken for 14 days at a dose of 0.25 mg / kg (base) per day. Strains of P. Vivax, resistant to primaquin (the so-called strains of the Cheson type), occur on the islands of the Pacific and in the countries of South-East Asia. In these cases, one of the recommended regimens is the primaquine administration at a dose of 0.25 mg / kg per day for 21 days.

When P. Falciparum is detected in the blood of non-immune individuals in cases of a mild course, the drugs of choice, in accordance with WHO recommendations, are mefloquine and artemisinin derivatives (artemether, artesunate, arteether); it is also possible to use halofantrine. In the absence of mefloquine and halofantrine and / or the presence of contraindications to the use of these drugs, quinine is prescribed in combination with antibiotics (tetracycline, doxycycline). Tetracycline is taken by 0.5 g twice daily for 7-10 days; it can be replaced with doxycycline in a daily dose of 0.1 g, the duration of administration is 7-10 days. In regions where P. Falciparum is resistant to mefloquine and quinine, a combination of mefloquine with artemisinin (artes} nat, artemether) is recommended for the treatment of uncomplicated tropical malaria. Effective treatment of uncomplicated tropical malaria with a combination of fan-candar and artesunate. Artemisinin preparations are widely used for the treatment of multiresistant tropical malaria in Southeast Asia, a number of countries in South America and Africa. They very quickly act both on the blood stages, and on gametocytes. However, these drugs are quickly removed from the body, so there are relapses of malaria. It is more expedient to prescribe them in combination with mefloquine in the following doses:

• artesunate: 4 mg / kg twice daily for 3 days; mefloquine: 15 mg / kg once on the 2nd day or at a dose of 25 mg / kg in two doses on the 2nd and 3rd day;
• Artemether: 3.2 mg / kg once daily for 3 days; mefloquine: 15 mg / kg once on the second day or at a dose of 25 mg / kg in two doses on the 2nd and 3rd day.

Treatment regimens for uncomplicated malaria

	Schemes of application
A drug	First dose, mg / kg	Subsequent doses, mg / kg (interval, h)	Duration of a course, days
Chlorokhin	10 (base)	10 - 1-2 days 5 - 3 days	3
Fansidar (sulfadoxine + pyrimethamine)	2.50-1.25	-	1
Quinine, kinimax, kinoform	10 (base)	7.5 (8)	7-10
Meflokhin	15 (base)	-	1
Halofantrine	8 (salt)	8 (6)	1
Artesunate	4	2 (12)	7th
Artemether	3.2	1.6 (24)	7.0
Quinine-tetracycline	10.0-1.5	10.0 (8) +5.0 (6)	10.0 + 7.0
Coartem (artemether + lumefantrine)	1.3 + 8.0	1.3-8.0 (8)	3.0

When the type of pathogen is not established, treatment is recommended to be carried out according to the treatment regimens for tropical malaria. If a patient has vomiting earlier than 30 minutes after ingestion of the prescribed antimalarial drug, the same dose should be re-taken. If vomiting occurred after 30-60 minutes after taking the pills, then additionally prescribe half the dose of this drug.

Patients with severe form of tropical malaria must be hospitalized in the intensive care unit or intensive care unit. Remedy for treatment of severe tropical malaria remains quinine. In the treatment of complicated forms (cerebral malaria, algid), the first dose (7 mg / kg) of quinine base is administered intravenously for 30 minutes. Then another 10 mg / kg is injected intravenously drip for 4 hours. Thus, the patient receives 17 mg / kg quinine base within the first 4.5 hours after initiation of treatment. In another scheme, an initial dose of 20 mg / kg of quinine base is administered for 4 hours. Both regimens are tolerated satisfactorily by patients, without cardiovascular or other disorders. The maintenance dose of 10 mg / kg of quinine base is prescribed at intervals of 8 hours, the duration of administration is 1.5-2 hours. It is advisable to combine quinine with tetracycline (250 mg four times a day for 7 days) or with doxycycline (0.1 g in day for 7-10 days). For the treatment of children, it is recommended to administer a shock dose (15 mg / kg) of quinine base intravenously drip in 5% glucose solution for 4 hours. The maintenance dose (10 mg / kg) is administered for 2 hours at intervals of 12 hours. The same dose is used and with intramuscular injection, but quinine is recommended to dilute five times in distilled water and distribute into two injections into different buttocks.

As an alternative preparation for the treatment of a complicated form of tropical malaria, artemeter is used at a daily dose of 3.2 mg / kg on the first day of treatment. In the next six days, it is administered in a dose of 1.6 mg / kg intramuscularly in combination with a single dose of mefloquine.

Patients with severe and complicated forms of malaria are prescribed intensive pathogenetic therapy. When rehydration should be feared swelling of the lungs and the brain, but no less dangerous and the state of hypovolemia. With unsuccessful rehydration, these patients may have insufficient tissue perfusion, acidosis, hypotension, shock and kidney failure. Developing anemia usually does not threaten the life of the patient, but if the hematocrit is reduced to 15-20%, then it is necessary to transfuse the erythrocyte mass or whole blood. Transfusion of fresh whole blood or concentrates of clotting factors and platelets is used in DIC syndrome. When hypoglycemia should be resorted to intravenous administration of 40% glucose solution.

The basis of treatment for edema of the brain is detoxification, dehydration, fighting with hypoxia of the brain and respiratory disorders (oxygen therapy, ventilation). According to the indications, anticonvulsants are administered. Experience in the treatment of cerebral malaria has demonstrated the inefficiency and even the risk of using osmotic diuretics: dextran with low molecular weight; adrenaline; prostacyclin; pentoxifylline; cyclosporine; hyperimmune sera. Do not recommend hyperbaric oxygenation.

With the development of acute renal failure or acute renal and hepatic insufficiency, the daily dose of quinine should be reduced to 10 mg kg because of possible cumulation of the drug and inject solutions at a rate of 20 drops per minute. In the initial period of acute renal failure, forced diuresis is carried out, and in the absence of effect and growth of azotemia - hemodialysis or peritoneal dialysis, usually giving a good result. With the development of hemoglobinuria fever, the drug that caused hemolysis is canceled. If necessary, it is replaced with other antimalarial medicines, concomitantly prescribe glucocorticides (prednisolone 1-2 mg / kg), detoxification therapy.

When the spleen ruptures, which usually develops in cases of rapid and significant organ enlargement, emergency surgical intervention is indicated.

To treat relapses of tropical malaria, a previously unused drug is used or the former is used, but in combination with other antimalarial medicines. The gamete-carrier is eliminated by primaquine for 1-3 days at usual therapeutic doses.

The effectiveness of malaria treatment is controlled by examining a thick drop of blood counting parasitemia in 1 μl. These studies are performed daily from the 1st to the 7th day after the initiation of etiotropic treatment. If parasites disappear during this time, further studies of blood products are carried out on the 14th, 21st and 28th days after the start of treatment.

[73], [74], [75], [76], [77], [78]

Efficiency mark

Efficacy of etiotropic treatment of malaria in malaria patients is assessed by three parameters: early inefficiency (RN), late inefficiency (PN) and effective treatment.

After taking an antimalarial drug, the patient may have vomiting (especially in children). It should be remembered that if vomiting occurred less than 30 minutes after taking the drug, you should re-take the same dose, after 30-60 minutes - half of the dose used.

Evaluation of the effectiveness of malaria treatment (WHO, 1996)

Early inefficiency (RN)	Deterioration or persistence of clinical signs of malaria in the presence of parasitemia within the first 3 days of the onset of specific therapy
Late inefficiency (MN)	Again the emergence of the characteristic clinical signs of malaria (including the development of a severe condition) in the presence of parasitemia from the 4th to the 14th day from the time of the initiation of specific therapy
Effectiveness of treatment	Absence of parasitemia after 14 days from the start of specific therapy in the absence of RN and PN criteria

[79], [80], [81], [82], [83], [84]

Radical treatment of malaria

Radical treatment of malaria is carried out simultaneously with stopping or immediately after it.

1. To prevent exoerythrocyte recurrence of malaria-vivax and malaria-ovale, primaquine (Primaquine) of 45 mg (27 mg of base) per day (3 tablets) is prescribed for 14 days or 6 tablets in order to influence the hypothoites . - Once a week - 6-8 weeks (with a deficiency of glucose-6-phosphate dehydrogenase). A clinical trial of tafenoquine (Tafenoquine), a primaquine analog, is taking place, but with higher clinical efficacy and a lower incidence of adverse reactions.
2. To exclude the transmission of malaria-falciparum (by affecting gametocytes), Primaxine (Primaquine) 45 mg (27 mg base) per day (3 tablets) is used for 3 days. Treatment is conducted in regions endemic for tropical malaria. When using Fansidar in the treatment of patients who have suffered a malaria-falsirarum, primaquine not administered because of the effective exposure pyrimethamine (Pyrimethamine), which is part of Fansidar on gametocytes Pl. Falciparum.

Treatment of severe and / or complicated malaria-falciparum is carried out in intensive care units, resuscitation. If drugs can not be taken orally, parenteral therapy is administered by one of the following drugs:

• Quinine dihydrochloride (quinine dihydrochloride) - 10-20 mg / kg (up to 2.0 g per day) / in 500 ml of 5% glucose solution, slowly, 2-3 times per day to a patient exiting the severe condition, then one of the oral medications for the treatment of uncomplicated malaria-falciparum;
• in modern conditions for the treatment of severe forms of malaria-falciparum in some countries, new drugs of plant origin are used (in Russia these preparations are not certified): Artemether (Artenam) - 160 mg on the first day, then 80 mg for 6 days; Artesunate - in / m (iv) 50 mg twice a day - 7 days; Artemisinine - in / m for 1200 mg - 7 days.

The pathogenetic treatment for malaria depends on the severity of malaria and the development of complications. Carry out detoxication therapy, correction of metabolic acidosis, hypoglycemia, prescribe diuretics, antihistamines, glucocorticosteroids (according to indications), vitamins, cardiovascular and other drugs. With anuria, peritoneal dialysis is possible. In the treatment of hemoglobinuric fever, primarily drugs that cause hemolysis are canceled, and a red blood cell transfusion is performed.

Reconvalvesent is discharged after the complete course of etiotropic parasitological treatment (stopping therapy) with 2-3 negative results of the blood test (thick drop). Patients who have undergone malaria-vivax and malaria-ovale, the subsequent course of treatment with a primaquin can be performed on an outpatient basis. For patients with malaria, follow-up for 1-1.5 months with repeated parasitologic examinations of a thick drop of blood every 7-10 days. Clinical examination of patients with malaria-vivax, malaria-ovale and malaria-malariae is carried out for two years, with the obligatory parasitological examination of a thick drop at any temperature increase.

Prevention

WHO is combating malaria worldwide under the "Roll Back Malaria" program, adopted in 1998. WHO has now set a new goal for the European Region - to eliminate the three-day malaria (P. Vivax) by 2010, and the tropical one by 2015 The most important link in the complex of measures is the timely detection and treatment of sources of infection.

Preventive measures in the outbreak focus on the timely detection and treatment of malaria, as well as parasite carriers (sources of infection), as well as on the fight against malaria vectors. Currently, there are no effective vaccines for active immunization against malaria.

Individual malaria prophylaxis when staying in an endemic focus is aimed at the prevention of infection and the prevention of a malarial attack. Prevention of infection consists in taking measures to protect against mosquito bites (use of repellents, nets on windows and doors, bedside curtains, clothing that closes hands and feet when staying outdoors in the evening and at night). In accordance with the recommendations of WHO, the prevention of a malarial attack consists in taking antimalarial drugs, it is recommended that it be administered only to nonimmune individuals who go to outbreaks with a high risk of contracting malaria and the lack of available medical care (remoteness of medical facilities, the impossibility of rapid blood test for malaria).

The need for use, duration and frequency of medication is determined only after consultation with an infectious disease doctor. It is important to identify contraindications for the use of chemotherapy drugs, the presence of severe concomitant diseases. Pregnant non-immune women, young children should not visit regions endemic for malaria.

Given the high resistance Pl. Falciparum to chloroquine, the standard for the prevention of malaria-falciparum, according to WHO recommendations, is currently mefloquine (250 mg once a week, 2 weeks before going to an endemic region and within 4 weeks after return). The use of other drugs (doxycycline, chloroquine in combination with proguanil, atovaquin combined with proguanil, primaquine and others) is determined by the infectious disease doctor, taking into account the epidemic situation in the region of stay and other factors mentioned above.

[85], [86], [87], [88], [89], [90], [91], [92], [93], [94], [95], [96]

Forecast

In most cases, mortality is due to tropical malaria, or rather, its cerebral form, occurring in 10% of cases of severe falciparum malaria. Lethal outcomes from other types of malaria are very rare. But tropical malaria, with timely diagnosis and proper treatment of malaria, ends in complete recovery.

For patients who have transferred tropical malaria, it is recommended to establish a follow-up medical examination for 1-1.5 months and conduct a parasitological examination of blood at 1-2-week intervals. The prophylaxis of patients suffering from malaria caused by P. Vivax. P. Ovale. P. Malariae, should be carried out for two years. Any increase in body temperature requires a laboratory blood test to detect malarial plasmodium in time.

[97], [98], [99], [100], [101], [102], [103], [104]