MALARIA 1 page

Malaria (from the colloquial Italian "mala" - bad, and "aria" - air) is an infection characterized by certain febrile disturbances caused by protozoan parasites of the class Sporozoa and of the family Plasmodiidae. Man is the intermediate host of these parasites, which undergo an asexual stage of development in the red corpuscles. The parasite undergoes a sexual phase of development in the Anopheles mosquito,which is hence the definitive host. Man acquires infection from the bite of such an infected mosquito. Clinically, malaria is characterized by periodic attacks of fever, associated with anemia and enlargement of the spleen, and if untreated, with cachexia and a deposit of black pigment in the various organs. The malady is amenable to treatment with quinine and several other synthetic compounds inimical to the life of the parasite.

Historic reference

Malaria was formerly supposed to be due to poisonous emanations from damp ground, hence the term "malaria", introduced into English literature about 1829. Hippocrates in his book on epidemics, noted the existence of periodic fevers,divided them into quotidian,tertian,quartan,and subtertian,and referred to the enlarged spleen. Celsus recognized 2 types of tertian fever, one benign and similar to quartan fever,the other in which the attack is of longer duration and far more severe in character, the fever occupying 36 of the 48 hours and not entirely subsiding in the remissions, but being only mitigated.

Columella, about 116 B.C., suggested that the virus of malaria emanated from marshes and associated the disease with insects originating in them which attacked man in swarms. Also in the time of Caesar, views were expressed by Varro that swamp air might be the cause of malaria and furthermore that animals, so small that the eye could not follow them, might transmit diseases by way of the mouth or nose. In view of our present knowledge, it is remarkable that Lancisi in 1718, should have associated marshes with the development of gnats, which insects he thought could not only introduce with their proboscides the putrefying organic matter of such swamps, but animalcules as well.

Etiology

The year 1880 was a most important one in the history of malaria, when Laveran first recognized the parasites of malaria while carrying on investigations as to the origin of the "pigmented bodies" and pigmented leukocytes. He observed not only spherical pigmented bodies, but also crescents, and in particular the flagellation of the male gamete, which demonstrated to him that these were living

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organisms. He proposed the name Oscillaria malarias on account of the movements of the flagellate body, but this had to be dropped as not valid, the generic name Oscillaria having been previously applied to another organism.

In 1894 Manson formulated the hypothesis of the mosquito transmission of malaria. He based this upon facts he observed in tracing the life-history of filaria and upon the fact that in malaria the flagellation of the male gametocyte does not take place for several minutes after the removal of the blood from the peripheral circulation. He also suggested that larvae might feed upon infected mosquitoes dying upon the water and thus acquire the disease.

Ross for 2 years caused mosquitoes to feed upon the blood of malarial patients which contained crescents, but as he used insects of the genera Culex and Aedes no development of the parasites in the tissues of the mosquitoes occurred,in 1897 he used eight dappled-wing mosquitoes {Anopheles Stephens) and in 2 of these, upon dissection, he noted the development of the pigmentary bodies to be different from anything he had observed in hundreds of dissections of other mosquitoes.

In 1886 Metschnikov, from observation of sporulating parasites in the brain capillaries at the autopsy of a malarial case, considered them to be coccidial in nature.

Four parasites, all of this genus, may give rise to malaria in man, the names of the species are Plasmodium vivax which produces benign tertian malaria, Plasmodium malarias - quartan malaria,Plasmodium ovale - another tertian parasite and Plasmodium falciparum, which causes malignant tertian malaria. Each of these species shows the following characters which are possessed by the genus, as it affects man.

One speaks of an "asexual cycle" of development of the parasite in man and a "sexual cycle" of development in the mosquito.

Trophozoite. The growing form of the parasite in the blood of man; it includes the ring and all stages onwards, except the fully grown gametocyte and the schizont.

Schizont. A form which is in process of dividing asexually; it is called "immature" when division has just begun and "mature" when division is complete, and the parasitized cell is just about to rupture.

Schizogony. A process of asexual reproduction by which the nucleus and cytoplasm divide into many subsidiary parts simultaneously, each part being a merozoite. The process occurs in the liver cells and red blood corpuscles of man.

Sporogony. A process or cycle of sexual reproduction, which results in the formation of sporozoites; in the mosquito.

Gametocyte. The stage of the parasite containing the gamete. The origin of these forms is not definitely known; they are probably derived from merozoites produced by schizogony in the blood stream.

Gametes. The male gamete or spermatozoon, and the female gamete or ovum before fertilization has taken place.

Zygote. The fertilized ovum.

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Ookinete. A zygote capable of moving.

Oocyst. An ookinete which has settled down, become rounded and covered with a membranous cyst wall.

Hemocoele. This is the body cavity functioning as the blood vascular system in insects.

The species of parasites causing malaria in man differ from each other in morphology, but the general course of their life-history is similar. All of the parasites have an asexual and a sexual cycle of development. The first known as the endogenous cycle, is passed in man and the process of reproduction during this cycle is called schizogony. The second or sexual, known as the exogenous cycle, is passed in some species of mosquito and the process of reproduction during this cycle being called sporogony.

P. vivax

Asexual forms.

Small trophozoites. The ring or signet-ring form. The rings of P. vivax, the benign tertian parasite, are stout, large rings, which measure about one-third the diameter of the red cell.

Large trophozoites. The term large "growing" forms is applied to all forms of malaria parasite, which have grown beyond the ring but have not yet reached a stage when they can be classified as schizonts on one hand, or full-grown gametocytes on the other.

The large trophozoites of P. vivax are very irregular in shape, and of delicate structure; many pseudopodial processes are seen because the parasites were in active amoeboid movement at the moment the film was made, and have died, and been fixed, in various postures. These are evidence of the capacity for active though restricted amoeboid movement, which the name "vivax" implies. The vacuolic area, which is present at the ring stage and is characteristic of it, is no longer seen. Another change has occurred; the parasite, in addition to growing large has, in the process of its metabolism, produced fine grains of brown pigment or hematin, and these are contained in its body. They are probably derived from the hemoglobin of the infected red cell.

Schizonts. The mature schizont of the species is a body which is itself as large as a normal red cell, so that the parasitized corpuscle becomes distended and larger than the normal. The nucleus of the parasite has, at this stage, divided into numerous fragments, each enclosed in a portion of cytoplasm, thus forming daughter parasites or merozoites. In mature schizonts of P. vivax there are about sixteen merozoites. The pigment of the parent, at this stage, is collected in a clump and there is a portion of cytoplasm, enclosing this pigment which has not been used up in the process of merozoite formation, this is residual material.

Sexual forms.

Gametocytes. The full-grown gametocyte of P. vivax is rounded. It occupies most of the enlarged infected red cell, and is the same size as a normal red cell to

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spite of this, it shows no sign of segmentation; the nucleus is still single and the cytoplasm undivided. The males and females, are distinguished from each other by the characters given below under P. falciparum, but the pigment remains scattered and the diagnosis is less easy. The gametocytes of P. vivax are commonly found in the peripheral blood about the end of the first week of parasitemia.

P. malariae

Asexual forms.

Small trophozoites. The rings of P. malariae, the quartan parasite,are large, stout rings which measure about one-third the diameter of the red cell.

Large trophozoites. The large trophozoites of this species are not of the flimsy amoeboid structure seen in P. vivax, but are much more solid-looking. They very frequently assume a characteristic "band" form lying across the diameter of the red cell. The band may be narrow or wide, and may have the edges almost parallel, and well defined. The pigment present is much coarser and blacker than in P. vivax.

Schizonts. The mature schizont of this species, although it also nearly fills the cell, is considerably smaller than that of P. vivax since the infected red cell never enlarges, as with P. vivax. In P. malariae, moreover, the nucleus and cytoplasm have segmented into only about eight merozoites. At this stage, the pigment is collected into a dense black clump, around which, in some cases, the merozoites are arranged in a rosette-like regular manner.

Sexual forms.

Gametocytes. The full-grown gametocyte is rounded and occupies most of the infected red cell, which, however, is not enlarged. The nucleus and cytoplasm are undivided, and the coarse black pigment is scattered through it. Males and females can be distinguished as below, but not easily. The gametocytes of P. malariae appear irregularly and late in the infection.

P. ovale

This parasite morphologically has some characters of P. vivax and others of P. malariae.

Asexual forms.

Small trophozoites. The rings are stout and large, occupying about one-third of the red cell.

Large trophozoites. The large trophozoites of this species are solid-looking, not amoeboid, and there are occasional band forms.

Schizonts. The mature schizonts of this species give rise to about twelve merozoites.

Sexual forms.

Gametocytes. These are indistinguishable from those of P. malariae except for the stippled decolourised red cell. They appear early in the infection.

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P. falciparum

Asexual forms.

Small trophozoites. The ring of P. falciparum, the parasite of malignant tertian malaria, is usually very delicate-looking and small, measuring only about one-fifth the diameter of the red cell. In P. falciparum again, the ring has frequently two nuclear dots of chromatin, which may either be placed close together on one side of the ring, or lie separate from each other, even on opposite sides of the ring. Further, in this parasite more commonly than in the other species, the nucleus of the ring may appear in the vacuolic white area. These delicate rings of P. falciparum may be seen on the margin of the red cell as if attached to the exterior of the corpuscle (marginal or accole forms), or may be drawn out in the process of spreading the film in a linear manner, with the nucleus elongated (bacillary forms). In this species, often more than one ring may occur in a red corpuscle; this condition of double or multiple infection of the cell is more frequent in malignant than in any of the other infections. But besides these very small rings, it is not unusual to find, in P. falciparum infections, rings of such a size and bulk that they cannot be distinguished from those of vivax, malariae or ovale. If therefore only one or two large stout rings are found in a preparation,it will be quite impossible to determine the species.

Large trophozoites. As we show in dealing with pathogenicity this parasite leaves the peripheral circulation as soon as it has passed the large ring stage, and completes its growth in the blood vessels of the internal organs. Consequently large trophozoites of this species are not found in the peripheral blood unless the patient is moribund.

Schizonts. This stage of the asexual cycle of P. falciparum remains in the internal organs and is not seen in the peripheral blood, except in moribund cases. The mature schizont contains about twenty-four merozoites.

Sexual forms.

Gametocytes. The full-grown gametocyte or mature sexual form in this species has'a characteristic shape, like that of a curved sausage, and is usually referred to as a crescent. This, together with the peculiarities in the life history of this species referred to above, by which multiplication during the asexual cycle takes place in the internal organs, has been accepted as a generic distinction by some authors; they therefore call the malignant tertian parasite Laverania falcipara instead of P. falciparum. The crescents can be distinguished as regards sex in the stained preparations. The male or, as it is called, the microgametocyte, has pale blue cytoplasm, with the blackish-brown pigment of the parasite distributed through it and a more diffuse arrangement of the large nucleus. The female or macrogametocyte has dark blue cytoplasm, with the pigment collected together, around the compact small nucleus. The red cells in which they lie are frequently only faintly visible, as a pale-staining convex line which extends across the concavity of the crescent. These forms do not appear in the blood simultaneously

Infectious diseases

with the rings, at the commencement of the infection, but are seen usually about ten days later. In the tropics they are often so scanty that they cannot be found.

Epidemiology

Conditions which favour the presence and breeding of anopheles mosquitoes tend to the increase of malaria, and vice versa, whatever favors access of those insects and the parasites they contain,also favours the acquisition of malaria.

In subtropical regions subtertian malaria is a primary infection in summer and early autumn, hence the popular term - "cestioo-autumnal fever". This peculiarity can be explained to some extent by the higher atmospheric temperature required for its development in the mosquito. Hence, though benign and subtertian forms are frequently associated,and the latter can be acquired at any time in the tropics,it is only in the summer and early autumn that subtertian can be acquired in more temperate zones. When the temperature falls below 15 °Ñ development of the oocyst in the mosquito is arrested, but when once the sporozoites have entered the salivary glands, they are capable of infecting man, even during the winter season.

Malaria incidence is usually endemic, but hyperendemicity is a distinct form, demanding for its production such an intensity of transmission that a high degree of tolerance to the effects of reinfection is induced in those who experience its effects over a number of years, especially as a result of repeated infections in early childhood.

Pathogenesis

Life history of the parasite comprises two cycles or phases of development:

a) schizogony in the tissues of man, which is succeeded by schizogony occurring

in the blood stream of man; these form the asexual cycle of the parasite;

b) sporogony, the sexual cycle, which occurs in the body of an anopheline

mosquito.

Schizogony. When the sporozoite is introduced into man's skin by the bite of an anopheline mosquito it passes into the blood stream from which it rapidly disappears to enter a parenchyma cell of the liver. Here a process of growth and multiplication occurs,known as preerythrocytic schizogony,which results in the development of a large schizont, containing thousands of tiny merozoites. The mature schizont ruptures about the seventh to the ninth day liberating the merozoites which enter the circulation and invade red blood corpuscles. This starts the phase of erythrocytic schizogony which, however, may not become demonstrable by the examination of blood films until one or two days later.

Erythrocytic schizogony occurs in the circulation and extends from the newly liberated merozoite which is ready to infect a fresh cell, to the rupture of the mature schizont with its contained daughter merozoites. This cycle occupies a period of forty-eight hours in PP. vivax, ovale, falciparum and seventy-two in P. malariae, for its completion. The merozoites attack fresh cells, and in them

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develop into rings, after which the parasites grow through the large trophozoite stage, attain full size, and then proceed to reproduce by division. As soon as this has commenced, when there is evidence that the nucleus has divided and the cytoplasm begun to segment, the term "immature schizont" is applied. Later, when the parasite has reached the stage at which it is fully segmented, and when the merozoites are just about to be liberated by the disruption of the red cells, it is called a "mature schizont". The distended cell ruptures, and the merozoites are thus liberated into the plasma. The residual material is at the same time set free, and,with its contained pigment,is quickly ingested by fixed endothelial cells of the blood vessels, or by wandering phagocytes, usually large mononuclears. Such pigmented leukocytes may be found in stained films if the blood is examined soon after the schizonts have ruptured. The liberated merozoite contains no pigment, immediately enters a fresh red cell and starts the cycle again. As a result of repetition of the erythrocytic cycle and progressive invasion of fresh cells, the infected person in the course of ten days or so develops fever; the period of incubation may, however, be shorter or much longer than this.

There is strong indirect evidence to suggest that in the case of P. vivax, P. ovale and P. malariae the tissue phase of the parasite does not end with the rupture of the pre-erythrocytic schizont and the invasion of the circulation by its merozoites. It is believed that a cycle, known as exoerythrocytic schizogony, continues in the tissues, some of the liberated merozoites invading fresh liver cells and again proceeding to schizogony. According to this hypothesis, even when parasites are absent from the blood, schizogony is continuing repeatedly in the tissues, persisting often for years. On occasions merozoites are discharged into the circulation where they infect red blood corpuscles and thus recommence erythrocytic schizogony, causing parasitaemia. No such evidence exists in the case of P. falciparum, and it is thought that when the preerythrocytic schizonts of this species have discharged their merozoites into the blood stream the cycle of the parasite in the tissues ends.

Sporogony. The sexual or sporogony cycle occurs almost entirely in the anopheline mosquito. In this method of reproduction there are, however, as we saw, preliminary, and also terminal, stages in the blood. Certain merozoites, instead of repeating the asexual cycle, become gametocytes, of which some are male and some are female. These are found in the peripheral blood. If they are taken up by the mosquito in biting,further development very quickly occurs,the remains of the infected red cell being discarded during the process. The asexual parasites ingested with the blood by the mosquito are destroyed in the gut; it is only the gametocytes which survive, and are able to infect the insect. In the case of P. falciparum, as we saw,the gametocytes are crescent-shaped,and the first step in the development is that they assume a rounded form like those of P. vivax and P. malariae. The next step is, that in the male, or microgametocyte, the pigment is suddenly observed to be in violent commotion and soon several filaments are extruded

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each of which contains a granule of the nuclear chromatin. These are extremely active, and it is they which caused the rapid movements of the pigment granules. They detach themselves and swim away; these are the male gametes or the microgametes, which correspond to spermatozoa. The female or macrogametocyte has meanwhile undergone a nuclear reduction process by which it is transformed into the female gamete or macrogamete. This is an unfertilized ovum, and it attracts the active microgametes, one of which penetrates and fertilizes it. After this, the ovum or zygote, as it is now called, is capable of slow movements and hence is known as an "ookinete". This passes between the cells lining the insect's gut, till it reaches the outer limiting membrane. It then ceases to move, becomes round and proceeds to grow, the membrane acting as a cyst wall. This stationary growing ookinete with its covering is called the oocyst. Since the zygote is simply the female malaria parasite after fertilization by the filamentous male gamete, there is still some pigment in it, and this can be detected inside the oocyst. The nucleus of the zygote divides repeatedly, and finally there are produced, inside the oocyst, thousands of minute thread-like structures called sporozoites. When the oocyst becomes mature it ruptures, and the contained sporozoites are set free in the insect's haemocoele, the circulation of which carries them to all parts of the mosquito's body.

Some of them invade the cells of the salivary glands, pass through them and reach the lumen,which communicates with the salivary ducts. The mosquito is now infective. When next it bites man, the salivary fluid containing the sporozoites passes into the skin wound. A mosquito may acquire and be able to transmit a double infection. It is possible for a single infective mosquito to transmit malaria to several people in succession, and at considerable intervals. The supply of sporozoites in the salivary ducts is replenished by a further passage of those in the hemocoele, through the gland cells, into the lumen.

The sporozoite is a narrow, slightly curved organism, it tapers at both ends, has an elongated central nucleus and is devoid of pigment. It is capable of slight undulatory movement As already noted, when it is inoculated into man it is carried in the blood stream to the cells of the liver, which it enters; there it rounds up, starts to grow, and so commences the asexual cycle in man.

The sexual cycle in the mosquito requires about eight to eighteen days for completion, depending on conditions such as moisture and temperature. In the case of P. malariae the sexual cycle in the mosquito is commonly as long as

four weeks.

The asexual cycle can be started in a person otherwise than by the bite of an infective mosquito, for example, by inoculating blood which contains asexual forms, into a fresh subject. If it happens that the only forms present in the infected person's blood are gametocytes, such as the crescents of malignant tertian malaria,no infection will result,as these can only infect the mosquito,and do not infect man.

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The first part of the cycle of sporogony described above, may be watched under the microscope, in ordinary fresh films of the blood containing fully developed gametocytes. The process can readily be followed on the slide, up to the exflagellation of the male gametocyte.

Alterations in the infected red corpuscles in malaria infections.

P. vivax. In the peripheral blood,infected corpuscles may be found containing any stage of parasite; as the organism grows, after the ring form, the red cell enlarges and, at the same time, becomes pale. If the preparation is heavily stained there may be seen on the infected corpuscle a very fine red stippling called Schufmer's dots; these are more plentiful, much smaller, and more constant than are the Maurer's spots in P. falciparum.

P. malariae. The infected- red cell is not enlarged, nor does it show constant colour changes; neither Schufmer's dots nor Maurer's spots are present, though dots (Ziemann's) are occasionally seen.

P. ovale. The red cell containing the parasite is frequently of oval shape with irregular margin. It is pale, but seldom notably enlarged and Schufmer's dots are present.

P. falciparum. The only forms of this parasite which are commonly found in peripheral blood are rings,or crescents,or both. The infected red cell is not enlarged by the presence of the rings, but its circular outline is altered when it contains a crescent There is no change in the color of the red cells such as the fairly constant pallor - often obscured by Schufmer's dots - of those infected with P. vivax, but a few blotchy marks of relatively large size, called Maurer's spots, may be seen.

The pigment of the parasite are the dots on the infected corpuscles. It should be remarked that the malaria pigment hematin, is in the body of the parasite, and that this derives it probably from the red cell. Since it only arises as a result of growth and metabolism, it is natural that the young r'ng f°rm should have none, and that the pigment should increase in proportion as the trophozoite grows at the expense of the red cell.

The conditions known as Maurer's and Schufmer's dots, are due to an altered staining reaction on the part of the cytoplasm of the red cells themselves. They are in the red cell, and not in the parasite, and are not pigment.

In addition to the changes in the red cell enumerated above, which depend on the particular species present, there is also, in infection by any malaria parasite, a varying degree of anemia. This may be very slight or extreme and there may, therefore, be seen in the uninfected red corpuscles some or all of the changes which have been mentioned under anemia.

Anatomic pathology

The pathology of malaria is based really upon subtertian infections (P. falciparum). Most of the lesions in the internal organs are due to infection of red

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blood corpuscles with consequent disturbance of the oxygen supply to the tissues. The vascular flow within the organs is disturbed by vascular collapse, obstruction of the smaller vessels by auto-agglutination, thrombosis, infarctions and similar effects brought about by the clumping together of parasitised cells. All these factors slow down the circulation and cause "ludging" (Knisely) which is thought to be mainly due to the production of a fibrin-like substance. Cardiac and vascular failure may ensue. In addition there are explosive discharges of protein from the liberated merozoites and the disintegration of disrupted red cells, defunct parasites and extrusion of pigment. The spleen, when grossly enlarged, used to be popularly known as the "ague cake". Although it is apt to fluctuate in size it is most certainly always swollen during an acute attack. On section the surface is dark, at times almost black, dark-red, purple or chocolate color from congestion and melanin pigmentation. In severe subtertian infections, the parenchyma may be so softened as to be almost diffluent and so swollen that the capsule is tightly stretched. When the pulp is washed, the malpighian bodies stand out as gray particles.

In chronic cases perisplenitis develops from stretching- or tearing of the capsule, so that rupture may occur spontaneously or as the result of violence. On microscopic examination the organ contains a large number of macrophage cells, the special cells of Billroth, fibrinous cords, and sinus-lining littoral cells. In the chronic stage there is replacement by fibrous tissue. The malpighian bodies shrink while the pigment becomes scattered. All erythrocytic stages of the parasites can be detected in the red cells (P. vivax or P. falciparum) as well as the merozoites set free in the pulp. Numerically they are fnore numerous than in any other organ.

Malaria pigment is readily recognized free within the tissue spaces and enclosed within the reticulo-endothelium, and especially in the mononuclear cells. In acute cases the reticuloendothelial system becomes blocked with pigment and in the later stages this is also replaced by fibrous tissue. Areas of thrombosis and hemorrhagic necrosis also occur.

The liver is usually congested, enlarged, pigmented, and olive-brown in color, especially in the left lobe which receives the splenic blood. Glisson's capsule which surrounds the portal system is thickened and stretched. In chronic malaria there is fibrosis and round-cell infiltration which originates, it is thought, from the cryptozoic or tissue stages of the parasites. In infancy and early childhood, the enlargement, is mainly due to sinusoidal dilatation; in later years, the congestion is mainly confined to the center of the lobule, and so the appearance resembles that, of the "nutmeg" liver of heart failure. The slaty gray color frequently encountered is due to deposits of pigment. Parasitized erythrocytes and melanin (hemozoin) pigment are found within Kupffer cells.

Date: 2014-12-21; view: 914