Human Malaria

The following discussion of human malaria is necessarily brief. Further details and references can be found in any textbook of human parasitology and, in more detail, in Boyd (1949) and Macdonald (1957).

Man has 4 recognized species of Plasmodium. P. falciparum (Welch, 1897) Schaudinn, 1902 is the cause of malignant tertian, aestivo-autumnal or falciparum malaria. Paroxysms of chills and fever occur every other day (i.e., on days 1 and 3, which accounts for the name "tertian"). The ring forms are about 1/6 to 1/5 the diameter of a red blood cell. The schizonts and merozoites ("segmenters") rarely occur in the peripheral circulation, but are found in clumped erythrocytes in the viscera. The schizonts are usually compact and rounded, with coarse, blackish pigment. The segmenters occupy 2/3 to 3/4 of the host cell and form 8 to 32 merozoites. The host erythrocyte is not enlarged but contains reddish clefts known as Maurer's dots and may also have bluish stippling. The macrogametes and microgametocytes are crescent- or bean-shaped, with pigment granules clustered around a central nucleus or scattered except at the poles. The microgametocytes have pale blue cytoplasm and a relatively large, pink nucleus when stained with Giemsa's stain. The macrogametes have darker blue cytoplasm and a more compact, red nucleus.

Plasmodium vivax (Grassi and Feletti, 1890) Labbe 1899 is the cause of benign tertian or vivax malaria. Paroxysms occur every other day as in falciparum malaria. The ring forms are about 1/3 to 1/2 the diameter of the host cell. The schizonts are highly active and sprawled out irregularly over the host cell, with small, brown pigment granules usually collected in a single mass. The host cell is enlarged, pale, and contains red dots known as Schuffner's dots. The segmenters nearly fill the host cell and produce 15 to 20 or occasionally up to 32 irregularly arranged merozoites. The macrogametes and microgametocytes are rounded, 10 to 14 u in diameter (i.e., larger than normal erythrocytes), and have fine, brown, evenly distributed pigment granules. The microgametocytes have pale blue cytoplasm and a relatively large, pink nucleus when stained with Giemsa's stain. The macrogametes are slightly larger, with darker blue cytoplasm and a small, red nucleus.

Plasmodium malariae (Laveran, 1881) Grassi and Feletti, 1890 is the cause of quartan or malariae malaria. This species also occurs naturally in chimpanzees in West Africa (Garnham, 1958). Paroxysms occur every 3 days (i.e., on days 1 and 4). The ring forms are similar to those of P. vivax. The schizonts are more compact and rounded or are drawn out in a band across the host cell; their pigment granules are blacker and coarser than those of P. vivax. The host cell is not enlarged and does not contain Schuffner's dots. The segmenters nearly fill the host cell and produce 6 to 12 (usually 8 or 9) merozoites arranged in a rosette. The macrogametes and microgametocytes are rounded and smaller than those of P. vivax. They do not quite fill the host cell and contain blacker and coarser pigment granules.

Plasmodium ovale Stephens, 1922 is a rare species which causes a tertian type of malaria. Its ring forms are similar to those of P. vivax. The schizonts are usually round, with brownish, coarse, somewhat scattered pigment granules. The host cell is oval, often fimbriated, not much enlarged, and contains Schuffner's dots. The segmenters occupy 3/4 of the host cell and produce 8 to 10 merozoites in a grape-like cluster. The macrogametes and microgametocytes are rounded, occupy 3/4 of the host cell and have coarse, black evenly distributed pigment granules.

A vivax-type Plasmodium, P. cynomolgi, occurs in macaques. Eyles, Coatney and Getz (1960) recently described accidental laboratory infections of 2 humans with P. c. bastianellii originally isolated from Macaca irusivom Malaya. They were able to infect 2 other humans experimentally by allowing them to be bitten by infected Anopheles freeborni mosquitoes. This finding and the presence of P. malariae in chimpanzees suggest that more than one of the human malarias may be zoonoses.

Pathogenesis

The malarial paroxysm is highly characteristic. It begins with a severe chill. The patient shivers uncontrollably, his teeth chatter, and he has gooseflesh, altho his temperature is actually above normal. The chill is followed by a burning fever, headache and sweating. This gradually subsides, the temperature falls, and after 6 to 10 hours the patient feels much better - until his next paroxysm. The destruction of erythrocytes causes anemia.

After a certain number of paroxysms, the attack of malaria subsides. Relapses may occur over a period of years in vivax and malariae malaria, but this is rarely the case in falciparum malaria.

In general, mortality from malaria is higher in children than in adults in endemic areas, because by the time the people become adult they have had repeated attacks, and those who have survived have developed a good deal of immunity. For this reason, if one wants to determine the incidence of malaria in an area, it is better to examine children than adults.

A highly fatal, cerebral form of malaria may occur in falciparum infections. It is due to clogging of the capillaries of the brain by agglutinated, infected erythrocytes. If enough clogging takes place in the viscera, a severe gastro-intestinal disease resembling typhoid, cholera or dysentery may occur. Another complication of falciparum malaria is blackwater fever, which gets its name from the color of the urine. There is tremendous destruction of the erythrocytes - 60 to 80% may be destroyed in 24 hours - accompanied by fever, intense jaundice and hemoglobinuria. Severe attacks are usually fatal. The cause of blackwater fever is not known, but it may involve some sort of immunological reaction which hemolyzes the erythrocytes.

Epidemiology

Malaria is transmitted by Anopheles mosquitoes. There are about 200 species of this genus, but not all are equally good vectors, and the epidemiology of the disease in any particular locality depends not only upon the terrain and climatic conditions, but also upon the particular vectors present, their breeding habits, food preferences, susceptibility to infection, etc. The subject is an extremely complex one and cannot be discussed in detail here. Three examples will suffice.

The principal malaria vector in southeastern United States is Anopheles quadrimaculatus. This species breeds best in clean, open water with dense aquatic vegetation and abundant flotage. It prefers bovine to human blood, however, so that the ratio of livestock to men in an area is an important factor in the transmission rate.

The principal malaria vector in the Solomon Islands is Anopheles farauti. It breeds in small ponds and puddles. During the Guadalcanal campaign of World War II, the profusion of shell holes, fox holes, road ruts, etc. provided ideal conditions for its propagation, and the result was an explosive outbreak of malaria. It was controlled by eliminating or draining the breeding places or spraying them with fuel oil.

These measures would not work in the Philippines, where the principal vector is Anopheles minimus flavirostris. This species breeds at the edges of slow-moving streams in the plains, hence quite different measures, such as stream clearing, straightening and flushing, must be used to prevent its breeding.

Malaria is primarily a disease of warmer climates nowadays, but at one time it was common in the temperate zone. Nevertheless, malaria is still the most important human disease from a global standpoint. Of the 1955 world population of 2,653 million, 1070 million lived in malarious areas, and 696 million of these were protected poorly or not at all from malaria. In 1955 there were still 200 to 225 million cases of malaria in the world, with more than 2 million deaths (Diehl, 1955).

Malaria control has eliminated or almost eliminated malaria from many parts of the world (Pampana and Russell, 1955; Russell, 1956, 1958; Anonymous, 1956), largely by use of residual spraying with DDT and other insecticides. At the end of World War II there were about 4 million cases of malaria a year in southern Europe from Spain to Bulgaria. In 1956 there were less than 10,000 cases in the same area.

Malaria was one of the causes of the decline of the Roman empire. The swampy land of the Roman Campagna made it almost uninhabitable because of the disease. There were 411,602 cases of malaria in Italy in 1945. Systematic spraying with DDT was begun in 1946, and as a result only 12 cases of indigenous malaria (both primary cases and relapses) were reported in 1953. In 1955 there were only 3.

During World War I, the British and French landed armies at Salonika, Greece, with the objective of driving into Germany thru the back door. Malaria wrecked their plans and immobilized their armies. There were 2 million cases of malaria in Greece in 1942. In 1950 there were 50,000, and in 1952 only 408.

In the Eastern Mediterranean countries, with a population of about 170 million, there were about 40 million cases of malaria a year in 1949. There are now about 14 million, and it has been shown that it is technically possible to eliminate malaria from the area.

Malaria has been completely eliminated from Sardinia and Sicily, and it is practically gone from Venezuela, Brazil, British Guiana, Argentina, Cyprus, Ceylon and parts of India, to mention a few of the places.

In the United States there were a million cases of malaria a year among a population of 25 million in 12 southern states during 1912 to 1915. Before that, malaria was an important disease thruout the midwest. Ackerknecht (1945) has given its history in that region from 1760 to 1900. The decrease of malaria in this country was due only in small part to measures aimed directly at the disease, but more to agricultural development and to other, still unknown, factors. It was almost entirely eliminated from the midwest, for instance, by farm land drainage.

After World War II an intensive campaign was started to wipe out malaria from this country. Residual spraying of dwellings, outhouses, barns, etc. was practiced in malarious areas. Mosquito larval control measures were intensified. An attempt was made to follow up every case diagnosed as malaria, to get a blood smear in order to be sure that it actually was malaria, and to treat it immediately in order to prevent it from being a source of further cases.

During 1949 less than 5000 cases were reported in the U.S. During 1955, 477 cases were reported. Of these, 64 were appraised by the U. S. Public Health Service, and only 29 were confirmed by blood smear as malaria. Only 4 were primary indigenous cases. Two were in California, 1 in Arizona, and the fourth - acquired by blood transfusion - in Illinois. In 1957, 157 cases were reported, of which 138 were appraised by the Public Health Service; 102 were confirmed, and 11 of these were primary indigenous cases (Dunn and Brody, 1959). In 1958, 94 cases were reported, of which 61 were confirmed. Seven of these were primary indigenous cases, 4 of them resulting from blood transfusions, and 1 natural case each originating in California, Arizona and possibly Pennsylvania (Brody and Dunn, 1959).

One outbreak of malaria illustrates what can happen if conditions are right (Brunetti, Fritz and Hollister, 1954). It occurred at a Campfire Girl camp at Lake Vera, California. A marine visited the camp on July 4, 1952, and spent the night. He had a malarial relapse while he was there, and was sleeping without a mosquito bar. Within a few weeks the first case appeared among the girls, and cases continued to appear until January or February. A total of 35 cases of vivax malaria occurred among that group of girls as the result of one night's exposure from one infected marine.

There are no obvious technical or economic reasons why malaria could not be eradicated from the Americas, Europe, Australia and much of Asia during the next quarter century, altho the situation is not so promising in tropical Africa (Williams, 1958). This can be done almost entirely by residual spraying of dwellings. The cost of protection has been found to vary from 11 to 45 cents per capita per year. Properly conducted, residual house spraying for 2 to 3 years will eradicate Plasmodium, altho the mosquito vector may persist. Some mosquitoes have developed a resistance to DDT, but this has always taken at least 6 years, so malaria can be eliminated before the mosquitoes become resistant.

New problems result from disease control, however. These are well illustrated by the effect of malaria control on the population of Ceylon. The birth rate on that island was 40 per 1000 in 1920, and it was still about the same in 1950. But the death rate in 1920 was 32 per 1000, while in 1950 it was 12 per 1000, and this decrease was due primarily to the elimination of malaria. This means that if both the present birth and death rates are maintained, the population of Ceylon will double in about 26 years. And how can all these additional millions be fed? (Stone, 1954).

Diagnosis

Malaria can be diagnosed with certainty only by finding and identifying the causative organisms in the blood. This is done by microscopic examination of smears stained with one of the Romanowsky stains; Giemsa's stain is best. At one time thin smears were used almost entirely, but thick, laked smears are much better, since they permit a much larger amount of blood to be examined in a given time. Identification of the species and stages requires skill and practice. An excellent guide with outstanding colored illustrations is that of Wilcox (1960).

Treatment

A number of drugs have been used in treating malaria. The first one was quinine, the most active ingredient of cinchona bark, which was identified in 1820 by Pelletier and Caventou. It is both suppressive and curative, but does not prevent relapses. Chemically it is 6-methoxy-alpha-(5-vinyl-2-quinuclidyl-4-quinoline-methanol).

Quinacrine (Atebrin, Atabrine, mepacrine) was discovered by Mauss and Mietsch (1933) in Germany. It is 2-chloro-5-diethylamino-isopentylamino-7-methoxyacridine dihydrochloride. It was used extensively during World War II when the Indonesian cinchona plantations were taken over by the Japanese. It is actually better than quinine. It is prophylactic against falciparum malaria and suppressive against vivax and malariae malarias. It cures attacks of the disease, but does not prevent relapses. One disadvantage is that it is a dye and stains the skin yellow.

Chloroquine (Aralen) is 7-chloro-4, 4-dimethylamino-1-methylbutylaminoquinoline. It was developed thru a crash drug-testing program during World War II in which the Americans tested over 14,000 compounds and the British about half as many. The results of the American effort are summarized by Wiselogle (1946). Chloroquine appeared too late to be used in that war except experimentally. It is the most effective drug known for the treatment and suppression of all types of malaria. The recommended therapeutic dose is 1.5 g in 3 days. Following its use, fever subsides in a day, and the parasites disappear from the blood in 2 or 3 days. The suppressive dose is 0.3 g weekly. Chloroquine does not prevent vivax malaria relapses, however.

Primaquine appeared even later than chloroquine, having been introduced in 1949. It is 8-(4-amino-1-methylbutyl-amino)-6-methoxyquinoline. It is most useful as a truly curative agent against vivax malaria, since it not only cures attacks but prevents relapses. It is best used in combination with chloroquine if the patient is having an attack, but can be used alone in between relapses to prevent further relapses. The dosage is 15 mg daily for 14 days. The effectiveness of this drug in preventing relapses was proven in returning Korean veterans.

Chlorguanide (Paludrine, Proguanil) was developed by the British during World War II. It is N-p-chlorophenyl-N-5-isopropylbiguanide. It showed a great deal of promise, but after it had been used for a while, resistant strains of Plasmodium appeared, and it is no longer being used.

Pyrimethamine (Daraprim, Malocide) was introduced by the British in 1951. Its discovery grew out of the World War II study. It is 2, 4-diamino-5-p-chlorophenyl-6-ethylpyrimidine. It is perhaps the best suppressive drug known, altho it is not recommended for the treatment of malarial attacks. In single weekly doses of 25 mg it completely suppresses all Plasmodium species and is prophylactic against P. falciparum and some strains of P. vivax. In addition, it destroys P. falciparum gametocytes, so that it has value in the epidemiological control of this type of malaria. It is being mixed with the salt for prophylaxis in some parts of the Americas. Unfortunately, resistant strains have appeared in some areas where it has been used, and its eventual value is uncertain.

Many other drugs have been used for treating malaria, but these are the most important. At present, the ones generally recommended are chloroquine, primaquine and pyrimethamine.