Malaria

Malaria is an ancient scourge, as evidenced by early Chinese and Hindu writings. During the fourth century B.C., the Greeks noticed its association with exposure to swamps and began drainage projects to control the disease. The Italians gave the disease its name, malaria, which means "bad air," in the seventeenth century. In early times, malaria ranged as far north as Siberia and as far south as Argentina. In 1902, Ronald Ross received a Nobel Prize for demonstrating the life cycle of the protozoan cause of malaria.

Malaria is the most common serious infectious disease worldwide. In 1955, the World Health Organization (WHO) began a program for the worldwide elimination of malaria. Initially there was great success, as WHO employed insecticides such as DDT against the mosquito vector, detected infected patients by obtaining blood smears, and provided treatment for those who were infected. Fifty-two nations undertook control programs and, by 1960, 10 of them had eradicated the disease. Unfortunately, strains of Anopheles mosquitoes resistant to insecticides began to appear, and in cooperation with bureaucracy and complacency, malaria began a rapid resurgence. In 1976, the World Health Organization acknowledged that the eradication program was a failure. Today there are 300 to 500 million people infected annually worldwide, with about 3 million deaths. More people are dying of the disease than when the eradication programs first began. ■ DDT, p. 797

Symptoms

The first symptoms of malaria are "flu"-like, with fever, headache, and pain in the joints and muscles. These symptoms generally begin about 2 weeks after the bite of an infected mosquito, but in some cases they can begin many weeks afterward. After 2 or 3 weeks of these symptoms, the pattern changes and symptoms tend to fall into three phases highly suggestive of malaria.

■ The patient abruptly feels cold and develops shaking chills that can last for as much as an hour (cold phase).

■ Following the chills, the temperature begins to rise steeply, often reaching 40°C (104°F) or more (hot phase).

■ After a number of hours of fever, the temperature falls, and drenching sweating occurs (wet phase). Except for fatigue, the patient feels well until 24 or 48 hours later, depending on the causative species, when the pattern of symptoms repeats.

Causative Agent

Human malaria is caused by protozoa of the genus Plasmodium. Four species are involved—P. vivax, P. falciparum, P. malariae, and P. ovale. These species differ in microscopic appearance and, in some instances, life cycle, type of disease produced, severity, and treatment. In recent years, the majority of patients diagnosed in the United States have been infected with P. vivax, but up to 30% have been infected with the more dangerous species, P. falciparum.

The Plasmodium life cycle is complex (figure 28.11), with a number of different forms that differ in microscopic appearance and antigenicity. In the human host, sporozoites, the infectious form injected by the mosquito, are carried by the bloodstream to the liver, where they infect liver cells. In these cells, each parasite enlarges and subdivides, producing thousands of mero-zoites. These merozoites are then released into the bloodstream and establish the cycle involving the erythrocytes. The parasite

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Perspective, Fourth Edition

732 Chapter 28 Blood and Lymphatic Infections

Blood channel

Liver cells-Cell nucleus

Sporozoite-

732 Chapter 28 Blood and Lymphatic Infections

Blood channel

Liver cells-Cell nucleus

Sporozoite-

® Gametocytes ingested by mosquito

® Gametocytes ingested by mosquito

Figure 28.11 Life Cycle of Plasmodium vivax (1) Infected Anopheles mosquito introduces Plasmodium vivax sporozoites into a capillary. (2) Sporozoites are carried to the liver and infect liver cells.They multiply, rupture the infected cell, and discharge thousands of merozoites into the blood channels of the liver. (3) The merozoites infect and differentiate in red blood cells (RBCs), becoming first a ring form, then a trophozoite, then a schizont.The schizont separates into merozoites, which break out of the cell and infect new RBCs. Some of the new infections repeat the previous sequence; in others, the infecting merozoite merely differentiates into a gametocyte. (4) An uninfected mosquito ingests gametocytes along with its blood meal. (5) In the mosquito digestive tract, the gametocytes are released from their RBC; other forms are digested. (6) The gametocytes develop into gametes, and fertilization takes place. (7) The resulting zygote develops into a motile form and penetrates the gut wall. (8) In the gut wall, the zygote forms an oocyst and multiplies asexually. (9) The cyst releases sporozoites that infect the mosquito's salivary glands.

grows and divides in the erythrocytes of the host. The earliest form resembles a ring, with a large pale food vacuole in the central area, with the nucleus and cytoplasm being pushed to the periphery. This develops into a larger motile trophozoite, which goes on to subdivide, producing a schizont. The infected ery-throcyte then breaks open, and the offspring of the division, called merozoites, are released into the plasma. The merozoites then enter new erythrocytes and multiply, repeating the cycle. Some merozoites that enter erythrocytes develop into gameto-cytes, however, which are specialized sexual forms different from the other circulating plasmodia in both their appearance and susceptibility to antimalarial medicines. These sexual forms do not rupture the red blood cells. They cannot develop further in the human host and are not important in causing the symptoms of malaria. They are, however, infectious for certain species of Anopheles mosquitoes and are thus ultimately responsible for the transmission of malaria from one person to another.

When a mosquito dines on a person's blood (see figure 28.11) it digests infected and uninfected erythrocytes, except that it only liberates the gametocytes from the erythrocytes that enclose them. Shortly after entering the intestine of the mosquito and stimulated by the drop in temperature, the male and female gametocytes change in form to become gametes. The male gametocyte transforms into about a half dozen tiny, whiplike gametes that swim about until they unite with the female gamete in much the same way as the sperm and ovum unite in higher animals. The resulting zygote transforms into a motile form that burrows into the wall of the midgut of the mosquito and forms a cyst. The cyst enlarges as the diploid nucleus undergoes meio-sis, dividing asexually into numerous offspring. The cyst then ruptures into the body cavity of the mosquito, and the released parasites, called sporozoites, find their way to the mosquito's salivary glands and saliva, from which they may be injected into a new human host.

Pathogenesis

The characteristic feature of malaria, recurrent bouts of fever followed by feeling healthy again, results from the erythrocytic cycle of growth and release of merozoites. Interestingly, the infections in all the millions of different red blood cells become nearly synchronous. Thus, cell rupture and release of daughter protozoa occur at roughly the same time for all infected cells, and each release causes a fever. For P. malariae, the growth cycle takes 72 hours, so that fever recurs every third day. For the other species, fevers generally occur every other day.

Infections by P. falciparum tend to be very severe, probably because all erythrocytes are susceptible to infection, whereas other Plasmodium species infect only young or old ery-throcytes. Thus, very high levels of parasitemia, meaning parasites in the bloodstream, can develop with P. falciparum infections. The infected red blood cells become rigid, in contrast to normal red cells, which are flexible. Also, they adhere to each other and to the walls of capillaries. These tiny blood vessels therefore become plugged, and the affected tissue becomes deprived of oxygen as a result. Involvement of the brain, or cerebral malaria, is particularly devastating, but almost any organ can be severely affected.

Plasmodium vivax and P. ovale malaria often relapse after treatment of the blood infection because treatment-resistant forms of the organisms continue to reside in the liver in a dormant state. Months later, they can begin multiplying in an exo-erythrocytic cycle; (exo- means "outside of," -erythrocytic refers to red blood cells). The exoerythrocytic cycle can initiate new erythrocytic cycles of infection after the earlier bloodstream infection has been cured.

The spleen characteristically enlarges in malaria to cope with the large amount of foreign material and abnormal red blood cells, which it removes from the circulation. Malaria is the most common cause of splenic rupture, which can occur with or without trauma.

Especially with P. falciparum, the parasites cause anemia by destroying red blood cells and converting the iron in hemoglobin to a form not readily recycled by the body. The large amount of foreign material in the bloodstream strongly stimulates the immune system. In some cases, the overworked immune system fails and immunodeficiency results.

Those who live continuously in areas where malaria is endemic develop some immunity to the lethal effects of the disease, which crosses the placenta and gives partial protection to the newborn. The greatest risk of death from malaria is to children over six months of age as this immunity wanes. Currently, worldwide, a child dies of malaria about every 40 seconds. Others at high risk of death are women with their first pregnancy, and individuals who move into an endemic area.

Epidemiology

Malaria was once common in both temperate and tropical areas of the world, and endemic malaria was only eliminated from the continental United States in the late 1940s. Today, malaria is predominantly a disease of warm climates, but 41% of the world's population live in endemic areas. Certain human-biting mosquito species of the genus Anopheles are biological vectors of malaria. Since suitable vectors are abundant in North America, the poten-

28.5 Protozoan Diseases 733

tial exists for the spread of malaria whenever it is introduced. Infected mosquitoes and humans constitute the reservoir for malaria. Malaria can be transmitted by, besides mosquitoes, blood transfusions or the sharing of syringes among drug users. Malaria contracted in this manner is easier to treat since it involves only red blood cells and not the liver; only sporozoites from mosquitoes can infect the liver. Some people of black African heritage are genetically resistant to P. vivax malaria because their red blood cells lack the receptors for the parasite. Also, some genetically determined blood diseases such as sickle cell anemia have survived over the eons, despite their negative effect on health, because they provide partial protection against malaria. ■ receptors, pp. 53, 466

Prevention and Treatment

Travelers to malarious areas, including 27 million Americans each year, can generally prevent symptomatic malaria, but not necessarily infection by the plasmodia, with weekly doses of chloro-quine. Using insect repellants and mosquito netting impregnated with insecticide, avoiding the outdoors from dusk to dawn, and wearing protective clothing all help avoid infection. After leaving malarious areas, people take primaquine to eliminate possible exoerythrocytic infection, which if untreated could cause recurrence of the disease.

Areas of the world with chloroquine-resistant strains of P. falciparum present an increasingly vexing problem since the only effective preventive medications can cause serious, even fatal reactions in some people. Travelers to such areas should consult with a health officer familiar with local conditions before deciding on a preventive regimen.

Unfortunately, the malaria problem is likely to worsen unless effective control is achieved soon. The world population is presently 6 billion, with 250 new births occurring every minute. Moreover, various computer models project the climate to warm significantly, resulting in an increase in the areas where malaria is likely to occur. The combination of increasing population, expanding areas where malaria can be easily transmitted, and the development of medication-resistant plasmodia and insecticide-resistant mosquitoes underscores the need for an effective control program.

In 1998, a new initiative called Roll Back Malaria was begun, linking the World Health Organization, the United Nations Childrens Fund (UNICEF), the United Nations Development Program, and the World Bank in the fight against malaria. Their goal is to halve malaria deaths by the year 2010, and halve deaths again by 2015. The initial focus is on detailed mapping of malarious areas using satellite imagery and climate information, and documenting the level of malaria treatment and prevention at the village level. The aim is to organize and fund a sustained effort to improve access to medical care, strengthen local health facilities, and promote the delivery of medications and insecticide impregnated mosquito netting. Besides Roll Back Malaria, other initiatives under way are designed to spur development of new antimalarial medications and to better fund vaccine and other research. In contrast to initiatives in the past, there

734 Chapter 28 Blood and Lymphatic Infections

734 Chapter 28 Blood and Lymphatic Infections

Mefloquine Resistance Map

No malaria reported Chloroquine-sensitive species Chloroquine-resistant species Chloroquine and mefloquine resistance Figure 28.12 Distribution of Malaria in 1996 The malaria range may expand greatly with global warming.

is now better understanding that malaria control must be part of overall economic development, since it is difficult for one to move forward without the other.

Scientists have been trying to perfect a vaccine against malaria for many years. The first major breakthrough was reported in 1976 from the laboratory of Dr. William Trager at the Rockefeller University. Trager described a method for the continuous in vitro cultivation of P. falciparum, allowing for the production of antigens from different stages of the organism's life cycle. Later on, other scientists using genetic engineering techniques cloned the genes responsible for these antigens and identified which antigens were potential vaccine candidates. A number of different vaccines are currently under development, including recombinant protein vaccines, and a 15-gene naked DNA vaccine. Current estimates are that it could take another decade before an effective vaccine is widely available. ■ DNA-based vaccines, p. 425

Treatment of malaria is complicated by the fact that different stages in the life cycle of the parasite respond to different medications. Chloroquine, and the newer, chemically related mefloquine, are generally effective against the erythrocytic stages, but will not cure the liver infection with P. vivax or kill the gameto-cytes of P. falciparum. Primaquine or a newer derivative, tafeno-quine, is generally effective against the exoerythrocytic stage and the P. falciparum gametocytes. Strains of chloroquine-resistant P. falciparum are now common in many parts of the world, and resistant strains of P. vivax have appeared in some areas (figure 28.12). Promising new medications such as a combination, ato-vaquone and proguanil, may help with this problem. Some patients infected with chloroquine-resistant strains respond to intravenous quinine or quinidine together with an oral medication such as tetracycline or a sulfa drug. ■ mefloquine, p. 529 Table 28.8 gives the main features of malaria.

Table 28.8 Malaria

Symptoms

Recurrent bouts of violent chills and fever alternating with feeling healthy

Incubation period

Varies with species; 6 to 37 days

Causative agent

Four species of protozoa of the genus Plasmodium

Pathogenesis

Cell rupture, release of protozoa cause fever; infected red blood cells adhere to each other and to walls of capillaries; vessels plug up, depriving tissue of oxygen; spleen enlarges in response to removing large amount of foreign material and many abnormal blood cells from the circulation

Epidemiology

Transmitted from person to person by bite of infected anopheline mosquito. Some individuals genetically resistant to infection

Prevention and treatment

Weekly doses of chloroquine while in malarial areas; after leaving, primaquine is given; other medicines for resistant strains; eradication of mosquito vectors; mosquito netting impregnated with insecticide; vaccines under development. Same medicines used in treatment; additional choices available for resistant strains

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