Malaria is the most clinically important parasitic disease worldwide. It kills as many as 2.7 million people annually. The human suffering and economic costs are enormous. Although malaria has been eradicated from temperate zones, it continues to pose a major public health threat to more than forty percent of the world's population.
EPIDEMIOLOGY AND TRANSMISSION
Currently, malaria occurs in one hundred countries and territories inhabited by a total of 2.4 billion people (see Figure 1). The World Health Organization estimates that there are 300 million to 500 million clinical cases annually, resulting in approximately 1.5 million to 2.7 million deaths. Ninety percent of the deaths are in children under five years of age living in sub-Saharan Africa. Other risk groups include pregnant women, internally displaced persons and refugees, and international travelers.
Malaria transmission occurs by the bite of an infective female Anopheles sp. mosquito. Although most cases are transmitted by mosquito, the infection can be passed from mother to the unborn child, or through contaminated blood products, needle sharing, or organ transplantation.
AGENT AND LIFE CYCLE
Human malaria infection is caused by one or more of four species of the intracellular parasite of the genus plasmodium. Plasmodium falciparum, P. vivax, P. ovale, and P. malariae differ in geographic distribution, microscopic appearance, clinical characteristics, and potential for conferring immunity in the host. Although P. vivax is the most common form of malaria worldwide, P. falciparum is the most severe, contributing to most of the morbidity and mortality.
The life cycle of the four species of human malaria consists of two phases: the sexual (sporogony) and asexual phases (schizogony; see Figure 2). Schizogony begins when an infective female anopheline mosquito injects sporozoites into the human host while taking a blood meal. The sporozoite stage of the parasite disappears from circulation within thirty minutes. Those avoiding the host immune system invade the liver and undergo development and multiplication to form schizonts. Over the next five to fifteen days, the schizonts mature, rupture the liver cell, and invade the circulation as merozoites. These merozoites bind to the red blood cell wall. They then penetrate the red blood cell, where they develop as ring forms and grow into trophozoites. Further division creates red blood cell merozoites which form a mature schizont. The blood cell swells and ruptures, releasing merozoites that go on to invade other red blood cells. Clinical symptoms result when the blood cell ruptures and releases cellular debris from infected cells into the bloodstream. The host response to these toxins produces the
classic paroxysms of fever and chills, which are closely timed with the cycles of red blood cell schizogony. The timing of the blood cell phase differs depending on the species of the parasite. P. vivax and P. ovale classically have cycles of forty-eight hours, P. malariae seventy-two hours, and P. falciparum forty-eight hours, although this may vary.
After a period of time, some of the merozoites develop into male and female sexual forms called gametocytes. The gametocytes are ingested by the female anopheline mosquito during a blood meal. Inside the mosquito's stomach, the male and female gametocyte fuse to form a zygote, which quickly becomes a mobile oökinete, which penetrates the stomach wall to form an oöcyst. The oöcyst then bursts, releasing sporozoites that migrate to the salivary glands, ready to be injected into a human host, thus completing the cycle. The parasite generally develops within the mosquito (sporogony) in nine to twelve days, but this time varies according to parasite species and external temperature.
P. vivax and P. ovale differ from the other two species in that some hepatic trophozoites, called hypnozoites, may remain dormant and persist in the liver for months to up to four years. Periodic release of merozoites formed from these hypnozoites can produce recurrent parasitemia and clinical symptoms. Recurrent parasitemia can also occur with P. falciparum and P. malariae, although these species do not form hypnozoites. Infection with these parasites may remain in the blood at subclinical levels because of either the host immune system or use of antimalarial drugs
that do not completely clear the blood-stage parasites. The level of parasitemia can increase weeks to months later, giving rise to another clinical attack. While P. falciparum rarely returns more than several months after the initial infection, P. malariae may become active again up to forty years after the infection.
CLINICAL DISEASE AND DIAGNOSIS
The clinical presentation of malaria is very nonspecific. The degree of natural and acquired immunity of the patient can influence the clinical course dramatically. Classic symptoms among nonimmune persons include fever, chills, sweats, body aches, headache, decreased appetite, nausea, vomiting, and diarrhea. Signs of malaria infection may include an enlarged liver and spleen, anemia, jaundice, low blood pressure, fast heart rate, and decreases in the number of white blood cells and platelets. Children may also show fretfulness, unusual crying, and sleep disturbances. The hallmark of malaria is the paroxysms (attacks) of these symptoms, which recur with predictable periodicity. P. vivax and P. ovale malaria classically cause symptoms every forty-eight hours, P. malariae every seventy-two hours. P. falciparum features irregular patterns. The presentation of these classic attacks is highly variable and may not occur at all early in the disease or in partially immune persons.
Life-threatening disease generally occurs only with P. falciparum infections and can progress from uncomplicated malaria within hours. Neurologic manifestations are the most common presentation of severe disease, often appearing as altered mental status, drowsiness, coma, or convulsions. Other important severe clinical conditions include renal failure, pulmonary distress, severe anemia, low blood sugar, and shock.
Malaria in pregnancy can have devastating effects, especially when caused by P. falciparum. In nonimmune pregnant women, malaria infections can lead to increased risk of maternal and fetal death. Among semi-immune pregnant women, low birth weight due to placental parasitemia represents the greatest risk factor for neonatal death.
Due to the nonspecific nature of malaria symptoms, the diagnosis cannot be made based on clinical signs and symptoms alone. Laboratory diagnostic tests must be performed on any patient suspected of having a malaria infection. The standard for diagnosing malaria is the microscopic visualization of parasites in red blood cells on Giemsa-stained thick and thin smears. Advantages of microscopy include high sensitivity and specificity among properly trained and supervised technicians. Microscopy also offers the ability to identify the infecting species and quantify the level of parasitemia. Immunochromatographic rapid diagnostic tests have been developed that may detect P. falciparum and non–P. falciparum infections. These require no special equipment and are relatively easy to use. The determination of parasite density is not possible with these dipsticks. Other less common methods used for diagnosing malaria infections include serologic tests using an enzyme-linked immunosorbent assay, radioimmunoassay techniques, and polymerase chain reaction.
To decrease morbidity and mortality from malaria infections, early diagnosis and prompt treatment
Chloroquine has long been the mainstay first-line therapy for uncomplicated P. falciparum infection used by malaria control programs; however, resistance to it now exists in most parts of the world. Sulfadoxine-pyrimethamine (SP) has replaced chloroquine in many countries. Resistance to SP has developed in Southeast Asia, parts of South America, and now in certain sites in sub-Saharan Africa. Other drugs commonly used for falciparum infections include quinine, quinidine, amodiaquine, mefloquine, halofantrine, artemisinin compounds, atovaquone, tetracycline, and clindamycin.
Chloroquine is the main drug used for infections with P. vivax, P. ovale, and P. malariae; however, there are reports of chloroquine-resistant P. vivax in parts of Oceania. Primaquine is used to eliminate the hypnozoites in P. vivax and P. ovale infections.
Four basic elements of an effective malaria control program include case management, selective and sustainable preventive measures, early detection of epidemics, and the strengthening of local capacity. Appropriate case management is imperative to malaria control programs. It consists of accurate diagnosis followed by rapid, effective treatment. The detection of malaria in children and pregnant women is especially important. Knowledge of mosquito behavior and relevant environmental, social, and economic features is extremely important for malaria prevention programs. These programs often consist of personal protection (e.g., repellents, insecticide-impregnated bednets), chemoprophylaxis (chemical agent to prevent malaria) for travelers or other high-risk persons, and selective mosquito control (e.g., insecticides, larvicides, environmental management). Malaria epidemics can occur when a community with little or no immunity moves into an area of intense malaria transmission. Epidemics often take place in times of socio-political instability (e.g., complex humanitarian emergencies). These may result in high numbers of deaths. Finally, to be able to control transmission, malaria-endemic countries need to integrate control efforts into the national health plan, strengthen in-country scientific capacity to perform malaria research, and mobilize community support for intervention programs.
JOHN R. MACARTHUR
S. PATRICK KACHUR
Bloland, P. B.; Lacritz, E. M.; Kazembe, P. N. et al. (1993). "Beyond Chloroquine: Implications of Drug Resistance for Evaluating Malaria Therapy Efficacy and Treatment Policy in Africa." Journal of Infectious Diseases 167:932–937.
Bruce-Chwatt, L. J. (1986). Chemotherapy of Malaria. Geneva: World Health Organization.
Gilles, H. M., and Warrell, D. A. (1993). Bruce-Chwatt's Essential Malariology, 3rd edition. London: Arnold.
Kachur, S. P., and Bloland, P. B. (1998). "Malaria." In Maxcy-Rosenau-Last's Public Health and Preventive Medicine, 14th edition, ed. R. B. Wallace. Stamford, CT: Appleton & Lange.
MacArthur, J. R.; Williams, H. A.; and Bloland, P. B. (2000). "Malaria in Complex Humanitarian Emergencies." Refuge 18(5):4–11.
Nwanyanwu, O. C.; Ziba, C.; MacHeso, A.; and Kazembe, P. (2000). "Efficacy of Sulphadoxine-pyrimethamine for Acute Uncomplicated Malaria Due to Plasmodium falciparum in Malawian Children under Five Years Old." Tropical Medicine and International Health 5:355–358.
White, N. J. (1996). "The Treatment of Malaria." New England Journal of Medicine 335:800–806.
World Health Organization (1993). A Global Strategy for Malaria Control. Geneva: Author.