6
The Parasite, the Mosquito, and the Disease

THE MALARIA PARASITE AND ITS LIFE CYCLE

An Ancient Parasite Shared by Many Vertebrates

Malaria is caused by plasmodia—ancient, single-celled protozoans transmitted to humans by the bites of female Anopheles mosquitoes. Plasmodia parasites have complex life cycles involving vertebrate and insect hosts (Figure 6-1). In addition to the four plasmodial species that infect humans, roughly 120 additional species infect various animals from reptiles to birds to higher apes. None of these animal parasites (except, very rarely, certain monkey strains) can be transmitted to humans, however. This degree of host specificity suggests a long association between humans and the four malaria species that infect them.

Four Plasmodium Species Cause Human Malaria

The four malaria species that produce human disease are Plasmodium vivax (also called tertian malaria), P. falciparum (also called malignant tertian malaria), P. malariae (also called quartan malaria), and P. ovale. Plasmodium vivax, which is prevalent in temperate as well as tropical and subtropical zones, has the widest geographical range because it can survive at lower temperatures within a mosquito than the other three parasites that infect humans. Plasmodium falciparum, the most lethal strain, is the most prevalent species throughout the tropics and subtropics. Plasmodium



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Saving Lives, Buying Time: Economics of Malaria Drugs in an Age of Resistance 6 The Parasite, the Mosquito, and the Disease THE MALARIA PARASITE AND ITS LIFE CYCLE An Ancient Parasite Shared by Many Vertebrates Malaria is caused by plasmodia—ancient, single-celled protozoans transmitted to humans by the bites of female Anopheles mosquitoes. Plasmodia parasites have complex life cycles involving vertebrate and insect hosts (Figure 6-1). In addition to the four plasmodial species that infect humans, roughly 120 additional species infect various animals from reptiles to birds to higher apes. None of these animal parasites (except, very rarely, certain monkey strains) can be transmitted to humans, however. This degree of host specificity suggests a long association between humans and the four malaria species that infect them. Four Plasmodium Species Cause Human Malaria The four malaria species that produce human disease are Plasmodium vivax (also called tertian malaria), P. falciparum (also called malignant tertian malaria), P. malariae (also called quartan malaria), and P. ovale. Plasmodium vivax, which is prevalent in temperate as well as tropical and subtropical zones, has the widest geographical range because it can survive at lower temperatures within a mosquito than the other three parasites that infect humans. Plasmodium falciparum, the most lethal strain, is the most prevalent species throughout the tropics and subtropics. Plasmodium

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Saving Lives, Buying Time: Economics of Malaria Drugs in an Age of Resistance FIGURE 6-1 Life cycle of a Plasmodium species that causes human malaria. malariae is patchily present over the same range as P. falciparum. Plasmodium ovale is found in tropical Africa, and occasionally in Asia and the western Pacific. Biologic and Genetic Diversity One of the remarkable features of human plasmodia is their biology, which allows these small yet genetically complex microbes to survive and exploit several different environments: the liver and blood cells of humans as well as the gut, vascular system, and salivary glands of mosquitoes. With the advent of molecular tools such as polymerase chain reaction (PCR), an understanding of the genetic diversity of plasmodial parasites (in particular P. falciparum) has emerged. It is now known that many infected patients from falciparum-endemic areas harbor parasites belonging to more than one genotype. Some carry as many as 10 genotypes detectable by currently available methods (Greenwood, 2002).

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Saving Lives, Buying Time: Economics of Malaria Drugs in an Age of Resistance The Journey of a Single Malaria Parasite from Mosquito to Human After mating, female anopheline mosquitoes require blood meals before each egg-laying. Human malaria begins when a female anopheline inoculates malaria acquired from a previous human blood meal. While probing for a capillary with her mouthpiece (basically, a pair of needle-like tubes), the infected female injects thread-like forms called sporozoites from her salivary glands. Although sporozoites in the salivary glands of wild-caught mosquitoes usually number around 1,000, only 8 to 10 sporozoites on average are transferred in a single mosquito bite. Nonetheless, even one sporozoite is capable of initiating a malaria infection. Within 30 to 60 minutes upon entering the human bloodstream, sporozoites migrate through the venous circulation to the liver. Before invading individual liver cells, they attach to cell receptors via a surface molecule known as a circumsporozoite protein. Over the next 5 to 25 days (the length of time depends on the particular malaria species), the sporozoite reproduces by asexual binary fission. Ultimately, each sporozoite generates 10,000 to 30,000 descendants contained within a cyst-like structure called a liver schizont. During this developmental period the patient remains symptom-free. Once the liver schizont ruptures, parasites flood out of the organ and invade circulating red blood cells (RBCs). The process of attachment and entry takes no longer than 30 seconds. Inside RBCs, the parasites derive energy from hemoglobin siphoned from the host cell. Using this metabolic fuel, the invading parasites grow and transform from delicate rings to larger amoeboid forms called trophozoites to a multinucleate blood schizont stage containing 8 to 24 daughter parasites. Mature blood schizonts of P. falciparum sequester deep within the venous microvasculature where, unlike ring-stages, they generally are undetectable on routine blood smears. This sequestration of RBCs containing mature stages of P. falciparum in the microvasculature of vital organs is the core pathological process in severe falciparum malaria. The organ distribution of sequestration determines the clinical syndrome (Pongponratn et al., 2003). For example, if sufficient numbers of P. falciparum schizonts attach to blood vessels in the brain, cerebral malaria can result (Adams et al., 2002), while in the placenta, adherent schizonts may reduce fetal blood supply and thus contribute to impaired fetal growth (Scherf et al., 2001). When the blood schizont finally ruptures, the next generation of parasites is released into the human bloodstream. Each of these parasites then enters a new RBC and continues the cycle of bloodstream infection.

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Saving Lives, Buying Time: Economics of Malaria Drugs in an Age of Resistance The Release of Bloodstream Parasites Triggers Symptoms and Amplifies Infection In a nonimmune patient, the release of parasites from blood schizonts triggers recurring attacks of fever, sweats, and chills. The periodicity (every 48 hours in P. vivax infection; every 72 hours in P. malariae infection) reflects the time needed for a single cycle of intra-erythrocytic growth and development for the respective species. Although P. falciparum also has a 48-hour growth cycle, its paroxysms are less predictable because the rupture of blood schizonts occurs in nonsynchronized waves. With each replicative cycle, the parasite load increases. In the case of P. falciparum infection, for example—assuming no host immune factors hold parasite growth in check—the total body parasite load increases roughly 8-to 10-fold every 48 hours. In a child, this rapid replication can yield a lethal parasite burden within a few parasite life cycles. Sexual-Stage Parasites Perpetuate Malaria in the Mosquito Certain malaria parasites contained within human RBCs also develop into male and female sexual forms known as gametocytes. Although gametocytes do not multiply or cause illness in the human, they perpetuate malaria in mosquitoes. Once siphoned from human blood by a female anopheline, male and female gametocytes produce a mature, fertilized oocyst in the insect midgut over 7 to 10 days. The oocyst then releases sporozoites, which penetrate many body sites, including the mosquito’s salivary glands. Assuming she lives long enough to feed again, with her next blood meal, the infected mosquito inoculates salivary sporozoites into a new human host, thus completing the Plasmodium life cycle. Chronically Infected Humans and Malaria Transmission In order to sustain malaria transmission, new female anophelines must be continuously infected. This requires a human reservoir containing abundant circulating gametocytes. Persons with recently acquired infections have mainly asexual parasites in their blood. However, chronically infected individuals who can tolerate ongoing bloodstream infection with malaria have many gametocytes. The relative contribution of such individuals to overall malaria transmission compared with less immune patients (typically children) in endemic areas has not been determined.

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Saving Lives, Buying Time: Economics of Malaria Drugs in an Age of Resistance Other Routes of Malaria Infection Rarely, malaria is acquired through non-mosquito-borne transmission. Infection can follow transfusion of malaria-tainted blood products as well as exposure to RBC-contaminated tissues (such as bone marrow) and transplanted organs. Malaria parasites can also pass through the placental barrier, sometimes leading to congenital infection in newborns. Recurrent Malaria: Relapse versus Recrudescence In the absence of reinfection, malaria that recurs following treatment falls into two categories: relapse and recrudescence. Malaria relapse is seen exclusively in P. vivax and P. ovale, and represents a reseeding of the bloodstream by dormant parasites (called hypnozoites) contained in the liver. Plasmodium falciparum and P. malariae do not produce hypnozoites. The recurrence of malaria in these species, conversely, reflects the proliferation of surviving blood-stage parasites from an earlier infection, an event called recrudescence. THE ANOPHELES VECTOR Only female mosquitoes of the genus Anopheles transmit human malaria. The genus includes roughly 400 species of Anopheles mosquitoes worldwide, of which 60 species are malaria vectors, and some 30 species are of major importance (Bruce-Chwatt, 1985). Anopheles gambiae, the principal malaria mosquito in sub-Saharan Africa, is a particularly effective malaria vector because of its strong preference for feeding on humans and its long life compared with some other anopheline species. Up to 10 percent of A. gambiae in certain areas of Africa carry P. falciparum sporozoites at a given time. A small number of such mosquitoes present a greater hazard to humans than a large number of other anopheline species (such as forest vectors) less likely to bite humans, and in whom sporozoite rates are as low as 0.1 percent. Worldwide Distribution of Anopheline Mosquitoes and Malaria Most anopheline mosquitoes live in tropical and subtropical regions, although some species also thrive in temperate climates and even survive the Arctic summer. As a rule, they do not breed at altitudes above 2,000-2,500 meters. Within these geographic bounds, there are many areas free of malaria, however, because transmission is highly dependent on local environmental and epidemiologic conditions.

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Saving Lives, Buying Time: Economics of Malaria Drugs in an Age of Resistance Table 6-1 lists 12 epidemiological zones of malaria, and their principal and secondary vectors (Bruce Chwatt, 1985). Anopheline Larval Habitats The site chosen by mosquitoes for egg-laying and development of larvae is known as the larval habitat. Anophelines prefer relatively clean water as their larval habitat, although species vary in the amount of sun exposure, temperature, salinity, and organic content they prefer in their breeding sites. Developmental Stages, Mating, Egg-Laying, and Adult Lifespan The four developmental stages of an anopheline mosquito are egg, larva, pupa, and adult (or imago). Adult males copulate in flight, providing females with sufficient sperm for all subsequent egg-laying. Females need at least two blood meals for their first batch of eggs to develop, and one blood meal for each successive batch. Since egg development takes about 48 hours, blood-seeking is repeated every 2-3 nights. Under optimal conditions, the average lifespan of an adult female anopheline is 3 weeks or longer (adult males, in contrast, usually live no more than a few days) unless external factors such as temperature, humidity, and natural enemies decrease longevity. When the mean ambient temperature exceeds 35oC, or humidity falls below 50 percent, longevity is significantly reduced, directly influencing the transmission of malaria. Feeding and Resting Behavior The male adult anopheline feeds on nectar, while the female adult feeds primarily upon blood. Females of most Anopheles species prefer warm-blooded animals, predominantly mammals. Some species prefer humans, and are termed anthropophagic or anthropophilic. Others prefer animals such as cattle, and are termed zoophagic or zoophilic. The distance over which a mosquito is attracted to its preferred blood source usually ranges between 7 and 20 meters. The time of anopheline feeding is, almost without exception, between dusk and dawn. Some species have early peaks of biting (for instance, the Central American vector A. albimanus, which feeds between 1900 to 2100 hours). Anopheles gambiae, the leading malaria vector in Africa, can feed over a much wider period (2200 to 0600 hours). If biting precedes the local bedtime, insecticide-treated (bed) nets (ITNs) offer little protection against malaria infection.

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Saving Lives, Buying Time: Economics of Malaria Drugs in an Age of Resistance TABLE 6-1 Twelve Epidemiological Zones of Malaria and Some of the Main and Secondary Vectors Zone Extension Main Malaria Vectors Local or Secondary Vectors   North American From the Great Lakes to southern Mexico A.(A.) freeborni A.(A.) quadrimaculatus A.(N.) albimanus   Central American Southern Mexico, the Caribbean islands, fringe of the South American coast A.(N.) albimanus A.(N.) aquasalis A.(N.) argyritarsis A.(N.) darlingi A.(N.) albitarsis A.(N.) allopha A.(A.) aztecus A.(A.) punctimacula   South American Most of the South American continent irregularly beyond the Tropic of Capricorn A.(N.) albimanus A.(N.) albitarsis A.(N.) aquasalis A.(N.) argyritarsis A.(N.) darlingi A.(A.) pseudopunctipennis A.(A.) punctimacula A.(K.) bellator A.(N.) braziliensis A.(K.) cruzi A.(N.) nuñeztovari   North Eurasian Within the Palaearctic region, excluding the Mediterranean coast of Europe A.(A.) atroparvus A.(A.) messeae A.(A.) sacharovi A.(A.) sinensis A.(C.) pattoni   Mediterranean Southern coast of Europe, north-western part of Africa, Asia Minor, and east beyond the Arab Sea A.(A.) atroparvus A.(A.) labranchiae A.(A.) sacharovi A.(A.) claviger A.(C.) hispaniola A.(A.) messeae A.(C.) pattoni   Afro-Arabian Africa north and south of the Tropic of Cancer including central part of the Arabian peninsula A.(C.) arabiensis A.(C.) pharoensis A.(C.) sergenti A.(C.) hispaniola A.(C.) multicolor   Afro-Tropical (formerly “Ethiopian”) Southern Arabia, most of the African continent, Madagascar and the islands south and north of it A.(C.) arabiensis A.(C.) funestus A.(C.) gambiae A.(C.) melas A.(C.) merus A.(C.) moucheti A.(C.) nili A.(C.) pharoensis   Indo-Iranian Northwest of the Persian Gulf and east of it including the Indian subcontinent A.(C.) culicifacies A.(C.) fluviatilis A.(C.) stephensi A.(C.) annularis A.(C.) pulcherrimus A.(A.) sacharovi A.(C.) superpictus

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Saving Lives, Buying Time: Economics of Malaria Drugs in an Age of Resistance Zone Extension Main Malaria Vectors Local or Secondary Vectors       A.(C.) tesselatus   Indo-Chinese Hills A triangular area including the Indo-Chinese peninsula, the north-western fringe beyond the Tropic of Cancer A.(C.) dirus (formerly A. balabacensis balabacensis) A.(C.) fluviatilis A.(C.) minimus A.(C.) annularis A.(C.) culicifacies A.(C.) maculatus A.(A.) nigerrimus   Malaysian Most of Indonesia, Malaysian peninsula Philippines and Timor A.(C.) aconitus A.(C.) balabacensis A.(A.) campestris A.(C.) dirus A.(A.) donaldi A.(C.) leucosphyrus A.(A.) letifer A.(C.) ludlowae A.(C.) maculatus A.(C.) minimus A.(A.) nigerrimus A.(C.) philippinensis A.(C.) subpictus A.(C.) sundaicus A.(A.) whartoni   Chinese Largely the coast of mainland China, Korea, Taiwan, Japan A.(C.) pattoni A.(A.) sinensis A.(A.) lesteri A.(A.)nigerrimus   Australasian Northern Australia, the island of New Guinea and the islands east of it to about 175° east of Greenwich, but excepting the malaria-free zone of the south-central Pacific A.(A.) bancrofti A.(C.) farauti A.(C.) punctulatus A.(C.) hilli A.(C.) karwari A.(C.) koliensis A.(C.) subpictus A.(C.) tesselatus Notes: 1. The malaria-free zone of the south-central Pacific includes New Caledonia, New Zealand, the Caroline Islands, Marianas, up to Hawaiian islands, east to Galapagos and Juan Fernandez, and rejoining the southern tip of New Zealand. 2. This table represents only a crude approximation of distribution of most important vectors of malaria. 3. Subgenera are indicated as follows: A. = Anopheles; C. = Cellia; K = Kerteszia; N. = Nyssorhynchus. SOURCE: Adapted from Table 7.2 in Bruce-Chwatt, LJ. 1985. Essential Malariology. 2nd ed. New York: John Wiley and Sons.

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Saving Lives, Buying Time: Economics of Malaria Drugs in an Age of Resistance After blood feeding, some female mosquitoes fly to a nearby wall or ceiling where they rest during daylight, often preferring lower sites within house interiors where the temperatures are cooler, and the humidity is higher. Such species are more suitable targets for indoor residual insecticide spraying (IRS) as a malaria control tool. Other anopheline species that seek secluded outdoor resting places are not suitable targets for IRS. Entomologic Inoculation Rate (EIR) A number of investigators, most notably Macdonald (Macdonald, 1952) have developed mathematical models of malaria transmission which attempt to correlate human infection with the prevalence of malaria infection in mosquitoes. The entomologic inoculation rate (EIR), an experimentally determined index, is a key input for such models. Simply put, the EIR equals the number of infectious bites per human per unit time, typically expressed per year. Across stable endemic areas of malaria transmission in Africa, EIRs vary from one infective bite every 3 years to several infective bites every night (Hay et al., 2000). Even across distances as short as 100 meters, transmission can vary substantially. PATHOGENICITY, IMMUNITY, AND DISEASE Species-Specific Risk of Death and Complications Among the four malaria parasites that infect humans, P. falciparum has the greatest risk of complications and death. In brief, the reasons are as follows. The P. falciparum merozoite can invade RBCs of all ages, potentially producing bloodstream parasitemias of 250,000/uL or higher. Plasmodium vivax and P. ovale preferentially infect only young RBCs, yielding parasitemias no higher than 50,000/uL. Plasmodium malariae infects only aging RBCs, resulting in parasite loads that generally are below 10,000/uL (Neva, 1977). All malaria parasites produce anemia due to red cell breakage and other mechanisms. In addition, P. falciparum-parasitized RBCs (in particular blood schizonts) are cytoadherent to endothelial cells that line small blood vessels throughout the body. In a heavily infected host, the end-organ damage resulting from the intravascular sequestration of parasites can produce a variety of life-threatening complications, most notably involving the brain. It has been suggested that falciparum parasite “strains” also can differ in virulence, despite the fact that no clear-cut genetic markers for virulence

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Saving Lives, Buying Time: Economics of Malaria Drugs in an Age of Resistance have yet been found in wild malaria parasites (Greenwood, 2002). Parasites causing severe malaria in Thailand, for example, have exhibited higher multiplication capacities as well as nonselective RBC invasion (Simpson et al., 1999; Chotivanich et al., 2000). On the host side of the equation, cytokines, reactive oxygen species, and nitrous oxide generated by the human immune system also contribute to disease severity in malaria (English and Newton, 2002). The following sections focus primarily on disease due to P. falciparum. Patterns of Immunity to Falciparum Malaria in Children and Adults Although few if any individuals ever become completely immune to malaria, humans living in P. falciparum-endemic areas can and do develop functional immunity (McGregor, 1974). In areas of high transmission, immunity is acquired in two stages: an initial phase of clinical immunity, followed by anti-parasite immunity resulting in limited parasite numbers, replication, and burden within the human host (Schofield, 2002). In other words, functional immunity results in a progressive ability to contain malaria parasitemia. In general, the acquisition of malaria immunity is slow, requiring numerous infective bites over time. Human and parasite genetic variability, parasite-induced immunosuppression, and other factors contribute to the final degree of protection (Mohan and Stevenson, 1998). Early in life, there is a grace period: in infants born to functionally immune mothers, transplacental antibody (maternal IgG) confers relative resistance to infection and severe clinical episodes of malaria for the first 6 months of life (Edozien et al., 1962). High levels of fetal hemoglobin also provide partial protection (Pasvol et al., 1976). Over the next few years, children exhibit enhanced susceptibility to severe and fatal malaria (Marsh, 1992). After this stage, clinical immunity—manifested as lower rates of disease despite persistent parasitemia—begins to operate, usually continuing into primary school years. This early clinical immunity is sometimes referred to as “clinical tolerance,” signifying the ability to remain asymptomatic despite a relatively high number of circulating parasites. Because individuals in malaria endemic areas rarely go more than a few months without a malaria challenge, immunity, once attained, generally persists as long as an individual remains in an area of stable transmission. This is true even in settings of low annual transmission (Mbogo et al., 1995). There is, however, a shift from severe malarial disease in children younger than 5 years toward severe disease in older age groups when entomological inoculation rates fall below 10 to 20 bites per year (Snow et al., 1997).

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Saving Lives, Buying Time: Economics of Malaria Drugs in an Age of Resistance Loss of Immunity The time span over which antimalarial immunity is lost probably varies from host to host. African expatriates (for example, graduate students attending European universities) lose some immunity over 2 to 3 years while remaining protected from severe disease (von Seidlein and Greenwood, 2003). Eventually, however waning immunity increases the risk of life-threatening complications. Rising cases in older-age individuals is generally the first indicator that immunity has been lost in an entire community (Carter and Mendis, 2002). Ironically, when malaria control in a previously high-transmission area proves successful, whole populations become vulnerable to epidemic malaria. The island of Madagascar, in the Indian Ocean, is a recent example. Malaria transmission was almost completely interrupted in the highlands of Madagascar between 1949 and 1960 by a combination of IRS and mass chloroquine treatment (Hamon et al., 1963). Following reemergence, a severe epidemic of falciparum malaria began in 1986. Over the next 2 years, high death rates occurred in all age groups (Mouchet et al., 1997). Subclinical Infections in Areas of Stable Transmission New evidence for chronic, subpatent malaria infection in areas of stable transmission has recently come from studies employing highly sensitive polymerase chain reaction (PCR), a method which amplifies small fragments of parasite DNA present in human blood. Using PCR techniques, two-thirds of blood samples obtained from microscopically negative children from a highly endemic area of Senegal were found to harbor P. falciparum parasites (Bottius et al., 1996). Combining PCR and microscopic results, 90 percent of the exposed population proved chronically infected. PCR analysis also has shown that parasites of many different genotypes may circulate simultaneously in individual subjects who are clinically well (Farnert et al., 1997). In areas of seasonal transmission, such as eastern Sudan, low levels of parasitemia detectable only by PCR persisted through the dry season in a surprisingly large proportion of individuals (Roper et al., 1996). Host Genetics and Malaria The best known conditions which alter human susceptibility to malaria are red blood cell polymorphisms. In 1948, Haldane hypothesized that the high gene frequencies of hemoglobinopathies in malaria-endemic areas may have resulted from malaria protective effects (Haldane, 1948). This led to an equilibrium, or “balanced polymorphism,” in which the homozygote disadvantage was balanced by the heterozygote advantage

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Saving Lives, Buying Time: Economics of Malaria Drugs in an Age of Resistance HIV, Malaria, and Pregnancy Currently, the most convincing evidence for a possible interaction between HIV-1 and malaria comes from studies of pregnant women. HIV-1 infected pregnant women in Malawi showed a higher prevalence and density of P. falciparum parasitemia than their non-HIV-1 infected counterparts (Steketee et al., 1996). This finding has been confirmed in other studies of pregnant African women (Ladner et al., 2002; van Eijk et al., 2003). Pregnant HIV-infected women also are more likely to be anemic (van den Broek et al., 1998; Meda et al., 1999; van Eijk et al., 2001) and to respond less well to intermittent preventive treatment with sulfadoxine-pyrimethamine than HIV uninfected women (Parise et al., 1998). Postnatal mortality in infants also is increased in mothers co-infected with HIV-1 and malaria than infants of mothers with only one infection (Bloland et al., 1995). An important question still unanswered is whether or not placental malaria increases mother-to-child HIV transmission. In a recent study of 746 HIV-positive mother-infant pairs in Uganda, the increased risk of mother-to-child transmission associated with placental malaria was 2.89 (Brahmbhatt et al., 2003); however another study completed in Kenya found no association between placental malaria and HIV transmission in utero or peripartum (Inion et al., 2003). NON-FALCIPARUM MALARIA Plasmodium vivax Plasmodium vivax malaria is widely distributed throughout the world—predominantly in Asia, the Western Pacific, and the Americas—and accounts for over half of all malaria infections outside Africa, and roughly 10 percent of infections in Africa (Mendis et al., 2001). It has recently made a comeback in Korea, Peru, Indonesia, and China (Sleigh et al., 1998; Sharma, 1999; Chai, 1999; Roper et al., 2000; Barcus et al., 2002), and currently produces an estimated 75 million acute malarial episodes every year (Sina, 2002). In humans, the fact that P. vivax invades only young RBCs (reticulocytes) limits its total parasite load and disease severity. In addition, P. vivax can only attach to human RBCs possessing the Duffy blood group cell surface antigen (Miller et al., 1976). Since most residents of West Africa lack genetic expression of the Duffy blood group antigen, the disease is essentially absent from the region. The hallmark of vivax malaria is its sudden, dramatic paroxysm, trig-

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Saving Lives, Buying Time: Economics of Malaria Drugs in an Age of Resistance gered by the cytokines interleukin-6 and tumor necrosis factor alpha (TNF-alpha) (Karunaweera et al., 1992a,b). Paroxysms recur every 48 hours, and may continue for several weeks if patients do not receive appropriate antimalarial treatment. The most common clinical consequence is anemia, although severe and fatal complications associated with lung injury (Torres et al., 1997; Carlini et al., 1999; Tanios et al., 2001), splenic rupture, and associated splenic pathology (Zingman and Viner, 1993) are occasionally reported. Rarely, cerebral complications also have followed pure P. vivax infections (Sachdev and Mohan, 1985; Beg et al., 2002). There are relatively few reports describing the effect of P. vivax malaria on pregnancy, although some investigators have linked it to maternal parasitemia and anemia, as well as low birth weight (Nosten et al., 1999; Singh et al., 1999). Of the four human malaria species, only P. vivax and P. ovale undergo true relapse—i.e., reseeding of the bloodstream from dormant parasites (called hypnozoites) in the liver. The likelihood and time interval between primary parasitemia and relapse varies according to environmental variables (Baird and Rieckmann, 2003). In general, strains from temperate regions are less likely to relapse (~30 percent risk), and they exhibit longer latency intervals (>6 months). Tropical strains have an 80 percent risk of relapse, often within several weeks of primary parasitemia (Garnham, 1988; Cogswell, 1992). Plasmodium malariae The geographic distribution of P. malariae—also called quartan malaria—roughly overlaps P. falciparum. Plasmodium malariae manifests acutely as a febrile illness with anemia. However, the most distinctive feature of P. malariae is its decades-long persistence. Chronic, subpatent infections have recrudesced following splenectomy (Tsuchida et al., 1982; Vinetz et al., 1998) or other surgeries unrelated to malaria (Chadee et al., 2000). The parasite also may be transmitted via blood transfusion many years after a blood donor has left an endemic region (Bruce-Chwatt, 1972). In a 20-year review of transfusion-associated malaria in the United States, P. malariae accounted for more cases than any other malarial species (Guerrero et al., 1983). In West Africa and Papua New Guinea, repeated or continuous infection with P. malariae infection also is associated with childhood nephrosis—a syndrome characterized by heavy protein loss in the urine, peripheral edema, and renal impairment (Hendrickse et al., 1972; White, 1996, 1997). The condition is usually steroid-resistant, and may progress to renal failure and death even after successful treatment of infection (Barsoum, 2000). Hyperreactive malarial splenomegaly (HMS, formerly known as tropical splenomegaly syndrome) is another chronic immune-mediated pathology

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Saving Lives, Buying Time: Economics of Malaria Drugs in an Age of Resistance associated with P. malariae, as well as P. falciparum and P. vivax (Hoffman et al., 1984; Piessens et al., 1985). Affected patients experience massive splenomegaly, abdominal pain, episodic prostration, and high mortality due to secondary infections (Crane, 1986). Plasmodium ovale Plasmodium ovale is the least studied of the malaria parasites that infect humans. Although transmitted sporadically on all continents, the parasite primarily affects residents of tropical Africa and New Guinea, where its prevalence among children averages between 2 to 10 percent (Faye et al., 2002). Overall, the parasite causes a relatively mild form of malaria that closely resembles P. vivax infection and is rarely fatal (Facer and Rouse, 1991). REFERENCES Abdalla S, Weatherall DJ, Wickramasinghe SN, Hughes M. 1980. The anaemia of P. falciparum malaria. British Journal of Haematology 46(2):171-183. Adams S, Brown H, Turner G. 2002. Breaking down the blood-brain barrier: Signaling a path to cerebral malaria? Trends in Parasitology 18(8):360-366. Aitman TJ, Cooper LD, Norsworthy PJ, Wahid FN, Gray JK, Curtis BR, McKeigue PM, Kwiatkowski D, Greenwood BM, Snow RW, Hill AV, Scott J. 2000. Malaria susceptibility and Cd36 mutation. Nature 405(6790):1015-1016. Allen S, Van de Perre P, Serufilira A, Lepage P, Carael M, DeClercq A, Tice J, Black D, Nsengumuremyi F, Ziegler J. 1991. Human immunodeficiency virus and malaria in a representative sample of childbearing women in Kigali, Rwanda. Journal of Infectious Diseases 164(1):67-71. Allen SJ, O’Donnell A, Alexander ND, Clegg JB. 1996. Severe malaria in children in Papua New Guinea. Quarterly Journal of Medicine 89(10):779-788. Allen SJ, O’Donnell A, Alexander ND, Alpers MP, Peto TE, Clegg JB, Weatherall DJ. 1997. Alpha+-thalassemia protects children against disease caused by other infections as well as malaria. Proceedings of the National Academy of Sciences of the United States of America 94(26):14736-14741. Alles HK, Mendis KN, Carter R. 1998. Malaria mortality rates in south Asia and in Africa: Implications for malaria control. Parasitology Today 14(9):369-375. Atzori C, Bruno A, Chichino G, Cevini C, Bernuzzi AM, Gatti S, Comolli G, Scaglia M. 1993. HIV-1 and parasitic infections in rural Tanzania. Annals of Tropical Medicine and Parasitology 87(6):585-593. Aucan C, Walley AJ, Hennig BJ, Fitness J, Frodsham A, Zhang L, Kwiatkowski D, Hill AV. 2003. Interferon-alpha receptor-1 (IFNAR1) variants are associated with protection against cerebral malaria in The Gambia. Genes and Immunity 4:275-282. Baird JK, Rieckmann KH. 2003. Can primaquine therapy for vivax malaria be improved? Trends in Parasitology 19(3):115-120. Barcus MJ, Laihad F, Sururi M, Sismadi P, Marwoto H, Bangs MJ, Baird JK. 2002. Epidemic malaria in the Menoreh Hills of Central Java. American Journal of Tropical Medicine and Hygiene 66(3):287-292.

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