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Saving Lives, Buying Time: Economics of Malaria Drugs in an Age of Resistance (2004)

Chapter: 6 The Parasite, the Mosquito, and the Disease

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Suggested Citation:"6 The Parasite, the Mosquito, and the Disease." Institute of Medicine. 2004. Saving Lives, Buying Time: Economics of Malaria Drugs in an Age of Resistance. Washington, DC: The National Academies Press. doi: 10.17226/11017.
×

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

Suggested Citation:"6 The Parasite, the Mosquito, and the Disease." Institute of Medicine. 2004. Saving Lives, Buying Time: Economics of Malaria Drugs in an Age of Resistance. Washington, DC: The National Academies Press. doi: 10.17226/11017.
×

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).

Suggested Citation:"6 The Parasite, the Mosquito, and the Disease." Institute of Medicine. 2004. Saving Lives, Buying Time: Economics of Malaria Drugs in an Age of Resistance. Washington, DC: The National Academies Press. doi: 10.17226/11017.
×
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.

Suggested Citation:"6 The Parasite, the Mosquito, and the Disease." Institute of Medicine. 2004. Saving Lives, Buying Time: Economics of Malaria Drugs in an Age of Resistance. Washington, DC: The National Academies Press. doi: 10.17226/11017.
×
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.

Suggested Citation:"6 The Parasite, the Mosquito, and the Disease." Institute of Medicine. 2004. Saving Lives, Buying Time: Economics of Malaria Drugs in an Age of Resistance. Washington, DC: The National Academies Press. doi: 10.17226/11017.
×
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.

Suggested Citation:"6 The Parasite, the Mosquito, and the Disease." Institute of Medicine. 2004. Saving Lives, Buying Time: Economics of Malaria Drugs in an Age of Resistance. Washington, DC: The National Academies Press. doi: 10.17226/11017.
×

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.

Suggested Citation:"6 The Parasite, the Mosquito, and the Disease." Institute of Medicine. 2004. Saving Lives, Buying Time: Economics of Malaria Drugs in an Age of Resistance. Washington, DC: The National Academies Press. doi: 10.17226/11017.
×

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

 

  1. North American

From the Great Lakes to southern Mexico

A.(A.) freeborni

A.(A.) quadrimaculatus

A.(N.) albimanus

 

  1. 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

 

  1. 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

 

  1. 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

 

  1. 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

 

  1. 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

 

  1. 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

 

  1. 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

Suggested Citation:"6 The Parasite, the Mosquito, and the Disease." Institute of Medicine. 2004. Saving Lives, Buying Time: Economics of Malaria Drugs in an Age of Resistance. Washington, DC: The National Academies Press. doi: 10.17226/11017.
×

Zone

Extension

Main Malaria Vectors

Local or Secondary Vectors

 

 

 

A.(C.) tesselatus

 

  1. 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

 

  1. 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

 

  1. Chinese

Largely the coast of mainland China, Korea, Taiwan, Japan

A.(C.) pattoni

A.(A.) sinensis

A.(A.) lesteri

A.(A.)nigerrimus

 

  1. 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.

Suggested Citation:"6 The Parasite, the Mosquito, and the Disease." Institute of Medicine. 2004. Saving Lives, Buying Time: Economics of Malaria Drugs in an Age of Resistance. Washington, DC: The National Academies Press. doi: 10.17226/11017.
×

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

Suggested Citation:"6 The Parasite, the Mosquito, and the Disease." Institute of Medicine. 2004. Saving Lives, Buying Time: Economics of Malaria Drugs in an Age of Resistance. Washington, DC: The National Academies Press. doi: 10.17226/11017.
×

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).

Suggested Citation:"6 The Parasite, the Mosquito, and the Disease." Institute of Medicine. 2004. Saving Lives, Buying Time: Economics of Malaria Drugs in an Age of Resistance. Washington, DC: The National Academies Press. doi: 10.17226/11017.
×
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

Suggested Citation:"6 The Parasite, the Mosquito, and the Disease." Institute of Medicine. 2004. Saving Lives, Buying Time: Economics of Malaria Drugs in an Age of Resistance. Washington, DC: The National Academies Press. doi: 10.17226/11017.
×

with respect to malaria. In particular, there is strong epidemiologic evidence that thalassemias (anemias caused by abnormalities in genes encoding hemoglobin), sickle cell hemoglobin, and glucose-6-phosphate dehydrogenase (G6PD) deficiency protect against severe falciparum malaria. Alpha thalassemias (Allen et al., 1997) and G6PD deficiency (Gilles et al., 1967; Ruwende et al., 1995) reduce the risk of death due to P. falciparum by about 50 percent, whereas a child with sickle cell trait in West Africa (in other words, a heterozygote) has a 90 percent reduced risk of illness and death from falciparum malaria (Gilles et al., 1967; Hill et al., 1991).

Hemoglobin C, like sickle cell hemoglobin, is another single point mutation found in West Africa. The homozygous state for hemoglobin C also confers a 90 percent protection against falciparum infection (Modiano et al., 2001). Hemoglobin E (which is mainly found in Southeast Asians) lessens the severity of acute falciparum malaria (Hutagalung et al., 1999) and also renders heterozygote RBCs relatively resistant to invasion by P. falciparum (Chotivanich et al., 2002).

Individual susceptibility to malaria or cerebral malaria may also be influenced by the genetically governed production of tumor necrosis factor-alpha (McGuire et al., 1994), CD36 (Aitman et al., 2000), nitric oxide synthase-2 (Kun et al., 1998), and the interferon-alpha receptor 1 (Aucan et al., 2003); family-based studies also have linked disease severity to genome regions encoding MHC (major histocompatibility complex), and cytokine genes (Jepson et al., 1997; Rihet et al., 1998). The genetic basis of cell-mediated and antibody-mediated immune responses in malaria is a rapidly evolving area of research.

CLINICAL FEATURES OF FALCIPARUM MALARIA

Falciparum malaria gives rise to a broad spectrum of disease from asymptomatic infection to fatal syndromes such as cerebral malaria, severe anemia, and multi-organ failure. The principal determinant of outcome is the immune status of the infected patient. With respect to its clinical features and consequences, malaria can therefore be broadly considered in three categories: disease in nonimmune individuals (for example, tourists, migrant workers and other non-immune persons in endemic areas); disease in children in endemic areas; and disease in pregnant women. Adults in endemic areas may also suffer periodic attacks, leading to clinical and especially economic consequences.

Malaria in the Nonimmune Host

In a nonimmune host, the traditional symptom complex heralding the onset of infection is the malaria paroxysm, a dramatic constellation of

Suggested Citation:"6 The Parasite, the Mosquito, and the Disease." Institute of Medicine. 2004. Saving Lives, Buying Time: Economics of Malaria Drugs in an Age of Resistance. Washington, DC: The National Academies Press. doi: 10.17226/11017.
×

fevers, chills, and sweats that accompanies RBC lysis at the end of a cycle of asexual parasite development. In many medical textbooks, periodic paroxysms (every 48 hours in untreated P. vivax and P. ovale—“tertian” malaria—and every 72 hours in untreated P. malariae—“quartan” malaria) are mentioned as virtually diagnostic of malaria. In fact, in today’s era of antimalarial chemotherapy, these periodic syndromes enshrined in the classical terminology of “tertian” and “quartan” malaria are seldom seen. In many patients, the onset of the febrile illness is nonspecific, and therefore indistinguishable from other common causes of fever. Plasmodium falciparum in particular causes irregular fevers that may occur daily, or even randomly within a 24-hour period.

In nonimmune subjects with falciparum malaria and overwhelming parasitemias (>106 parasitized RBCs per microliter, or more than 20 percent of circulating RBCs), anemia develops within days of the initial paroxysm. Additional clinical features and/or laboratory findings predictive of a “severe” or life-threatening course are prostration, shock, altered consciousness, respiratory distress (from acidotic breathing or pulmonary edema), convulsions, abnormal bleeding, jaundice, excretion of hemoglobin in urine, low blood sugar, elevated blood levels of lactic acid, and worsening kidney function (WHO, 2000).

Table 6-2 compares the frequency and prognostic value of severe manifestations and complications of P. falciparum malaria in adults and children.

A Delphi analysis published in 1990 estimated the case fatality risk attributable to highly drug-resistant (R3) P. falciparum infection—treated or untreated—at 2 to 5 percent in previously healthy African children aged 6 to 59 months brought to a primary health clinic in an area where malaria was hyperendemic or holoendemic (Sudre et al., 1990). Untreated falciparum malaria in a nonimmune host carries a risk of death of up to 20 to 30 percent (Behrens and Curtis, 1993; Alles et al., 1998; Carter and Mendis, 2002). Untreated severe falciparum malaria (as defined by WHO criteria, see Table 6-2) is almost uniformly fatal in all hosts (White and Pongtavornpinyo, 2003).

Malaria in Children
Overview in Endemic Areas

In contrast to the nonimmune adult with falciparum malaria (who will generally suffer one or more malaria paroxysms), the most common clinical manifestation of falciparum malaria in children in endemic settings is an entirely nonspecific febrile illness. In fact, in many parts of Africa, malaria is so ubiquitous—as an asymptomatic blood infection and an illness—that

Suggested Citation:"6 The Parasite, the Mosquito, and the Disease." Institute of Medicine. 2004. Saving Lives, Buying Time: Economics of Malaria Drugs in an Age of Resistance. Washington, DC: The National Academies Press. doi: 10.17226/11017.
×

TABLE 6-2 Severe Manifestations of P. falciparum Malaria in Adults and Childrena

Prognostic Valueb

 

Frequencyb

Children

Adults

 

Children

Adults

Clinical manifestations

+

(?)c

Prostration

+++

+++

+++

+

Impaired consciousness

+++

++

+++

+++

Respiratory distress (acidotic breathing)

+++

+

+

++

Multiple convulsions

+++

+

+++

+++

Circulatory collapse

+

+

+++

+++

Pulmonary edema (radiological)

+/-

+

+++

++

Abnormal bleeding

+/-

+

++

+

Jaundice

+

+++

+

+

Hemoglobinuria

+/-

+

Laboratory findings

+

+

Severe anemia

+++

+

+++

+++

Hypoglycemia

+++

++

+++

+++

Acidosis

+++

++

+++

+++

Hyperlactatemia

+++

++

+/-

++

Hyperparasitemia

++

+

++

++

Renal impairment

+

+++

aSee the section on severe malaria in children.

bOn a scale from + to +++; +/- indicates infrequent occurrence.

cData not available.

SOURCE: World Health Organization. 2000. Severe falciparum malaria. Transactions of the Royal Society of Tropical Medicine and Hygiene. 94 (suppl 1). Table 1, on p. S1/2 of this supplement, was incomplete. A corrected version was printed and inserted into the supplement.

Suggested Citation:"6 The Parasite, the Mosquito, and the Disease." Institute of Medicine. 2004. Saving Lives, Buying Time: Economics of Malaria Drugs in an Age of Resistance. Washington, DC: The National Academies Press. doi: 10.17226/11017.
×

for practical purposes it cannot be diagnosed solely on clinical features or microscopy.

Why similar infections produce vastly different outcomes in different subjects is one of malaria’s central, unsolved mysteries. Even among children with identical parasitemias, one child may be moribund with coma or severe anemia, while another is attending school or playing without apparent illness. One consequence of malaria’s often uneventful course in endemic areas is a relative nonchalance on the part of patients, parents, and health care workers toward the disease.

Some diseases like malaria are so common it’s almost like information over-load. It’s malaria, okay. Malaria again, okay. Malaria again. Once in medical school we had a visiting pathologist—I forgot what country he came from—and he said: I went to the mortuary yesterday and I was doing post mortems, and all the spleens which were being passed off as normal are malaria spleens. [So he asked] why are you passing all of these spleens as normal? And the reply was: well almost everybody here has a spleen like that.

Irene Agyepong, MD, Ghana Health Service (2002)

Viewed objectively, however, malaria exacts a chilling toll of morbidity and mortality on children. Over 90 percent of all cases of life-threatening malaria occur in sub-Saharan African children (Marsh et al., 1995), and malaria causes at least 20 percent of all deaths in children under 5 years of age in Africa (UNICEF, 2002).

Although the original World Health Organization (WHO) proposed definition of “severe malaria” was based on clinical observations in Southeast Asian adults, the multisystem nature of this syndrome also is seen in life-threatening manifestations of falciparum malaria in children in Africa, and other regions (Waller et al., 1995; Marsh et al., 1995; Allen et al., 1996). Common hallmarks of severe malaria in African children are altered consciousness, convulsions, hypoglycemia, acidosis, and anemia. The next sections will review these complications in further detail.

Severe Anemia

Anemia is a consistent marker of severe malaria in children as well as adults. Severe malarial anemia is defined as a hemoglobin concentration less than or equal to 5 g/dL in a patient with P. falciparum malaria. Until recently, overt destruction of parasitized RBCs and splenic filtration were

Suggested Citation:"6 The Parasite, the Mosquito, and the Disease." Institute of Medicine. 2004. Saving Lives, Buying Time: Economics of Malaria Drugs in an Age of Resistance. Washington, DC: The National Academies Press. doi: 10.17226/11017.
×

thought to be the principal causes of severe malarial anemia. Today, however, an accelerated destruction of unparasitized red cells has been identified as a leading contributor to severe malarial anemia as well as anemia in uncomplicated malaria (Price et al., 2001). This destruction reflects reduced red cell deformability and immune-mediated membrane damage (Newton and Krishna, 1998). Malaria also induces bone marrow suppression, leading to decreased production of RBCs (Abdalla et al., 1980). Finally, malaria-specific processes often are compounded by other contributors to tropical childhood anemia such as nutritional iron deficiency and hookworm infection.

There are three principal ways in which malaria can contribute to death in young children. First, an overwhelming acute infection, which frequently presents as seizures or coma (cerebral malaria), may kill a child directly and quickly. Second, repeated malaria infections contribute to the development of severe anaemia, which substantially increases the risk of death. Third, low birth weight—frequently the consequence of malaria infection in pregnant women—is the major risk factor for death in the first month of life.

WHO, Africa Malaria Report, 2003

Children with severe anemia tend to be younger than those with cerebral malaria, but the two conditions often overlap. Overall, case fatality rates for children hospitalized for severe anemia alone range from 5 to 15 percent (Waller et al., 1995). Morbidity and mortality due to malarial anemia have increased with the spread of chloroquine-resistant parasites across Africa (Bloland et al., 1993; Trape et al., 1998).

Respiratory Distress and Metabolic Acidosis

Although respiratory signs and symptoms are common in mild and moderate malaria (O’Dempsey et al., 1993), until recently, metabolic acidosis producing respiratory distress was an underappreciated feature of life-threatening malaria in African children (Taylor et al., 1993; Marsh et al., 1995). Metabolic acidosis carries a 24 percent case fatality rate when it occurs alone, and a 35 percent risk of death when associated with cerebral malaria and/or anemia (Marsh et al., 1995). Many experts now consider respiratory distress to be the single most important prognostic factor and main indication for blood transfusion in children with malaria and severe anemia (Newton et al., 1992).

A second important cause of respiratory distress in children with malaria is lower respiratory tract infection (English et al., 1996). In some

Suggested Citation:"6 The Parasite, the Mosquito, and the Disease." Institute of Medicine. 2004. Saving Lives, Buying Time: Economics of Malaria Drugs in an Age of Resistance. Washington, DC: The National Academies Press. doi: 10.17226/11017.
×

cases, this is the principal cause of respiratory symptoms in a patient who also is (coincidentally) parasitemic. Alternatively, there is mounting evidence that many children with severe malaria have dual infections (Berkley et al., 1999).

Cerebral Malaria

“Cerebral malaria” represents an advanced stage in the spectrum of P. falciparum asexual parasitemia and altered consciousness. In research settings, the definition is met when a child with bloodstream parasites and no other obvious cause of impaired consciousness (for example, meningitis) is unable to localize a painful stimulus after the correction of hypoglycemia and exclusion of other brain disorders. The Blantyre coma scale (Molyneux et al., 1989) is a clinical research instrument for assessing children not yet able to speak. The Blantyre coma scale produces a total score from 0 (worst) to 5 (best) based on motor response, verbal response, and eye movements. In general, a child with cerebral malaria will register a Blantyre coma score ≤ 2 or occasionally 3 (WHO, 2000).

I saw this one child—I still remember him—he had cerebral malaria and it was a real struggle for his life but he survived. We were all so excited. Six months later I met this child with his mother. He had developed neurologic sequelae; he was hyperactive, not paying attention in school. I just felt a sense of disappointment… If this child had never had that bad malaria—in spite of having pulled through—maybe he wouldn’t be in this state.

Irene Agyepong, Ghana Health Service (2002)

African children with cerebral malaria usually enter a coma following a 1- to 3-day history of fever. The coma may develop quickly, accompanied by one or more convulsions as well as an arched back, posturing, an altered respiratory pattern and/or gaze abnormalities (Molyneux et al., 1989). Other acute neurologic features include a generalized decrease in muscle tone, cranial nerve palsies (Warrell, 1996), and retinal abnormalities including hemorrhage (Lewallen et al., 1999). Convulsions, both generalized and focal, ultimately complicate 50-80 percent of cerebral malaria episodes in children.

In endemic areas, full-blown cerebral malaria typically occurs in children under 5 years of age, and is rarely seen above the age of 10 in children who have been exposed to P. falciparum from birth.

Suggested Citation:"6 The Parasite, the Mosquito, and the Disease." Institute of Medicine. 2004. Saving Lives, Buying Time: Economics of Malaria Drugs in an Age of Resistance. Washington, DC: The National Academies Press. doi: 10.17226/11017.
×
Death Due to Cerebral Malaria

The reported hospital case fatality rate of cerebral malaria in children ranges from 10 to 40 percent, but in recent studies it has averaged about 16 percent (White et al., 1987; Molyneux et al., 1989; Waller et al., 1995). Most deaths occur within 24 hours of starting treatment, and are preceded by progressive brainstem dysfunction, respiratory arrest, and/or overwhelming acidosis (Newton and Krishna, 1998). African children with cerebral malaria who survive generally regain consciousness within 48 to 72 hours of appropriate treatment.

Chronic Neurologic Impairment Following Cerebral Malaria

Chronic neurologic sequelae following falciparum malaria are usually seen in patients with protracted seizures, prolonged coma and/or hypoglycemia (Brewster et al., 1990). In Africa, about 13 percent of children who survive cerebral malaria have neurological sequelae, among them ataxia, hemiplegia, speech disorders, and blindness (Taylor and Molyneux, 2002). Late neurologic consequences also include unsteady gait, paralysis, and cognitive and behavioral deficits (Newton and Warrell, 1998). Epilepsy and EEG abnormalities following cerebral malaria have probably been underestimated in past studies; recent data suggest that the relative risk of epileptic discharges following cerebral malaria or malaria plus seizures is increased nearly twofold compared to children who have not suffered severe malaria (Otieno et al., 2002).

Some students become dull, they don’t understand the lessons … sometimes they even become like fools, they become abnormal.

Primary school teacher, Muheza, Tanzania (2002)

Some chronic neurologic deficits (for example, gait disturbance, unilateral weakness, and cortical blindness) may resolve after several months. An estimated 2 percent of children who recover from malaria infections affecting the brain suffer from learning impairments and disabilities due to brain damage, including epilepsy, and spasticity (Murphy and Breman, 2001). Furthermore, repeated episodes of fever and illness reduce appetite and restrict play, social interaction, and educational opportunities, thereby contributing to poor development.

Suggested Citation:"6 The Parasite, the Mosquito, and the Disease." Institute of Medicine. 2004. Saving Lives, Buying Time: Economics of Malaria Drugs in an Age of Resistance. Washington, DC: The National Academies Press. doi: 10.17226/11017.
×

People dying of malaria … that’s over a million deaths a year. But there are ten times, 20 times, 100 times more people that develop severe complications of malaria that are desperately life threatening but do survive. And as part of this survival, there are risks … from behavioral disturbances and difficulties in learning through to very severe disabilities such as spasticity, total paralysis down one side of the body … to deafness and blindness and epilepsy. Many of those children with epilepsy may die because they fall into fires or down wells.”

Bob Snow, Kenya Medical Research Institute (2002)

Hypoglycemia

Prolonged hypoglycemia can produce death and/or chronic neurologic damage. Hypoglycemia associated with falciparum malaria (defined as a blood glucose concentration of less than 2.2 mmol/L or 40 mg/dL) has two discrete etiologies. It may reflect metabolic acidosis (i.e., hyperlactatemia) seen in severe malaria or, in quinine-treated patients, it may reflect quinine-stimulated insulin secretion. Metabolic acidosis is usually present on admission to the hospital and carries a poor prognosis, while hyperinsulinemia tends to appear after the first 12 to 24 hours of treatment (White et al., 1983).

In one study, 13 to 32 percent of children with severe malaria developed hypoglycemia as a complication of their illness (Taylor et al., 1988).

Severe Malaria in Adults versus Children

Most cases of severe malaria in adults occur in regions outside Africa. However, even in malaria-endemic areas of Africa, some adults still suffer and die from severe malaria. The clinical spectrum of illness in these individuals is different from that seen in children. Whereas children are more likely to develop severe anemia, hypoglycemia, or convulsions, adults with severe malaria are more likely to develop jaundice, acute kidney damage, or acute pulmonary edema. Recovery from cerebral malaria in adults is slower than in children although neurologic sequelae are less frequent (occurring in less than 3 percent of adult cases compared with 10 percent of pediatric cases). Kidney failure due to acute tubular necrosis is another important cause of death. Acute pulmonary edema in malaria results from increased capillary permeability, the same pathophysiologic process that leads to acute respiratory distress syndrome. The mortality of severe falciparum malaria in adults who are appropriately treated can reach 15 to 20 percent.

Suggested Citation:"6 The Parasite, the Mosquito, and the Disease." Institute of Medicine. 2004. Saving Lives, Buying Time: Economics of Malaria Drugs in an Age of Resistance. Washington, DC: The National Academies Press. doi: 10.17226/11017.
×

Severe malaria in pregnancy (see below) is associated with additional complications—particularly hypoglycemia, and pulmonary edema—and a higher mortality.

Malaria in Pregnancy

The clinical course of falciparum malaria during pregnancy depends in large part on the immune status of the woman, which, in turn, is influenced by her previous exposure to malaria.

Clinical Consequences in Low-Transmission Areas

In areas of low transmission, falciparum malaria is an important cause of maternal morbidity and mortality in women of all parities. Pregnant women with little or no immunity are two to three times more likely to develop severe disease than non-pregnant adults living under the same conditions (Luxemburger et al., 1997). In addition, if they develop severe disease, they risk a 20 to 30 percent chance of dying (Meek, 1988). Complications to which pregnant malaria-infected women with low immunity are especially susceptible include high fever, low blood sugar, severe hemolytic anemia, cerebral malaria, and pulmonary edema (Looareesuwan et al., 1985).

Malaria in pregnant women with low immunity also affects the developing fetus and the newborn, causing abortion, stillbirth, premature delivery, and low birth weight (Menon, 1972; Nosten et al., 1994). Babies born to nonimmune mothers with malaria at the time of childbirth may develop parasitemia and illness in the first few weeks of life (Quinn et al., 1982). Specific clinical features in infected newborns include fever, lethargy, anemia, and enlargement of liver and spleen.

Clinical Consequences in High-transmission Areas

In sub-Saharan Africa, close to 45 percent of women have malarial infection during pregnancy (Steketee, et al., 1996b), and almost half of women who are pregnant for the first time (primigravidae) will be parasitemic on their first antenatal visit (Menendez, 1995). Pregnant women are more likely to have blood parasites and high parasitemias than non-pregnant women of the same age (Brabin, 1983; Garin et al., 1985; Steketee and Wirima, 1996). For the semi-immune mother, the major risk of malaria during pregnancy is maternal anemia (Shulman et al., 1996), especially during first pregnancies (Greenwood et al., 1994).

In high-transmission areas, placental parasitemia also is common, especially among primigravidae, even when peripheral blood smears are nega-

Suggested Citation:"6 The Parasite, the Mosquito, and the Disease." Institute of Medicine. 2004. Saving Lives, Buying Time: Economics of Malaria Drugs in an Age of Resistance. Washington, DC: The National Academies Press. doi: 10.17226/11017.
×

tive (McGregor et al., 1983; Nyirjesy et al., 1993). The most common consequence of placental malaria is intrauterine growth retardation (McGregor et al., 1983; Steketee and Wirima, 1996). In a model based on multiple published studies, Guyatt and Snow (2001) recently found that African babies born to mothers whose placentas were infected at the time of delivery were twice as likely to be underweight at birth, and that their risk of death during the first year of life was three times higher than babies of normal birth weight.

Pathogenesis of Placental Malaria

In placental malaria, the organ is a privileged site of parasite replication. Most (but not all) placental isolates of P. falciparum bind to chondroitin sulphate A (CSA) expressed on the surface of maternal placental cells (Duffy and Fried, 2003). Over time, antibodies inhibiting parasite adhesion to CSA develop, reducing the likelihood of heavy placental infection after first or second pregnancies (Fried et al., 1998).

HIV and Malaria

The growing epidemic of HIV/AIDS in malaria-endemic areas of sub-Saharan Africa has prompted many investigators to explore possible interactions between the two infections. Although several early studies—including six hospital-based cross-sectional and longitudinal studies in African children and adults (Nguyen-Dinh et al., 1987; Simooya et al., 1988; Colebunders et al., 1990; Muller and Moser, 1990; Greenberg et al., 1991; Allen et al., 1991; Kalyesubula et al., 1997)—failed to reveal convincing links between malaria and HIV, one study in rural Tanzania found a significantly increased prevalence of asymptomatic malarial parasitemia in HIV-1 positive adults (Atzori et al., 1993), and two studies found higher death rates due to severe malaria in HIV-1 positive adults (Leaver et al., 1990; Niyongabo et al., 1994). In retrospect, small patient numbers, and a failure to take into account the different degrees of immunosuppression found at different stages of HIV-1 infection were weaknesses of many of these early investigations.

More recent case-control (Francesconi et al., 2001) and longitudinal epidemiologic studies (Whitworth et al., 2000; French et al., 2001) have confirmed an association between HIV infection, clinical malaria, and P. falciparum parasitemia, particularly among individuals with advanced HIV disease as measured by falling CD4 lymphocyte counts. Symptomatic P. falciparum infection also appears to increase HIV-1 viral loads (Hoffman et al., 1999).

Suggested Citation:"6 The Parasite, the Mosquito, and the Disease." Institute of Medicine. 2004. Saving Lives, Buying Time: Economics of Malaria Drugs in an Age of Resistance. Washington, DC: The National Academies Press. doi: 10.17226/11017.
×
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-

Suggested Citation:"6 The Parasite, the Mosquito, and the Disease." Institute of Medicine. 2004. Saving Lives, Buying Time: Economics of Malaria Drugs in an Age of Resistance. Washington, DC: The National Academies Press. doi: 10.17226/11017.
×

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

Suggested Citation:"6 The Parasite, the Mosquito, and the Disease." Institute of Medicine. 2004. Saving Lives, Buying Time: Economics of Malaria Drugs in an Age of Resistance. Washington, DC: The National Academies Press. doi: 10.17226/11017.
×

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).

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Suggested Citation:"6 The Parasite, the Mosquito, and the Disease." Institute of Medicine. 2004. Saving Lives, Buying Time: Economics of Malaria Drugs in an Age of Resistance. Washington, DC: The National Academies Press. doi: 10.17226/11017.
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Suggested Citation:"6 The Parasite, the Mosquito, and the Disease." Institute of Medicine. 2004. Saving Lives, Buying Time: Economics of Malaria Drugs in an Age of Resistance. Washington, DC: The National Academies Press. doi: 10.17226/11017.
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Page 156
Suggested Citation:"6 The Parasite, the Mosquito, and the Disease." Institute of Medicine. 2004. Saving Lives, Buying Time: Economics of Malaria Drugs in an Age of Resistance. Washington, DC: The National Academies Press. doi: 10.17226/11017.
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Suggested Citation:"6 The Parasite, the Mosquito, and the Disease." Institute of Medicine. 2004. Saving Lives, Buying Time: Economics of Malaria Drugs in an Age of Resistance. Washington, DC: The National Academies Press. doi: 10.17226/11017.
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Suggested Citation:"6 The Parasite, the Mosquito, and the Disease." Institute of Medicine. 2004. Saving Lives, Buying Time: Economics of Malaria Drugs in an Age of Resistance. Washington, DC: The National Academies Press. doi: 10.17226/11017.
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Suggested Citation:"6 The Parasite, the Mosquito, and the Disease." Institute of Medicine. 2004. Saving Lives, Buying Time: Economics of Malaria Drugs in an Age of Resistance. Washington, DC: The National Academies Press. doi: 10.17226/11017.
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Suggested Citation:"6 The Parasite, the Mosquito, and the Disease." Institute of Medicine. 2004. Saving Lives, Buying Time: Economics of Malaria Drugs in an Age of Resistance. Washington, DC: The National Academies Press. doi: 10.17226/11017.
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Suggested Citation:"6 The Parasite, the Mosquito, and the Disease." Institute of Medicine. 2004. Saving Lives, Buying Time: Economics of Malaria Drugs in an Age of Resistance. Washington, DC: The National Academies Press. doi: 10.17226/11017.
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Page 162
Suggested Citation:"6 The Parasite, the Mosquito, and the Disease." Institute of Medicine. 2004. Saving Lives, Buying Time: Economics of Malaria Drugs in an Age of Resistance. Washington, DC: The National Academies Press. doi: 10.17226/11017.
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Page 163
Suggested Citation:"6 The Parasite, the Mosquito, and the Disease." Institute of Medicine. 2004. Saving Lives, Buying Time: Economics of Malaria Drugs in an Age of Resistance. Washington, DC: The National Academies Press. doi: 10.17226/11017.
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Page 164
Suggested Citation:"6 The Parasite, the Mosquito, and the Disease." Institute of Medicine. 2004. Saving Lives, Buying Time: Economics of Malaria Drugs in an Age of Resistance. Washington, DC: The National Academies Press. doi: 10.17226/11017.
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Suggested Citation:"6 The Parasite, the Mosquito, and the Disease." Institute of Medicine. 2004. Saving Lives, Buying Time: Economics of Malaria Drugs in an Age of Resistance. Washington, DC: The National Academies Press. doi: 10.17226/11017.
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Suggested Citation:"6 The Parasite, the Mosquito, and the Disease." Institute of Medicine. 2004. Saving Lives, Buying Time: Economics of Malaria Drugs in an Age of Resistance. Washington, DC: The National Academies Press. doi: 10.17226/11017.
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For more than 50 years, low-cost antimalarial drugs silently saved millions of lives and cured billions of debilitating infections. Today, however, these drugs no longer work against the deadliest form of malaria that exists throughout the world. Malaria deaths in sub-Saharan Africa—currently just over one million per year—are rising because of increased resistance to the old, inexpensive drugs. Although effective new drugs called “artemisinins” are available, they are unaffordable for the majority of the affected population, even at a cost of one dollar per course.

Saving Lives, Buying Time: Economics of Malaria Drugs in an Age of Resistance examines the history of malaria treatments, provides an overview of the current drug crisis, and offers recommendations on maximizing access to and effectiveness of antimalarial drugs. The book finds that most people in endemic countries will not have access to currently effective combination treatments, which should include an artemisinin, without financing from the global community. Without funding for effective treatment, malaria mortality could double over the next 10 to 20 years and transmission will intensify.

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