Malaria

DEFINITION: One of the world’s most serious and potentially fatal diseases, malaria is the result of a parasite transmitted into the bloodstream by mosquito bites. It is most common in subtropical zones, especially in Africa, Asia, and Latin America

ALSO KNOWN AS: Paludism

ANATOMY OR SYSTEM AFFECTED: Blood, immune system, liver, spleen

CAUSES: Transmission of parasitic infection via mosquitoes

SYMPTOMS: Recurrent bouts of severe fever, chills, sweating, vomiting; damage to kidneys, blood, brain, and liver

DURATION: Acute to long-term

TREATMENTS: Drug therapy (chloroquine, mefloquine)

Causes and Symptoms

Malaria in humans is caused by transfer into the bloodstream, through the saliva of the Anopheles mosquito, of the protozoan (single-cell) Plasmodium parasite. There are several different strains of the malaria parasite, all belonging to the phylum Sporozoa. This classification is connected with the importance of spores in the organism’s reproductive cycle.

Serious and potentially lethal malarial infections in humans are primarily associated with P. falciparum. Other Plasmodium parasites that can produce infection are P. vivax (formerly present in temperate climate zones but now found only in the subtropics), P. malariae (also only subtropical), and P. ovale (quite rare, and mainly limited to West Africa), and P. knowlesi.

Other Plasmodium parasites infect only nonhuman primates (P. cynomolgi, for example), only rodents (four different species), or only birds (P. cathemerium and P. gallinaceum). The latter two species have been used widely in experimental testing of antimalarial vaccines.

Note that only one mosquito genus, Anopheles—and only the female Anopheles mosquito—serves as a in transmitting malaria. The reason is surprisingly simple: Only the female Anopheles nourishes itself (usually at night) by piercing the skin of its victim and sucking small quantities of blood. The males feed mainly on fruit juices.

In the most common scenario, the mosquito ingests the Plasmodium parasite when it sucks the blood of an already infected human. This phase is followed by several others—all connected with the reproductive processes of the same (both sexual and asexual)—until the mosquito passes later generations of the onto another human host, who then becomes infected. The protozoan’s first, sexual stage of reproduction occurs when male emit flagella that seek out and join their female counterpart, producing a fertilized zygote.

Once lodged in the gut tissue of the mosquito in the form of an oocyst, a further, asexual stage of reproduction occurs through what is called “sporogony.” The oocyst releases myriad spores. They spread rapidly throughout the body of the mosquito. Many enter the insect host’s salivary glands, from which they are transferred into the blood of the next human bitten by the mosquito. The further development of the spores in the human produces the disease symptoms associated with malaria.

Once transmitted into the human host through the mosquito saliva, the parasite spores flow quickly through the blood, entering the liver. Their next transformation occurs once they lodge themselves in the cells of the liver, becoming what are called “ trophozoites.”

As they feed off the liver cells, the trophozoites grow and burst open. This process of asexual multiplication in the liver is referred to as “hepatic schozogony.” At that stage, the parasite has multiplied many hundreds of times, producing the actual agent of malarial disease, merozoites.

If the parasite is P. vivax, then this phase may not occur immediately, as a result of a state of dormancy in the parasitic trophozoites. In this case, months or even years can pass before the merozoites are released. Even then, the delayed release is still not final. This explains why some malaria-infected individuals experience a cyclical disappearance of symptoms, followed some time later by a resurgence of the latent disease.

When released from the trophozoites, the merozoites quickly invade the red blood cells of the host. The damage that they inflict leads to anemic reactions as the number of healthy blood cells in the organism decreases. It is not only the liver that is affected; the disease can also spread to the spleen.

Once the effects of malaria begin to take hold in the blood and various organs of the body, certain symptoms will appear. There is an onset of fever, probably caused by the release of a pyrogen (a fever-inducing agent) by the reacting to the diseased situation of red blood cells that have been attacked by the malaria parasite. Since this release of may follow an irregular pattern, fever can come and go, seemingly sporadically.

Meanwhile, as the number of parasitized red blood cells increases, infected red blood cells begin to attach themselves to the inside tissue of of the internal organs. The effect is blockage of the necessary free flow of blood. If pressure builds because of this blockage, then blood vessels themselves may burst.

Such internal hemorrhages allow the directionless dispersion of infected blood within the body, increasing the anemic symptoms that are characteristic of malaria. Perhaps the most dramatic sign of blocked blood vessels occurs if and when the parasitized cells affect the blood flow to the brain. In such cases, convulsions occur, eventually leading to coma.

Treatment and Therapy

Long before researchers could explain the causes of malaria, treatment of its symptoms, primarily manifested in spells of fever, involved giving the patient doses of quinine. As knowledge of the disease increased, different forms of treatment evolved. Such developments occurred not only as new discoveries emerged. They also became necessary as the malaria parasite itself evolved genetically, in effect developing its own immunity to quinine-based treatment.

Several compounds were developed in the later decades of the twentieth century to or, more recently, to replace complete on quinine.

Depending on the Plasmodium species coming into contact with it, the alkaloid quinine could kill the parasitical organism at key stages in its reproductive activity. Sometimes, however, toxic side effects accompanied the use of quinine in malaria cases. These negative effects eventually sparked research aimed at producing synthetic drugs that could be as effective as quinine in preventing malaria, even though they might not be as effective in treating the disease once contracted. The earliest synthetic antimalarials, introduced between 1926 and the early 1950s, included pamaquine, the first synthetic; mepacrine; and chloroquine and primaquine, two well-known drugs from the mid-1940s through the 1950s. These synthetic agents intervened to stop reproduction of the malaria parasite at different points in its life span. Depending on which preventive drug was taken, treatment might have to begin well before expected exposure, during the period of exposure, or for a certain period after being present in a malaria-infected area.

Several generations of antimalarial drugs are on the market. But such progress in options has not effectively resolved the problem of endemic malaria in regions of the world where those most in need lack either information programs or the financial means to obtain necessary drugs.

According to the US Centers for Disease Control and Prevention (CDC), the preferred oral treatment for malaria is the drug artemether-lumefantrine (brand name Coartem). The CDC also recommended other antimalarial drugs including atovaquone-proguanil (Malarone), quinine, and mefloquine.

Research involving to protect against malarial infection has tended to follow one of two main approaches: vaccines to combat the of spores directly and vaccines to block one or several stages of the parasite’s life cycle. Some vaccines have been developed by extracting spores from the blood of infected patients and using methods such as radiation to reduce their potency. Injection of these weakened agents into the blood can induce formation of antibodies that can fight invasive spores coming from an outside source (mosquito saliva) into a potential host organism. Researchers have tended to concentrate more on isolating antigens that the body produces naturally to fight invasive spores and merozoites, analyzing them, and attempting to use to produce effective synthetic antigens.

The World Health Organization (WHO) recommended two novel vaccines against malaria, RTS,S/AS01 and R21/Matrix-M, in 2021 and 2023, respectively. Both combat P. falciparum malaria transmission by targeting a protein antigen on the spore and thus preventing its attack on human liver cells. In trials, RTS,S demonstrated a 30 to 50 percent efficacy in reducing malaria in infants and children and a 13 percent drop in all-cause mortality in children under two. R21 had an efficacy of up to 75 percent. Combined with traditional, nonmedicinal infection controls such as treated bed nets, the interventions could prevent up to 90 percent of cases.

Observation over a long period of time has provided statistical evidence that in a number of subtropical areas where malaria is endemic, fatalities from the disease are more frequent among children than among adults. The reason for this is linked to the adult population’s prior exposure to one or more nonlethal malarial infections. In essence, the adult body’s production of natural antigens seems to neutralize the effects of blood cells that have become carriers. If they remain in the bloodstream, these antigens reduce the susceptibility to what, in children, takes the form of a sudden invasion of infected and (for the body’s immune system) unrecognizable blood cells transmitted through Anopheles mosquito bites. Children who are infected with HIV or malnourished are also at higher risk of developing severe cases of malaria.

There is therefore an entire field of malaria research dealing with the body’s own immune responses. Where malaria is concerned, researchers pay particular attention both to the challenge of understanding how immunity can build in populations living in endemic zones, and to the possibility of increasing the efficiency of certain body organs that naturally affect the bloodstream in ways that can impede the spread of the parasite’s damage.

Attention has focused, for example, on the internal functions of the spleen. The can prevent the progress of intravascular pathogens in general by reducing the flow of infected red blood cells to other organs and isolating them in a chemical state that renders them less directly dangerous to the body. This capacity is called “splenic filtration.” Although research has not yet identified an effective way to use externally applied medications to enhance this facet of the spleen’s natural defense system, this represents a serious prospect for another potential treatment to complement, if not replace, preventive drugs and synthetic antigens.

Once it was clear that malaria was transmitted by mosquitoes, the most logical tactic to prevent spread of the disease involved campaigns to eradicate, or at least diminish the life chances of, Anopheles. Thus, drainage of swamp areas (a costly but effective measure where possible), public health measures to guard against insalubrious concentrations of stagnant water, and insecticide spraying have been practiced throughout the world to combat Anopheles. During World War II and until the late 1950s, DDT was the insecticide of choice. When the harmful side effects of DDT for humans and the environment became apparent, legislation in most but not all countries banned the chemical. Research has since aimed at, but not fully succeeded in, developing safer insecticides that can approach DDT’s levels of efficiency.

Research into other avenues for intervention remains ongoing. Scientists have investigated potential uses for genetically engineered or modified bacteria, for instance, but concerns remained over the potential risks in the wild. In 2023, however, researchers discovered the naturally occurring Delftia tsuruhatensis TC1 bacterium, which produces an antimalarial substance called harmane that disrupts spore reproduction within an infected Anopheles mosquito. Experiments showed a 75 percent reduction in oocyte production in inoculated mosquitoes, indicating significant promise as a potential infection control agent.

Perspective and Prospects

Research into malarial disease and its biological origins advanced rather slowly, with most major advances occurring fairly late in the nineteenth century. It was in 1897 that a surgeon in the British Indian army, Sir Ronald Ross, following British tropical disease expert Sir Patrick Manson’s suggestions, announced his discovery that malaria was transmitted to humans by mosquitoes. There had been earlier theories concerning the role of mosquitoes, some going back as far as the early eighteenth century in Italy (where the term “malaria,” meaning “bad air,” had originated).

It took the work of a French military doctor in Algeria, Alphonse Laveran, to show, under a microscope, the ongoing activity of parasites in the blood of malaria patients. Laveran also did postmortem studies of malaria victims’ blood and organs and found a dark pigment composed mainly of iron that came from the parasites’ apparent and waste disposal of vital in the red blood cells. He became the first to posit that malaria was a disease of red blood cells and that it was caused by an invasion of parasites.

From there, it was a question of finding how the parasites entered the human bloodstream. This was the result of Ross’s observation in India of a particular variety of mosquito larvae (later identified as the small brown Anopheles, distinct from Culex varieties commonly observed in the daytime) collected from stagnant waters in the region. When Ross followed Manson’s that mosquitoes hatched from these larvae should be induced to feed from a known malaria patient, he found that only a few insects survived the next few days. When these were dissected, he found oocysts embedded on the wall of the mosquitoes’ gut. Microscopic analysis showed that they contained the same dark pigment that Laveran had found in the blood of malaria victims in Algeria.

Both Ross (in 1902) and Laveran (in 1907) received Nobel Prizes in recognition of their work, Ross in medicine and Laveran in or medicine. Other contributors, notably the Italian Giovanni Batista Grassi, carried on significant work in the same first decade of the twentieth century that paralleled (or, according to Grassi, may have been accomplished before) Ross’s studies.

The most important, and ultimately correct, suggestion by Grassi was that there must be significant transformations—and in fact multiple stages of reproduction—between the sporozoite phase of parasite dissemination via mosquito saliva and the merozoite phase, when the attacking parasite can destroy red blood cells in the human host. Later researchers finally provided, in 1934, convincing evidence that there was a sequence of sexual and asexual phases of reproduction (the later labeled “schizogony”) in the life cycle of the Plasmodium parasite.

Over the years, other researchers helped broaden the understanding of malaria, its causes, and treatment. Despite the obvious costs paid during the first half of the twentieth century involving debilitation and loss of human lives in areas where malaria was endemic, truly major breakthroughs occurred only during the extraordinary conditions created by World War II. The fact that large numbers of troops were sent from North America and Europe to areas in East, South, and Southeast Asia as well as Africa meant that the danger of widespread malarial infection could hamper strategic operations. Distribution of all forms of preventive equipment, including both mosquito nets and insect repellents, was destined to become standard procedure in tropical zones. Doses of quinine were also part of each soldier’s medical supply packet.

Both the Centers for Disease Control (CDC) and the World Health Organization (WHO) state that malaria is completely treatable and curable. The United States eliminated the disease in the early 1950s, and forty-three other countries and one territory had done so by early 2024. According to the CDC, about 2,000 cases of malaria are reported in the US each year, mainly by people who had recently traveled to foreign countries; locally acquired transmission, though rare, has also occurred, and in the summer of 2023, the US experienced its first outbreaks of locally acquired malaria in two decades.

The high concentration of Anopheles mosquitoes in Africa and other subtropical areas with limited resources and access to treatment has meant malaria continues to be a large source of global illness and deaths, however. In 2021, the WHO reported that about half the world's population was at risk of malaria. Additionally, according to the WHO, there were 249 million new cases of malaria and 608,000 deaths in 85 countries in 2022. Malaria and deaths from the disease disproportionately occur in Africa, with 94 percent of all cases worldwide and 95 percent of all malaria deaths occurring on that continent. Children under five accounted for 80 percent of all malaria deaths in Africa. Routine nationwide childhood immunization against malaria began in January 2024 in Cameroon, with about twenty other African nations set to follow suit later that same year.

Many factors have led to increased disease in the early 2020s, after decades of declines. Rising temperatures, increased humidity, stagnant water from flooding events, and insecticide resistance have contributed to longer mosquito lives and spread, while Plasmodium strains have been evolving drug resistance. Meanwhile, population displacement due to extreme weather and conflict, substandard housing, supply chain disruptions from the global COVID-19 pandemic, and food insecurity set the stage for increased transmission and worse illness.

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