Plasmodium falciparum is aunicellularprotozoanparasite ofhumans and is the deadliest species ofPlasmodium that causesmalaria in humans.[2] The parasite is transmitted through the bite of a femaleAnophelesmosquito and causes the disease's most dangerous form, falciparum malaria.P. falciparum is therefore regarded as the deadliest parasite in humans. It is also associated with the development of blood cancer (Burkitt's lymphoma) and is classified as aGroup 2A (probable) carcinogen.
The species originated from the malarial parasiteLaverania found ingorillas, around 10,000 years ago.[3][4]Alphonse Laveran was the first to identify the parasite in 1880, and named itOscillaria malariae.Ronald Ross discovered its transmission by mosquito in 1897.Giovanni Battista Grassi elucidated the complete transmission from a femaleanopheline mosquito to humans in 1898. In 1897,William H. Welch created the namePlasmodium falciparum, whichICZN formally adopted in 1954.P. falciparum assumes several different forms during its life cycle. The human-infective stage aresporozoites from thesalivary gland of a mosquito. The sporozoites grow and multiply in theliver to becomemerozoites. These merozoites invade theerythrocytes (red blood cells) to formtrophozoites,schizonts andgametocytes, during which the symptoms of malaria are produced. In the mosquito, the gametocytes undergo sexual reproduction to azygote, which turns intoookinete. Ookinete formsoocytes from which sporozoites are formed.
In 2022, some 249 million cases of malaria worldwide resulted in an estimated 608,000 deaths, with 80 percent being 5 years old or younger.[5] Nearly all malaria related deaths are caused byP. falciparum, and 95% of such cases occur inAfrica. In Sub-Saharan Africa, almost 100% of cases were due toP. falciparum, whereas in most other regions where malaria is endemic, other, less virulent plasmodial species predominate.[6]
Laveran's drawing of various stages ofP. falciparum as seen on fresh blood (1880).
Falciparum malaria was familiar to theancient Greeks, who gave the general nameπυρετός (pyretós) "fever".[7]Hippocrates (c. 460–370 BCE) gave several descriptions ontertian fever and quartan fever.[8] It was prevalent throughout the ancient Egyptian and Roman civilizations.[9] It was the Romans who named the disease "malaria"—mala for bad, andaria for air, as they believed that the disease was spread by contaminated air, ormiasma which had been proven wrong in the modern area.[8][10]
A German physician,Johann Friedrich Meckel, must have been the first to seeP. falciparum but without knowing what it was. In 1847, he reported the presence of black pigment granules from the blood and spleen of a patient who died of malaria. The French Army physicianCharles Louis Alphonse Laveran, while working at Bône Hospital (nowAnnaba in Algeria), correctly identified the parasite as a causative pathogen of malaria in 1880. He presented his discovery before theFrench Academy of Medicine in Paris and published it inThe Lancet in 1881. He gave it the scientific nameOscillaria malariae.[10] However, his discovery was received with skepticism, mainly because by that time, leading physicians such asTheodor Albrecht Edwin Klebs andCorrado Tommasi-Crudeli claimed that they had discovered a bacterium (which they calledBacillus malariae) as the pathogen of malaria. Laveran's discovery was only widely accepted after five years whenCamillo Golgi confirmed the parasite using better microscopes and staining techniques. Laveran was awarded theNobel Prize in Physiology or Medicine in 1907 for his work. In 1900, the Italian zoologistGiovanni Battista Grassi categorizedPlasmodium species based on the timing of fever in the patient; malignant tertian malaria was caused byLaverania malariae (nowP. falciparum), benign tertian malaria byHaemamoeba vivax (nowP. vivax), and quartan malaria byHaemamoeba malariae (nowP. malariae).[11]
The British physicianPatrick Manson formulated themosquito-malaria theory in 1894; until that time, malarial parasites were believed to be spread in air as miasma, a Greek word for pollution.[10] His colleagueRonald Ross of the Indian Medical Service validated the theory while working in India. Ross discovered in 1897 that malarial parasites lived in certain mosquitoes. The next year, he demonstrated that a malarial parasite of birds could be transmitted by mosquitoes from one bird to another. Around the same time, Grassi demonstrated thatP. falciparum was transmitted in humans only by femaleanopheline mosquito (in his caseAnopheles claviger).[12] Ross, Manson and Grassi were nominated for the Nobel Prize in Physiology or Medicine in 1902. Under controversial circumstances, only Ross was selected for the award.[13]
There was a long debate on the taxonomy. It was only in 1954 theInternational Commission on Zoological Nomenclature officially approved the binomialPlasmodium falciparum.[14] The valid genusPlasmodium was created by two Italian physiciansEttore Marchiafava andAngelo Celli in 1885. The Greek wordplasma means "mould" or "form";oeidēs means "to see" or "to know." The species name was introduced by an American physicianWilliam Henry Welch in 1897.[15] It is derived from the Latinfalx, meaning "sickle" andparum meaning "like or equal to another".[14]
P. falciparum is now generally accepted to have evolved fromLaverania (a subgenus ofPlasmodium found in apes) species present in gorillas in Western Africa.[16][17] Genetic diversity indicates that the human protozoan emerged around 10,000 years ago.[3][4] The closest relative ofP. falciparum isP. praefalciparum, a parasite ofgorillas, as supported bymitochondrial,apicoplastic andnuclear DNA sequences.[18][19][20] These two species are closely related to thechimpanzee parasiteP. reichenowi, which was previously thought to be the closest relative ofP. falciparum.P. falciparum was also once thought to originate from a parasite of birds.[21]
Levels of geneticpolymorphism are extremely low within theP. falciparum genome compared to that of closely related, ape infecting species ofPlasmodium (includingP. praefalciparum).[22][18] This suggests that the origin ofP. falciparum in humans is recent, as a singleP. praefalciparum strain became capable of infecting humans.[18] The genetic information ofP. falciparum has signaled a recent expansion that coincides with the agricultural revolution. The development of extensive agriculture likely increased mosquito population densities by giving rise to more breeding sites, which may have triggered the evolution and expansion ofP. falciparum.[23]
Blood smear from aP. falciparumculture (K1 strain - asexual forms) - several red blood cells have ring stages inside them. Close to the center is a schizont and on the left a trophozoite.Ring forms in red blood cells (Giemsa stain)
P. falciparum does not have a fixed structure but undergoes continuous change during its life cycle. A sporozoite is spindle-shaped and 10–15 μm long. In the liver, it grows into an ovoid schizont of 30–70 μm in diameter. Each schizont produces merozoites, each of which is roughly 1.5 μm in length and 1 μm in diameter. In the erythrocyte the merozoite forms a ring-like structure, becoming a trophozoite. A trophozoite feeds on the haemoglobin and forms a granular pigment calledhaemozoin. Unlike those of otherPlasmodium species, the gametocytes ofP. falciparum are elongated and crescent-shaped, by which they are sometimes identified. A mature gametocyte is 8–12 μm long and 3–6 μm wide. The ookinete is also elongated measuring about 18–24 μm. An oocyst is rounded and can grow up to 80 μm in diameter.[24] Microscopic examination of a blood film reveals only early (ring-form) trophozoites and gametocytes that are in the peripheral blood. Mature trophozoites or schizonts do not appear in peripheral blood smears, as these are usually sequestered in the tissues. On occasion, faint, comma-shaped, red dots are seen on the erythrocyte surface. These dots areMaurer's cleft and are secretory organelles that produce proteins and enzymes essential for nutrient uptake and immune evasion processes.[25]
The apical complex, which is a combination of organelles, is an important structure. It contains secretory organelles called rhoptries and micronemes, which are vital for mobility, adhesion, host cell invasion, and parasitophorous vacuole formation.[26] As anapicomplexan, it harbours a plastid, anapicoplast, similar to plantchloroplasts, which they probably acquired by engulfing (or being invaded by) aeukaryoticalga and retaining the algal plastid as a distinctiveorganelleencased within four membranes. The apicoplast is involved in the synthesis oflipids and several other compounds and provides an attractive drug target. During the asexual blood stage of infection, an essential function of the apicoplast is to produce the isoprenoid precursorsisopentenyl pyrophosphate (IPP) anddimethylallyl pyrophosphate (DMAPP) via theMEP (non-mevalonate) pathway.[27]
In 1995 the Malaria Genome Project was set up to sequence the genome ofP. falciparum. The genome of itsmitochondrion was reported in 1995, that of the nonphotosyntheticplastid known as the apicoplast in 1996,[28] and the sequence of the first nuclearchromosome (chromosome 2) in 1998. The sequence of chromosome 3 was reported in 1999 and the entire genome was reported on 3 October 2002.[29] The roughly 24-megabase genome is extremely AT-rich (about 80%) and is organised into 14 chromosomes. Just over 5,300 genes were described. Many genes involved inantigenic variation are located in thesubtelomeric regions of the chromosomes. These are divided into thevar,rif, andstevor families. Within the genome, there exist 59var, 149rif, and 28stevor genes, along with multiplepseudogenes and truncations. It is estimated that 551, or roughly 10%, of the predicted nuclear-encodedproteins are targeted to theapicoplast, while 4.7% of theproteome is targeted to the mitochondria.[29]
Anopheles mosquito, the carrier ofPlasmodium falciparum
Humans are the intermediate hosts in which asexual reproduction occurs, and female anopheline mosquitoes are the definitive hosts harbouring the sexual reproduction stage.[30]
Infection in humans begins with the bite of an infected femaleAnopheles mosquito. Out of about 460 species ofAnophelesmosquito, more than 70 species transmit falciparum malaria.[31]Anopheles gambiae is one of the best known and most prevalent vectors, particularly in Africa.[32]
The infective stage called thesporozoite is released from the salivary glands through the proboscis of the mosquito to enter through the skin during feeding.[33] The mosquito saliva contains antihemostatic and anti-inflammatory enzymes that disruptblood clotting and inhibit the pain reaction. Typically, each infected bite contains 20–200 sporozoites.[26] A proportion of sporozoites invade liver cells (hepatocytes).[34] The sporozoites move in the bloodstream bygliding, which is driven by a motor made up of the proteinsactin andmyosin beneath theirplasma membrane.[35]
Entering the hepatocytes, the parasite loses itsapical complex and surface coat and transforms into atrophozoite. Within theparasitophorous vacuole of the hepatocyte, it undergoes 13–14 rounds of mitosis which produce asyncytial cell (coenocyte) called a schizont. This process is called schizogony. A schizont contains tens of thousands of nuclei. From the surface of the schizont, tens of thousands of haploid (1n) daughter cells called merozoites emerge. The liver stage can produce up to 90,000 merozoites,[36] which are eventually released into the bloodstream in parasite-filled vesicles called merosomes.[37]
Merozoites use theapicomplexan invasion organelles (apical complex, pellicle, and surface coat) to recognize and enter the host erythrocyte (red blood cell). The merozoites first bind to the erythrocyte in a random orientation. It then reorients such that the apical complex is in proximity to the erythrocyte membrane. The parasite forms a parasitophorous vacuole, to allow for its development inside theerythrocyte.[38] This infection cycle occurs in a highly synchronous fashion, with roughly all of the parasites throughout the blood in the same stage of development. This precise clocking mechanism is dependent on the human host's owncircadian rhythm.[39]
Within the erythrocyte, the parasite metabolism depends on the digestion ofhaemoglobin. The clinical symptoms of malaria such as fever, anemia, and neurological disorder are produced during the blood stage.[34]
The parasite can also alter the morphology of the erythrocyte, causing knobs on the erythrocyte membrane. Infected erythrocytes are often sequestered in various human tissues or organs, such as the heart, liver, and brain. This is caused by parasite-derived cell surface proteins being present on the erythrocyte membrane, and it is these proteins that bind to receptors in human cells. Sequestration in the brain causes cerebral malaria, a very severe form of the disease, which increases the victim's likelihood of death.[40]
After invading the erythrocyte, the parasite loses its specific invasion organelles (apical complex and surface coat) and de-differentiates into a round trophozoite located within a parasitophorous vacuole. The trophozoite feeds on the haemoglobin of the erythrocyte, digesting its proteins and converting (bybiocrystallization) the remaining heme into insoluble and chemically inert β-hematincrystals called haemozoin.[41][42] The young trophozoite (or "ring" stage, because of its morphology on stained blood films) grows substantially before undergoing multiplication.[43]
At the schizont stage, the parasite replicates its DNA multiple times and multiple mitotic divisions occur asynchronously.[44][45] Cell division and multiplication in the erythrocyte is called erythrocytic schizogony. Each schizont forms 16-18 merozoites.[43] The red blood cells are ruptured by the merozoites. The liberated merozoites invade fresh erythrocytes. A free merozoite is in the bloodstream for roughly 60 seconds before it enters another erythrocyte.[38]
The duration of one complete erythrocytic schizogony is approximately 48 hours. This gives rise to the characteristic clinical manifestations of falciparum malaria, such as fever and chills, corresponding to the synchronous rupture of the infected erythrocytes.[46]
Some merozoites differentiate into sexual forms, male and femalegametocytes. These gametocytes take roughly 7–15 days to reach full maturity, through the process called gametocytogenesis. These are then taken up by a femaleAnopheles mosquito during a blood meal.[47]
The time of appearance of the symptoms from infection (calledincubation period) is shortest forP. falciparum amongPlasmodium species. An average incubation period is 11 days,[46] but may range from 9 to 30 days. In isolated cases, prolonged incubation periods as long as 2, 3 or even 8 years have been recorded.[48] Pregnancy and co-infection withHIV are important conditions for delayed symptoms.[49] Parasites can be detected from blood samples by the 10th day after infection (pre-patent period).[46]
Within the mosquito midgut, the female gamete maturation process entails slight morphological changes, becoming more enlarged and spherical. The male gametocyte undergoes a rapid nuclear division within 15 minutes, producing eightflagellatedmicrogametes by a process called exflagellation.[50] The flagellated microgamete fertilizes the femalemacrogamete to produce adiploid cell called azygote. The zygote then develops into anookinete. The ookinete is a motile cell, capable of invading other organs of the mosquito. It traverses theperitrophic membrane of the mosquito midgut and crosses the midgut epithelium. Once through the epithelium, the ookinete enters thebasal lamina and settles into an immotileoocyst. For several days, the oocyst undergoes 10 to 11 rounds of cell division to create asyncytial cell (sporoblast) containing thousands of nuclei. Meiosis takes place inside the sporoblast to produce over 3,000 haploid daughter cells called sporozoites on the surface of the mother cell.[51] Immature sporozoites break through the oocyst wall into thehaemolymph. They migrate to the mosquito salivary glands where they undergo further development and become infective to humans.[34]
Effects of plant secondary metabolites onP. falciparum
Mosquitoes are known to forage on plant nectar for sugar meal, the primary source of energy and nutrients for their survival and other biological process such as host seeking for blood or searching for oviposition sites.[52] Researchers have recently discovered that mosquitoes are very selective about their sugar meal sources.[53] For exampleAnopheles mosquitoes prefer some plants over others, specifically those containing compounds that hinder the development and survival of malaria parasites inside the mosquito.[54] This discovery offers an opportunity to look into what could be playing a role in these behavior changes in mosquitoes and also find out what they ingest when they foraged on the selected plants. In other studies, it has been shown that sources of sugars and some secondary metabolites e.g. ricinine, have contrasting effects on mosquito capacity to transmit the parasites malaria.[55]
Plasmodium falciparum ishaploid (one set of chromosomes) during its reproductive stages in human blood and liver. When a mosquito takes a blood meal from aplasmodium infected human host, this meal may include haploid microgametes and macrogametes. Such gametes can fuse within the mosquito to form a diploid (2N) plasmodiumzygote, the only diploid stage in the life cycle of these parasites.[56] The zygote can undergo another round ofchromosome replication to form an ookinete (4N) (see Figure: Life cycle of plasmodium). The ookinete that differentiates from the zygote is a highly mobile stage that invades the mosquito midgut. The ookinetes can undergomeiosis involving two meiotic divisions leading to the release of haploid sporozoites (see Figure).[56] The sporozoite is an elongated crescent-shaped invasive stage. These sporozoites may migrate to the mosquito's salivary glands and can enter a human host when the mosquito takes a blood meal. The sporozoite then can move to the human host liver and infecthepatocytes.
The profile of genes encoded by plasmodium that are employed in meiosis has some overlap with the profile of genes employed in meiosis in other more well-studied organisms, but is more divergent and is lacking some components of the meiotic process found in other organisms.[56] During plasmodium meiosis,recombination occurs between homologous chromosomes as in other organisms.
A single anopheline mosquito can transmit hundreds ofP. falciparum sporozoites in a single bite under experimental conditions, but, in nature, the number is generally less than 80.[57] The sporozoites do not enter the bloodstream directly, but rather remain in the skin for two to three hours. About 15–20% of the sporozoites enter the lymphatic system, where they activatedendritic cells, which send them for destruction by T lymphocytes (CD8+ T cells). At 48 hours after infection,Plasmodium-specific CD8+ T cells can be detected in thelymph nodes connected to the skin cells.[58] Most of the sporozoites remaining in the skin tissue are subsequently killed by theinnate immune system. The sporozoite glycoprotein specifically activatesmast cells. The mast cells then producesignaling molecules such asTNFα and MIP-2, which activate cell eaters (professional phagocytes) such asneutrophils andmacrophages.[59]
Only a small number (0.5-5%) of sporozoites enter the bloodstream into the liver. In the liver, the activated CD8+ T cells from the lymph bind the sporozoites through thecircumsporozoite protein (CSP).[58]Antigen presentation by dendritic cells in the skin tissue to T cells is also a crucial process. From this stage onward, the parasites produce different proteins that help suppress communication of the immune cells.[60] Even at the height of the infection, when red blood cells (RBCs) are ruptured, the immune signals are not strong enough to activate macrophages ornatural killer cells.[61]
AlthoughP. falciparum is easily recognized by the human immune system while in the bloodstream, it evades immunity by producing over 2,000 cell membrane antigens.[62] The initial infective stage sporozoites produce circumsporozoite protein (CSP), which binds to hepatocytes.[63] Binding to and entering into the hepatocytes is aided by thrombospondin-related anonymous protein (TRAP).[64] TRAP and other secretory proteins (including sporozoite microneme protein essential for cell traversal 1, SPECT1 and SPECT2) from microneme allow the sporozoite to move through the blood, avoiding immune cells and penetrating hepatocytes.[65]
During erythrocyte invasion, merozoites release merozoite cap protein-1 (MCP1), apical membrane antigen 1 (AMA1), erythrocyte-binding antigens (EBA), myosin A tail domain interacting protein (MTIP), andmerozoite surface proteins (MSPs).[62] Of these MSPs, MSP1 and MSP2 are primarily responsible for avoiding immune cells.[66] The virulence ofP. falciparum is mediated by erythrocyte membrane proteins, which are produced by the schizonts and trophozoites inside the erythrocytes and are displayed on the erythrocyte membrane.PfEMP1 is the most important, capable of acting as both an antigen and an adhesion molecule.[67]
The clinical symptoms of falciparum malaria are produced by the rupture and destruction of erythrocytes by the merozoites. High fever, called paroxysm, is the most basic indication. The fever has a characteristic cycle of hot stage, cold stage, and sweating stages.[68] Since each erythrocytic schizogony takes a cycle of 48 hours, i.e., two days, the febrile symptom appears every third day. This is the reason the infection is classically named tertian malignant fever (tertian, a derivative of a Latin word that means "third").[69][70] The most common symptoms arefever (>92% of cases),chills (79%),headaches (70%), andsweating (64%).Dizziness,malaise,muscle pain,abdominal pain,nausea,vomiting, milddiarrhea, anddry cough are also generally associated.High heart rate,jaundice,pallor,orthostatic hypotension,enlarged liver, andenlarged spleen are also diagnosed.[46]
The insoluble β-hematin crystal,haemozoin, produced from the digestion of haemoglobin of the RBCs is the main agent that affects body organs. Acting as a blood toxin, haemozoin-containing RBCs cannot be attacked by phagocytes during the immune response to malaria.[71] The phagocytes can ingest free haemozoins liberated after the rupture of RBCs by which they are induced to initiate chains ofinflammatory reaction that results in increased fever.[72][73] It is the haemozoin that is deposited in body organs such as the spleen and liver, as well as in kidneys and lungs, to cause their enlargement and discolouration.[74][75] Because of this, haemozoin is also known as malarial pigment.[76][77]
Unlike other forms of malaria, which show regular periodicity of fever, falciparum, though exhibiting a 48-hour cycle, usually presents as irregular bouts of fever. This difference is due to the ability ofP. falciparum merozoites to invade a large number of RBCs sequentially without coordinated intervals, which is not seen in other malarial parasites.[68]P. falciparum is therefore responsible for almost all severe human illnesses and deaths due to malaria, in a condition called pernicious or complicated or severe malaria. Complicated malaria occurs more commonly in children under age 5,[46] and sometimes in pregnant women (a condition specifically calledpregnancy-associated malaria).[78] Women become susceptible to severe malaria during their first pregnancy. Susceptibility to severe malaria is reduced in subsequent pregnancies due to increased antibody levels against variant surfaceantigens that appear on infected erythrocytes.[79] But increased immunity in the mother increases susceptibility to malaria in newborn babies.[78]
P. falciparum works via sequestration, a process by which group of infected RBCs are clustered, which is not exhibited by any other species of malarial parasites.[80] The mature schizonts change the surface properties of infected erythrocytes, causing them to stick to blood vessel walls (cytoadherence). This leads to obstruction of the microcirculation and results in dysfunction of multiple organs, such as the brain incerebral malaria.[81]
Cerebral malaria is the most dangerous condition of any malarial infection and the most severe form ofneurological disorders. According to the WHO definition, the clinical symptom is indicated by coma and diagnosis by a high level of merozoites in the peripheral blood samples.[82][83] It is the deadliest form of malaria, and to it are attributed to 0.2 million to over a million annual deaths throughout the ages. Most deaths are of children of below 5 years of age.[84][85] It occurs when the merozoites invade the brain and cause brain damage of varying degrees. Death is caused by oxygen deprivation (hypoxia) due to inflammatory cytokine production and vascular leakage induced by the merozoites.[86] Among the surviving individuals, persistent medical conditions such as neurological impairment,intellectual disability, andbehavioural problems exist. Among them,epilepsy is the most common condition, and cerebral malaria is the leading cause of acquired epilepsy among African children.[87]
The reappearance of falciparum symptom, a phenomenon called recrudescence, is often seen in survivors.[88] Recrudescence can occur even after successful antimalarial medication.[89][90] It may take a few months or even several years. In some individuals, it takes as long as three years.[91] In isolated cases, the duration can reach or exceed 10 years.[92][93] It is also a common incident among pregnant women.[94][95]
Relative incidence of Plasmodium species by country of origin for imported cases to non-endemic countries, showingP. falciparum (red) predominating in areas including Africa and the Caribbean.[96]The Z(T) normalized index of temperature suitability forP. falciparum displayed by week across an average year.
P. falciparum is endemic in 84 countries,[97] and is found in all continents except Europe. Historically, it was present in most European countries, but improved health conditions led to the disappearance in the early 20th century.[98] The only European country where it used to be historically prevalent, and from where we got the name malaria, Italy had been declared malaria-eradicated country. In 1947, the Italian government launched the National Malaria Eradication Program, and following, an anti-mosquito campaign was implemented using DDT.[99] The WHO declared Italy free of malaria in 1970.[100]
There were an estimated 263 million cases of malaria worldwide in 2023, resulting in an estimated 597,000 deaths.[97] The infection is most prevalent in Africa, where 95% of malaria deaths occur.[97] Children under five years of age are most affected, and 67% of malaria deaths occurred in this age group. 80% of the infection is found in Sub-Saharan Africa, 7% in South-East Asia, and 2% in the Eastern Mediterranean. Nigeria has the highest incidence, with 27% of the total global cases. Outside Africa, India has the highest incidence, with 4.5% of the global burden. Europe is regarded as a malaria-free region. Historically, the parasite and its disease had been most well-known in Europe. But medical programmes since the early 20th century, such as insecticide spraying, drug therapy, and environmental engineering, resulted in complete eradication in the 1970s.[101] It is estimated that approximately 2.4 billion people are at constant risk of infection.[102]
In 1640, Huan del Vego first employed thetincture of thecinchona bark for treating malaria; the native Indians ofPeru and Ecuador had been using it even earlier for treating fevers. Thompson (1650) introduced this "Jesuits' bark" toEngland. Its first recorded use there was by John Metford ofNorthampton in 1656.Morton (1696) presented the first detailed description of the clinical picture of malaria and of its treatment with cinchona.Gize (1816) studied the extraction of crystallinequinine from the cinchona bark andPelletier andCaventou (1820) inFrance extracted pure quininealkaloids, which they named quinine andcinchonine.[103][104] The total synthesis of quinine was achieved by American chemists R.B. Woodward and W.E. Doering in 1944. Woodward received the Nobel Prize in Chemistry in 1965.[105]
Attempts to make synthetic antimalarials began in 1891.Atabrine, developed in 1933, was used widely throughout the Pacific in World War II, but was unpopular because of its adverse effects.[106] In the late 1930s, the Germans developedchloroquine, which went into use in the North African campaigns. Creating a secret military project calledProject 523,Mao Zedong encouraged Chinese scientists to find new antimalarials after seeing the casualties in the Vietnam War.Tu Youyou discoveredartemisinin in the 1970s from sweet wormwood (Artemisia annua). This drug became known to Western scientists in the late 1980s and early 1990s and is now a standard treatment. Tu won the Nobel Prize in Physiology or Medicine in 2015.[107]
The choice of ACT is based on the level of resistance to the constituents in the combination. Artemisinin and its derivatives are not appropriate for monotherapy. As a second-line antimalarial treatment, when initial treatment does not work, an alternative ACT known to be effective in the region is recommended, such as artesunate plus tetracycline ordoxycycline orclindamycin, andquinine plus tetracycline or doxycycline or clindamycin. Any of these combinations is to be given for 7 days. For pregnant women, the recommended first-line treatment during thefirst trimester is quinine plus clindamycin for 7 days.[108] Artesunate plus clindamycin for 7 days is indicated if this treatment fails. For travellers returning to nonendemic countries,atovaquone/proguanil, artemether/lumefantrineany and quinine plus doxycycline or clindamycin are recommended.[108]
For adults,intravenous (IV) orintramuscular (IM) artesunate is recommended.[108] Quinine is an acceptable alternative if parenteral artesunate is not available.[108]
For children, especially in the malaria-endemic areas of Africa, artesunate IV or IM, quinine (IV infusion or divided IM injection), and artemether IM are recommended.[108]
Parenteral antimalarials should be administered for a minimum of 24 hours, irrespective of the patient's ability to tolerate oral medication earlier.[108] Thereafter, complete treatment is recommended including a complete course of ACT or quinine plus clindamycin or doxycycline.[108]
RTS,S is the only candidate for the malaria vaccine to have gone through clinical trials.[109] Analysis of the results of the phase III trial (conducted between 2011 and 2016) revealed a rather low efficacy (20-39% depending on age, with up to 50% in 5–17-month aged babies), indicating that the vaccine will not lead to full protection and eradication.[110]
On October 6, 2021, the World Health Organization recommended malaria vaccination for children at risk.[111]
TheInternational Agency for Research on Cancer (IARC) has classified malaria due toP. falciparum as a Group 2A carcinogen, meaning that the parasite is probably a cancer-causing agent in humans.[112] Its association with a blood cell (lymphocyte) cancer calledBurkitt's lymphoma is established. Burkitt's lymphoma was discovered byDenis Burkitt in 1958 by African children, and he later speculated that the cancer was likely due to certain infectious diseases. The geographic distribution of endemic Burkitt's lymphoma, concentrated in equatorial Africa andPapua New Guinea, closely mirrors regions of holoendemicP. falciparum transmission, providing early epidemiological evidence of a link between malaria and the cancer.[113] In 1964, a virus, later calledEpstein–Barr virus (EBV) after the discoverers, was identified from the cancer cells. The virus was subsequently proved to be the direct cancer agent and is now classified asGroup 1 carcinogen.[114]
In 1989, it was realised that EBV requires other infections such as malaria to cause lymphocyte transformation. It was reported that the incidence of Burkitt's lymphoma decreased with effective treatment of malaria over several years.[115] The actual role played byP. falciparum remained unclear for the next two-and-half decades. EBV had been known to induce lymphocytes to become cancerous using its viral proteins (antigens such asEBNA-1,EBNA-2,LMP1, andLMP2A).[116][117] From 2014, it became clear thatP. falciparum contributes to the development of the lymphoma.P. falciparum-infected erythrocytes directly bind toB lymphocytes through the CIDR1α domain of PfEMP1. This binding activatestoll-like receptors (TLR7 andTLR10) causing continuous activation of lymphocytes to undergo proliferation and differentiation intoplasma cells, thereby increasing the secretion ofIgM andcytokines.[118] This, in turn, activates an enzyme calledactivation-induced cytidine deaminase (AID), which tends to cause mutation in the DNA (bydouble-strand break) of EBV-infected lymphocytes. The damaged DNA undergoes uncontrolledreplication, thus making the cell cancerous.[119]
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