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Plasmodium falciparum is a unicellular protozoan parasite of humans, and the deadliest species of Plasmodium that causes malaria in humans.[2] The parasite is transmitted through the bite of a female Anopheles mosquito and causes the disease's most dangerous form, falciparum malaria. It is responsible for around 50% of all malaria cases.[3][4] P. falciparum is therefore regarded as the deadliest parasite in humans, causing 405,000 deaths in 2018. It is also associated with the development of blood cancer (Burkitt's lymphoma) and is classified as Group 2A carcinogen.

The species originated from the malarial parasite Laverania found in gorillas, around 10,000 years ago.[5] Alphonse Laveran was the first to identify the parasite in 1880, and named it Oscillaria malariae. Ronald Ross discovered its transmission by mosquito in 1897. Giovanni Battista Grassi elucidated the complete transmission from a female anopheline mosquito to humans in 1898. In 1897, unicellular protozoan parasite of humans, and the deadliest species of Plasmodium that causes malaria in humans.[2] The parasite is transmitted through the bite of a female Anopheles mosquito and causes the disease's most dangerous form, falciparum malaria. It is responsible for around 50% of all malaria cases.[3][4] P. falciparum is therefore regarded as the deadliest parasite in humans, causing 405,000 deaths in 2018. It is also associated with the development of blood cancer (Burkitt's lymphoma) and is classified as Group 2A carcinogen.

The species originated from the malarial parasite Laverania found in gorillas, around 10,000 years ago.[5] Alphonse Laveran was the first to identify the parasite in 1880, and named it Oscillaria malariae. Ronald Ross discovered its transmission by mosquito in 1897. Giovanni Battista Grassi elucidated the complete transmission from a female anopheline mosquito to humans in 1898. In 1897, William H. Welch created the name Plasmodium falciparum, which ICZN formally adopted in 1954. P. falciparum assumes several different forms during its life cycle. The human-infective stage are sporozoites from the salivary gland of a mosquito. The sporozoites grow and multiply in the liver to become merozoites. These merozoites invade the erythrocytes (RBCs) to form trophozoites, schizonts and gametocytes, during which the symptoms of malaria are produced. In the mosquito, the gametocytes undergo sexual reproduction to a zygote, which turns into ookinete. Ookinete forms oocytes from which sporozoites are formed.

As of the World Health Organization World Malaria Report 2019, there were 228 million cases of malaria worldwide in 2018, resulting in an estimated 405,000 deaths. Nearly all malarial deaths are caused by P. falciparum, and 94% of such cases occur in Africa.[6] Children under five years of age are most affected, accounting for 61% of the total deaths.[7] In Sub-Saharan Africa, over 75% of cases were due to P. falciparum, whereas in most other malarial countries, other, less virulent plasmodial species predominate.[8]

RTS,S is the only candidate as malaria vaccine to have gone through clinical trials.[71] 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.[72]

Cancer

The International Agency for Research on Cancer (IARC) has classified malaria due to P. falciparum as Group 2A carcinogen, meaning that the parasite is probably a cancer-causing agent in humans.[73] Its association with a blood cell (lymphocyte) cancer called Burkitt's lymphoma is established. Burkit's lymphoma was discovered by Denis Burkitt in 1958 from African children, and he later speculated that the cancer was likely due to certain infectious diseases. In 1964, a virus, later called Epstein–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 as Group 1 carcinogen.[74] In 1989, it was realised that EBV requires other infec

In 1640, Huan del Vego first employed the tincture of the cinchona bark for treating malaria; the native Indians of Peru and Ecuador had been using it even earlier for treating fevers. Thompson (1650) introduced this "Jesuits' bark" to England. Its first recorded use there was by John Metford of Northampton 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 crystalline quinine from the cinchona bark and Pelletier and Caventou (1820) in France extracted pure quinine alkaloids, which they named quinine and cinchonine.[65][66] 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.[67]

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.[68] In the late 1930s, the Germans developed chloroquine, which went into use in the North African campaigns. Creating a secret military project called Project 523, Mao Zedong encouraged Chinese scientists to find new antimalarials after seeing the casualties in the Vietnam War. Tu Youyou discovered artemisinin in the 1970s from sweet wormwood (Atabrine, developed in 1933, was used widely throughout the Pacific in World War II, but was unpopular because of its adverse effects.[68] In the late 1930s, the Germans developed chloroquine, which went into use in the North African campaigns. Creating a secret military project called Project 523, Mao Zedong encouraged Chinese scientists to find new antimalarials after seeing the casualties in the Vietnam War. Tu Youyou discovered artemisinin 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.[69]

According to WHO guidelines 2010,[70] artemisinin-based combination therapies (ACTs) are the recommended first-line antimalarial treatments for uncomplicated malaria caused by P. falciparum. WHO recommends combinations such as artemether/lumefantrine, artesunate/amodiaquine, artesunate/mefloquine, artesunate/sulfadoxine-pyrimethamine, and dihydroartemisinin/piperaquine.[70]

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 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 o

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 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 or doxycycline or clindamycin, and quinine 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 the first trimester is quinine plus clindamycin for 7 days.[70] 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.[70]

For adults, intravenous (IV) or intramuscular (IM) artesunate is recommended.[70] Quinine is an acceptable alternative if parenteral artesunate is not available.[70]

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.[70]

Parenteral antimalarials should be administered f

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.[70]

Parenteral antimalarials should be administered for a minimum of 24 hours, irrespective of the patient's ability to tolerate oral medication earlier.[70] Thereafter, complete treatment is recommended including complete course of ACT or quinine plus clindamycin or doxycycline.[70]

RTS,S is the only candidate as malaria vaccine to have gone through clinical trials.[71] 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.[72]

Cancer

The International Agency for Research on Cancer (IA

The International Agency for Research on Cancer (IARC) has classified malaria due to P. falciparum as Group 2A carcinogen, meaning that the parasite is probably a cancer-causing agent in humans.[73] Its association with a blood cell (lymphocyte) cancer called Burkitt's lymphoma is established. Burkit's lymphoma was discovered by Denis Burkitt in 1958 from African children, and he later speculated that the cancer was likely due to certain infectious diseases. In 1964, a virus, later called Epstein–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 as Group 1 carcinogen.[74] In 1989, it was realised that EBV requires other infections such as with malaria to cause lymphocyte transformation. It was reported that the incidence of Burkitt's lymphoma decreased with effective treatment of malaria over several years.[75] The actual role played by P. 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 as EBNA-1, EBNA-2, LMP-1, and LMP2A).[76][77] From 2014, it became clear that P. falciparum contributes to the development of the lymphoma. P. falciparum-infected erythrocytes directly bind to B lymphocytes through the CIDR1α domain of PfEMP1. This binding activates toll-like receptors (TLR7 and TLR10) causing continuous activation of lymphocytes to undergo proliferation and differentiation into plasma cells, thereby increasing the secretion of IgM and cytokines.[78] This in turn activates an enzyme called activation-induced cytidine deaminase (AID), which tends to cause mutation in the DNA (by double-strand break) of an EBV-infected lymphocytes. The damaged DNA undergoes uncontrolled replication, thus making the cell cancerous.[79]

Influence on the human genome