and neurological disorder are produced during the blood stage. 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 on human cells. sequestration in the brain causes cerebral malaria, a very severe form of the disease, which increases the victim's likelihood of death. trophozoite 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 erythrocyte, digesting its proteins and converting (by biocrystallization) the remaining heme into an insoluble and chemically inert β-hematin crystals called haemozoin. the young trophozoite (or "ring" stage, because of its morphology on stained blood films) grows substantially before undergoing multiplication. schizont at the schizont stage, the parasite replicates its dna multiple times and multiple mitotic divisions occur asynchronously. cell division and multiplication in the erythrocyte is called erythrocytic schizogony. each schizont forms 16-18 merozoites. 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. 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. gametocyte some merozoites differentiate into sexual forms, male and female gametocytes. these gametocytes take roughly 7–15 days to reach full maturity, through the process called gametocytogenesis. these are then taken up by a female anopheles mosquito during a blood meal. incubation period the time of appearance of the symptoms from infection (called incubation period) is shortest for p. falciparum among plasmodium species. an average incubation period is 11 days, 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. pregnancy and co-infection with hiv are important conditions for delayed symptoms. parasites can be detected from blood samples by the 10th day after infection (pre-patent period). in mosquitoes 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 eight flagellated microgametes by a process called exflagellation. the flagellated microgamete fertilizes the female macrogamete to produce a diploid cell called a zygote. the zygote then develops into an ookinete. the ookinete is a motile cell, capable of invading other organs of the mosquito. it traverses the peritrophic membrane of the mosquito midgut and crosses the midgut epithelium. once through the epithelium, the ookinete enters the basal lamina, and settles to an immotile oocyst. for several days, the oocyst undergoes 10 to 11 rounds of cell division to create a syncytial 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. immature sporozoites break through the oocyst wall into the haemolymph. they migrate to the mosquito salivary glands where they undergo further development and become infective to humans. interaction with human immune system immune response a single anopheline mosquito can transmit hundreds of p. falciparum sporozoites in a single bite under experimental conditions. but in nature the number is generally less than 80. the sporozoites do not enter the blood stream directly and remain in the skin tissue for 2 to 3 hours. about 15–20% sporozoites enter the lymphatic system where they activate dendritic 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 the lymph nodes connected to the skin cells. most of the sporozoites remaining in the skin tissue are subsequently killed by the innate immune system. the sporozoite glycoprotein specifically activates mast cells. the mast cells then produce signaling molecules such as tnfα and mip-2, which activate cell eaters (professional phagocytes) such as neutrophils and macrophages. only a small number (0.5-5%) of sporozoites enter the blood stream into the liver. in the liver, the activated cd8+ t cells from the lymph bind the sporozoites through the circumsporozoite protein (csp). 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 in suppressing communication of the immune cells. even at the height of the infection when red blood cells (rbcs) are ruptured, the immune signals are not strong enough to activate macrophages or natural killer cells. immune system evasion although p. falciparum is easily recognized by human immune system while in the bloodstream, it evades immunity by producing over 2,000 cell membrane antigens. the initial infective stage sporozoites produce circumsporozoite protein (csp), which binds to hepatocytes. binding to and entry into the hepatocytes is aided by another protein, thrombospondin-related anonymous protein (trap). 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. 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), and merozoite surface proteins (msps). of these msps, msp1 and msp2 are primarily responsible for avoiding immune cells. the virulence of p. 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. pathogenicity main article: malaria 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. 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 latin word that means "third"). the most common symptoms are fever (>92% of cases), chills (79%), headaches (70%), and sweating (64%). dizziness, malaise, muscle pain, abdominal pain, nausea, vomiting, mild diarrhea, and dry cough are also generally associated. high heartrate, jaundice, pallor, orthostatic hypotension, enlarged liver, and enlarged spleen are also diagnosed. the insoluble β-hematin crystals, haemozoin, produced from digestion of haemoglobin of the rbcs is the main agent that affect body organs. acting as a blood toxin, haemozoin-containing rbcs cannot be attacked by phagocytes during immune response to malaria. the phagocytes can ingest free haemozoins liberated after the rupture of rbcs by which they are induced to initiate chains of inflammatory reaction that results in increased fever. 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. because of this, haemozoin is also known as malarial pigment. unlike other malarias, which show regular periodicity of fever, falciparum, though exhibiting a 48-hour cycle, usually presents as irregular bouts of fever. this difference is due the ability of p. falciparum merozoites to invade a large number of rbcs sequentially without coordinated intervals, which is not seen in other malarial parasites. 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, and sometimes in pregnant women (a condition specifically called pregnancy-associated malaria). 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 surface antigens that appear on infected erythrocytes. but increased immunity in the mother increases susceptibility to malaria in newborn babies. 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. 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 in cerebral malaria. cerebral malaria is the most dangerous condition of any malarial infection and the most severe form of neurological disorders. according to the who definition, the clinical symptom is indicated by coma and diagnosis by high level of merozoites in the peripheral blood samples. 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. it occurs when the merozoites invade the brain and causes brain damage of varying degrees. death is caused by oxygen deprivation (hypoxia) due to inflammatory cytokine production and vascular leakage induced by the merozoites. among the surviving individuals, persistent medical conditions such as neurological impairment, intellectual disability, and behavioural problems exist. among them, epilepsy is the most common condition, and cerebral malaria is the leading cause of acquired epilepsy among african children. the reappearance of falciparum symptom, a phenomenon called recrudescence, is often seen in survivors. recrudescence can occur even after successful antimalarial medication. it may take a few months or even several years. in some individuals, it takes as along as three years. in isolated cases, the duration can reach or exceed 10 years. it is also a common incident among pregnant women. distribution and epidemiology relative incidence of plasmodium species by country of origin for imported cases to non-endemic countries, showing p. falciparum (red) predominating in areas including africa and the caribbean. p. falciparum is endemic in 84 countries, 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. 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. the who declared italy free of malaria in 1970. there were 247 million cases of malaria worldwide in 2021, resulting in an estimated 619,000 deaths. the infection is most prevalent in africa, where 94% of malaria deaths occur. 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 the 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. it is estimated that approximately 2.4 billion people are at constant risk of infection. treatment history