hepatocytes, multiplying asexually and asymptomatically for a period of 8–30 days. after a potential dormant period in the liver, these organisms differentiate to yield thousands of merozoites, which, following rupture of their host cells, escape into the blood and infect red blood cells to begin the erythrocytic stage of the life cycle. the parasite escapes from the liver undetected by wrapping itself in the cell membrane of the infected host liver cell. within the red blood cells, the parasites multiply further, again asexually, periodically breaking out of their host cells to invade fresh red blood cells. several such amplification cycles occur. thus, classical descriptions of waves of fever arise from simultaneous waves of merozoites escaping and infecting red blood cells. some p. vivax sporozoites do not immediately develop into exoerythrocytic-phase merozoites, but instead, produce hypnozoites that remain dormant for periods ranging from several months (7–10 months is typical) to several years. after a period of dormancy, they reactivate and produce merozoites. hypnozoites are responsible for long incubation and late relapses in p. vivax infections, although their existence in p. ovale is uncertain. the parasite is relatively protected from attack by the body's immune system because for most of its human life cycle it resides within the liver and blood cells and is relatively invisible to immune surveillance. however, circulating infected blood cells are destroyed in the spleen. to avoid this fate, the p. falciparum parasite displays adhesive proteins on the surface of the infected blood cells, causing the blood cells to stick to the walls of small blood vessels, thereby sequestering the parasite from passage through the general circulation and the spleen. the blockage of the microvasculature causes symptoms such as those in placental malaria. sequestered red blood cells can breach the blood–brain barrier and cause cerebral malaria. genetic resistance main article: human genetic resistance to malaria according to a 2005 review, due to the high levels of mortality and morbidity caused by malaria—especially the p. falciparum species—it has placed the greatest selective pressure on the human genome in recent history. several genetic factors provide some resistance to it including sickle cell trait, thalassaemia traits, glucose-6-phosphate dehydrogenase deficiency, and the absence of duffy antigens on red blood cells. the impact of sickle cell trait on malaria immunity illustrates some evolutionary trade-offs that have occurred because of endemic malaria. sickle cell trait causes a change in the haemoglobin molecule in the blood. normally, red blood cells have a very flexible, biconcave shape that allows them to move through narrow capillaries; however, when the modified haemoglobin s molecules are exposed to low amounts of oxygen, or crowd together due to dehydration, they can stick together forming strands that cause the cell to distort into a curved sickle shape. in these strands, the molecule is not as effective in taking or releasing oxygen, and the cell is not flexible enough to circulate freely. in the early stages of malaria, the parasite can cause infected red cells to sickle, and so they are removed from circulation sooner. this reduces the frequency with which malaria parasites complete their life cycle in the cell. individuals who are homozygous (with two copies of the abnormal haemoglobin beta allele) have sickle-cell anaemia, while those who are heterozygous (with one abnormal allele and one normal allele) experience resistance to malaria without severe anaemia. although the shorter life expectancy for those with the homozygous condition would tend to disfavour the trait's survival, the trait is preserved in malaria-prone regions because of the benefits provided by the heterozygous form. liver dysfunction liver dysfunction as a result of malaria is uncommon and usually only occurs in those with another liver condition such as viral hepatitis or chronic liver disease. the syndrome is sometimes called malarial hepatitis. while it has been considered a rare occurrence, malarial hepatopathy has seen an increase, particularly in southeast asia and india. liver compromise in people with malaria correlates with a greater likelihood of complications and death. diagnosis main article: diagnosis of malaria the blood film is the gold standard for malaria diagnosis. ring-forms and gametocytes of plasmodium falciparum in human blood due to the non-specific nature of malaria symptoms, diagnosis is typically suspected based on symptoms and travel history, then confirmed with a laboratory test to detect the presence of the parasite in the blood (parasitological test). in areas where malaria is common, the world health organization (who) recommends clinicians suspect malaria in any person who reports having fevers, or who has a current temperature above 37.5 °c without any other obvious cause. malaria should be suspected in children with signs of anemia: pale palms or a laboratory test showing hemoglobin levels below 8 grams per deciliter of blood. in areas of the world with little to no malaria, the who recommends only testing people with possible exposure to malaria (typically travel to a malaria-endemic area) and unexplained fever. malaria is usually confirmed by the microscopic examination of blood films or by antigen-based rapid diagnostic tests (rdt). microscopy – i.e. examining giemsa-stained blood with a light microscope – is the gold standard for malaria diagnosis. microscopists typically examine both a "thick film" of blood, allowing them to scan many blood cells in a short time, and a "thin film" of blood, allowing them to clearly see individual parasites and identify the infecting plasmodium species. under typical field laboratory conditions, a microscopist can detect parasites when there are at least 100 parasites per microliter of blood, which is around the lower range of symptomatic infection. microscopic diagnosis is relatively resource intensive, requiring trained personnel, specific equipment, electricity, and a consistent supply of microscopy slides and stains. in places where microscopy is unavailable, malaria is diagnosed with rdts, rapid antigen tests that detect parasite proteins in a fingerstick blood sample. a variety of rdts are commercially available, targeting the parasite proteins histidine rich protein 2 (hrp2, detects p. falciparum only), lactate dehydrogenase, or aldolase. the hrp2 test is widely used in africa, where p. falciparum predominates. however, since hrp2 persists in the blood for up to five weeks after an infection is treated, an hrp2 test sometimes cannot distinguish whether someone currently has malaria or previously had it. additionally, some p. falciparum parasites in the amazon region lack the hrp2 gene, complicating detection. rdts are fast and easily deployed to places without full diagnostic laboratories. however they give considerably less information than microscopy, and sometimes vary in quality from producer to producer and lot to lot. serological tests to detect antibodies against plasmodium from the blood have been developed, but are not used for malaria diagnosis due to their relatively poor sensitivity and specificity. highly sensitive nucleic acid amplification tests have been developed, but are not used clinically due to their relatively high cost, and poor specificity for active infections. classification malaria is classified into either "severe" or "uncomplicated" by the world health organization (who). it is deemed severe when any of the following criteria are present, otherwise it is considered uncomplicated. decreased consciousness significant weakness such that the person is unable to walk inability to feed two or more convulsions low blood pressure (less than 70 mmhg in adults and 50 mmhg in children) breathing problems circulatory shock kidney failure or haemoglobin in the urine bleeding problems, or hemoglobin less than 50 g/l (5 g/dl) pulmonary oedema blood glucose less than 2.2 mmol/l (40 mg/dl) acidosis or lactate levels of greater than 5 mmol/l a parasite level in the blood of greater than 100,000 per microlitre (μl) in low-intensity transmission areas, or 250,000 per μl in high-intensity transmission areas cerebral malaria is defined as a severe p. falciparum-malaria presenting with neurological symptoms, including coma (with a glasgow coma scale less than 11, or a blantyre coma scale less than 3), or with a coma that lasts longer than 30 minutes after a seizure. prevention an anopheles stephensi mosquito shortly after obtaining blood from a human (the droplet of blood is expelled as a surplus). this mosquito is a vector of malaria, and mosquito control is an effective way of reducing its incidence. methods used to prevent malaria include medications, mosquito elimination and the prevention of bites. as of 2022, there is one vaccine for malaria (known as rts,s) which is licensed for use. the presence of malaria in an area requires a combination of high human population density, high anopheles mosquito population density and high rates of transmission from humans to mosquitoes and from mosquitoes to humans. if any of these is lowered sufficiently, the parasite eventually disappears from that area, as happened in north america, europe, and parts of the middle east. however, unless the parasite is eliminated from the whole world, it could re-establish if conditions revert to a combination that favors the parasite's reproduction. furthermore, the cost per person of eliminating anopheles mosquitoes rises with decreasing population density, making it economically unfeasible in some areas. prevention of malaria may be more cost-effective than treatment of the disease in the long run, but the initial costs required are out of reach of many of the world's poorest people. there is a wide difference in the costs of control (i.e. maintenance of low endemicity) and elimination programs between countries. for example, in china—whose government in 2010 announced a strategy to pursue malaria elimination in the chinese provinces—the required investment is a small proportion of public expenditure on health. in contrast, a similar programme in tanzania would cost an estimated one-fifth of the public health budget. in 2021, the world health organization confirmed that china has eliminated malaria. in areas where malaria is common, children under five years old often have anaemia, which is sometimes due to malaria. giving children with anaemia in these areas preventive antimalarial medication improves red blood cell levels slightly but does not affect the risk of death or need for hospitalisation. mosquito control further information: mosquito control man spraying kerosene oil in standing water, panama canal zone, 1912 vector control refers to methods used to decrease malaria by reducing the levels of transmission by mosquitoes. for individual protection, the most effective insect repellents are based on deet or picaridin. however, there is insufficient evidence that mosquito repellents can prevent malaria infection. insecticide-treated nets (itns) and indoor residual spraying (irs) are effective, have been commonly used to prevent malaria, and their use has contributed significantly to the decrease in malaria in the 21st century. itns and irs may not be sufficient to eliminate the disease, as these interventions depend on how many people use nets, how many gaps in insecticide there are (low coverage areas), if people are not protected when outside of the home, and an increase in mosquitoes that are resistant to insecticides. modifications to people's houses to prevent mosquito exposure may be an important long term prevention measure. walls where indoor residual spraying of ddt has been applied. the mosquitoes remain on the wall until they fall down dead on the floor. insecticide-treated nets a mosquito net in use. mosquito nets help keep mosquitoes away from people and reduce infection rates and transmission of malaria. nets are not a perfect barrier and are often treated with an insecticide designed to kill the mosquito before it has time to find a way past the net. insecticide-treated nets (itns) are estimated to be twice as effective as untreated nets and offer greater than 70% protection compared with no net. between 2000 and 2008, the use of itns saved the lives of an estimated 250,000 infants in sub-saharan africa. about 13% of households in sub-saharan countries owned itns in 2007 and 31% of african households were estimated to own at least one itn in 2008. in 2000, 1.7 million (1.8%) african children living in areas of the world where malaria is common were protected by an itn. that number increased to 20.3 million (18.5%) african children using itns in 2007, leaving 89.6 million children unprotected and to 68% african children using mosquito nets in 2015. most nets are impregnated with pyrethroids, a class of insecticides with low toxicity. they are most effective when used from dusk to dawn. it is recommended to hang a large "bed net" above the center of a bed and either tuck the edges under the mattress or make sure it is large enough such that it touches