Severe Malaria

Malaria is a mosquito-borne infectious disease that affects vertebrates and ''Anopheles'' mosquitoes. Human malaria causes symptoms that typically include fever, fatigue, vomiting, and headaches. In severe cases, it can cause jaundice, seizures, coma, or death. Symptoms usually begin 10 to 15 days after being bitten by an infected ''Anopheles'' mosquito. If not properly treated, people may have recurrences of the disease months later. In those who have recently survived an infection, reinfection usually causes milder symptoms. This partial resistance disappears over months to years if the person has no continuing exposure to malaria. The mosquitoes themselves are harmed by malaria, causing reduced lifespans in those infected by it.

Malaria is caused by single-celled microorganisms of the genus ''Plasmodium''. It is spread exclusively through bites of infected female ''Anopheles'' mosquitoes. The mosquito bite introduces the parasites from the mosquito's saliva into the blood. The parasites travel to the liver, where they mature and reproduce. Five species of ''Plasmodium'' commonly infect humans. The three species associated with more severe cases are '' P. falciparum'' (which is responsible for the vast majority of malaria deaths), '' P. vivax'', and '' P. knowlesi'' (a simian malaria that spills over into thousands of people a year). '' P. ovale'' and '' P. malariae'' generally cause a milder form of malaria. Malaria is typically diagnosed by the microscopic examination of blood using blood films, or with antigen-based rapid diagnostic tests. Methods that use the polymerase chain reaction to detect the parasite's DNA have been developed, but they are not widely used in areas where malaria is common, due to their cost and complexity.

The risk of disease can be reduced by preventing mosquito bites through the use of mosquito nets and insect repellents or with mosquito-control measures such as spraying insecticides and draining standing water. Several medications are available to prevent malaria for travellers in areas where the disease is common. Occasional doses of the combination medication sulfadoxine/pyrimethamine are recommended in infants and after the first trimester of pregnancy in areas with high rates of malaria. As of 2023, two malaria vaccines have been endorsed by the World Health Organization. The recommended treatment for malaria is a combination of antimalarial medications that includes artemisinin. The second medication may be either mefloquine (noting first its potential toxicity and the possibility of death), lumefantrine, or sulfadoxine/pyrimethamine. Quinine, along with doxycycline, may be used if artemisinin is not available. In areas where the disease is common, malaria should be confirmed if possible before treatment is started due to concerns of increasing drug resistance. Resistance among the parasites has developed to several antimalarial medications; for example, chloroquine-resistant ''P. falciparum'' has spread to most malaria-prone areas, and resistance to artemisinin has become a problem in some parts of Southeast Asia.

The disease is widespread in the tropical and subtropical regions that exist in a broad band around the equator. This includes much of sub-Saharan Africa, Asia, and Latin America. In 2023, some 263 million cases of malaria worldwide resulted in an estimated 597,000 deaths. Around 95% of the cases and deaths occurred in sub-Saharan Africa. Rates of disease decreased from 2010 to 2014, but increased from 2015 to 2021. According to UNICEF, nearly every minute, a child under five died of malaria in 2021, and "many of these deaths are preventable and treatable". Malaria is commonly associated with poverty and has a significant negative effect on economic development. In Africa, it is estimated to result in losses of US$12 billion a year due to increased healthcare costs, lost ability to work, and adverse effects on tourism. The malaria caseload in India was slashed by 69 per cent from 6.4 million (64 lakh) in 2017 to two million (20 lakh) in 2023. Similarly, the estimated malaria deaths decreased from 11,100 to 3,500 (a 68-per cent decrease) in the same period.

Etymology

The term ''malaria'' originates from Medieval 'bad air', a part of miasma theory; the disease was formerly called ''ague'' or ''marsh fever'' due to its association with swamps and marshland. The term appeared in English at least as early as 1768. Malaria was once common in most of Europe and North America, where it is no longer endemic, though imported cases do occur.
The scientific study of malaria is called malariology.

Signs and symptoms

Adults with malaria tend to experience chills and fever—classically in periodic intense bouts lasting around six hours, followed by a period of sweating and fever relief—as well as headache, fatigue, abdominal discomfort, and muscle pain. Children tend to have more general symptoms: fever, cough, vomiting, and diarrhea.

Initial manifestations of the disease—common to infection with all malaria parasite species—are similar to flu-like symptoms, and can resemble other conditions such as sepsis, gastroenteritis, and viral diseases. The presentation may include headache, fever, shivering, joint pain, vomiting, hemolytic anemia, jaundice, hemoglobin in the urine, retinal damage, and convulsions.

The classic symptom of malaria is paroxysm—a cyclical occurrence of sudden coldness followed by shivering and then fever and sweating, occurring every two days ( tertian fever) in ''P. vivax'' and ''P. ovale'' infections, and every three days ( quartan fever) for ''P. malariae''. ''P. falciparum'' infection can cause recurrent fever every 36–48 hours, or a less pronounced and almost continuous fever.

Symptoms typically begin 10–15 days after the initial mosquito bite, but can occur as late as several months after infection with some ''P. vivax'' strains. Travellers taking preventative malaria medications may develop symptoms once they stop taking the drugs.

Severe malaria is usually caused by ''P. falciparum'' (often referred to as falciparum malaria). Symptoms of falciparum malaria arise 9–30 days after infection. Individuals with cerebral malaria frequently exhibit neurological symptoms, including abnormal posturing, nystagmus, conjugate gaze palsy (failure of the eyes to turn together in the same direction), opisthotonus, seizures, or coma.

Complications

Malaria has several serious complications, including the development of respiratory distress, which occurs in up to 25% of adults and 40% of children with severe ''P. falciparum'' malaria. Possible causes include respiratory compensation of metabolic acidosis, noncardiogenic pulmonary oedema, concomitant pneumonia, and severe anaemia. Although rare in young children with severe malaria, acute respiratory distress syndrome occurs in 5–25% of adults and up to 29% of pregnant women. Coinfection of HIV with malaria increases mortality. Kidney failure is a feature of blackwater fever, where haemoglobin from lysed red blood cells leaks into the urine.

Infection with ''P. falciparum'' may result in cerebral malaria, a form of severe malaria that involves encephalopathy. It is associated with retinal whitening, which may be a useful clinical sign in distinguishing malaria from other causes of fever. An enlarged spleen, enlarged liver or both of these, severe headache, low blood sugar, and haemoglobin in the urine with kidney failure may occur. Complications may include spontaneous bleeding, coagulopathy, and shock.

Cerebral malaria can bring about death within forty-eight hours of the first symptoms of the infection being evident.

Malaria during pregnancy can cause stillbirths, infant mortality, miscarriage, and low birth weight, particularly in ''P. falciparum'' infection, but also with ''P. vivax''.

Cause

Malaria is caused by infection with parasites in the genus ''Plasmodium''. In humans, malaria is caused by six ''Plasmodium'' species: '' P. falciparum'', '' P. malariae'', '' P. ovale curtisi'', '' P. ovale wallikeri'', '' P. vivax'' and '' P. knowlesi''. Among those infected, ''P. falciparum'' is the most common species identified (~75%) followed by ''P. vivax'' (~20%). Although ''P. falciparum'' traditionally accounts for the majority of deaths, recent evidence suggests that ''P. vivax'' malaria is associated with potentially life-threatening conditions about as often as with a diagnosis of ''P. falciparum'' infection. ''P. vivax'' proportionally is more common outside Africa. Some cases have been documented of human infections with several species of ''Plasmodium'' from higher apes, but except for ''P. knowlesi''—a zoonotic species that causes malaria in macaques—these are mostly of limited public health importance.

The ''Anopheles'' mosquitos initially get infected by ''Plasmodium'' by taking a blood meal from a previously ''Plasmodium'' infected person or animal. Parasites are then typically introduced by the bite of an infected ''Anopheles'' mosquito. Some of these inoculated parasites, called "sporozoites", probably remain in the skin, but others travel in the bloodstream to the liver, where they invade hepatocytes. They grow and divide in the liver for 2–10 days, with each infected hepatocyte eventually harboring up to 40,000 parasites. The infected hepatocytes break down, releasing these invasive ''Plasmodium'' cells, called "merozoites", into the bloodstream. In the blood, the merozoites rapidly invade individual red blood cells, replicating over 24–72 hours to form 16–32 new merozoites. The infected red blood cell lyses, and the new merozoites infect new red blood cells, resulting in a cycle that continuously amplifies the number of parasites in an infected person. Over rounds of this infection cycle, a small portion of parasites do not replicate, but instead develop into early sexual stage parasites called male and female "gametocytes". These gametocytes develop in the bone marrow for 11 days, then return to the blood circulation to await uptake by the bite of another mosquito. Once inside a mosquito, the gametocytes undergo sexual reproduction, and eventually form daughter sporozoites that migrate to the mosquito's salivary glands to be injected into a new host when the mosquito bites.

The liver infection causes no symptoms; all symptoms of malaria result from the infection of red blood cells. Symptoms develop once there are more than around 100,000 parasites per milliliter of blood. Many of the symptoms associated with severe malaria are caused by the tendency of ''P. falciparum'' to bind to blood vessel walls, resulting in damage to the affected vessels and surrounding tissue. Parasites sequestered in the blood vessels of the lung contribute to respiratory failure. In the brain, they contribute to coma. In the placenta they contribute to low birthweight and preterm labor, and increase the risk of abortion and stillbirth. The destruction of red blood cells during infection often results in anemia, exacerbated by reduced production of new red blood cells during infection.

Only female mosquitoes feed on blood; male mosquitoes feed on plant nectar and do not transmit the disease. Females of the mosquito genus ''Anopheles'' prefer to feed at night. They usually start searching for a meal at dusk, and continue through the night until they succeed. However, in Africa, due to the extensive use of bed nets, they began to bite earlier, before bed-net time. Malaria parasites can also be transmitted by blood transfusions, although this is rare.

Recurrent malaria

Symptoms of malaria can recur after varying symptom-free periods. Depending upon the cause, recurrence can be classified as either recrudescence, relapse, or reinfection. Recrudescence is when symptoms return after a symptom-free period due to failure to remove blood-stage parasites by adequate treatment. Relapse is when symptoms reappear after the parasites have been eliminated from the blood but have persisted as dormant hypnozoites in liver cells. Relapse commonly occurs between 8 and 24 weeks after the initial symptoms and is often seen in ''P. vivax'' and ''P. ovale'' infections. ''P. vivax'' malaria cases in temperate areas often involve overwintering by hypnozoites, with relapses beginning the year after the mosquito bite. Reinfection means that parasites were eliminated from the entire body but new parasites were then introduced. Reinfection cannot readily be distinguished from relapse and recrudescence, although recurrence of infection within two weeks of treatment ending is typically attributed to treatment failure. People may develop some immunity when exposed to frequent infections.

Pathophysiology

Malaria infection develops via two phases: one that involves the liver (exoerythrocytic phase), and one that involves red blood cells, or erythrocytes (erythrocytic phase). When an infected mosquito pierces a person's skin to take a blood meal, sporozoites in the mosquito's saliva enter the bloodstream and migrate to the liver where they infect 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.

The parasites multiply asexually within red blood cells, periodically breaking out to infect new ones. This repeated cycle results in synchronized waves of merozoites escaping and invading red blood cells, which cause the characteristic fever patterns.

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

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 effect 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.

Effects on vaccine response

Malaria infection affects the immune responses following vaccination for various diseases. For example, malaria suppresses immune responses to polysaccharide vaccines. A potential solution is to give curative treatment before vaccination in areas where malaria is present.

Diagnosis

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.

In sub-Saharan Africa, testing is low, with only about one in four (28%) of children with a fever receiving medical advice or a rapid diagnostic test in 2021. There was a 10-percentage point gap in testing between the richest and the poorest children (33% vs 23%). Additionally, a greater proportion of children in Eastern and Southern Africa (36%) were tested than in West and Central Africa (21%). According to UNICEF, 61% of children with a fever were taken for advice or treatment from a health facility or provider in 2021. Disparities are also observed by wealth, with an 18 percentage point difference in care-seeking behaviour between children in the richest (71%) and the poorest (53%) households.

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 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. Some ''P. falciparum'' species also have genetic deletions of the genes coding for the HRP2 antigen; leading to possible false negative results. Rapid tests also cannot quantify the parasite burden in a person. 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 hemoglobin 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

Methods used to prevent malaria include medications, mosquito elimination and the prevention of bites. As of 2023, there are two malaria vaccines, approved for use in children by the WHO: RTS,S and R21. 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 2023, the World Health Organization confirmed that Azerbaijan, Tajikistan, and Belize have 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

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.

Insecticide-treated nets

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. According to UNICEF, only 36% of households had sufficient ITNs for all household members in 2019. 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. The percentage of children sleeping under ITNs in sub-Saharan Africa increased from less than 40% in 2011 to over 50% in 2021. 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 the ground. ITNs are beneficial towards pregnancy outcomes in malaria-endemic regions in Africa but more data is needed in Asia and Latin America.

In areas of high malaria resistance, piperonyl butoxide (PBO) combined with pyrethroids in mosquito netting is effective in reducing malaria infection rates. Questions remain concerning the durability of PBO on nets as the effect on mosquito mortality was not sustained after twenty washes in experimental trials.

UNICEF notes that the use of insecticide-treated nets has been increased since 2000 through accelerated production, procurement and delivery, stating that "over 2.5 billion ITNs have been distributed globally since 2004, with 87% (2.2 billion) distributed in sub-Saharan Africa. In 2021, manufacturers delivered about 220 million ITNs to malaria endemic countries, a decrease of 9 million ITNs compared with 2020 and 33 million less than were delivered in 2019". As of 2021, 66% of households in sub-Saharan Africa had ITNs, with figures "ranging from 31 per cent in Angola in 2016 to approximately 97 per cent in Guinea-Bissau in 2019". Slightly more than half of the households with an ITN had enough of them to protect all members of the household, however.

Indoor residual spraying

Indoor residual spraying is the spraying of insecticides on the walls inside a home. After feeding, many mosquitoes rest on a nearby surface while digesting the bloodmeal, so if the walls of houses have been coated with insecticides, the resting mosquitoes can be killed before they can bite another person and transfer the malaria parasite. As of 2006, the World Health Organization recommends 12 insecticides in IRS operations, including DDT and the pyrethroids cyfluthrin and deltamethrin. This public health use of small amounts of DDT is permitted under the Stockholm Convention, which prohibits its agricultural use. One problem with all forms of IRS is insecticide resistance. Mosquitoes affected by IRS tend to rest and live indoors, and due to the irritation caused by spraying, their descendants tend to rest and live outdoors, meaning that they are less affected by the IRS. Communities using insecticide treated nets, in addition to indoor residual spraying with 'non-pyrethroid-like' insecticides found associated reductions in malaria. Additionally, the use of 'pyrethroid-like' insecticides in addition to indoor residual spraying did not result in a detectable additional benefit in communities using insecticide treated nets.

Housing modifications

Housing is a risk factor for malaria and modifying the house as a prevention measure may be a sustainable strategy that does not rely on the effectiveness of insecticides such as pyrethroids. The physical environment inside and outside the home that may improve the density of mosquitoes are considerations. Examples of potential modifications include how close the home is to mosquito breeding sites, drainage and water supply near the home, availability of mosquito resting sites (vegetation around the home), the proximity to live stock and domestic animals, and physical improvements or modifications to the design of the home to prevent mosquitoes from entering, such as window screens.

In addition to installing window screens, house screening measures include screening ceilings, doors, and eaves. In 2021, the World Health Organization's (WHO) Guideline Development Group conditionally recommended screening houses in this manner to reduce malaria transmission. However, the WHO does point out that there are local considerations that need to be addressed when incorporating these techniques. These considerations include the delivery method, maintenance, house design, feasibility, resource needs, and scalability.

Several studies have suggested that screening houses can have a significant effect on malaria transmission. Beyond the protective barrier screening provides, it also does not call for daily behavioral changes in the household. Screening eaves can also have a community-level protective effect, ultimately reducing mosquito-biting densities in neighboring houses that do not have this intervention in place.

In some cases, studies have used insecticide-treated (e.g., transfluthrin) or untreated netting to deter mosquito entry. One widely used intervention is the In2Care BV EaveTube. In 2021, In2Care BV received funding from the United States Agency for International Development to develop a ventilation tube that would be installed in housing walls. When mosquitoes approach households, the goal is for them to encounter these EaveTubes instead. Inside these EaveTubes is insecticide-treated netting that is lethal to insecticide-resistant mosquitoes. This approach to mosquito control is called the Lethal House Lure method. The WHO is currently evaluating the efficacy of this product for widespread use.

Mass drug administration

Mass drug administration (MDA) involves the administration of drugs to the entire population of an area regardless of disease status. A subtype, known as seasonal malaria chemoproprophylaxis (or chemoprevention) involves giving those vulnerable to complications from malaria (such as young children under 5, or pregnant women) medications to prevent malaria. This may be done during certain seasons, where mosquitos are more likely to spread the disease. Malaria vaccination, when combined with seasonal chemoprevention has been shown to prevent more cases of malaria compared to vaccination alone.

A 2021 Cochrane review on the use of community administration of ivermectin found that, to date, low quality evidence shows no significant effect on reducing incidence of malaria transmission from the community administration of ivermectin.

Mosquito-targeted drug delivery

One potential way to reduce the burden of malaria is to target the infection in mosquitoes, before it enters the mammalian host (during sporogeny). Drugs may be used for this purpose which have unacceptable toxicity profiles in humans. For example, aminoquinoline derivates show toxicity in humans, but this has not been shown in mosquitoes. Primaquine is particularly effective against ''Plasmodium'' gametocytes. Likewise, pyrroloquinazolinediamines show unacceptable toxicity in mammals, but it is unknown whether this is the case in mosquitoes. Pyronaridine, thiostrepton, and pyrimethamine have been shown to dramatically reduce ookinete formation in ''P. berghei'', while artefenomel, NPC-1161B, and tert-butyl isoquine reduce exflagellation in ''P. Falciparum''.

Other mosquito control methods

People have tried a number of other methods to reduce mosquito bites and slow the spread of malaria. Efforts to decrease mosquito larvae by decreasing the availability of open water where they develop, or by adding substances to decrease their development, are effective in some locations. Electronic mosquito repellent devices, which make very high-frequency sounds that are supposed to keep female mosquitoes away, have no supporting evidence of effectiveness. There is a low certainty evidence that fogging may have an effect on malaria transmission. Larviciding by hand delivery of chemical or microbial insecticides into water bodies containing low larval distribution may reduce malarial transmission. There is insufficient evidence to determine whether larvivorous fish can decrease mosquito density and transmission in the area.

Medications

There are a number of medications that can help prevent or interrupt malaria in travellers to places where infection is common. Many of these medications are also used in treatment. In places where ''Plasmodium'' is resistant to one or more medications, three medications— mefloquine, doxycycline, or the combination of atovaquone/proguanil (''Malarone'')—are frequently used for prevention. Doxycycline and the atovaquone/proguanil are better tolerated while mefloquine is taken once a week. Areas of the world with chloroquine-sensitive malaria are uncommon. Antimalarial mass drug administration to an entire population at the same time may reduce the risk of contracting malaria in the population, however the effectiveness of mass drug administration may vary depending on the prevalence of malaria in the area. Other factors such as drug administration plus other protective measures such as mosquito control, the proportion of people treated in the area, and the risk of reinfection with malaria may play a role in the effectiveness of mass drug treatment approaches.

The protective effect does not begin immediately, and people visiting areas where malaria exists usually start taking the drugs one to two weeks before they arrive, and continue taking them for four weeks after leaving (except for atovaquone/proguanil, which only needs to be started two days before and continued for seven days afterward). The use of preventive drugs is often not practical for those who live in areas where malaria exists, and their use is usually given only to pregnant women and short-term visitors. This is due to the cost of the drugs, side effects from long-term use, and the difficulty in obtaining antimalarial drugs outside of wealthy nations. During pregnancy, medication to prevent malaria has been found to improve the weight of the baby at birth and decrease the risk of anaemia in the mother. The use of preventive drugs where malaria-bearing mosquitoes are present may encourage the development of partial resistance.

Giving antimalarial drugs to infants through intermittent preventive therapy can reduce the risk of having malaria infection, hospital admission, and anaemia.

Mefloquine is more effective than sulfadoxine-pyrimethamine in preventing malaria for HIV-negative pregnant women. Cotrimoxazole is effective in preventing malaria infection and reduce the risk of getting anaemia in HIV-positive women. Giving Dihydroartemisinin/piperaquine and mefloquine in addition to the daily cotrimoxazole to HIV-positive pregnant women seem to be more efficient in preventing malaria infection than cotrimoxazole alone.

Prompt treatment of confirmed cases with artemisinin-based combination therapies (ACTs) may also reduce transmission.

Research on malaria vaccines

Malaria vaccines have been another goal of research. The first promising studies demonstrating the potential for a malaria vaccine were performed in 1967 by immunising mice with live, radiation- attenuated sporozoites, which provided significant protection to the mice upon subsequent injection with normal, viable sporozoites. Since the 1970s, there has been considerable progress in developing similar vaccination strategies for humans.

In 2013, WHO and the malaria vaccine funders group set a goal to develop vaccines designed to interrupt malaria transmission with malaria eradication's long-term goal. The first vaccine, called RTS,S, was approved by European regulators in 2015. As of 2023, two malaria vaccines have been licensed for use. Other approaches to combat malaria may require investing more in research and greater primary health care. Continuing surveillance will also be important to prevent the return of malaria in countries where the disease has been eliminated.

As of 2019 it is undergoing pilot trials in 3 sub-Saharan African countries—Ghana, Kenya and Malawi—as part of the WHO's Malaria Vaccine Implementation Programme (MVIP).

Immunity (or, more accurately, tolerance) to ''P. falciparum'' malaria does occur naturally, but only in response to years of repeated infection. An individual can be protected from a ''P. falciparum'' infection if they receive about a thousand bites from mosquitoes that carry a version of the parasite rendered non-infective by a dose of X-ray irradiation. The highly polymorphic nature of many ''P. falciparum'' proteins results in significant challenges to vaccine design. Vaccine candidates that target antigens on gametes, zygotes, or ookinetes in the mosquito midgut aim to block the transmission of malaria. These transmission-blocking vaccines induce antibodies in the human blood; when a mosquito takes a blood meal from a protected individual, these antibodies prevent the parasite from completing its development in the mosquito. Other vaccine candidates, targeting the blood-stage of the parasite's life cycle, have been inadequate on their own. For example, SPf66 was tested extensively in areas where the disease was common in the 1990s, but trials showed it to be insufficiently effective.

As of 2020, the RTS,S vaccine has been shown to reduce the risk of malaria by about 40% in children in Africa. A preprint study of the R21 vaccine has shown 77% vaccine efficacy.

In 2021, researchers from the University of Oxford reported findings from a Phase IIb trial of a candidate malaria vaccine, R21/Matrix-M, which demonstrated efficacy of 77% over 12-months of follow-up. This vaccine is the first to meet the World Health Organization's Malaria Vaccine Technology Roadmap goal of a vaccine with at least 75% efficacy.

Germany-based BioNTECH SE is developing an mRNA-based malaria vaccine BNT165 which has recently initiated a Phase 1 study linicaltrials.gov identifier: NCT05581641in December 2022. The vaccine, based on the circumsporozoite protein (CSP) is being tested in adults aged 18–55 yrs at 3 dose levels to select a safe and tolerable dose of a three-dose schedule. Unlike GSK's RTS,S (AS01) and Serum Institute of India's R21/MatrixM, BNT-165 is being studied in adult age groups meaning it could be developed for Western travelers as well as those living in endemic countries. For the travelers profile, a recent commercial assessment forecast potential gross revenues of BNT-165 at $479m (2030) 5-yrs post launch, POS-adjusted revenues.

Others

Community participation and health education strategies promoting awareness of malaria and the importance of control measures have been successfully used to reduce the incidence of malaria in some areas of the developing world. Recognising the disease in the early stages can prevent it from becoming fatal. Education can also inform people to cover over areas of stagnant, still water, such as water tanks that are ideal breeding grounds for the parasite and mosquito, thus cutting down the risk of the transmission between people. This is generally used in urban areas where there are large centers of population in a confined space and transmission would be most likely in these areas. Intermittent preventive therapy is another intervention that has been used successfully to control malaria in pregnant women and infants, and in preschool children where transmission is seasonal.

Treatment

Malaria is treated with antimalarial medications; the ones used depend on the type and severity of the disease. While medications against fever are commonly used, their effects on outcomes are not clear. Providing free antimalarial drugs to households may reduce childhood deaths when used appropriately. Programmes which presumptively treat all causes of fever with antimalarial drugs may lead to overuse of antimalarials and undertreat other causes of fever. Nevertheless, the use of malaria rapid-diagnostic kits can help to reduce over-usage of antimalarials.

Uncomplicated malaria

Simple or uncomplicated malaria may be treated with oral medications. Artemisinin drugs are effective and safe in treating uncomplicated malaria. Artemisinin in combination with other antimalarials (known as artemisinin-combination therapy, or ACT) is about 90% effective when used to treat uncomplicated malaria. The most effective treatment for ''P. falciparum'' infection is the use of ACT, which decreases resistance to any single drug component. Artemether-lumefantrine (six-dose regimen) is more effective than the artemether-lumefantrine (four-dose regimen) or other regimens not containing artemisinin derivatives in treating falciparum malaria. Another recommended combination is dihydroartemisinin and piperaquine. Artemisinin-naphthoquine combination therapy showed promising results in treating falciparum malaria but more research is needed to establish its efficacy as a reliable treatment. Artesunate plus mefloquine performs better than mefloquine alone in treating uncomplicated falciparum malaria in low transmission settings. Atovaquone-proguanil is effective against uncomplicated falciparum with a possible failure rate of 5% to 10%; the addition of artesunate may reduce failure rate. Azithromycin monotherapy or combination therapy has not shown effectiveness in treating ''Plasmodium falciparum'' or ''Plasmodium vivax'' malaria. Amodiaquine plus sulfadoxine-pyrimethamine may achieve less treatment failures when compared to sulfadoxine-pyrimethamine alone in uncomplicated falciparum malaria. There is insufficient data on chlorproguanil-dapsone in treating uncomplicated falciparum malaria. The addition of primaquine with artemisinin-based combination therapy for falciparum malaria reduces its transmission at day 3–4 and day 8 of infection. Sulfadoxine-pyrimethamine plus artesunate is better than sulfadoxine-pyrimethamine plus amodiaquine in controlling treatment failure at day 28. However, the latter is better than the former in reducing gametocytes in blood at day 7.

Infection with ''P. vivax'', ''P. ovale'' or ''P. malariae'' usually does not require hospitalisation. Treatment of ''P. vivax'' malaria requires both elimination of the parasite in the blood with chloroquine or with artemisinin-based combination therapy and clearance of parasites from the liver with an 8-aminoquinoline agent such as primaquine or tafenoquine. These two drugs act against blood stages as well, the extent to which they do so still being under investigation.

To treat malaria during pregnancy, the WHO recommends the use of quinine plus clindamycin early in the pregnancy (1st trimester), and ACT in later stages (2nd and 3rd trimesters). There is limited safety data on the antimalarial drugs in pregnancy.

Severe and complicated malaria

Cases of severe and complicated malaria are almost always caused by infection with ''P. falciparum''. The other species usually cause only febrile disease. Severe and complicated malaria cases are medical emergencies since mortality rates are high (10% to 50%).

Recommended treatment for severe malaria is the intravenous use of antimalarial drugs. For severe malaria, parenteral artesunate was superior to quinine in both children and adults. In another systematic review, artemisinin derivatives (artemether and arteether) were as efficacious as quinine in the treatment of cerebral malaria in children. Treatment of severe malaria involves supportive measures that are best done in a critical care unit. This includes the management of high fevers and the seizures that may result from it. It also includes monitoring for poor breathing effort, low blood sugar, and low blood potassium. Artemisinin derivatives have the same or better efficacy than quinolones in preventing deaths in severe or complicated malaria. Quinine loading dose helps to shorten the duration of fever and increases parasite clearance from the body. There is no difference in effectiveness when using intrarectal quinine compared to intravenous or intramuscular quinine in treating uncomplicated/complicated falciparum malaria. There is insufficient evidence for intramuscular arteether to treat severe malaria. The provision of rectal artesunate before transfer to hospital may reduce the rate of death for children with severe malaria. In children with malaria and concomitant hypoglycaemia, sublingual administration of glucose appears to result in better increases in blood sugar after 20 minutes when compared to oral administration, based on very limited data.

Cerebral malaria is the form of severe and complicated malaria with the worst neurological symptoms. There is insufficient data on whether osmotic agents such as mannitol or urea are effective in treating cerebral malaria. Routine phenobarbitone in cerebral malaria is associated with fewer convulsions but possibly more deaths. There is no evidence that steroids would bring treatment benefits for cerebral malaria.

Managing cerebral malaria

Cerebral malaria usually makes a patient comatose. If the cause of the coma is in doubt, testing for other locally prevalent causes of encephalopathy (bacterial, viral or fungal infection) should be carried out. In areas where there is a high prevalence of malaria infection (e.g. tropical region) treatment can start without testing first. To manage the cerebral malaria when confirmed the following can be done:

* People who are in coma should be given meticulous nursing care ( monitor vital signs, turn patient every 2 hours, avoid lying the patient in a wet bed etc.)
* A sterile urethral catheter should be inserted to help with urinating
* To aspirate stomach content, a sterile nasogastric tube should be inserted.
* In the occasion of convulsions, a slow intravenous injection of benzodiazepine is administered.

There is insufficient evidence to show that blood transfusion is useful in either reducing deaths for children with severe anaemia or in improving their haematocrit in one month. There is insufficient evidence that iron chelating agents such as deferoxamine and deferiprone improve outcomes of those with malaria falciparum infection.

Monoclonal antibodies

A 2022 clinical trial shows that a monoclonal antibody mAb L9LS offers protection against malaria. It binds the ''Plasmodium falciparum'' circumsporozoite protein (CSP-1), essential to disease, and makes it ineffective.

Resistance

Drug resistance poses a growing problem in 21st-century malaria treatment. In the 2000s (decade), malaria with partial resistance to artemisins emerged in Southeast Asia. Resistance is now common against all classes of antimalarial drugs apart from artemisinins. Treatment of resistant strains became increasingly dependent on this class of drugs. The cost of artemisinins limits their use in the developing world. Malaria strains found on the Cambodia–Thailand border are resistant to combination therapies that include artemisinins, and may, therefore, be untreatable. Exposure of the parasite population to artemisinin monotherapies in subtherapeutic doses for over 30 years and the availability of substandard artemisinins likely drove the selection of the resistant phenotype. Resistance to artemisinin has been detected in Cambodia, Myanmar, Thailand, and Vietnam, and there has been emerging resistance in Laos. Resistance to the combination of artemisinin and piperaquine was first detected in 2013 in Cambodia, and by 2019 had spread across Cambodia and into Laos, Thailand and Vietnam (with up to 80 percent of malaria parasites resistant in some regions).

There is insufficient evidence in unit packaged antimalarial drugs in preventing treatment failures of malaria infection. However, if supported by training of healthcare providers and patient information, there is improvement in compliance of those receiving treatment.

Prognosis

When properly treated, people with malaria can usually expect a complete recovery. However, severe malaria can progress extremely rapidly and cause death within hours or days. In the most severe cases of the disease, fatality rates can reach 20%, even with intensive care and treatment. Over the longer term, developmental impairments have been documented in children who have had episodes of severe malaria. Chronic infection without severe disease can occur in an immune-deficiency syndrome associated with a decreased responsiveness to ''Salmonella'' bacteria and the Epstein–Barr virus.

During childhood, malaria causes anaemia during a period of rapid brain development, and also direct brain damage resulting from cerebral malaria. Some survivors of cerebral malaria have an increased risk of neurological and cognitive deficits, behavioural disorders, and epilepsy. Malaria prophylaxis was shown to improve cognitive function and school performance in clinical trials when compared to placebo groups.

Epidemiology

The WHO estimates that in 2021 there were 247 million total cases of malaria resulting in 619,000 deaths. Children under five years old are the most affected, accounting for 67% of malaria deaths worldwide in 2019. About 125 million pregnant women are at risk of infection each year; in Sub-Saharan Africa, maternal malaria is associated with up to 200,000 estimated infant deaths yearly. Since 2015, the WHO European Region has been free of malaria. The last country to report an indigenous malaria case was Tajikistan in 2014. There are about 1300–1500 malaria cases per year in the United States. The United States eradicated malaria as a major public health concern in 1951, though small outbreaks persist. Locally acquired mosquito-borne malaria occurred in the United States in 2003, when eight cases of locally acquired ''P. vivax'' malaria were identified in Florida, and again in May 2023, in four cases, as well as one case in Texas, and in August in one case in Maryland. About 900 people died from the disease in Europe between 1993 and 2003. Both the global incidence of disease and resulting mortality have declined in recent years. According to the WHO and UNICEF, deaths attributable to malaria in 2015 were reduced by 60% from a 2000 estimate of 985,000, largely due to the widespread use of insecticide-treated nets and artemisinin-based combination therapies. Between 2000 and 2019, malaria mortality rates among all ages halved from about 30 to 13 per 100,000 population at risk. During this period, malaria deaths among children under five also declined by nearly half (47%) from 781,000 in 2000 to 416,000 in 2019.

Malaria is presently endemic in a broad band around the equator, in areas of the Americas, many parts of Asia, and much of Africa. Eighty-five to ninety percent of malaria fatalities occur in Sub-Saharan Africa. An estimate for 2009 reported that countries with the highest death rate per 100,000 of population were Ivory Coast (86.15), Angola (56.93) and Burkina Faso (50.66). A 2010 estimate indicated the deadliest countries per population were Burkina Faso, Mozambique and Mali. The Malaria Atlas Project aims to map global levels of malaria, providing a way to determine the global spatial limits of the disease and to assess disease burden. This effort led to the publication of a map of ''P. falciparum'' endemicity in 2010 and an update in 2019. As of 2021, 84 countries have endemic malaria.

The geographic distribution of malaria within large regions is complex, and malaria-afflicted and malaria-free areas are often found close to each other. Malaria is prevalent in tropical and subtropical regions because of rainfall, consistent high temperatures and high humidity, along with stagnant waters where mosquito larvae readily mature, providing them with the environment they need for continuous breeding. In drier areas, outbreaks of malaria have been predicted with reasonable accuracy by mapping rainfall. Malaria is more common in rural areas than in cities. For example, several cities in the Greater Mekong Subregion of Southeast Asia are essentially malaria-free, but the disease is prevalent in many rural regions, including along international borders and forest fringes. In contrast, malaria in Africa is present in both rural and urban areas, though the risk is lower in the larger cities.

According to the World Health Organization's 2023 World Malaria Report, there were an estimated 263 million malaria cases globally in 2023, up from 252 million in 2022. The number of malaria deaths stood at 597,000 in 2023, a slight decrease from 600,000 in 2022. The African region continues to bear a disproportionate share of the global malaria burden, accounting for approximately 94% of all cases and 95% of deaths.

Climate change

Climate change is likely to affect malaria transmission, but the degree of effect and the areas affected is uncertain. Greater rainfall in certain areas of India, and following an El Niño event is associated with increased mosquito numbers.

Since 1900 there has been substantial change in temperature and rainfall over Africa. However, factors that contribute to how rainfall results in water for mosquito breeding are complex, incorporating the extent to which it is absorbed into soil and vegetation for example, or rates of runoff and evaporation. Recent research has provided a more in-depth picture of conditions across Africa, combining a malaria climatic suitability model with a continental-scale model representing real-world hydrological processes.

Changes in geographic distribution

Climate change has led to shifts in malaria-endemic regions, with the disease expanding into higher altitudes and previously malaria-free areas.
Rising temperatures allow mosquitoes to survive in regions that were once too cold for them, including highland areas in Africa, South America, and parts of Asia.
A study analyzing malaria cases in Ethiopian and Colombian highlands found a strong correlation between increased temperatures and malaria incidence, demonstrating that climate change has made previously inhospitable areas suitable for transmission.

Increased transmission season

Malaria transmission is highly sensitive to temperature and rainfall patterns. Climate change has led to longer transmission seasons in tropical regions, where mosquitoes can breed year-round due to prolonged periods of high humidity and warm temperatures. Research suggests that in parts of sub-Saharan Africa, the malaria transmission season has lengthened by several months, particularly in regions where warming has pushed temperatures into the optimal range for ''Plasmodium falciparum'' development. In regions such as West Africa and parts of India, increasing temperatures and prolonged rainy seasons have contributed to a rise in malaria cases. Some studies predict that by 2050, many malaria-endemic areas will experience a 20–30% increase in transmission duration due to warming trends.

Effects of extreme weather events

Extreme weather events, such as heavy rainfall, flooding, and droughts, are increasing in frequency and intensity due to climate change, creating favorable conditions for malaria outbreaks. Flooding provides ideal breeding grounds for mosquitoes by forming stagnant water pools, while droughts can also exacerbate malaria by forcing human populations to store water in open containers, which serve as mosquito habitats. This effect has been observed in parts of sub-Saharan Africa and South Asia, where prolonged drought periods were followed by spikes in malaria cases. A review of malaria outbreaks linked to climate variability found that El Niño events, which increase rainfall and temperatures in malaria-endemic regions, have been associated with significant surges in cases.

Resistance and adaptation of vectors

Higher temperatures accelerate the development of ''Plasmodium'' parasites within mosquitoes, potentially leading to increased transmission efficiency. Additionally, rising temperatures and changing environmental conditions have been linked to the spread of insecticide resistance in mosquito populations, complicating malaria control efforts. A global survey found that ''Anopheles'' mosquitoes in Africa, Asia, and South America have developed increased resistance to commonly used insecticides such as pyrethroids.

Urbanization and malaria trends

Urbanization has a great effect on malaria. There are better healthcare and infrastructure in the cities which then reduce malaria. Whereas poorer areas with bad sanitation allow mosquitoes to thrive which then increase malaria. Some African cities have more malaria cases compared to suburban areas. In Bangkok, it has been shown that malaria has dropped due to better control.

History

Although the parasite responsible for ''P. falciparum'' malaria has been in existence for 50,000–100,000 years, the population size of the parasite did not increase until about 10,000 years ago, concurrently with advances in agriculture and the development of human settlements. Close relatives of the human malaria parasites remain common in chimpanzees. Some evidence suggests that the ''P. falciparum'' malaria may have originated in gorillas.

References to the unique periodic fevers of malaria are found throughout history. Ancient Indian physician Sushruta believed that the disease was caused due to biting insects, long before the Roman Columella associated the disease with insects from swamps. Hippocrates described periodic fevers, labelling them tertian, quartan, subtertian and quotidian. Malaria may have contributed to the decline of the Roman Empire, and was so pervasive in Rome that it was known as the " Roman fever". Several regions in ancient Rome were considered at-risk for the disease because of the favourable conditions present for malaria vectors. This included areas such as southern Italy, the island of Sardinia, the Pontine Marshes, the lower regions of coastal Etruria and the city of Rome along the Tiber. The presence of stagnant water in these places was preferred by mosquitoes for breeding grounds. Irrigated gardens, swamp-like grounds, run-off from agriculture, and drainage problems from road construction led to the increase of standing water.

Malaria is not referenced in the medical books of the Mayans or Aztecs. Despite this, antibodies against malaria have been detected in some South American mummies, indicating that some malaria strains in the Americas might have a pre-Columbian origin. European settlers and the West Africans they enslaved likely brought malaria to the Americas starting in the 16th century.

Scientific studies on malaria made their first significant advance in 1880, when Charles Louis Alphonse Laveran—a French army doctor working in the military hospital of Constantine in Algeria—observed parasites inside the red blood cells of infected people for the first time. He, therefore, proposed that malaria is caused by this organism, the first time a protist was identified as causing disease. For this and later discoveries, he was awarded the 1907 Nobel Prize for Physiology or Medicine. A year later, Carlos Finlay, a Cuban doctor treating people with yellow fever in Havana

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