Malaria

Malaria is a

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.^[25] Children tend to have more general symptoms: fever, cough, vomiting, and diarrhea.^[25]

Initial manifestations of the disease—common to all malaria species—are similar to

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.[25] Travellers taking preventative malaria medications may develop symptoms once they stop taking the drugs.^[25]

Severe malaria is usually caused by P. falciparum (often referred to as falciparum malaria). Symptoms of falciparum malaria arise 9–30 days after infection.^[26] 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.^[26]

Complications

Malaria has several serious

Malaria in pregnant women is an important cause of stillbirths, infant mortality, miscarriage, and low birth weight,^[33] particularly in P. falciparum infection, but also with P. vivax.^[34]

Cause

Malaria is caused by infection with

The Anopheles mosquitos initially get infected by Plasmodium by taking a blood meal from a previously Plasmodium infected person.

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.[46] However, in Africa, due to the extensive use of bed nets, they began to bite earlier, before bed-net time.^[47] Malaria parasites can also be transmitted by blood transfusions, although this is rare.^[48]

Recurrent malaria

Symptoms of malaria can recur after varying symptom-free periods. Depending upon the cause, recurrence can be classified as either

Malaria infection develops via two phases: one that involves the

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.^[54] The parasite escapes from the liver undetected by wrapping itself in the cell membrane of the infected host liver cell.^[55]

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.^[54]

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.^[51] After a period of dormancy, they reactivate and produce merozoites. Hypnozoites are responsible for long incubation and late relapses in P. vivax infections,^[51] although their existence in P. ovale is uncertain.^[56]

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.^[57] The blockage of the microvasculature causes symptoms such as those in placental malaria.^[58] Sequestered red blood cells can breach the blood–brain barrier and cause cerebral malaria.^[59]

Genetic resistance

According to a 2005 review, due to the high levels of

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.^[64] 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.^[64]

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

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%).[19] 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.^[19]

Malaria is usually confirmed by the microscopic examination of

Malaria is classified into either "severe" or "uncomplicated" by the World Health Organization (WHO).^[13] It is deemed severe when any of the following criteria are present, otherwise it is considered uncomplicated.^[66]

• Decreased consciousness
• Significant weakness such that the person is unable to walk
• Inability to feed
• Two or more
  convulsions
• mmHg
  in adults and 50 mmHg in children)
• Breathing problems
• Circulatory shock
• 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

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.^[14][68] 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.^[69]

Prevention of malaria may be more cost-effective than treatment of the disease in the long run, but the

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.^[79] Between 2000 and 2008, the use of ITNs saved the lives of an estimated 250,000 infants in Sub-Saharan Africa.^[80] According to UNICEF, only 36% of households had sufficient ITNs for all household members in 2019.^[81] 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^[82] and to 68% African children using mosquito nets in 2015.^[83] The percentage of children sleeping under ITNs in sub-Saharan Africa increased from less than 40% in 2011 to over 50% in 2021.^[19] Most nets are impregnated with pyrethroids, a class of insecticides with low toxicity. They are most effective when used from dusk to dawn.^[84] 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.^[85] ITNs are beneficial towards pregnancy outcomes in malaria-endemic regions in Africa but more data is needed in Asia and Latin America.^[86]

In areas of high malaria resistance, piperonyl butoxide (PBO) combined with pyrethroids in mosquito netting is effective in reducing malaria infection rates.^[87] Questions remain concerning the durability of PBO on nets as the impact on mosquito mortality was not sustained after twenty washes in experimental trials.^[87]

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".^[20] 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".^[20] Slightly more than half of the households with an ITN had enough of them to protect all members of the household, however.^[20]

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.

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.^[76][93] 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,^[76] such as window screens.

Mass drug administration

Mass drug administration (MDA) involves the administration of drugs to the entire population of an area regardless of disease status.^[94] A 2021 Cochrane review on the use of community administration of ivermectin found that, to date, low quality evidence shows no significant impact on reducing incidence of malaria transmission from the community administration of ivermectin.^[95]

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.^[96] Electronic mosquito repellent devices, which make very high-frequency sounds that are supposed to keep female mosquitoes away, have no supporting evidence of effectiveness.^[97] There is a low certainty evidence that fogging may have an effect on malaria transmission.^[98] Larviciding by hand delivery of chemical or microbial insecticides into water bodies containing low larval distribution may reduce malarial transmission.^[99] There is insufficient evidence to determine whether larvivorous fish can decrease mosquito density and transmission in the area.^[100]

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.^[101] Doxycycline and the atovaquone/proguanil are better tolerated while mefloquine is taken once a week.^[101] Areas of the world with chloroquine-sensitive malaria are uncommon.^[102] 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.^[103] 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.^[103]

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).

Giving antimalarial drugs to infants through intermittent preventive therapy can reduce the risk of having malaria infection, hospital admission, and anaemia.[108]

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.^[109] Giving sulfadoxine-pyrimethamine for three or more doses as intermittent preventive therapy is superior than two doses for HIV-positive women living in malaria-endemic areas.^[110]

Prompt treatment of confirmed cases with artemisinin-based combination therapies (ACTs) may also reduce transmission.^[111]

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.^[112]

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.^[113] The first vaccine, called RTS,S, was approved by European regulators in 2015.^[114] As of 2023, two malaria vaccine have been licensed for use.^[14] Other approaches to combat malaria may require investing more in research and greater primary health care.^[115] Continuing surveillance will also be important to prevent the return of malaria in countries where the disease has been eliminated.^[116]

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).^[117]

Immunity (or, more accurately,

As of 2020, the RTS,S vaccine has been shown to reduce the risk of malaria by about 40% in children in Africa.[68]^[123] A preprint study of the R21 vaccine has shown 77% vaccine efficacy.^{[needs update][124]}

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.^[125]

Germany-based BioNTECH SE are developing an mRNA-based malaria vaccine BN165 ^[126] which has recently initiated a Phase 1 study [clinicaltrials.gov identifier: NCT05581641] in December 2022. The vaccine, based on the circumsporozite protein (CSP) is being tested in adults aged 18–55 yrs at 3 dose levels to select a safe and tolerable dose of a 3-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.^[127]

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.^[128] 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.^[129] Intermittent preventive therapy is another intervention that has been used successfully to control malaria in pregnant women and infants,^[130] and in preschool children where transmission is seasonal.^[131]

Treatment

Malaria is treated with

Uncomplicated malaria

Simple or uncomplicated malaria may be treated with oral medications. Artemisinin drugs are effective and safe in treating uncomplicated malaria.

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).^[157][158] There is limited safety data on the antimalarial drugs in pregnancy.^[159]

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.^[160] Severe and complicated malaria cases are medical emergencies since mortality rates are high (10% to 50%).^[161]

Recommended treatment for severe malaria is the

Cerebral malaria is the form of severe and complicated malaria with the worst neurological symptoms.[171] There is insufficient data on whether osmotic agents such as mannitol or urea are effective in treating cerebral malaria.^[172] Routine phenobarbitone in cerebral malaria is associated with fewer convulsions but possibly more deaths.^[173] There is no evidence that steroids would bring treatment benefits for cerebral malaria.^[174]

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.^[35] To manage the cerebral malaria when confirmed the following can be done:

• Patients 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.^[175]

There is insufficient evidence to show that blood transfusion is useful in either reducing deaths for children with severe anaemia or in improving their

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.^[178]

Resistance

Drug resistance poses a growing problem in 21st-century malaria treatment.^[179] In the 2000s (decade), malaria with partial resistance to artemisins emerged in Southeast Asia.^[180][181] 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.^[182] Malaria strains found on the Cambodia–Thailand border are resistant to combination therapies that include artemisinins, and may, therefore, be untreatable.^[183] 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.^[184] Resistance to artemisinin has been detected in Cambodia, Myanmar, Thailand, and Vietnam,^[185] and there has been emerging resistance in Laos.^[186][187] 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).^[188]

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.^[189]

Prognosis

When properly treated, people with malaria can usually expect a complete recovery.

During childhood, malaria causes anaemia during a period of rapid brain development, and also direct brain damage resulting from cerebral malaria.[192] Some survivors of cerebral malaria have an increased risk of neurological and cognitive deficits, behavioural disorders, and epilepsy.^[194] Malaria prophylaxis was shown to improve cognitive function and school performance in clinical trials when compared to placebo groups.^[192]

Epidemiology

The WHO estimates that in 2021 there were 247 million new cases of malaria resulting in 619,000 deaths.^[5] Children under five years old are the most affected, accounting for 67% of malaria deaths worldwide in 2019.^[196] 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.^[33] Since 2015, the WHO European Region has been free of malaria. The last country to report an indigenous malaria case was Tajikistan in 2014.^[5] There are about 1300–1500 malaria cases per year in the United States.^[29] The United States eradicated malaria as a major public health concern in 1951,^[197] though small outbreaks persist.^[198] 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,^[199] and in August in one case in Maryland.^[200] About 900 people died from the disease in Europe between 1993 and 2003.^[74] 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%^[83] from a 2000 estimate of 985,000, largely due to the widespread use of insecticide-treated nets and artemisinin-based combination therapies.^[80] 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.^[81]

Malaria is presently endemic in a broad band around the equator, in areas of the Americas, many parts of Asia, and much of Africa; in Sub-Saharan Africa, 85–90% of malaria fatalities occur.^[201] 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).^[202] A 2010 estimate indicated the deadliest countries per population were Burkina Faso, Mozambique and Mali.^[203] 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.^[204][205] This effort led to the publication of a map of P. falciparum endemicity in 2010 and an update in 2019.^{[206][207][208]} As of 2021, 84 countries have endemic malaria.^[5]

The geographic distribution of malaria within large regions is complex, and malaria-afflicted and malaria-free areas are often found close to each other.^[209] 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.^[210] In drier areas, outbreaks of malaria have been predicted with reasonable accuracy by mapping rainfall.^[211] 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.^[212] In contrast, malaria in Africa is present in both rural and urban areas, though the risk is lower in the larger cities.^[213]

Climate change

Since 1900 there has been substantial change in temperature and rainfall over Africa.[216] 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.^[217] 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.^[217]

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^[218] 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.^[219]

References to the unique periodic fevers of malaria are found throughout history.

The term malaria originates from Mediaeval Italian: mala aria—"bad air", a part of miasma theory; the disease was formerly called ague or marsh fever due to its association with swamps and marshland.^[225] The term appeared in English at least as early as 1768.^[226] Malaria was once common in most of Europe and North America,^[227] where it is no longer endemic,^[228] though imported cases do occur.^[229]

Malaria is not referenced in the medical books of the

In 1896, Amico Bignami discussed the role of mosquitoes in malaria.^[241] In 1898, Bignami, Giovanni Battista Grassi and Giuseppe Bastianelli succeeded in showing experimentally the transmission of malaria in humans, using infected mosquitoes to contract malaria themselves which they presented in November 1898 to the Accademia dei Lincei.^[238]

The first effective treatment for malaria came from the bark of

Quinine was the predominant malarial medication until the 1920s when other medications began to appear. In the 1940s, chloroquine replaced quinine as the treatment of both uncomplicated and severe malaria until resistance supervened, first in Southeast Asia and South America in the 1950s and then globally in the 1980s.[245]

The medicinal value of

Plasmodium vivax was used between 1917 and the 1940s for

malariotherapy—deliberate injection of malaria parasites to induce a fever to combat certain diseases such as tertiary syphilis. In 1927, the inventor of this technique, Julius Wagner-Jauregg, received the Nobel Prize in Physiology or Medicine for his discoveries. The technique was dangerous, killing about 15% of patients, so it is no longer in use.^[251]

The first pesticide used for indoor residual spraying was

Paris Green to places with standing water.^[253]

Names

Various types of malaria have been called by the names below:[254]

Name	Pathogen	Notes
algid malaria	Plasmodium falciparum	severe malaria affecting the circulatory shock
bilious malaria	Plasmodium falciparum	severe malaria affecting the liver and causing vomiting and jaundice
cerebral malaria	Plasmodium falciparum	severe malaria affecting the cerebrum
congenital malaria	various plasmodia	Plasmodium introduced from the mother via the fetal circulation
pernicious malaria	Plasmodium falciparum	severe malaria leading to grave illness
malignant malaria	Plasmodium falciparum	severe malaria leading to death
falciparum malaria, Plasmodium falciparum malaria,	Plasmodium falciparum
ovale malaria, Plasmodium ovale malaria	Plasmodium ovale
quartan malaria, malariae malaria, Plasmodium malariae malaria	Plasmodium malariae	paroxysms every fourth day (quartan), counting the day of occurrence as the first day
quotidian malaria	Plasmodium falciparum, Plasmodium vivax, Plasmodium knowlesi	paroxysms daily (quotidian)
tertian malaria	Plasmodium falciparum, Plasmodium ovale, Plasmodium vivax	paroxysms every third day (tertian), counting the day of occurrence as the first
transfusion malaria	various plasmodia	Plasmodium introduced by blood transfusion, needle sharing, or needlestick injury
vivax malaria, Plasmodium vivax malaria	Plasmodium vivax

Eradication efforts

Danube delta

, 1929

Malaria has been successfully eliminated or significantly reduced in certain areas, but not globally. Malaria was once common in the United States, but the US eliminated malaria from most parts of the country in the early 20th century using vector control programs, which combined the monitoring and treatment of infected humans, draining of

water management practices, and advances in sanitation, including greater use of glass windows and screens in dwellings.^[255] The use of the pesticide DDT and other means eliminated malaria from the remaining pockets in southern states of the US the 1950s, as part of the National Malaria Eradication Program.^[256] Most of Europe, North America, Australia, North Africa and the Caribbean, and parts of South America, Asia and Southern Africa have also eliminated malaria.^[257] The WHO defines "elimination" (or "malaria-free") as having no domestic transmission (indigenous cases) for the past three years. They also define "pre-elimination" and "elimination" stages when a country has fewer than 5 or 1, respectively, cases per 1000 people at risk per year. In 2021, the total of international and national funding for malaria control and elimination was $3.5 billion – only half of what is estimated to be needed.^[19] According to UNICEF, to achieve the goal of a malaria-free world, annual funding would need to more than double to reach the US$6.8 billion target.^[19]

In parts of the world with rising living standards, the elimination of malaria was often a collateral benefit of the introduction of window screens and improved sanitation.

larvaciding with insecticides, ecological controls such as draining mosquito breeding grounds or introducing fish to eat larvae and indoor residual spraying

(IRS) with insecticides.

Initial WHO program (1955–1969)

In 1955 the WHO launched the Global Malaria Eradication Program (GMEP).^[260] The program relied largely on DDT for mosquito control and rapid diagnosis and treatment to break the transmission cycle.^[261] The program eliminated the disease in "North America, Europe, the former Soviet Union",^[262] and in "Taiwan, much of the Caribbean, the Balkans, parts of northern Africa, the northern region of Australia, and a large swath of the South Pacific"^[258] and dramatically reduced mortality in Sri Lanka and India.^[263]

However, failure to sustain the program, increasing mosquito tolerance to DDT, and increasing parasite tolerance led to a resurgence. In many areas early successes partially or completely reversed, and in some cases rates of transmission increased.^[264] Experts tie malarial resurgence to multiple factors, including poor leadership, management and funding of malaria control programs; poverty; civil unrest; and increased irrigation. The evolution of resistance to first-generation drugs (e.g. chloroquine) and to insecticides exacerbated the situation.^[265][266] The program succeeded in eliminating malaria only in areas with "high socio-economic status, well-organized healthcare systems, and relatively less intensive or seasonal malaria transmission".^[262]

For example, in Sri Lanka, the program reduced cases from about one million per year before spraying to just 18 in 1963^[267][268] and 29 in 1964. Thereafter the program was halted to save money and malaria rebounded to 600,000 cases in 1968 and the first quarter of 1969. The country resumed DDT vector control but the mosquitoes had evolved resistance in the interim, presumably because of continued agricultural use. The program switched to malathion, but despite initial successes, malaria continued its resurgence into the 1980s.^[263][269]

Due to vector and parasite resistance and other factors, the feasibility of eradicating malaria with the strategy used at the time and resources available led to waning support for the program.^[270] WHO suspended the program in 1969^[260][270] and attention instead focused on controlling and treating the disease. Spraying programs (especially using DDT) were curtailed due to concerns over safety and environmental effects, as well as problems in administrative, managerial and financial implementation.^[264] Efforts shifted from spraying to the use of bednets impregnated with insecticides and other interventions.^[262][271]

Post-1969

Target 6C of the Millennium Development Goals included reversal of the global increase in malaria incidence by 2015, with specific targets for children under five years old.^[272] Since 2000, support for malaria eradication increased, although some actors in the global health community (including voices within the WHO) view malaria eradication as a premature goal and suggest that the establishment of strict deadlines for malaria eradication may be counterproductive as they are likely to be missed.^[273] One of the targets of Goal 3 of the UN's Sustainable Development Goals is to end the malaria epidemic in all countries by 2030.

In 2006, the organization Malaria No More set a public goal of eliminating malaria from Africa by 2015, and the organization claimed they planned to dissolve if that goal was accomplished. In 2007, World Malaria Day was established by the 60th session of the World Health Assembly. As of 2018, they are still functioning.^[274]

As of 2012^[update], The Global Fund to Fight AIDS, Tuberculosis, and Malaria has distributed 230 million insecticide-treated nets intended to stop mosquito-borne transmission of malaria.^[275] The U.S.-based Clinton Foundation has worked to manage demand and stabilize prices in the artemisinin market.^[276] Other efforts, such as the Malaria Atlas Project, focus on analysing climate and weather information required to accurately predict malaria spread based on the availability of habitat of malaria-carrying parasites.^[204] The Malaria Policy Advisory Committee (MPAC) of the World Health Organization (WHO) was formed in 2012, "to provide strategic advice and technical input to WHO on all aspects of malaria control and elimination".^[277]

In 2015 the WHO targeted a 90% reduction in malaria deaths by 2030,^[278] and Bill Gates said in 2016 that he thought global eradication would be possible by 2040.^[279] According to the WHO's World Malaria Report 2015, the global mortality rate for malaria fell by 60% between 2000 and 2015. The WHO targeted a further 90% reduction between 2015 and 2030,^[280] with a 40% reduction and eradication in 10 countries by 2020.^[281] However, the 2020 goal was missed with a slight increase in cases compared to 2015.^[282] Additionally, UNICEF reported that the number of malaria deaths for all ages increased by 10% between 2019 and 2020, in part due to service disruptions related to the COVID-19 pandemic, before experiencing a minor decline in 2021.^[19]

Before 2016, the Global Fund against HIV/AIDS, Tuberculosis and Malaria had provided 659 million ITN (insecticide treated bed nets), organise support and education to prevents malaria. The challenges are high due to the lack of funds, the fragile health structure and the remote indigenous population that could be hard to reach and educate. Most of indigenous population rely on self-diagnosis, self-treatment, healer, and traditional medicine. The WHO applied for fund to the Gates Foundation which favour the action of malaria eradication in 2007.^[283] Six countries, the United Arab Emirates, Morocco, Armenia, Turkmenistan, Kyrgyzstan, and Sri Lanka managed to have no endemic cases of malaria for three consecutive years and certified malaria-free by the WHO despite the stagnation of the funding in 2010.^[272] The funding is essential to finance the cost of medication and hospitalisation cannot be supported by the poor countries where the disease is widely spread. The goal of eradication has not been met; nevertheless, the decrease rate of the disease is considerable.

While 31 out of 92 endemic countries were estimated to be on track with the WHO goals for 2020, 15 countries reported an increase of 40% or more between 2015 and 2020.^[282] Between 2000 and 30 June 2021, twelve countries were certified by the WHO as being malaria-free. Argentina and Algeria were declared free of malaria in 2019.^[282][284] El Salvador and China were declared malaria-free in the first half of 2021.^[285][286]

Regional disparities were evident: Southeast Asia was on track to meet WHO's 2020 goals, while Africa, Americas, Eastern Mediterranean and West Pacific regions were off-track.^[282] The six Greater Mekong Subregion countries aim for elimination of P. falciparum transmitted malaria by 2025 and elimination of all malaria by 2030, having achieved a 97% and 90% reduction of cases respectively since 2000.^[282] Ahead of World Malaria Day, 25 April 2021, WHO named 25 countries in which it is working to eliminate malaria by 2025 as part of its E-2025 initiative.^[287]

A major challenge to malaria elimination is the persistence of malaria in border regions, making international cooperation crucial.^[288]

In 2018, WHO announced that Paraguay was free of malaria, after a national malaria eradication effort that began in 1950.^[289]

As of 2019, the eradication process is ongoing, but it will be difficult to achieve a world free of malaria with the current approaches and tools.

In March 2023, the WHO certified Azerbaijan and Tajikistan as malaria-free,^[290] and Belize in June 2023.^[291] Cabo Verde, the latest country to eradicate Malaria, was certified in January 2024, bringing the total number of countries and territories certified malaria-free to 44.^[292]

Society and culture

See also: World Malaria Day

Economic impact

Malaria is not just a disease commonly associated with poverty: some evidence suggests that it is also a cause of poverty and a major hindrance to economic development.^[21][22] Although tropical regions are most affected, malaria's furthest influence reaches into some temperate zones that have extreme seasonal changes. The disease has been associated with major negative economic effects on regions where it is widespread. During the late 19th and early 20th centuries, it was a major factor in the slow economic development of the American southern states.^[293]

A comparison of average per capita

GDP in 1995, adjusted for parity of purchasing power, between countries with malaria and countries without malaria gives a fivefold difference (US$1,526 versus US$8,268). In the period 1965 to 1990, countries where malaria was common had an average per capita GDP that increased only 0.4% per year, compared to 2.4% per year in other countries.^[294]

Poverty can increase the risk of malaria since those in poverty do not have the financial capacities to prevent or treat the disease. In its entirety, the economic impact of malaria has been estimated to cost Africa US$12 billion every year. The economic impact includes costs of health care, working days lost due to sickness, days lost in education, decreased productivity due to brain damage from cerebral malaria, and loss of investment and tourism.

outpatient visits, and up to 40% of public health spending.^[295]

Cerebral malaria is one of the leading causes of neurological disabilities in African children.

socioeconomic consequences that extend beyond the immediate effects of the disease.^[296]

Counterfeit and substandard drugs

Sophisticated

counterfeits have been found in several Asian countries such as Cambodia,^[297] China,^[298] Indonesia, Laos, Thailand, and Vietnam, and are a major cause of avoidable death in those countries.^[299] The WHO said that studies indicate that up to 40% of artesunate-based malaria medications are counterfeit, especially in the Greater Mekong region. They have established a rapid alert system to rapidly report information about counterfeit drugs to relevant authorities in participating countries.^[300] There is no reliable way for doctors or lay people to detect counterfeit drugs without help from a laboratory. Companies are attempting to combat the persistence of counterfeit drugs by using new technology to provide security from source to distribution.^[301]

Another clinical and public health concern is the proliferation of substandard antimalarial medicines resulting from inappropriate concentration of ingredients, contamination with other drugs or toxic impurities, poor quality ingredients, poor stability and inadequate packaging.[302] A 2012 study demonstrated that roughly one-third of antimalarial medications in Southeast Asia and Sub-Saharan Africa failed chemical analysis, packaging analysis, or were falsified.^[303]

War

Throughout history, the contraction of malaria has played a prominent role in the fates of government rulers, nation-states, military personnel, and military actions.

Nobel Prize in Medicine-winner Ronald Ross (himself a malaria survivor), published a book titled The Prevention of Malaria that included a chapter titled "The Prevention of Malaria in War". The chapter's author, Colonel C. H. Melville, Professor of Hygiene at Royal Army Medical College in London, addressed the prominent role that malaria has historically played during wars: "The history of malaria in war might almost be taken to be the history of war itself, certainly the history of war in the Christian era. ... It is probably the case that many of the so-called camp fevers, and probably also a considerable proportion of the camp dysentery, of the wars of the sixteenth, seventeenth and eighteenth centuries were malarial in origin."^[305] In British-occupied India the cocktail gin and tonic may have come about as a way of taking quinine, known for its antimalarial properties.^[306]

Malaria was the most significant health hazard encountered by U.S. troops in the South Pacific during World War II, where about 500,000 men were infected.^[307] According to Joseph Patrick Byrne, "Sixty thousand American soldiers died of malaria during the African and South Pacific campaigns."^[308]

Significant financial investments have been made to procure existing and create new antimalarial agents. During

U.S. Army Medical Research Institute of Infectious Diseases of the US Armed Forces.^[309]

Additionally, initiatives have been founded such as Malaria Control in War Areas (MCWA), established in 1942, and its successor, the Communicable Disease Center (now known as the Centers for Disease Control and Prevention, or CDC) established in 1946. According to the CDC, MCWA "was established to control malaria around military training bases in the southern United States and its territories, where malaria was still problematic".^[310]

Research

The Malaria Eradication Research Agenda (malERA) initiative was a consultative process to identify which areas of research and development (R&D) must be addressed for worldwide eradication of malaria.^[311][312]

Medications

Malaria parasites contain

fatty acid biosynthesis. Over 400 proteins have been found to be produced by apicoplasts and these are now being investigated as possible targets for novel antimalarial drugs.^[313]

With the onset of drug-resistant Plasmodium parasites, new strategies are being developed to combat the widespread disease. One such approach lies in the introduction of synthetic

B vitamins.^[314][315] Antimalarial drugs using synthetic metal-based complexes are attracting research interest.^[316][317]

• (+)-SJ733: Part of a wider class of experimental drugs called spiroindolone. It inhibits the ATP4 protein of infected red blood cells that cause the cells to shrink and become rigid like the aging cells. This triggers the immune system to eliminate the infected cells from the system as demonstrated in a mouse model. As of 2014, a Phase 1 clinical trial to assess the safety profile in human is planned by the Howard Hughes Medical Institute.^[318]
• NITD246 and
  NITD609: Also belonged to the class of spiroindolone and target the ATP4 protein.^[318]

On the basis of molecular docking outcomes, compounds 3j, 4b, 4h, 4m were exhibited selectivity towards PfLDH. The post docking analysis displayed stable dynamic behavior of all the selected compounds compared to Chloroquine. The end state thermodynamics analysis stated 3j compound as a selective and potent PfLDH inhibitor.[319]

New targets

Targeting Plasmodium liver-stage parasites selectively is emerging as an alternative strategy in the face of resistance to the latest frontline combination therapies against blood stages of the parasite.^[320]

In research conducted in 2019, using experimental analysis with knockout (KO) mutants of Plasmodium berghei, the authors were able to identify genes that are potentially essential in the liver stage. Moreover, they generated a computational model to analyse pre–erytrocytic development and liver–stage metabolism. Combining both methods they identified seven metabolic subsystems that become essential compared to the blood stage. Some of these metabolic pathways are fatty acid synthesis and elongation, tricarboxylic acid, amino acid and heme metabolism among others.^[320]

Specifically, they studied 3 subsystems: fatty acid synthesis and elongation, and amino sugar biosynthesis. For the first two pathways they demonstrated a clear dependence of the liver stage on its own fatty acid metabolism.^[320]

They proved for the first time the critical role of amino sugar biosynthesis in the liver stage of P. berghei. The uptake of N–acetyl–glucosamine appears to be limited in the liver stage, being its synthesis needed for the parasite development.^[320]

These findings and the computational model provide a basis for the design of antimalarial therapies targeting metabolic proteins.^[320][321]

Other

A non-chemical vector control strategy involves genetic manipulation of malaria mosquitoes. Advances in genetic engineering technologies make it possible to introduce foreign DNA into the mosquito genome and either decrease the lifespan of the mosquito, or make it more resistant to the malaria parasite. Sterile insect technique is a genetic control method whereby large numbers of sterile male mosquitoes are reared and released. Mating with wild females reduces the wild population in the subsequent generation; repeated releases eventually eliminate the target population.^[79]

biological control of malaria transmission.^[323]

In one study, a genetically modified strain of Anopheles stephensi was created that no longer supported malaria transmission, and this resistance was passed down to mosquito offspring.^[324]

Gene drive is a technique for changing wild populations, for instance to combat or eliminate insects so they cannot transmit diseases (in particular mosquitoes in the cases of malaria,^[325] zika,^[326] dengue and yellow fever).^[278]

In a study conducted in 2015, researchers observed a specific interaction between malaria and co-infection with the

erythrocytes, or red blood cells. Given that Plasmodium has a predilection for older host erythrocytes, the increased erythrocyte destruction and ensuing erythropoiesis result in a predominantly younger erythrocyte population, which in turn leads to a decrease in Plasmodium population.^[327]

Notably, this effect appears to be largely independent of the host's immune control of Plasmodium.

Finally, a review article published in December 2020 noted a correlation between malaria-endemic regions and COVID-19 case fatality rates.^[328] The study found that, on average, regions where malaria is endemic reported lower COVID-19 case fatality rates compared to regions without endemic malaria.

In 2017, a bacterial strain of the genus Serratia was genetically modified to prevent malaria in mosquitos^[329][330] and in 2023, it has been reported that the bacterium Delftia tsuruhatensis naturally prevents the development of malaria by secreting a molecule called Harmane.^{[331][332][333]}

Other animals

While none of the main four species of malaria parasite that cause human infections are known to have

Global warming is expected to increase the prevalence and global distribution of avian malaria, as elevated temperatures provide optimal conditions for parasite reproduction.^[340]

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Further reading

• ISBN 978-90-420-0721-5
  .
• Guidelines for the treatment of malaria (3rd ed.). World Health Organization. 2015.
  ISBN 978-92-4-154912-7. Archived from the original
  on April 25, 2015.
• Jarvis B (29 July 2019). "How Mosquitoes Changed Everything". The New Yorker. Retrieved 8 August 2019.
• "Tightening the handle on malaria". Nature Methods (Editorial). 16 (4): 271. 28 March 2019.
  PMID 30923375
  . A day dedicated to raising awareness of the disease is a good opportunity to ask how far malaria research has come and which methods are needed for further breakthroughs.

External links

Wikipedia's health care articles can be viewed offline with the Medical Wikipedia app.

• WHO site on malaria
• CDC site on malaria
• PAHO site on malaria