Malaria

Malaria

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Malaria

Malaria is a mosquito-borne infectious disease of humans and other animals caused by protists (a type of microorganism) of the genus Plasmodium. It begins with a bite from an infected female mosquito, which introduces the protists via its saliva into the circulatory system, and ultimately to the liver where they mature and reproduce. The disease causes symptoms that typically include fever and headache, which in severe cases can progress to coma or death. Malaria is widespread in tropical and subtropical regions in a broad band around the equator, including much of Sub-Saharan Africa, Asia, and the Americas.

Five species of Plasmodium can infect and be transmitted by humans. The vast majority of deaths are caused by P. falciparum while P. vivax, P. ovale, and P. malariae cause a generally milder form of malaria that is rarely fatal. The zoonotic species P. knowlesi, prevalent in Southeast Asia, causes malaria in macaques but can also cause severe infections in humans. Malaria is prevalent in tropical and subtropical regions because rainfall, warm temperatures, and stagnant waters provide habitats ideal for mosquito larvae. Disease transmission can be reduced by preventing mosquito bites by distribution of mosquito nets and insect repellents, or with mosquito-control measures such as spraying insecticides and draining standing water.

Malaria is typically diagnosed by the microscopic examination of blood using blood films, or with antigen-based rapid diagnostic tests. Modern techniques that use the polymerase chain reaction to detect parasite DNA have also been developed, but these are not widely used in malaria-endemic areas due to their cost and complexity. The World Health Organization has estimated that in 2010, there were 216 million documented cases of malaria. That year, between 655,000 and 1.2 million people died from the disease (roughly 2000–3000 per day),] many of whom were children in Africa. The actual number of deaths is not known with certainty, as precise statistics are unavailable in many rural areas, and many cases are undocumented. Malaria is commonly associated with poverty and may also be a major hindrance to economic development.

Despite a need, no effective vaccine currently exists, although efforts to develop one are ongoing. Several medications are available to prevent malaria in travelers to malaria-endemic countries (prophylaxis). A variety of antimalarial medications are available. Severe malaria is treated with intravenous or intramuscular quinine or, since the mid-2000s, the artemisinin derivative artesunate, which is superior to quinine in both children and adults and is given in combination with a second anti-malarial such as mefloquine. Resistance has developed to several antimalarial drugs; for example, chloroquine-resistant P. falciparum has spread to most malarial areas, and emerging resistance to artemisinin has become a problem in some parts of Southeast Asia.

Signs and symptoms

The typical fever patterns of the different types of malaria

The signs and symptoms of malaria typically begin 8–25 days following infection;] however, symptoms may occur later in those who have taken antimalarial medications as prevention.] Initial manifestations of the disease—common to all malaria species—are similar to flu-like symptoms,] and can resemble other conditions such as septicemia, gastroenteritis, and viral diseases.] The presentation may include headache, fever, shivering, arthralgia (joint pain), vomiting, hemolytic anemia, jaundice, hemoglobinuria, retinal damage,] and convulsions. Approximately 30% of people however will no longer have a fever upon presenting to a health care facility. Owing to the non-specific nature of disease presentation, diagnosis of malaria in non-endemic countries requires a high degree of suspicion, which might be elicited by any of the following: recent travel history, splenomegaly (enlarged spleen), fever without localizing signs, thrombocytopenia, and hyperbilirubinemia combined with a normal peripheral blood leukocyte count.]

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

Severe malaria is usually caused by P. falciparum (often referred to as falciparum malaria), and typically arises 9–14 days after infection. Splenomegaly, severe headache, hepatomegaly (enlarged liver), hypoglycemia, and hemoglobinuria with renal failure may occur. Renal failure is a feature of blackwater fever, where hemoglobin from lysed red blood cells leaks into the urine.] Cerebral malaria is a form of severe malaria that involves encephalopathy specifically related to P. falciparum infection. It is associated with retinal whitening, which may be a useful clinical sign in distinguishing malaria from other causes of fever.] 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

There are a number of serious complications of malaria. Among these is 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. Acute respiratory distress syndrome (ARDS) may develop in 5–25% in adults and up to 29% of pregnant women but is rare in young children.] Coinfection with HIV and malaria increases mortality,] an effect that may be attributed to the increased viral load caused by malaria, and the increased susceptibility to malaria infection caused by HIV infection.]

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

Cause

Malaria parasites are from the genus Plasmodium (phylum Apicomplexa). In humans, malaria is caused by P. falciparum, P. malariae, P. ovale, P. vivax and P. knowlesi.]] Among those infected, P. falciparum is the most common species identified (~75%) followed by P. vivax (~20%).] P. falciparum accounts for the majority of deaths;] non-falciparum species have been found to be the cause of about 14% of cases of severe malaria in some groups.] P. vivax proportionally is more common outside of Africa.] There have been documented human infections with several species of Plasmodium from higher apes; however, with the exception of P. knowlesi—a zoonotic species that causes malaria in macaques]—these are mostly of limited public health importance.]

Life cycle

The life cycle of malaria parasites: A mosquito causes infection by taking a blood meal. First, sporozoites enter the bloodstream, and migrate to the liver. They infect liver cells, where they multiply into merozoites, rupture the liver cells, and return to the bloodstream. Then, the merozoites infect red blood cells, where they develop into ring forms, trophozoites and schizonts that in turn produce further merozoites. Sexual forms are also produced, which, if taken up by a mosquito, will infect the insect and continue the life cycle.

In the life cycle of Plasmodium, a female Anopheles mosquito (the definitive host) transmits a motile infective form (called the sporozoite) to a vertebrate host such as a human (the secondary host), thus acting as a transmission vector. A sporozoite travels through the blood vessels to liver cells (hepatocytes), where it reproduces asexually, producing thousands of merozoites. These infect new red blood cells and initiate a series of asexual multiplication cycles that produce 8 to 24 new infective merozoites, at which point the cells burst and the infective cycle begins anew.] In a process called gametocytogenesis, other merozoites develop into immature gametes, or gametocytes. When a fertilised mosquito bites an infected person, gametocytes are taken up with the blood and mature in the mosquito gut. The male and female gametocytes fuse and form zygotes (ookinetes), which develop into new sporozoites. The sporozoites migrate to the insect’s salivary glands, ready to infect a new vertebrate host. The sporozoites are injected into the skin, alongside saliva, when the mosquito takes a subsequent blood meal. This type of transmission is occasionally referred to as anterior station transfer.]

Only female mosquitoes feed on blood; male mosquitoes feed on plant nectar, and thus do not transmit the disease. The females of the Anopheles genus of mosquito prefer to feed at night. They usually start searching for a meal at dusk, and will continue throughout the night until taking a meal.] Malaria parasites can also be transmitted by blood transfusions, although this is rare.]

Recurrent malaria

Malaria recurs after treatment for three reasons. Recurrence (recrudescence) occurs when parasites are not cleared by treatment, whereas reinfection indicates complete clearance with new infection established from a separate infective mosquito bite; both can occur with any malaria parasite species. Relapse is specific to P. vivax and P. ovale and involves re-emergence of blood-stage parasites from latent parasites (hypnozoites) in the liver.]

Describing a case of malaria as cured by observing the disappearance of parasites from the bloodstream can, therefore, be deceptive. The longest incubation period reported for a P. vivax infection is 30 years.] P. vivax malaria cases in temperate areas often involve overwintering by hypnozoites, with relapses beginning the year after the mosquito bite.]

Pathogenesis

Ring-forms and gametocytes of Plasmodium falciparum in human blood

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.]

Within the red blood cells, the parasites multiply further, again asexually, periodically breaking out of their host cells to invade fresh red blood cells. Several such amplification cycles occur. Thus, classical descriptions of waves of fever arise from simultaneous waves of merozoites escaping and infecting red blood cells.]

Some P. vivax sporozoites do not immediately develop into exoerythrocytic-phase merozoites, but instead produce hypnozoites that remain dormant for periods ranging from several months (7–10 months is typical) to several years. After a period of dormancy, they reactivate and produce merozoites. Hypnozoites are responsible for long incubation and late relapses in P. vivax infections,] although their existence in P. ovale is uncertain.]

Micrograph of a placenta from a stillbirth due to maternal malaria. H&E stain. Red blood cells are anuclear; blue/black staining in bright red structures (red blood cells) indicate foreign nuclei from the parasites

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 in placental malaria.] Sequestered red blood cells can breach the blood–brain barrier and cause cerebral malaria.]

Although the red blood cell surface adhesive proteins (called PfEMP1, for P. falciparum erythrocyte membrane protein 1) are exposed to the immune system, they do not serve as good immune targets because of their extreme diversity; there are at least 60 variations of the protein within a single parasite and even more variants within whole parasite populations. The parasite switches through a broad repertoire of PfEMP1 surface proteins, thereby avoiding detection by protective antibodies.]

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 conditions and diseases may provide some resistance to it including sickle cell trait, thalassaemias, glucose-6-phosphate dehydrogenase deficiency, and the presence of Duffy antigens on the subject’s red blood cells.

The impact of sickle cell trait on malaria immunity is of particular interest. Sickle cell trait causes a defect in the hemoglobin molecule in the blood. Instead of retaining the biconcave shape of a normal red blood cell, the modified hemoglobin S molecule causes the cell to sickle or distort into a curved shape. Due to the sickle shape, the molecule is not as effective in taking or releasing oxygen, and therefore malaria parasites cannot complete their life cycle in the cell. Individuals who are homozygous (with two copies of the abnormal hemoglobin beta allele) have sickle-cell disease, while those who are heterozygous (with one abnormal allele and one normal allele) experience resistance to malaria. Although the potential risk of death for those with the homozygous condition seems to be unfavourable to population survival, the trait is preserved because of the benefits provided by the heterozygous form.

Malarial hepatopathy

Liver dysfunction as a result of malaria is rare and is usually a result of a coexisting liver condition such as viral hepatitis or chronic liver disease. The syndrome is sometimes called malarial hepatitis, although inflammation of the liver (hepatitis) does not actually occur. While traditionally considered a rare occurrence, malarial hepatopathy has seen an increase in malaria-endemic areas, particularly in Southeast Asia and India. Liver compromise in people with malaria correlates with a greater likelihood of complications and death.

Diagnosis

The blood film is the gold standard for malaria diagnosis.

Malaria is typically diagnosed by the microscopic examination of blood using blood films or using antigen-based rapid diagnostic tests (RDT). Microscopy is the most commonly used method to detect the malaria parasite—about 165 million blood smears were performed in 2010. Despite its widespread usage, diagnosis by microscopy suffers from two main drawbacks: many settings (especially rural) are not equipped to perform the test, and the accuracy of the results depends on both the skill of the person reading the smear and the levels of the parasite in the blood. The sensitivity of blood films ranges from 75–90% in optimum conditions, to as low as 50%. Commercially available RDTs are often more accurate than blood smears at predicting the presence of malaria parasites, but they are widely variable in diagnostic sensitivity and specificity depending on manufacturer, and are unable to tell how many parasites are present.

In regions where laboratory tests are readily available, malaria should be suspected, and tested for, in any unwell patient who has been in an area where malaria is endemic. In areas that cannot afford laboratory diagnostic tests, it has become routine to use only a history of subjective fever as the indication to treat for malaria—a presumptive approach exemplified by the common teaching “fever equals malaria unless proven otherwise”. The drawback of this practice, however, is overdiagnosis of malaria and mismanagement of non-malarial fever, which wastes limited resources, erodes confidence in the health care system, and contributes to drug resistance. Although polymerase chain reaction-based tests have been developed, these are not widely implemented in malaria-endemic regions as of 2012, due to their complexity.]

Classification

Malaria is divided into severe and uncomplicated by the World Health Organization (WHO).] Severe malaria is diagnosed 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 or 50 mmHg in children)

Breathing problems

Circulatory shock

Kidney failure or hemoglobin in the urine

Bleeding problems, or hemoglobin less than 5 g/dl

Pulmonary edema

Low 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 2%

According to the WHO, cerebral malaria is defined as a severe P. falciparum-malaria presenting neurological symptoms, including coma (with a Glasgow coma scale rating of greater than 11, or a Blantyre coma scale greater than 3), or with a coma that lasts longer than 30 minutes after a seizure.

Prevention

An Anopheles stephensi mosquito shortly after obtaining blood from a human (the droplet of blood is expelled as a surplus). This mosquito is a vector of malaria, and mosquito control is an effective way of reducing its incidence.

Methods used to prevent malaria include medications, mosquito eradication and the prevention of bites. The presence of malaria in an area requires a combination of high human population density, high 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 will eventually disappear from that area, as happened in North America, Europe and much of the Middle East. However, unless the parasite is eliminated from the whole world, it could become re-established if conditions revert to a combination that favours the parasite’s reproduction. Many countries are seeing an increasing number of imported malaria cases owing to extensive travel and migration.

Many researchers argue that prevention of malaria may be more cost-effective than treatment of the disease in the long run, but the capital costs required are out of reach of many of the world’s poorest people. There is a wide disparity 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 program in Tanzania would cost an estimated one-fifth of the public health budget.

Vector control

Man spraying kerosene oil to protect against mosquitoes carrying malaria, Panama Canal Zone 1912

Insecticide-treated mosquito nets (ITNs) and indoor residual spraying (IRS) have been shown to be highly effective vector control interventions in preventing malaria morbidity and mortality among children in malaria-endemic settings. IRS is the practice of spraying insecticides on the interior walls of homes in malaria-affected areas. After feeding, many mosquito species rest on a nearby surface while digesting the bloodmeal, so if the walls of dwellings have been coated with insecticides, the resting mosquitoes can be killed before they can bite another victim and transfer the malaria parasite. As of 2006, the World Health Organization advises the use of 12 insecticides in IRS operations, including DDT as well as alternative insecticides (such as the pyrethroids permethrin and deltamethrin). This public health use of small amounts of DDT is permitted under the Stockholm Convention on Persistent Organic Pollutants (POPs), which prohibits the agricultural use of DDT.

One problem with all forms of IRS is insecticide resistance via evolution. Mosquitoes that are 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 not as affected—if affected at all—by the IRS, which greatly reduces its effectiveness as a defense mechanism.

Mosquito nets create a protective barrier against malaria-carrying mosquitoes that bite at night.

Mosquito nets help keep mosquitoes away from people and significantly reduce infection rates and transmission of malaria. The nets are not a perfect barrier and they are often treated with an insecticide designed to kill the mosquito before it has time to search for a way past the net. Insecticide-treated nets are estimated to be twice as effective as untreated nets and offer greater than 70% protection compared with no net. Although ITNs are proven to be very effective against malaria, only about 13% of households in sub-Saharan countries own them. A recommended practice for usage is to hang a large “bed net” above the center of a bed to drape over it completely with the edges tucked in. Pyrethroid-treated nets and long-lasting insecticide-treated nets offer the best personal protection, and are most effective when used from dusk to dawn.

Other methods

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. Recognizing the disease in the early stages can stop the disease 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.

Medications

Several drugs, most of which are used for treatment of malaria, can be taken to prevent contracting the disease during travel to endemic areas. Chloroquine may be used where the parasite is still sensitive. However, due to resistance one of three medications—mefloquine (Lariam), doxycycline (available generically), or the combination of atovaquone and proguanil hydrochloride (Malarone)—is frequently needed. Doxycycline and the atovaquone and proguanil combination are the best tolerated; mefloquine is associated with high rates of neurological and psychiatric symptoms.

The prophylactic effect does not begin immediately upon starting the drugs, so people temporarily visiting malaria-endemic areas usually begin taking the drugs one to two weeks before arriving and should continue taking them for four weeks after leaving (with the exception of atovaquone proguanil that only needs to be started two days prior and continued for seven days afterwards). Generally, these drugs are taken daily or weekly, at a lower dose than is used for treatment of a person who contracts the disease. Use of prophylactic drugs is seldom practical for full-time residents of malaria-endemic areas, and their use is usually restricted to short-term visitors and travelers to malarial regions. This is due to the cost of purchasing the drugs, negative adverse effects from long-term use, and because some effective anti-malarial drugs are difficult to obtain outside of wealthy nations. The use of prophylactic drugs where malaria-bearing mosquitoes are present may encourage the development of partial immunity.

Treatment

Disability-adjusted life year for malaria per 100,000 inhabitants in 2004

   no data

   <10

  0–100

  100–500

   500–1000

   1000–1500

  1500–2000

   2000–2500

  2500–2750

   2750–3000

   3000–3250

   3250–3500

   ≥3500

The treatment of malaria depends on the severity of the disease; whether people can take oral drugs or must be admitted depends on the assessment and the experience of the clinician.

Uncomplicated malaria

Uncomplicated malaria may be treated with oral medications. The most effective strategy for P. falciparum infection is the use of artemisinins in combination with other antimalarials (known as artemisinin-combination therapy), which reduces the ability of the parasite to develop resistance to any single drug component. These additional antimalarials include amodiaquine, lumefantrine, mefloquine or sulfadoxine/pyrimethamine. Another recommended combination is dihydroartemisinin and piperaquine. In the 2000s (decade), malaria with partial resistance to artemisins emerged in Southeast Asia.

Severe malaria

Severe malaria requires the parenteral administration of antimalarial drugs. Until the mid-2000s the most used treatment for severe malaria was quinine, but artesunate has been shown to be superior to quinine in both children and adults. Treatment of severe malaria also involves supportive measures that are optimally performed in a critical care unit, including management of high fevers (hyperpyrexia) and the subsequent seizures that may result from it, and monitoring for respiratory depression, hypoglycemia, and hypokalemia.] Infection with P. vivax, P. ovale or P. malariae is usually treated on an outpatient basis (while a person is at home). Treatment of P. vivax requires both treatment of blood stages (with chloroquine or ACT) as well as clearance of liver forms with primaquine.

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 suffered episodes of severe malaria.

Malaria causes widespread anemia during a period of rapid brain development, and also direct brain damage. This neurologic damage results from cerebral malaria to which children are more vulnerable. 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

Map showing the distribution of malaria in the world : ♦ Elevated occurrence of chloroquine- or multi-resistant malaria : ♦ Occurrence of chloroquine-resistant malaria : ♦ No Plasmodium falciparum or chloroquine-resistance : ♦ No malaria

Based on documented cases, the WHO estimates that there were 216 million cases of malaria in 2010 resulting in 655,000 deaths. This is equivalent to roughly 2000 deaths every day.] A 2012 study estimated the number of documented and undocumented deaths in 2010 was 1.24 million. The majority of cases (65%) occur in children under 15 years old. Pregnant women are also especially vulnerable: 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.] There are about 10,000 malaria cases per year in Western Europe, and 1300–1500 in the United States.]

Malaria is presently endemic in a broad band around the equator, in areas of the Americas, many parts of Asia, and much of Africa; however, it is in sub-Saharan Africa where 85–90% of malaria fatalities occur. An estimate for 2009 reported that countries with the highest death rate per 100,000 of population were Ivory Coast with 86.15, Angola (56.93) and Burkina Faso (50.66). An estimate for 2010 said the deadliest countries per population were Burkina Faso, Mozambique and Mali. The Malaria Atlas Project aims to map global endemic levels of malaria, providing a means with which 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. As of 2010, about 100 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 in which 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.

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 recorded history, beginning in 2700 BC in China. 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 River. The presence of stagnant water in these places was preferred by mosquitoes for breeding grounds. Irrigated gardens, swamp-like grounds, runoff from agriculture, and drainage problems from road construction led to the increase of standing water.

British doctor Ronald Ross received the Nobel Prize for Physiology or Medicine in 1902 for his work on malaria.

The term malaria originates from Medieval Italian: mala aria — “bad air”; the disease was formerly called ague or marsh fever due to its association with swamps and marshland. Malaria was once common in most of Europe and North America, where it is no longer endemic, though imported cases do occur.

Malaria was the most important health hazard encountered by U.S. troops in the South Pacific during World War II, where about 500,000 men were infected. According to Joseph Patrick Byrne, “Sixty thousand American soldiers died of malaria during the African and South Pacific campaigns.” 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. The malarial parasite was called Plasmodium by the Italian scientists Ettore Marchiafava and Angelo Celli. A year later, Carlos Finlay, a Cuban doctor treating people with yellow fever in Havana, provided strong evidence that mosquitoes were transmitting disease to and from humans. This work followed earlier suggestions by Josiah C. Nott, and work by Sir Patrick Manson, the “father of tropical medicine”, on the transmission of filariasis.

In April 1894, a Scottish physician Sir Ronald Ross visited Sir Patrick Manson at his house on Queen Anne Street, London. This visit was the start of four years of collaboration and fervent research that culminated in 1898 when Ross, who was working in the Presidency General Hospital in Calcutta, proved the complete life-cycle of the malaria parasite in mosquitoes. He thus proved that the mosquito was the vector for malaria in humans by showing that certain mosquito species transmit malaria to birds. He isolated malaria parasites from the salivary glands of mosquitoes that had fed on infected birds. For this work, Ross received the 1902 Nobel Prize in Medicine. After resigning from the Indian Medical Service, Ross worked at the newly established Liverpool School of Tropical Medicine and directed malaria-control efforts in Egypt, Panama, Greece and Mauritius. The findings of Finlay and Ross were later confirmed by a medical board headed by Walter Reed in 1900. Its recommendations were implemented by William C. Gorgas in the health measures undertaken during construction of the Panama Canal. This public-health work saved the lives of thousands of workers and helped develop the methods used in future public-health campaigns against the disease.

Artemisia annua contains the antimalarial drug artemisin.

The first effective treatment for malaria came from the bark of cinchona tree, which contains quinine. This tree grows on the slopes of the Andes, mainly in Peru. The indigenous peoples of Peru made a tincture of cinchona to control malaria. The Jesuits introduced the treatment to Europe around 1640; by 1677, it was included in the London Pharmacopoeia as an antimalarial treatment. It was not until 1820 that the active ingredient, quinine, was extracted from the bark, isolated and named by the French chemists Pierre Joseph Pelletier and Joseph Bienaimé Caventou.

Quinine become the predominant malarial medication until the 1920s, when other medications began to be developed. 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. Artemisinins, discovered by Chinese scientist Tu Youyou in the 1970s from the plant Artemisia annua, became the recommended treatment for P. falciparum malaria, administered in combination with other antimalarials as well as in severe disease.

The first pesticide used for indoor residual spraying was DDT. Although it was initially used exclusively to combat malaria, its use quickly spread to agriculture. In time, pest control, rather than disease control, came to dominate DDT use, and this large-scale agricultural use led to the evolution of resistant mosquitoes in many regions. The DDT resistance shown by Anopheles mosquitoes can be compared to antibiotic resistance shown by bacteria. During the 1960s, awareness of the negative consequences of its indiscriminate use increased, ultimately leading to bans on agricultural applications of DDT in many countries in the 1970s. Before DDT, malaria was successfully eradicated or controlled in tropical areas like Brazil and Egypt by removing or poisoning the breeding grounds of the mosquitoes or the aquatic habitats of the larva stages, for example by applying the highly toxic arsenic compound Paris Green to places with standing water.

Malaria vaccines have been an elusive goal of research. The first promising studies demonstrating the potential for a malaria vaccine were performed in 1967 by immunizing 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 a considerable effort to develop similar vaccination strategies within humans.

Society and culture

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. Tropical regions are affected most; however, malaria’s furthest extent reaches into some temperate zones with 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.

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 ($1,526 USD versus $8,268 USD). In countries where malaria is common, average per capita GDP has risen (between 1965 and 1990) only 0.4% per year, compared to 2.4% per year in other countries.

Poverty is both a cause and effect 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 $12 billion USD 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. The disease has a heavy burden in some countries, where it may be responsible for 30–50% of hospital admissions, up to 50% of outpatient visits, and up to 40% of public health spending.

The cognitive abilities and school performance are impaired in sub-groups of people (with either cerebral malaria or uncomplicated malaria) when compared with healthy controls. Studies comparing cognitive functions before and after treatment for severe malarial illness continued to show significantly impaired school performance and cognitive abilities even after recovery. Consequently, severe and cerebral malaria have far-reaching socioeconomic consequences that extend beyond the immediate effects of the disease.

[edit]Counterfeit and substandard drugs

Sophisticated counterfeits have been found in several Asian countries such as Cambodia, China, Indonesia, Laos, Thailand, and Vietnam, and are an important cause of avoidable death in those countries. The WHO said that studies indicate that up to 40% of artesunate-based malaria medications are counterfeit, especially in the Greater Mekong region and have established a rapid alert system to enable information about counterfeit drugs to be rapidly reported to the relevant authorities in participating countries. 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.

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. 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.]

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.] In 1910, 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.”

Significant financial investments have been made to procure existing and create new anti-malarial agents. During World War I and World War II, inconsistent supplies of the natural anti-malaria drugs cinchona bark and quinine prompted substantial funding into research and development of other drugs and vaccines. American military organizations conducting such research initiatives include the Navy Medical Research Center, Walter Reed Army Institute of Research, and the U.S. Army Medical Research Institute of Infectious Diseases of the US Armed Forces.

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”.

Eradication efforts

Several notable attempts are being made to eliminate the parasite from sections of the world, or to eradicate it worldwide. In 2006, the organization Malaria No More set a public goal of eliminating malaria from Africa by 2015, and the organization plans to dissolve if that goal is accomplished. Several malaria vaccines are in clinical trials, which are intended to provide protection for children in endemic areas and reduce the speed of transmission of the disease. As of 2012, The Global Fund to Fight AIDS, Tuberculosis and Malaria has distributed 230 million insecticide-treated nets intended to stop mosquito-born transmission of malaria. The U.S.-based Clinton Foundation has worked to manage demand and stabilize prices in the artemisinin market. Other efforts, such as the Malaria Atlas Project focus on analysing climate and weather information required to accurately predict the spread of malaria based on the availability of habitat of malaria-carrying parasites.

Malaria has been successfully eliminated or greatly reduced in certain areas. Malaria was once common in the United States and southern Europe, but vector control programs, in conjunction with the monitoring and treatment of infected humans, eliminated it from those regions. Several factors contributed to malarial eradication, such as the draining of wetland breeding grounds for agriculture and other changes in water management practices, and advances in sanitation, including greater use of glass windows and screens in dwellings. Malaria was eliminated from most parts of the USA in the early 20th century by such methods, and the use of the pesticide DDT and other means eliminated it from the remaining pockets in the South in the 1950s. (see National Malaria Eradication Program) In Suriname, the disease has been cleared from its capital city and coastal areas through a three-pronged approach initiated by the Global Malaria Eradication program in 1955, involving: vector control through the use of DDT and IRS; regular collection of blood smears from the population to identify existing malaria cases; and providing chemotherapy to all affected individuals. Bhutan is pursuing an aggressive malaria elimination strategy, and has achieved a 98.7% decline in microscopy-confirmed cases from 1994 to 2010. In addition to vector control techniques such as IRS in high-risk areas and thorough distribution of long-lasting ITNs, factors such as economic development and increasing access to health services have contributed to Bhutan’s successes in reducing malaria incidence.

Research

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. An effective vaccine is not yet available for malaria, although several are under development. 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 endemic areas in the 1990s, but clinical trials showed it to be insufficiently effective. Several potential vaccines targeting the pre-erythrocytic stage of the parasite’s life cycle are being developed, with RTS,S showing the most promising results so far. In 2006, the Malaria Vaccine Advisory Committee to the WHO outlined a “Malaria Vaccine Technology Roadmap” that has as one of its landmark objectives to “develop and license a first-generation malaria vaccine that has a protective efficacy of more than 50% against severe disease and death and lasts longer than one year” by 2015.

Malaria parasites contain apicoplasts, an organelle usually found in plants, complete with their own functioning genomes. These apicoplasts are thought to have originated through the endosymbiosis of algae and play a crucial role in various aspects of parasite metabolism, for example in 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 anti-malarial drugs.

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 pyridoxal-amino acid adducts, which are taken up by the parasite and ultimately interfere with its ability to create several essential B-vitamins.

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 males mosquitoes are reared and released. Mating with wild females reduces the wild population in the subsequent generation; repeated releases eventually eradicate the target population.

In other animals

Nearly 200 parasitic Plasmodium species have been identified that infect birds, reptiles, and other mammals, and about 30 species naturally infect non-human primates. Some of the malaria parasites that affect non-human primates (NHP) serve as model organisms for human malarial parasites, such as P. coatneyi (a model for P. falciparum) and P. cynomolgi (P. vivax). Diagnostic techniques used to detect parasites in NHP are similar to those employed for humans. Avian malaria primarily affects species of the order Passeriformes, and poses a substantial threat to birds of Hawaii, the Galapagos, and other archipelagoes. The parasite P. relictum is known to play a role in limiting the distribution and abundance of endemic Hawaiian birds. Global warming is expected to increase the prevalence and global distribution of avian malaria, as elevated temperatures provide optimal conditions for parasite reproduction.

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