Malaria 

is a mosquito-borne infectious disease of humans caused by eukaryotic protists of the

genus Plasmodium. It is widespread in tropical and subtropical regions, including much of Sub-Saharan
Africa, Asia and the Americas. The disease results from the multiplication of malaria parasites withinred
blood cells, causing symptoms that typically include fever and headache, in severe cases progressing
to coma, and death.

Four species of Plasmodium can infect and be transmitted by humans. Severe disease is largely caused
by Plasmodium falciparum. Malaria caused byPlasmodium vivax, Plasmodium ovale and Plasmodium
malariae is generally a milder disease that is rarely fatal. A fifth species, Plasmodium knowlesi, is
azoonosis that causes malaria in macaques but can also infect humans.[1][2]

Malaria transmission can be reduced by preventing mosquito bites by distribution of inexpensive mosquito

nets and insect repellents, or by mosquito-control measures such as spraying insecticides inside houses
and draining standing water where mosquitoes lay their eggs. Although many are under development, the
challenge of producing a widely available vaccine that provides a high level of protection for a sustained
period is still to be met.[3] Two drugs are also available to prevent malaria in travellers to malaria-
endemic countries (prophylaxis).

A variety of antimalarial medications are available. In the last 5 years, treatment of P.

falciparum infections in endemic countries has been transformed by the use of combinations of drugs
containing an artemisinin derivative. Severe malaria is treated with intravenous or intramuscular quinine
or, increasingly, the artemisinin derivative artesunate [4] which is superior to quinine in both children and
adults.[5] Resistance has developed to several antimalarial drugs, most notably chloroquine.[6]

Each year, there are more than 225 million cases of malaria,[7] killing around 781,000 people each year
according to the latest WHO Report, 2.23% of deaths worldwide. The majority of deaths are of young
children in sub-Saharan Africa.[8] Ninety percent of malaria-related deaths occur in sub-Saharan Africa.
Malaria is commonly associated with poverty, and can indeed be a cause of poverty[9] and a major
hindrance to economic development.

Contents
 [hide]

1 Signs and symptoms

2 Cause

o 2.1 Life cycle

3 Pathogenesis

o 3.1 Genetic resistance
 4 Diagnosis

o 4.1 Blood films

o 4.2 Antigen tests

o 4.3 Molecular methods

o 4.4 Differential

5 Prevention

o 5.1 Medications

o 5.2 Vector control

o 5.3 Indoor residual spraying

o 5.4 Vaccination

o 5.5 Other methods

6 Treatment

7 Epidemiology

8 History

o 8.1 Prevention

o 8.2 Discovery of the parasite

o 8.3 Discovery of mosquito

transmission

o 8.4 The liver stage

o 8.5 In vitro culture

o 8.6 History of treatment

9 Society and culture

o 9.1 Counterfeit drugs

o 9.2 War

o 9.3 Popular culture

10 Research

11 References

12 External links

[edit]Signs and symptoms

Main symptoms of malaria.[10]

Typical fever patterns of malaria

Symptoms of malaria include fever, shivering, arthralgia (joint pain), vomiting, anemia (caused

by hemolysis), hemoglobinuria, retinal damage,[11] andconvulsions. The classic symptom of malaria is
cyclical occurrence of sudden coldness followed by rigor and then fever and sweating lasting four to six
hours, occurring every two days in P. vivax and P. ovale infections, while every three days for P.
malariae.[12] P. falciparum can have recurrent fever every 36–48 hours or a less pronounced and almost
continuous fever. For reasons that are poorly understood, but that may be related to high intracranial
pressure, children with malaria frequently exhibit abnormal posturing, a sign indicating severe brain
damage.[13] Malaria has been found to cause cognitive impairments, especially in children. It 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.[14][15] Cerebral
malaria is associated with retinal whitening,[16] which may be a useful clinical sign in distinguishing malaria
from other causes of fever.[17]

Severe malaria is almost exclusively caused by P. falciparum infection, and usually arises 6–14 days after
infection.[18] Consequences of severe malaria include coma and death if untreated—young children and
pregnant women are especially vulnerable. Splenomegaly (enlarged spleen), severe headache,
cerebral ischemia, 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. Severe malaria can progress extremely rapidly and cause death within hours or
days.[18] In the most severe cases of the disease, fatality rates can exceed 20%, even with intensive care
and treatment.[19] In endemic areas, treatment is often less satisfactory and the overall fatality rate for all
cases of malaria can be as high as one in ten.[20] Over the longer term, developmental impairments have
been documented in children who have suffered episodes of severe malaria.[21]

[edit]Cause

A Plasmodium sporozoite traverses the cytoplasm of a mosquito midgut epithelial cell in this false-color electron micrograph.

Malaria parasites are members of the genus Plasmodium (phylum Apicomplexa). In humans malaria is

caused by P. falciparum, P. malariae, P. ovale, P. vivax and P. knowlesi.[22][23] P. falciparum is the most
common cause of infection, and is also responsible for about 90% of the deaths from malaria.
[24]
Parasitic Plasmodium species also infect birds, reptiles, monkeys, chimpanzees and rodents.[25] There
have been documented human infections with severalsimian species of malaria, namely P. knowlesi, P.
inui, P. cynomolgi,[26] P. simiovale, P. brazilianum, P. schwetzi and P. simium; however, with the exception
of P. knowlesi, these are mostly of limited public health importance.[27]

Malaria parasites contain apicoplasts, an organelle usually found in plants, complete with their own
functioning genomes. These apicoplast are thought to have originated through the endosymbiosis of
algae[28] and play a crucial role in various aspects of parasite metabolism e.g. fatty acid bio-synthesis.
[29]
 To date, 466 proteins have been found to be produced by apicoplasts[30] and these are now being
looked at as possible targets for novel anti-malarial drugs.

[edit]Life cycle
The parasite's secondary (intermediate) hosts are humans and other vertebrates. Female mosquitoes of
the Anopheles genus are primary hosts and transmission vectors. Young mosquitoes first ingest the
malaria parasite by feeding on an infected human carrier and the infected Anopheles mosquitoes
carry Plasmodium sporozoites in their salivary glands. A mosquito becomes infected when it takes a
blood meal from an infected human. Once ingested, the parasite gametocytes taken up in the blood will
further differentiate into male or female gametes and then fuse in the mosquito's gut. This produces
anookinete that penetrates the gut lining and produces an oocyst in the gut wall. When the oocyst
ruptures, it releases sporozoites that migrate through the mosquito's body to the salivary glands, where
they are then ready to infect a new human host. This type of transmission is occasionally referred to as
anterior station transfer.[31] The sporozoites are injected into the skin, alongside saliva, when the mosquito
takes a subsequent blood meal.

Only female mosquitoes feed on blood while male mosquitoes feed on plant nectar,[32] thus males do not
transmit the disease. The females of the Anophelesgenus 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.[33]
[edit]Recurrent malaria

Malaria recurs after treatment for three reasons. 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.[18] Approximately one in five of P. vivax malaria cases in temperate areas
involve overwintering by hypnozoites (i.e., relapses begin the year after the mosquito bite).[34]

[edit]Pathogenesis

Further information: Plasmodium falciparum biology

The life cycle of malaria parasites in the human body. A mosquito infects a person by taking a blood meal. First, sporozoites
enter the bloodstream, and migrate to the liver. They infect liver cells (hepatocytes), where they multiply into merozoites,
rupture the liver cells, and escape back into the bloodstream. Then, the merozoites infect red blood cells, where they
develop into ring forms, trophozoites and schizonts which in turn produce further merozoites. Sexual forms (gametocytes)
are also produced, which, if taken up by a mosquito, will infect the insect and continue the life cycle.

Malaria develops via two phases: an exoerythrocytic and an erythrocytic phase. The exoerythrocytic
phase involves infection of the hepatic system, or liver, whereas the erythrocytic phase involves infection
of the erythrocytes, or red blood cells. 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. Within minutes
of being introduced into the human host, the sporozoites infect hepatocytes, multiplying asexually and
asymptomatically for a period of 8–30 days.[35] Once 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, thus beginning the erythrocytic stage of the life cycle.[35] The parasite escapes from the liver
undetected by wrapping itself in the cell membrane of the infected host liver cell.[36]

Within the red blood cells, the parasites multiply further, again asexually, periodically breaking out of their
hosts 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 and P. ovale sporozoites do not immediately develop into exoerythrocytic-phase

merozoites, but instead produce hypnozoites that remain dormant for periods ranging from several
months (6–12 months is typical) to as long as three years. After a period of dormancy, they reactivate and
produce merozoites. Hypnozoites are responsible for long incubation and late relapses in these two
species of malaria.[37]

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.[38] This "stickiness" is the main factor giving rise
tohemorrhagic complications of malaria. High endothelial venules (the smallest branches of the
circulatory system) can be blocked by the attachment of masses of these infected red blood cells. The
blockage of these vessels causes symptoms such as in placental and cerebral malaria. In cerebral
malaria the sequestrated red blood cells can breach the blood brain barrier possibly leading to coma.[39]

Although the white blood cell surface adhesive proteins (called PfEMP1, for Plasmodium
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 effectively limitless versions within parasite populations.[38] The parasite
switches between a broad repertoire of PfEMP17 surface proteins, thus staying one step ahead of the
pursuing immune system.

Some merozoites turn into male and female gametocytes. Since the gametocytes are formed in the blood
of the vertebrate host, the vertebrate host is the definitive host of the disease. If a mosquito pierces the
skin of an infected person, it potentially picks up gametocytes within the blood. Fertilization and sexual
recombination of the parasite occurs in the mosquito's gut. New sporozoites develop and travel to the
mosquito's salivary gland, completing the cycle. Pregnant women are especially attractive to the
mosquitoes,[40] and malaria in pregnant women is an important cause of stillbirths, infant mortality and low
birth weight,[41] particularly in P. falciparum infection, but also in other species infection, such as P. vivax.
[42]

[edit]Genetic resistance
Main article:  Genetic resistance to malaria

Malaria is thought to have been the greatest selective pressure on the human genome in recent history.
[43]
 This is due to the high levels of mortality and morbidity caused by malaria, especially the P.
falciparum species. A number of diseases may provide some resistance to it including sickle cell
disease, thalassaemias, glucose-6-phosphate dehydrogenase, Duffy antigens, and possibly others.

[edit]Diagnosis

The mainstay of malaria diagnosis has been the microscopic examination of blood.[44] Although blood is
the sample most frequently used to make a diagnosis, both saliva and urine have been investigated as
alternative, less invasive specimens.[45]

Areas that cannot afford laboratory diagnostic tests often use only a history of subjective fever as the
indication to treat for malaria. Using Giemsa-stained blood smears from children in Malawi, one study
showed that when clinical predictors (rectal temperature, nailbed pallor, and splenomegaly) were used as
treatment indications, rather than using only a history of subjective fevers, a correct diagnosis increased
from 2% to 41% of cases, and unnecessary treatment for malaria was significantly decreased.[46]

[edit]Blood films

Species Appearance Periodicity Liver persistent

Plasmodium vivax tertian yes

 Plasmodium ovale tertian yes

Plasmodium
tertian no
falciparum

Plasmodium malariae quartan no

The most economic, preferred, and reliable diagnosis of malaria is microscopic examination of blood
films because each of the four major parasite species has distinguishing characteristics. Two sorts of
blood film are traditionally used. Thin films are similar to usual blood films and allow species identification
because the parasite's appearance is best preserved in this preparation. Thick films allow the
microscopist to screen a larger volume of blood and are about eleven times more sensitive than the thin
film, so picking up low levels of infection is easier on the thick film, but the appearance of the parasite is
much more distorted and therefore distinguishing between the different species can be much more
difficult. With the pros and cons of both thick and thin smears taken into consideration, it is imperative to
utilize both smears while attempting to make a definitive diagnosis.[47]

From the thick film, an experienced microscopist can detect parasite levels (or parasitemia) down to as
low as 0.0000001% of red blood cells. Diagnosis of species can be difficult because the early
trophozoites ("ring form") of all four species look identical and it is never possible to diagnose species on
the basis of a single ring form; species identification is always based on several trophozoites.

One important thing to note is that P. malariae and P. knowlesi (which is the most common cause of
malaria in South-east Asia) look very similar under the microscope. However, P. knowlesi parasitemia
increases very fast and causes more severe disease than P. malariae, so it is important to identify and
treat infections quickly. Therefore modern methods such as PCR (see "Molecular methods" below)
or monoclonal antibody panels that can distinguish between the two should be used in this part of the
world.[48]

[edit]Antigen tests
See also:  Malaria antigen detection tests
For areas where microscopy is not available, or where laboratory staff are not experienced at malaria
diagnosis, there are commercial antigen detection tests that require only a drop of blood.
[49]
Immunochromatographic tests (also called: Malaria Rapid Diagnostic Tests, Antigen-Capture Assay or
"Dipsticks") have been developed, distributed and fieldtested. These tests use finger-stick or venous
blood, the completed test takes a total of 15–20 minutes, and the results are read visually as the
presence or absence of colored stripes on the dipstick, so they are suitable for use in the field. The
threshold of detection by these rapid diagnostic tests is in the range of 100 parasites/µl of blood
(commercial kits can range from about 0.002% to 0.1% parasitemia) compared to 5 by thick film
microscopy. One disadvantage is that dipstick tests are qualitative but not quantitative – they can
determine if parasites are present in the blood, but not how many.

The first rapid diagnostic tests were using P. falciparum glutamate dehydrogenase as antigen.[50] PGluDH
was soon replaced by P.falciparum lactate dehydrogenase, a 33 kDa oxidoreductase [EC 1.1.1.27]. It is
the last enzyme of the glycolytic pathway, essential for ATP generation and one of the most abundant
enzymes expressed by P.falciparum. PLDH does not persist in the blood but clears about the same time
as the parasites following successful treatment. The lack of antigen persistence after treatment makes the
pLDH test useful in predicting treatment failure. In this respect, pLDH is similar to pGluDH. Depending on
which monoclonal antibodies are used, this type of assay can distinguish between all five different
species of human malaria parasites, because of antigenic differences between their pLDH isoenzymes.

[edit]Molecular methods
Molecular methods are available in some clinical laboratories and rapid real-time assays (for
example, QT-NASBA based on the polymerase chain reaction)[51] are being developed with the hope of
being able to deploy them in endemic areas.

PCR (and other molecular methods) is more accurate than microscopy. However, it is expensive, and
requires a specialized laboratory. Moreover, levels of parasitemia are not necessarily correlative with the
progression of disease, particularly when the parasite is able to adhere to blood vessel walls. Therefore
more sensitive, low-tech diagnosis tools need to be developed in order to detect low levels of parasitemia
in the field.[52]

[edit]Differential

Fever and septic shock are commonly misdiagnosed as severe malaria in Africa, leading to a failure to
treat other life-threatening illnesses. In malaria-endemic areas, parasitemia does not ensure a diagnosis
of severe malaria, because parasitemia can be incidental to other concurrent disease. Recent
investigations suggest that malarial retinopathy is better (collective sensitivity of 95% and specificity of
90%) than any other clinical or laboratory feature in distinguishing malarial from non-malarial coma.[53]

[edit]Prevention
Anopheles albimanus mosquito feeding on a human arm. This mosquito is a vector of malaria and mosquito control is a very
effective way of reducing the incidence of malaria.

Methods used in order to prevent the spread of disease, or to protect individuals in areas where malaria is
endemic, include prophylactic drugs, mosquito eradication and the prevention of mosquito bites.

The continued existence 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 sooner or later disappear
from that area, as happened in North America, Europe and much of 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.[citation needed] 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. Economic adviser Jeffrey Sachs estimates that malaria can be controlled for US$3 billion in aid
per year.[54]

A 2008 study that examined international financing of malaria control found large regional variations in the
levels of average annual per capita funding ranging from US$0.01 in Myanmar to US$147 in Suriname.
The study found 34 countries where the funding was less than US$1 per capita, including 16 countries
where annual malaria support was less than US$0.5. The 16 countries included 710 million people or
50% of the global population exposed to the risks of malaria transmission, including seven of the poorest
countries in Africa (Côte d'Ivoire, Republic of the Congo, Chad, Mali, Democratic Republic of the Congo,
Somalia, and Guinea) and two of the most densely populated stable endemic countries in the world
(Indonesia and India).[55]

Brazil, Eritrea, India, and Vietnam, unlike many other developing nations, have successfully reduced the
malaria burden. Common success factors have included conducive country conditions, a targeted
technical approach using a package of effective tools, data-driven decision-making, active leadership at
all levels of government, involvement of communities, decentralized implementation and control of
finances, skilled technical and managerial capacity at national and sub-national levels, hands-on technical
and programmatic support from partner agencies, and sufficient and flexible financing.[56]

[edit]Medications
Main article:  Malaria prophylaxis

Several drugs, most of which are also used for treatment of malaria, can be taken preventively. Modern
drugs used include mefloquine (Lariam), doxycycline (available generically), and the combination
of atovaquone and proguanil hydrochloride (Malarone). Doxycycline and the atovaquone and proguanil
combination are the best tolerated with mefloquine associated with higher rates of neurological and
psychiatric symptoms.[57] The choice of which drug to use depends on which drugs the parasites in the
area are resistant to, as well as side-effects and other considerations. The prophylactic effect does not
begin immediately upon starting taking the drugs, so people temporarily visiting malaria-endemic areas
usually begin taking the drugs one to two weeks before arriving and must continue taking them for 4
weeks after leaving (with the exception of atovaquone proguanil that only needs be started 2 days prior
and continued for 7 days afterwards). Generally, these drugs are taken daily or weekly, at a lower dose
than would be used for treatment of a person who had actually contracted 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 side effects from long-term use, and because some effective anti-malarial
drugs are difficult to obtain outside of wealthy nations.

Quinine was used historically, however the development of more effective alternatives such
as quinacrine, chloroquine, and primaquine in the 20th century reduced its use. Today, quinine is not
generally used for prophylaxis. The use of prophylactic drugs where malaria-bearing mosquitoes are
present may encourage the development of partial immunity.[58]

[edit]Vector control
Further information: Mosquito control

Efforts to eradicate malaria by eliminating mosquitoes have been successful in some 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. In some areas, the
draining of wetland breeding grounds and better sanitation were adequate. 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 by 1951[59] (see National Malaria
Eradication Program). In 2002, there were 1,059 cases of malaria reported in the US, including eight
deaths, but in only five of those cases was the disease contracted in the United States.
Before DDT, malaria was successfully eradicated or controlled also in several tropical areas by removing
or poisoning the breeding grounds of the mosquitoes or the aquatic habitats of the larva stages, for
example by filling or applying oil to places with standing water. These methods have seen little application
in Africa for more than half a century.[60]

Sterile insect technique is emerging as a potential mosquito control method. Progress towards transgenic,
or genetically modified, insects suggest that wild mosquito populations could be made malaria-resistant.
Researchers at Imperial College London created the world's first transgenic malaria mosquito,[61] with the
first plasmodium-resistant species announced by a team at Case Western Reserve University in Ohio in
2002.[62] Successful replacement of current populations with a new genetically modified population, relies
upon a drive mechanism, such as transposable elements to allow for non-Mendelian inheritance of the
gene of interest. However, this approach contains many difficulties and success is a distant prospect.
[63]
 An even more futuristic method of vector control is the idea that lasers could be used to kill flying
mosquitoes.[64]

[edit]Indoor residual spraying

Main articles:  Indoor residual spraying and  DDT use against malaria

Indoor residual spraying (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 mosquitos will be
killed before they can bite another victim, transferring the malaria parasite.

The first pesticide used for IRS was DDT.[59] 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. The overuse of anti-bacterial soaps and antibiotics led to antibiotic resistance in
bacteria, similar to how overspraying of DDT on crops led to DDT resistance in Anopheles mosquitoes.
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. Since the use of DDT
has been limited or banned for agricultural use for some time, DDT may now be more effective as a
method of disease-control.

Although DDT has never been banned for use in malaria control and there are several other insecticides
suitable for IRS, some advocates have claimed that bans are responsible for tens of millions of deaths in
tropical countries where DDT had once been effective in controlling malaria. Furthermore, most of the
problems associated with DDT use stem specifically from its industrial-scale application in agriculture,
rather than its use in public health.[65]
The World Health Organization (WHO) currently advises the use of 12 different insecticides in IRS
operations, including DDT as well as alternative insecticides (such as the
pyrethroids permethrin anddeltamethrin).[66] 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.[67]However, because of its legacy, many developed countries previously discouraged DDT
use even in small quantities.[68]

One problem with all forms of Indoor Residual Spraying is insecticide resistance via evolution of
mosquitos. According to a study published on Mosquito Behavior and Vector Control, mosquito species
that are affected by IRS are endophilic species (species that tend to rest and live indoors), and due to the
irritation caused by spraying, their evolutionary descendants are trending towards becoming exophilic
(species that tend to rest and live out of doors), meaning that they are not as affected—if affected at all—
by the IRS, rendering it somewhat useless as a defense mechanism.[69]
[edit]Mosquito nets and bedclothes
Main article:  Mosquito net

Mosquito nets help keep mosquitoes away from people and greatly reduce the infection 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 (ITNs) are
estimated to be twice as effective as untreated nets and offer greater than 70% protection compared with
no net.[70] Although ITNs are proven to be very effective against malaria, less than 2% of children in urban
areas in Sub-Saharan Africa are protected by ITNs. Since theAnopheles mosquitoes feed at night, the
preferred method is to hang a large "bed net" above the center of a bed such that it drapes down and
covers the bed completely.

[edit]Vaccination
Main article:  Malaria vaccine

Immunity (or, more accurately, tolerance) does occur naturally, but only in response to repeated infection
with multiple strains of malaria.[71] Vaccines for malaria are under development, with no completely
effective vaccine yet available. The first promising studies demonstrating the potential for a malaria
vaccine were performed in 1967 by immunizing mice with live, radiation-attenuatedsporozoites, providing
protection to about 60% of the mice upon subsequent injection with normal, viable sporozoites.[72] Since
the 1970s, there has been a considerable effort to develop similar vaccination strategies within humans. It
was determined that an individual can be protected from a P. falciparum infection if they receive over
1,000 bites from infected yet irradiated mosquitoes.[73]

[edit]Other methods
Education in recognizing the symptoms of malaria has reduced the number of cases in some areas of the
developing world by as much as 20%. Recognizing the disease in the early stages can also stop the
disease from becoming a killer. Education can also inform people to cover over areas of stagnant, still
water e.g. Water Tanks which are ideal breeding grounds for the parasite and mosquito, thus cutting
down the risk of the transmission between people. This is most put in practice in urban areas where there
are large centers of population in a confined space and transmission would be most likely in these areas.

The Malaria Control Project is currently using downtime computing power donated by individual
volunteers around the world (see Volunteer computing and BOINC) to simulate models of the health
effects and transmission dynamics in order to find the best method or combination of methods for malaria
control. This modeling is extremely computer intensive due to the simulations of large human populations
with a vast range of parameters related to biological and social factors that influence the spread of the
disease. It is expected to take a few months using volunteered computing power compared to the 40
years it would have taken with the current resources available to the scientists who developed the
program.[74]

An example of the importance of computer modeling in planning malaria eradication programs is shown in

the paper by Águas and others. They showed that eradication of malaria is crucially dependent on finding
and treating the large number of people in endemic areas with asymptomatic malaria, who act as a
reservoir for infection.[75] The malaria parasites do not affect animal species and therefore eradication of
the disease from the human population would be expected to be effective.

Other interventions for the control of malaria include mass drug administrations and intermittent

preventive therapy.

Furthering attempts to reduce transmission rates, a proposed alternative to mosquito nets is the mosquito
laser, or photonic fence, which identifies female mosquitoes and shoots them using a medium-
powered laser.[76] The device is currently undergoing commercial development, although instructions for
a DIY version of the photonic fence have also been published.[77]

Another way of reducing the malaria transmitted to humans from mosquitoes has been developed by the
University of Arizona. They have engineered a mosquito to become resistant to malaria. This was
reported on the 16 July 2010 in the journal PLoS Pathogens.[78] With the ultimate end being that the
release of this GM mosquito into the environment, Gareth Lycett, a malaria researcher from Liverpool
School of Tropical Medicine told the BBC that "It is another step on the journey towards potentially
assisting malaria control through GM mosquito release."[79]

[edit]Treatment

Further information: Antimalarial drug

When properly treated, a patient with malaria can expect a complete recovery.[80] The treatment of malaria
depends on the severity of the disease; whether patients who can take oral drugs have to be admitted
depends on the assessment and the experience of the clinician. Uncomplicated malaria is treated with
oral drugs. The most effective strategy for P. falciparum infection recommended byWHO is the use of
artemisinins in combination with other antimalarials artemisinin-combination therapy, ACT, in order to
avoid the development of drug resistance against artemisinin-based therapies.

Severe malaria requires the parenteral administration of antimalarial drugs. Until recently the most used
treatment for severe malaria was quinine but artesunate has been shown to be superior to quinine in both
children [81] and adults.[82] Treatment of severe malaria also involves supportive measures.

Infection with P. vivax, P. ovale or P. malariae is usually treated on an outpatient basis. Treatment of P.
vivax requires both treatment of blood stages (with chloroquine or ACT) as well as clearance of liver
forms with primaquine.

[edit]Epidemiology

Countries which have regions where malaria is endemic as of 2003 (coloured yellow).[83] Countries in green are free of
indigenous cases of malaria in all areas.

Disability-adjusted life year for malaria per 100,000 inhabitants in 2002.

  no data
  ≤10
  10–50
  50–100
  100–250
  250–500
  500–1000
  1000–1500
  1500–2000
  2000–2500
  2500–3000
  3000–3500
  ≥3500

It is estimated that malaria causes 250 million cases of fever and approximately one million deaths
annually.[84] The vast majority of cases occur in children under 5 years old;[85] pregnant women are also
especially vulnerable. Despite efforts to reduce transmission and increase treatment, there has been little
change in which areas are at risk of this disease since 1992.[86] Indeed, if the prevalence of malaria stays
on its present upwards course, the death rate could double in the next twenty years.[87] Precise statistics
are unknown because many cases occur in rural areas where people do not have access to hospitals or
the means to afford health care. As a consequence, the majority of cases are undocumented.[87]

Although co-infection with HIV and malaria does cause increased mortality, this is less of a problem than
with HIV/tuberculosis co-infection, due to the two diseases usually attacking different age-ranges, with
malaria being most common in the young and active tuberculosis most common in the old.[88] Although
HIV/malaria co-infection produces less severe symptoms than the interaction between HIV and TB, HIV
and malaria do contribute to each other's spread. This effect comes from malaria increasing viral load and
HIV infection increasing a person's susceptibility to malaria infection.[89]

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.[90] The geographic distribution of malaria within large regions is complex, and malaria-afflicted and
malaria-free areas are often found close to each other.[91] In drier areas, outbreaks of malaria can be
predicted with reasonable accuracy by mapping rainfall.[92] Malaria is more common in rural areas than in
cities; this is in contrast to dengue fever where urban areas present the greater risk.[93] For example,
several cities in Vietnam, Laos and Cambodia are essentially malaria-free, but the disease is present in
many rural regions.[94] By contrast, in Africa malaria is present in both rural and urban areas, though the
risk is lower in the larger cities.[95] The global endemic levels of malaria have not been mapped since the
1960s. However, the Wellcome Trust, UK, has funded the Malaria Atlas Project[96] to rectify this, providing
a more contemporary and robust means with which to assess current and future malaria disease burden.

[edit]History

Main article:  History of malaria

Malaria has infected humans for over 50,000 years, and Plasmodium may have been a
human pathogen for the entire history of the species.[97] Close relatives of the human malaria parasites
remain common in chimpanzees.[98] Some new evidence suggests that the most virulent strain of human
malaria may have originated in gorillas.[99]

References to the unique periodic fevers of malaria are found throughout recorded history, beginning in
2700 BC in China.[100] Malaria may have contributed to the decline of the Roman Empire,[101] and was so
pervasive in Rome that it was known as the "Roman fever".[102] The term malaria originates
from MedievalItalian: mala aria — "bad air"; the disease was formerly called ague or marsh fever due to
its association with swamps and marshland.[103] Malaria was once common in most of Europe and North
America,[104] where it is no longer endemic,[105] though imported cases do occur.[106]

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.[107] According to Joseph Patrick Byrne,
"Sixty thousand American soldiers died of malaria during the African and South Pacific campaigns."[108]

[edit]Prevention

An early effort at malaria prevention occurred in 1896, just before the mosquito malaria link was
confirmed in India by a British physician, Ronald Ross. An 1896 Uxbridge malaria outbreak prompted
health officer, Dr. Leonard White, to write a report to the Massachusetts State Board of Health, which led
to study of mosquito-malaria links, and the first efforts for malaria prevention.
[109]
Massachusetts State pathologist Theobald Smith, asked that White's son collect mosquito specimens
for further analysis, and that citizens 1) add screens to windows, and 2) drain collections of water.
[109]
 Carlos Finlay was also engaged in mosquito related research, and mosquito borne disease theory, in
the 1880s in Cuba, basing his work on the study of Yellow Fever.

[edit]Discovery of the parasite

Dr. Probert's Malarial Remedy,

"Will cure chills and fever, dyspepsia & c. Will cure bilious fever, liver complaint & c.", c.1881, New York
A continuous P. falciparum culture was established in 1976

Scientific studies on malaria made their first significant advance in 1880, when a French army doctor
working in the military hospital of Constantine in Algerianamed Charles Louis Alphonse Laveran observed
parasites for the first time, inside the red blood cells of people suffering from malaria. He, therefore,
proposed that malaria is caused by this organism, the first time a protist was identified as causing
disease.[110] 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 andAngelo Celli.[111]

[edit]Discovery of mosquito transmission

A year later, Carlos Finlay, a Cuban doctor treating patients with yellow fever in Havana, provided strong
evidence that mosquitoes were transmitting disease to and from humans.[112] This work followed earlier
suggestions by Josiah C. Nott,[113] and work by Patrick Manson on the transmission of filariasis.[114]

It was Britain's Sir Ronald Ross, working in the Presidency General Hospital in Calcutta, who finally
proved in 1898 that malaria is transmitted by mosquitoes. He did this 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.[115] 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.[116] 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 inthe 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.

[edit]The liver stage

Shortt and Garnham discovered the pre-erythrocytic liver stage, first in the primate parasite P.
cynomolgi and subsequently the human malarias P. vivax [117]and P. falciparum.[118] Further work
confirmed the transformation of sporozoites from mosquitoes into liver forms, essentially completing
documentation of the lifecycle.[119]

[edit]In vitro culture

The first successful continuous in vitro malaria culture was established in 1976 by William Trager and
James B. Jensen, which facilitated research into the molecular biology of the parasite and the
development of new drugs.[120][121]

[edit]History of treatment
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 inPeru. The indigenous peoples of Peru made a tincture of
cinchona to control malaria. The Jesuits noted the efficacy of the practice and introduced the treatment to
Europe during the 1640s, where it was rapidly accepted.[122] 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.[123] In the 20th century, chloroquine replaced quinine as
treatment of both uncomplicated and severe falciparum malaria until resistance supervened. Artemisinins,
discovered by Chinese scientists in the 1970s, are now recommended treatment for falciparum malaria,
administered in combination with other antimalarials as well as in severe disease.

[edit]Society and culture

Malaria is not just a disease commonly associated with poverty but 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.[124] 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.[125]

Poverty is both cause and effect, however, since the poor do not have the financial capacities to prevent
or treat the disease. The lowest income group in Malawi carries (1994) the burden of having 32% of their
annual income used on this disease compared with the 4% of household incomes from low-to-high
groups.[126] 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.[85] In some countries with a heavy malaria burden, the disease may account for
as much as 40% of public health expenditure, 30–50% of inpatient admissions, and up to 50% of
outpatient visits.[127]

A study on the effect of malaria on IQ in a sample of Mexicans found that exposure during the birth year
to malaria eradication was associated with increases in IQ. It also increased the probability of
employment in a skilled occupation. The author suggests that this may be one explanation for the Flynn
effect and that this may be an important explanation for the link between national malaria burden and
economic development.[128] A literature review of 44 papers states that cognitive abilities and school
performance were shown to be impaired in sub-groups of patients (with either cerebral malaria or
uncomplicated malaria) when compared with healthy controls. Studies comparing cognitive functions
before and after treatment for acute malarial illness continued to show significantly impaired school
performance and cognitive abilities even after recovery. Malaria prophylaxis was shown to improve
cognitive function and school performance in clinical trials when compared to placebo groups.[129]

[edit]Counterfeit drugs
Sophisticated counterfeits have been found in several Asian countries such as Cambodia,[130] China,
[131]
 Indonesia, Laos, Thailand, Vietnam and are an important cause of avoidable death in those countries.
[132]
 WHO have 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.[133] 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.

[edit]War

Throughout history, the contraction of malaria (via natural outbreaks as well as via infliction of the disease
as a biological warfare agent) has played a prominent role in the fortunes of government rulers, nation-
states, military personnel, and military actions. "Malaria Site: History of Malaria During Wars" addresses
the devastating impact of malaria in numerous well-known conflicts, beginning in June 323 B.C. That
site's authors note: "Many great warriors succumbed to malaria after returning from the warfront and
advance of armies into continents was prevented by malaria. In many conflicts, more troops were killed by
malaria than in combat."[134] The Centers for Disease Control ("CDC") traces the history of malaria and its
impacts farther back, to 2700 BCE.[135]

In 1910, Nobel Prize in Medicine-winner Ronald Ross (himself a malaria survivor), published a book

titled The Prevention of Malaria that included the chapter: "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 and advised: "A specially
selected medical officer should be placed in charge of these operations with executive and disciplinary
powers [...]."

Significant financial investments have been made to fund procure existing and create new anti-malarial
agents. During World War I and World War II, the supplies of the natural anti-malaria drugs,cinchona
bark and quinine, proved to be inadequate to supply military personnel and substantial funding was
funnelled 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.[134]

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) 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" and, during these activities, to "train state and local health department officials in malaria
control techniques and strategies." The CDC's Malaria Division continued that mission, successfully
reducing malaria in the United States, after which the organization expanded its focus to include
"prevention, surveillance, and technical support both domestically and internationally."[135]

[edit]Popular culture

 Joseph Conrad, author of the novella Heart of Darkness (published in serial form in 1899 and as

a novella in 1902), contracted malaria while on a four-month steamboat voyage along the Congo
River.[136] One character in the book, an ivory trader named Kurtz, dies from the disease[136] and
the novella's narrator, Charles Marlow, is weakened by it.
 In making the movie The African Queen (1951), most of the crew and the leading lady, Katharine
Hepburn, endured malaria.[137][138][139]
 In the movie Apocalypse Now (1979), Captain Benjamin L. Willard is a special operations veteran
stationed in Southeast Asia during the Vietnam war. Willard is assigned a classified mission to
assassinate rogue soldier, Colonel Walter E. Kurtz, who has gone insane and is commanding a
legion of his own Montagnard troops in neutral Cambodia. Upon finding Kurtz's location, Willard
narrates: "It smelled like slow death in there, malaria, and nightmares. This was the end of the river,
all right."[140]
 In Barbara Kingsolver's novel, The Poisonwood Bible (1998), Ruth May – the youngest daughter
of an American Christian missionary who brings his family to live in the Belgian Congo of the late
1950s – stops taking her quinine tablets and contracts malaria.[141]
[edit]Research
With the onset of drug resistant Plasmodium parasites, new strategies are required to combat the
widespread disease. One such approach lies in the introduction of synthetic pyridoxal-amino acid
adducts, which are channelled into the parasite. Thus, trapped upon phosphorylation by plasmodial PdxK
(pyridoxine/pyridoxal kinase), the proliferation of Plasmodium parasites is effectively hindered by a novel
compound, PT3, a cyclic pyridoxyl-tryptophan methyl ester, without harming human cells.[142]

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 WHO site on malaria

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