Malaria 

is a mosquito-borne infectious disease caused by a eukaryotic protist of the genus Plasmodium.

It is widespread in tropical and subtropical regions, including parts of the Americas (22 countries), Asia,
and Africa. Each year, there are more than 250 million cases of malaria,[1] killing between one and three
million people, the majority of whom are young children in sub-Saharan Africa.[2] 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[3] and a major hindrance to economic development.

Five species of the plasmodium parasite can infect humans: the most serious forms of the disease are
caused by Plasmodium falciparum. Malaria caused by Plasmodium vivax, Plasmodium
ovale and Plasmodium malariae causes milder disease in humans that is not generally fatal. A fifth
species,Plasmodium knowlesi, is a zoonosis that causes malaria in macaques but can also infect
humans.[4][5]

Malaria is naturally transmitted by the bite of a female Anopheles mosquito. When a mosquito bites an

infected person, a small amount of blood is taken, which contains malaria parasites. These develop within
the mosquito, and about one week later, when the mosquito takes its next blood meal, the parasites are
injected with the mosquito's saliva into the person being bitten. After a period of between two weeks and
several months (occasionally years) spent in the liver, the malaria parasites start to multiply within red
blood cells, causing symptoms that include fever, and headache. In severe cases the disease worsens
leading to hallucinations, coma, and death.

A wide variety of antimalarial drugs are available to treat malaria. 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.[6] Several drugs are also available to prevent
malaria in travellers to malaria-endemic countries (prophylaxis). Resistance has developed to several
antimalarial drugs, most notably chloroquine.[7]

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.[8]

Signs and symptoms

Main symptoms of malaria.[9]

Typical fever patterns in Malaria

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

by hemolysis), hemoglobinuria, retinal damage,[10] 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.[11] 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.[12] 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.[13][14] Cerebral
malaria is associated with retinal whitening,[15] which may be a useful clinical sign in distinguishing malaria
from other causes of fever.[16]

Severe malaria is almost exclusively caused by P. falciparum infection, and usually arises 6–14 days after
infection.[17] 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 withrenal
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.[17] In the most severe cases of the disease, fatality rates can exceed 20%, even with intensive care
and treatment.[18] 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.[19] Over the longer term, developmental impairments have
been documented in children who have suffered episodes of severe malaria.[20]

Chronic malaria is seen in both P. vivax and P. ovale, but not in P. falciparum. Here, the disease can
relapse months or years after exposure, due to the presence of latent parasites 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.
[17]
 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).[21]

Causes

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

[edit]Malaria parasites
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 responsible for about 80% of all malaria cases, 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
several simian 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]Mosquito vectors and the Plasmodium life cycle

The parasite's primary (definitive) hosts and transmission vectors are female mosquitoes of
the Anopheles genus, while humans and other vertebrates are secondary hosts. Young mosquitoes first
ingest the malaria parasite by feeding on an infected human carrier and the
infected Anopheles mosquitoes carryPlasmodium 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 gut. This produces an ookinetethat 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, thus males 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.[32]

[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 in humans 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.[33] 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.
[33]
 The parasite escapes from the liver undetected by wrapping itself in the cell membrane of the infected
host liver cell.[34]

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.[35]

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.[36] 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.[37]
Although the red 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.[36] The parasite
switches between a broad repertoire of PfEMP1 surface proteins, thus staying one step ahead of the
pursuing immune system.

Some merozoites turn into male and female gametocytes. 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, thereby defining the mosquito as the definitive host of the disease.
New sporozoites develop and travel to the mosquito's salivary gland, completing the cycle. Pregnant
women are especially attractive to the mosquitoes,[38] and malaria in pregnant women is an important
cause of stillbirths, infant mortality and low birth weight,[39]particularly in P. falciparum infection, but also in
other species infection, such as P. vivax.[40]

[edit]Diagnosis

Further information: Romanowsky stain,  Malaria antigen detection tests

Blood smear from a P. falciparum culture(K1 strain). Several red blood cells have ring stages inside them. Close to the
center there is a schizont and on the left a trophozoite.

Since Charles Laveran first visualised the malaria parasite in blood in 1880,[41] the mainstay of malaria
diagnosis has been the microscopic examination of blood.

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.[42]
Although blood is the sample most frequently used to make a diagnosis, both saliva and urine have been
investigated as alternative, less invasive specimens.[41]

[edit]Symptomatic diagnosis
Areas that cannot afford even simple 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 21% to 41% of cases, and unnecessary treatment for malaria was significantly
decreased.[43]

[edit]Microscopic examination of blood films

For more details on individual parasites, see  P. falciparum,  P. vivax, P. ovale,  P. malariae,  P. knowlesi.

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.[44]

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. knowlesiparasitemia
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.[45]

[edit]Antigen tests
Further information: 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.
[46]
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.[47] 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)[48] 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.[49]

[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 favors the parasite's reproduction.[citation needed] Many countries are seeing an increasing
number of imported malaria cases due 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.[50]

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).[51]

Brazil, Eritrea, India, and Vietnam have, unlike many other developing nations, successfully reduced the
malaria burden. Common success factors 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.[52]

[edit]Prophylactic drugs
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.[53] 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.[54]

[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.[55] 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.[56]
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,[57] with the
first plasmodium-resistant species announced by a team at Case Western Reserve University in Ohio in
2002.[58] 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.
[59]
 An even more futuristic method of vector control is the idea that lasers could be used to kill flying
mosquitoes.[60]
[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.[55] 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.[61]

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).[62] 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.[63]However, because of its legacy, many developed countries previously discouraged DDT
use even in small quantities.[64]

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.[65]
[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.[66] 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.

The distribution of mosquito nets impregnated with insecticides such as permethrin or deltamethrin has
been shown to be an extremely effective method of malaria prevention, and it is also one of the most
cost-effective methods of prevention. These nets can often be obtained for around US$2.50 to US$3.50
(€2 to €3) from the United Nations, the World Health Organization (WHO), and others. ITNs have been
shown to be the most cost-effective prevention method against malaria and are part of WHO’s Millennium
Development Goals (MDGs).

While some experts argue that international organizations should distribute ITNs and LLINs to people for
free in order to maximize coverage (since such a policy would reduce price barriers), others insist that
cost-sharing between the international organization and recipients would lead to greater usage of the net
(arguing that people will value a net more if they pay for it). Additionally, proponents of cost-sharing argue
that such a policy ensures that nets are efficiently allocated to those people who most need them (or are
most vulnerable to infection). Through a "selection effect", they argue, those people who most need the
bed nets will choose to purchase them, while those less in need will opt out.

However, a randomized controlled trial study of ITNs uptake among pregnant women in Kenya,
conducted by economists Pascaline Dupas and Jessica Cohen, found that cost-sharing does not
necessarily increase the usage intensity of ITNs, nor does it induce uptake by those most vulnerable to
infection, as compared to a policy of free distribution.[67] In some cases, cost-sharing can actually
decrease demand for mosquito nets by erecting a price barrier. Dupas and Cohen’s findings support the
argument that free distribution of ITNs can be more effective than cost-sharing in both increasing
coverage and saving lives. In a cost-effectiveness analysis, Dupas and Cohen note that "cost-sharing is
at best marginally more cost-effective than free distribution, but free distribution leads to many more lives
saved."[67]

The researchers base their conclusions about the cost-effectiveness of free distribution on the proven
spillover benefits of increased ITN usage.[68] When a large number of nets are distributed in one
residential area, their chemical additives help reduce the number of mosquitoes in the environment. With
fewer mosquitoes in the environment, the chances of malaria infection for recipients and non-recipients
are significantly reduced. (In other words, the importance of the physical barrier effect of ITNs decreases
relative to the positive externality effect[clarification needed  What does phrase 'positive externality effect' mean?] of the nets in creating
a mosquito-free environment when ITNs are highly concentrated in one residential cluster or community.)

For maximum effectiveness, the nets should be re-impregnated with insecticide every six months. This
process poses a significant logistical problem in rural areas. New technologies like Olyset or DawaPlus
allow for production of long-lasting insecticidal mosquito nets (LLINs), which release insecticide for
approximately 5 years,[69] and cost about US$5.50. ITNs protect people sleeping under the net and
simultaneously kill mosquitoes that contact the net. Some protection is also provided to others by this
method, including people sleeping in the same room but not under the net. However, mathematical
modeling has highlighted certain conditions whereby disease transmission may be exacerbated after bed
nets have lost their insecticidal properties.[70] Although ITN users are still protected by the physical barrier
of the netting, non-users could experience an increased bite rate as mosquitoes are deflected away from
the non-lethal bed net users.[70]

While distributing mosquito nets is a major component of malaria prevention, community education and
awareness on the dangers of malaria are associated with distribution campaigns to make sure people
who receive a net know how to use it. "Hang Up" campaigns, such as the ones conducted by volunteers
of the International Red Cross and Red Crescent Movement consist of visiting households that received a
net at the end of the campaign or just before the rainy season, ensuring that the net is being used
properly and that the people most vulnerable to malaria, such as young children and the elderly, sleep
under it. A study conducted by the CDC in Sierra Leone showed a 22 percent increase in net utilization
following a personal visit from a volunteer living in the same community promoting net usage. A study
in Togo showed similar improvements.[71]
Mosquito nets are often unaffordable to people in developing countries, especially for those most at risk.
Only 1 out of 20 people in Africa own a bed net. Nets are also often distributed though vaccine campaigns
using voucher subsidies, such as the measles campaign for children. A study among Afghan refugees in
Pakistan found that treating top-sheets and chaddars (head coverings) with permethrin has similar
effectiveness to using a treated net, but is much cheaper.[72] Another alternative approach uses spores of
the fungus Beauveria bassiana, sprayed on walls and bed nets, to kill mosquitoes. While some
mosquitoes have developed resistance to chemicals, they have not been found to develop a resistance to
fungal infections.[73]

[edit]Vaccination
Further information: Malaria vaccine

Immunity (or, more accurately, tolerance) does occur naturally, but only in response to repeated infection
with multiple strains of malaria.[74]

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-attenuated sporozoites, providing protection to about 60% of the mice
upon subsequent injection with normal, viable sporozoites.[75] 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,
irradiated mosquitoes.[76]

It has been generally accepted that it is impractical to provide at-risk individuals with this vaccination
strategy, but that has been recently challenged with work being done by Dr. Stephen Hoffman, one of the
key researchers who originally sequenced the genome of Plasmodium falciparum. His work most recently
has revolved around solving the logistical problem of isolating and preparing the parasites equivalent to
1000 irradiated mosquitoes for mass storage and inoculation of human beings. The company has recently
received several multi-million dollar grants from the Bill & Melinda Gates Foundation and the U.S.
government to begin early clinical studies in 2007 and 2008.[77] The Seattle Biomedical Research Institute
(SBRI), funded by the Malaria Vaccine Initiative, assures potential volunteers that "the [2009] clinical trials
won't be a life-threatening experience. While many volunteers [in Seattle] will actually contract malaria,
the cloned strain used in the experiments can be quickly cured, and does not cause a recurring form of
the disease. Some participants will get experimental drugs or vaccines, while others will get placebo."[78]

Instead, much work has been performed to try and understand the immunological processes that provide
protection after immunization with irradiated sporozoites. After the mouse vaccination study in 1967,[75] it
was hypothesized that the injected sporozoites themselves were being recognized by the immune
system, which was in turn creating antibodies against the parasite. It was determined that the immune
system was creating antibodies against the circumsporozoite protein (CSP) which coated the sporozoite.
[79]
 Moreover, antibodies against CSP prevented the sporozoite from invading hepatocytes.[80] CSP was
therefore chosen as the most promising protein on which to develop a vaccine against the malaria
sporozoite. It is for these historical reasons that vaccines based on CSP are the most numerous of all
malaria vaccines.

Presently, there is a huge variety of vaccine candidates on the table. Pre-erythrocytic vaccines (vaccines
that target the parasite before it reaches the blood), in particular vaccines based on CSP, make up the
largest group of research for the malaria vaccine. There have been recent breakthroughs in vaccines that
seek to avoid more severe pathologies of malaria by preventing adherence of the parasite to
blood venules and placenta, but financing is not yet in place for trials.[81] Other potential vaccines include
those that seek to induce immunity to the blood stages of the infection and transmission-blocking
vaccines that would stop the development of the parasite in the mosquito right after the mosquito has
taken a bloodmeal from an infected person.[82] It is hoped that the knowledge of the P.
falciparum genome, the sequencing of which was completed in 2002,[83] will provide targets for new drugs
or vaccines.[84]

The first vaccine developed that has undergone field trials, is the SPf66, developed by Manuel Elkin
Patarroyo in 1987. It presents a combination of antigens from the sporozoite (using CS repeats) and
merozoite parasites. During phase I trials a 75% efficacy rate was demonstrated and the vaccine
appeared to be well tolerated by subjects and immunogenic. The phase IIb and III trials were less
promising, with the efficacy falling to between 38.8% and 60.2%. A trial was carried out in Tanzania in
1993 demonstrating the efficacy to be 31% after a years follow up, however the most recent (though
controversial) study in The Gambia did not show any effect. Despite the relatively long trial periods and
the number of studies carried out, it is still not known how the SPf66 vaccine confers immunity; it
therefore remains an unlikely solution to malaria. The CSP was the next vaccine developed that initially
appeared promising enough to undergo trials. It is also based on the circumsporoziote protein, but
additionally has the recombinant (Asn-Ala-Pro15Asn-Val-Asp-Pro)2-Leu-Arg(R32LR) protein covalently
bound to a purified Pseudomonas aeruginosa toxin (A9). However at an early stage a complete lack of
protective immunity was demonstrated in those inoculated. The study group used in Kenya had an 82%
incidence of parasitaemia whilst the control group only had an 89% incidence. The vaccine intended to
cause an increased T-lymphocyte response in those exposed, this was also not observed.

The efficacy of Patarroyo's vaccine has been disputed with some US scientists concluding in The
Lancet (1997) that "the vaccine was not effective and should be dropped" while the Colombian accused
them of "arrogance" putting down their assertions to the fact that he came from a developing country.
The RTS,S/AS02A vaccine is the candidate furthest along in vaccine trials. It is being developed by a
partnership between the PATH Malaria Vaccine Initiative (a grantee of the Gates Foundation),
thepharmaceutical company, GlaxoSmithKline, and the Walter Reed Army Institute of Research.[85] In the
vaccine, a portion of CSP has been fused to the immunogenic "S antigen" of the hepatitis Bvirus;
this recombinant protein is injected alongside the potent AS02A adjuvant.[82] In October 2004, the
RTS,S/AS02A researchers announced results of a Phase IIb trial, indicating the vaccine reduced infection
risk by approximately 30% and severity of infection by over 50%. The study looked at over
2,000 Mozambican children.[86] More recent testing of the RTS,S/AS02A vaccine has focused on the
safety and efficacy of administering it earlier in infancy: In October 2007, the researchers announced
results of a phase I/IIb trial conducted on 214 Mozambican infants between the ages of 10 and 18 months
in which the full three-dose course of the vaccine led to a 62% reduction of infection with no serious side-
effects save some pain at the point of injection.[87] Further research will delay this vaccine from
commercial release until around 2011.[88]

On 6 April 2010, Crucell, a Dutch biopharmaceutical company, has signed a binding letter of agreement
with GlaxoSmithKline Biologicals (GSK) to collaborate on developing malaria vaccine candidate.

[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.[89]

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.[90] 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.[91] The device is currently undergoing commercial development, although instructions for
a DIY version of the photonic fence have also been published.[92]

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.[93] 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."[94]

[edit]Treatment

Further information: Antimalarial drug

The treatment of malaria depends on the severity of the disease. Uncomplicated malaria is treated with
oral drugs. Whether patients who can take oral drugs have to be admitted depends on the assessment
and the experience of the clinician. Severe malaria requires the parenteral administration of antimalarial
drugs. The traditional treatment for severe malaria has been quinine but there is evidence that
the artemisinins are also superior for the treatment of severe malaria.[citation needed] A large clinical trial is
currently under way to compare the efficacy of quinine and artesunate in the treatment of severe malaria
in African children.[citation needed]

Active malaria infection with P. falciparum is a medical emergency requiring hospitalization. Infection

with P. vivax, P. ovale or P. malariae can often be treated on an outpatient basis. Treatment of malaria
involves supportive measures as well as specific antimalarial drugs. Most antimalarial drugs are produced
industrially and are sold at pharmacies. However, as the cost of such medicines are often too high for
most people in the developing world, some herbal remedies (such as Artemisia annua tea)[95] have also
been developed, and have gained support from international organisations such as Médecins Sans
Frontières. When properly treated, a patient with malaria can expect a complete recovery.[96]

[edit]Counterfeit drugs
Sophisticated counterfeits have been found in several Asian countries such as Cambodia,[97] China,
[98]
 Indonesia, Laos, Thailand, Vietnam and are an important cause of avoidable death in those countries.
[99]
 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.[100] 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]Epidemiology

Further information: Diseases of poverty,  Tropical disease

Countries which have regions where malaria is endemic as of 2003 (coloured yellow).[101] 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

The World Health Organization estimate that malaria causes about 250 million cases of fever and
approximately one million deaths annually.[102] The vast majority of cases occur in children under 5 years
old;[103] 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.
[104]
 Indeed, if the prevalence of malaria stays on its present upwards course, the death rate could double
in the next twenty years.[105] 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.[105]
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.[106] 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.[107]

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.[108] The geographic distribution of malaria within large regions is complex, and malaria-afflicted and
malaria-free areas are often found close to each other.[109] In drier areas, outbreaks of malaria can be
predicted with reasonable accuracy by mapping rainfall.[110] Malaria is more common in rural areas than in
cities; this is in contrast to dengue fever where urban areas present the greater risk.[111] For example,
several cities in Vietnam, Laos and Cambodia are essentially malaria-free, but the disease is present in
many rural regions.[112] By contrast, in Africa malaria is present in both rural and urban areas, though the
risk is lower in the larger cities.[113] The global endemic levels of malaria have not been mapped since the
1960s. However, the Wellcome Trust, UK, has funded the Malaria Atlas Project[114] to rectify this, providing
a more contemporary and robust means with which to assess current and future malaria disease burden.

[edit]History

Further information: 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.[115] Close relatives of the human malaria parasites
remain common in chimpanzees.[116]

References to the unique periodic fevers of malaria are found throughout recorded history, beginning in
2700 BC in China.[117] Malaria may have contributed to the decline of the Roman Empire,[118] and was so
pervasive in Rome that it was known as the "Roman fever".[119] 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.[120] Malaria was once common in most of Europe and North
America,[121] where it is no longer endemic,[122] though imported cases do occur.[123]

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.[124] Sixty thousand American soldiers died
of malaria during the North African and South Pacific campaigns.[125]
[edit]Treatment

Scientific studies on malaria made their first significant advance in 1880, when a French army doctor
working in the military hospital of Constantine in Algeria named Charles Louis Alphonse Laveranobserved
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.[126] 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.[127] 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.[128] This work followed earlier suggestions by Josiah C. Nott,[129] and work by Patrick Manson on
the transmission of filariasis.[130]

Advertisements from Natchez, Mississippi of a popular malaria cure. October 1935.

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.[131] 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.[132] 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.

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.[133] 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.[134]

In the early 20th century, before antibiotics became available, Julius Wagner-Jauregg discovered that

patients with syphilis could be treated by intentionally infecting them with malaria; the resulting fever
would kill the syphilis spirochetes, and quinine could be administered to control the malaria. Although
some patients died from malaria, this was considered preferable to the almost-certain death from syphilis.
[135]

A continuous P. falciparum culture was established in 1976

The first successful continuous 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.[136][137]

Although the blood stage and mosquito stages of the malaria life cycle were identified in the 19th and
early 20th centuries, it was not until the 1980s that the latent liver form of the parasite was observed.[138]
[139]
 The discovery of this latent form of the parasite explained why people could appear to be cured of
malaria but suffer relapse years after the parasite had disappeared from their bloodstreams.