Malaria 1

Malaria

MalariaClassification and external resources

Ring-forms and gametocytes of Plasmodium falciparum in human blood.

ICD-10 B50. [1]

ICD-9 084 [2]

OMIM 248310 [3]

DiseasesDB 7728 [4]

MedlinePlus 000621 [5]

eMedicine med/1385 [6] emerg/305 [7] ped/1357 [8]

MeSH C03.752.250.552 [9]

Malaria is a mosquito-borne infectious disease of humans caused by eukaryotic protists of the genus Plasmodium. Itis widespread in tropical and subtropical regions, including much of Subsaharan Africa, Asia and the Americas. Thedisease results from the multiplication of malaria parasites within red blood cells, causing symptoms that typicallyinclude 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 byPlasmodium falciparum. Malaria caused by Plasmodium vivax, Plasmodium ovale and Plasmodium malariae isgenerally a milder disease that is rarely fatal. A fifth species, Plasmodium knowlesi, is a zoonosis that causes malariain macaques but can also infect humans[10] [11] .Malaria transmission can be reduced by preventing mosquito bites by distribution of inexpensive mosquito nets andinsect repellents, or by mosquito-control measures such as spraying insecticides inside houses and draining standingwater where mosquitoes lay their eggs. Although many are under development, the challenge of producing a widelyavailable vaccine that provides a high level of protection for a sustained period is still to be met.[12] Two drugs arealso 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

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artesunate [13] which is superior to quinine in both children and adults.[14] Resistance has developed to severalantimalarial drugs, most notably chloroquine.[15]

Each year, there are more than 225 million cases of malaria,[16] killing around 781,000 people each year according tothe latest WHO Report [17]. The majority of deaths are of young children in sub-Saharan Africa.[18] Ninety percentof malaria-related deaths occur in sub-Saharan Africa. Malaria is commonly associated with poverty, and can indeedbe a cause of poverty[19] and a major hindrance to economic development.

Signs and symptoms

Main symptoms of malaria.[20]

Typical fever patterns of malaria

Symptoms of malaria include fever, shivering, arthralgia (joint pain),vomiting, anemia (caused by hemolysis), hemoglobinuria, retinaldamage,[21] and convulsions. The classic symptom of malaria iscyclical occurrence of sudden coldness followed by rigor and thenfever and sweating lasting four to six hours, occurring every two daysin P. vivax and P. ovale infections, while every three days for P.malariae.[22] P. falciparum can have recurrent fever every 36–48 hoursor a less pronounced and almost continuous fever. For reasons that arepoorly understood, but that may be related to high intracranialpressure, children with malaria frequently exhibit abnormal posturing,a sign indicating severe brain damage.[23] Malaria has been found tocause cognitive impairments, especially in children. It causeswidespread anemia during a period of rapid brain development andalso direct brain damage. This neurologic damage results from cerebralmalaria to which children are more vulnerable.[24] [25] Cerebral malariais associated with retinal whitening,[26] which may be a useful clinicalsign in distinguishing malaria from other causes of fever.[27]

Severe malaria is almost exclusively caused by P. falciparum infection,and usually arises 6–14 days after infection.[28] Consequences ofsevere malaria include coma and death if untreated—young childrenand pregnant women are especially vulnerable. Splenomegaly(enlarged spleen), severe headache, cerebral ischemia, hepatomegaly (enlarged liver), hypoglycemia, andhemoglobinuria with renal failure may occur. Renal failure is a feature of blackwater fever, where hemoglobin fromlysed red blood cells leaks into the urine. Severe malaria can progress extremely rapidly and cause death withinhours or days.[28] In the most severe cases of the disease, fatality rates can exceed 20%, even with intensive care andtreatment.[29] In endemic areas, treatment is often less satisfactory and the overall fatality rate for all cases of malariacan be as high as one in ten.[30] Over the longer term, developmental impairments have been documented in childrenwho have suffered episodes of severe malaria.[31]

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Cause

A Plasmodium sporozoite traverses the cytoplasmof a mosquito midgut epithelial cell in this

false-color electron micrograph.

Malaria parasites are members of the genus Plasmodium (phylumApicomplexa). In humans malaria is caused by P. falciparum, P.malariae, P. ovale, P. vivax and P. knowlesi.[32] [33] P. falciparum isthe most common cause of infection and is responsible for about 80%of all malaria cases, and is also responsible for about 90% of the deathsfrom malaria.[34] Parasitic Plasmodium species also infect birds,reptiles, monkeys, chimpanzees and rodents.[35] There have beendocumented human infections with several simian species of malaria,namely P. knowlesi, P. inui, P. cynomolgi,[36] P. simiovale, P.brazilianum, P. schwetzi and P. simium; however, with the exceptionof P. knowlesi, these are mostly of limited public health importance.[37]

Malaria parasites contain apicoplasts, an organelle usually found inplants, complete with their own functioning genomes. These apicoplastare thought to have originated through the endosymbiosis of algae[38]

and play a crucial role in various aspects of parasite metabolism e.g.fatty acid bio-synthesis.[39] To date, 466 proteins have been found to beproduced by apicoplasts[40] and these are now being looked at as possible targets for novel anti-malarial drugs.

Life cycleThe parasite's secondary (intermediate) hosts are humans and other vertebrates. Female mosquitoes of the Anophelesgenus are primary hosts and transmission vectors. Young mosquitoes first ingest the malaria parasite by feeding onan infected human carrier and the infected Anopheles mosquitoes carry Plasmodium sporozoites in their salivaryglands. A mosquito becomes infected when it takes a blood meal from an infected human. Once ingested, theparasite gametocytes taken up in the blood will further differentiate into male or female gametes and then fuse in themosquito's gut. This produces an ookinete that penetrates the gut lining and produces an oocyst in the gut wall. Whenthe oocyst ruptures, it releases sporozoites that migrate through the mosquito's body to the salivary glands, wherethey are then ready to infect a new human host. This type of transmission is occasionally referred to as anteriorstation transfer.[41] The sporozoites are injected into the skin, alongside saliva, when the mosquito takes a subsequentblood meal.Only female mosquitoes feed on blood while male mosquitoes feed on plant nectar,[42] thus males do not transmit thedisease. The females of the Anopheles genus of mosquito prefer to feed at night. They usually start searching for ameal at dusk, and will continue throughout the night until taking a meal. Malaria parasites can also be transmitted byblood transfusions, although this is rare.[43]

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 mosquitobite; both can occur with any malaria parasite species. Relapse is specific to P. vivax and P. ovale and involvesre-emergence of blood-stage parasites from latent parasites (hypnozoites) in the liver. Describing a case of malaria ascured by observing the disappearance of parasites from the bloodstream can, therefore, be deceptive. The longestincubation period reported for a P. vivax infection is 30 years.[28] Approximately one in five of P. vivax malariacases in temperate areas involve overwintering by hypnozoites (i.e., relapses begin the year after the mosquitobite).[44]

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Pathogenesis

The life cycle of malaria parasites in the humanbody. A mosquito infects a person by taking a

blood meal. First, sporozoites enter thebloodstream, and migrate to the liver. They infectliver cells (hepatocytes), where they multiply into

merozoites, rupture the liver cells, and escapeback into the bloodstream. Then, the merozoitesinfect red blood cells, where they develop intoring forms, trophozoites and schizonts which inturn produce further merozoites. Sexual forms

(gametocytes) are also produced, which, if takenup by a mosquito, will infect the insect and

continue the life cycle.

Malaria develops via two phases: an exoerythrocytic and anerythrocytic phase. The exoerythrocytic phase involves infection of thehepatic system, or liver, whereas the erythrocytic phase involvesinfection of the erythrocytes, or red blood cells. When an infectedmosquito pierces a person's skin to take a blood meal, sporozoites inthe mosquito's saliva enter the bloodstream and migrate to the liver.Within minutes of being introduced into the human host, thesporozoites infect hepatocytes, multiplying asexually andasymptomatically for a period of 8–30 days.[45] Once in the liver, theseorganisms differentiate to yield thousands of merozoites, which,following rupture of their host cells, escape into the blood and infectred blood cells, thus beginning the erythrocytic stage of the lifecycle.[45] The parasite escapes from the liver undetected by wrappingitself in the cell membrane of the infected host liver cell.[46]

Within the red blood cells, the parasites multiply further, againasexually, periodically breaking out of their hosts to invade fresh redblood cells. Several such amplification cycles occur. Thus, classicaldescriptions of waves of fever arise from simultaneous waves ofmerozoites escaping and infecting red blood cells.Some P. vivax and P. ovale sporozoites do not immediately develop into exoerythrocytic-phase merozoites, butinstead 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 areresponsible for long incubation and late relapses in these two species of malaria.[47]

The parasite is relatively protected from attack by the body's immune system because for most of its human life cycleit resides within the liver and blood cells and is relatively invisible to immune surveillance. However, circulatinginfected blood cells are destroyed in the spleen. To avoid this fate, the P. falciparum parasite displays adhesiveproteins 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.[48] This "stickiness" isthe main factor giving rise to hemorrhagic complications of malaria. High endothelial venules (the smallest branchesof the circulatory system) can be blocked by the attachment of masses of these infected red blood cells. The blockageof these vessels causes symptoms such as in placental and cerebral malaria. In cerebral malaria the sequestrated redblood cells can breach the blood brain barrier possibly leading to coma.[49]

Although the white blood cell surface adhesive proteins (called PfEMP1, for Plasmodium falciparum erythrocytemembrane protein 1) are exposed to the immune system, they do not serve as good immune targets, because of theirextreme diversity; there are at least 60 variations of the protein within a single parasite and effectively limitlessversions within parasite populations.[48] The parasite switches between a broad repertoire of PfEMP17 surfaceproteins, 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 thevertebrate host, the vertebrate host is the definitive host of the disease. If a mosquito pierces the skin of an infectedperson, it potentially picks up gametocytes within the blood. Fertilization and sexual recombination of the parasiteoccurs in the mosquito's gut. New sporozoites develop and travel to the mosquito's salivary gland, completing thecycle. Pregnant women are especially attractive to the mosquitoes,[50] and malaria in pregnant women is animportant cause of stillbirths, infant mortality and low birth weight,[51] particularly in P. falciparum infection, butalso in other species infection, such as P. vivax.[52]

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Genetic resistanceMalaria is thought to have been the greatest selective pressure on the human genome in recent history.[53] This is dueto the high levels of mortality and morbidity caused by malaria, especially the P. falciparum species. A number ofdiseases may provide some resistance to it including sickle cell disease, thalassaemias, glucose-6-phosphatedehydrogenase, Duffy antigens, and possibly others.

DiagnosisThe mainstay of malaria diagnosis has been the microscopic examination of blood.[54] Although blood is the samplemost frequently used to make a diagnosis, both saliva and urine have been investigated as alternative, less invasivespecimens.[55]

Areas that cannot afford laboratory diagnostic tests often use only a history of subjective fever as the indication totreat for malaria. Using Giemsa-stained blood smears from children in Malawi, one study showed that when clinicalpredictors (rectal temperature, nailbed pallor, and splenomegaly) were used as treatment indications, rather thanusing only a history of subjective fevers, a correct diagnosis increased from 2% to 41% of cases, and unnecessarytreatment for malaria was significantly decreased.[56]

Blood films

Species Appearance Periodicity Liver persistent

Plasmodium vivax tertian yes

Plasmodium ovale tertian yes

Plasmodium falciparum tertian no

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

Malaria 6

used. Thin films are similar to usual blood films and allow species identification because the parasite's appearance isbest preserved in this preparation. Thick films allow the microscopist to screen a larger volume of blood and areabout 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 speciescan be much more difficult. With the pros and cons of both thick and thin smears taken into consideration, it isimperative to utilize both smears while attempting to make a definitive diagnosis.[57]

From the thick film, an experienced microscopist can detect parasite levels (or parasitemia) down to as low as0.0000001% of red blood cells. Diagnosis of species can be difficult because the early trophozoites ("ring form") ofall four species look identical and it is never possible to diagnose species on the basis of a single ring form; speciesidentification 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 inSouth-east Asia) look very similar under the microscope. However, P. knowlesi parasitemia increases very fast andcauses more severe disease than P. malariae, so it is important to identify and treat infections quickly. Thereforemodern methods such as PCR (see "Molecular methods" below) or monoclonal antibody panels that can distinguishbetween the two should be used in this part of the world.[58]

Antigen testsFor areas where microscopy is not available, or where laboratory staff are not experienced at malaria diagnosis, thereare commercial antigen detection tests that require only a drop of blood.[59] Immunochromatographic tests (alsocalled: Malaria Rapid Diagnostic Tests, Antigen-Capture Assay or "Dipsticks") have been developed, distributed andfieldtested. These tests use finger-stick or venous blood, the completed test takes a total of 15–20 minutes, and theresults are read visually as the presence or absence of colored stripes on the dipstick, so they are suitable for use inthe 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. Onedisadvantage is that dipstick tests are qualitative but not quantitative – they can determine if parasites are present inthe blood, but not how many.The first rapid diagnostic tests were using P. falciparum glutamate dehydrogenase as antigen.[60] PGluDH was soonreplaced by P.falciparum lactate dehydrogenase, a 33 kDa oxidoreductase [EC 1.1.1.27]. It is the last enzyme of theglycolytic 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 thisrespect, pLDH is similar to pGluDH. Depending on which monoclonal antibodies are used, this type of assay candistinguish between all five different species of human malaria parasites, because of antigenic differences betweentheir pLDH isoenzymes.

Molecular methodsMolecular methods are available in some clinical laboratories and rapid real-time assays (for example, QT-NASBAbased on the polymerase chain reaction)[61] are being developed with the hope of being able to deploy them inendemic areas.PCR (and other molecular methods) is more accurate than microscopy. However, it is expensive, and requires aspecialized laboratory. Moreover, levels of parasitemia are not necessarily correlative with the progression ofdisease, particularly when the parasite is able to adhere to blood vessel walls. Therefore more sensitive, low-techdiagnosis tools need to be developed in order to detect low levels of parasitemia in the field.[62]

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DifferentialFever and septic shock are commonly misdiagnosed as severe malaria in Africa, leading to a failure to treat otherlife-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 malarialretinopathy is better (collective sensitivity of 95% and specificity of 90%) than any other clinical or laboratoryfeature in distinguishing malarial from non-malarial coma.[63]

Prevention

Anopheles albimanus mosquito feeding on ahuman arm. This mosquito is a vector of malariaand 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 protectindividuals in areas where malaria is endemic, include prophylacticdrugs, mosquito eradication and the prevention of mosquito bites.The continued existence of malaria in an area requires a combinationof high human population density, high mosquito population densityand high rates of transmission from humans to mosquitoes and frommosquitoes to humans. If any of these is lowered sufficiently, theparasite will sooner or later disappear from that area, as happened inNorth America, Europe and much of Middle East. However, unless theparasite is eliminated from the whole world, it could becomere-established if conditions revert to a combination that favours theparasite's reproduction. Many countries are seeing an increasingnumber 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 thelong run, but the capital costs required are out of reach of many of the world's poorest people. Economic adviserJeffrey Sachs estimates that malaria can be controlled for US$3 billion in aid per year.[64]

A 2008 study that examined international financing of malaria control found large regional variations in the levels ofaverage annual per capita funding ranging from US$0.01 in Myanmar to US$147 in Suriname. The study found 34countries where the funding was less than US$1 per capita, including 16 countries where annual malaria support wasless than US$0.5. The 16 countries included 710 million people or 50% of the global population exposed to the risksof 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 stableendemic countries in the world (Indonesia and India).[65]

Brazil, Eritrea, India, and Vietnam, unlike many other developing nations, have successfully reduced the malariaburden. Common success factors have included conducive country conditions, a targeted technical approach using apackage of effective tools, data-driven decision-making, active leadership at all levels of government, involvementof communities, decentralized implementation and control of finances, skilled technical and managerial capacity atnational and sub-national levels, hands-on technical and programmatic support from partner agencies, and sufficientand flexible financing.[66]

MedicationsSeveral 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.[67] 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

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malaria-endemic areas usually begin taking the drugs one to two weeks before arriving and must continue takingthem for 4 weeks after leaving (with the exception of atovaquone proguanil that only needs be started 2 days priorand continued for 7 days afterwards). Generally, these drugs are taken daily or weekly, at a lower dose than would beused for treatment of a person who had actually contracted the disease. Use of prophylactic drugs is seldom practicalfor full-time residents of malaria-endemic areas, and their use is usually restricted to short-term visitors and travelersto malarial regions. This is due to the cost of purchasing the drugs, negative side effects from long-term use, andbecause 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 forprophylaxis. The use of prophylactic drugs where malaria-bearing mosquitoes are present may encourage thedevelopment of partial immunity.[68]

Vector controlEfforts to eradicate malaria by eliminating mosquitoes have been successful in some areas. Malaria was oncecommon in the United States and southern Europe, but vector control programs, in conjunction with the monitoringand treatment of infected humans, eliminated it from those regions. In some areas, the draining of wetland breedinggrounds and better sanitation were adequate. Malaria was eliminated from most parts of the USA in the early 20thcentury by such methods, and the use of the pesticide DDT and other means eliminated it from the remainingpockets in the South by 1951[69] (see National Malaria Eradication Program). In 2002, there were 1,059 cases ofmalaria reported in the US, including eight deaths, but in only five of those cases was the disease contracted in theUnited States.Before DDT, malaria was successfully eradicated or controlled also in several tropical areas by removing orpoisoning the breeding grounds of the mosquitoes or the aquatic habitats of the larva stages, for example by filling orapplying oil to places with standing water. These methods have seen little application in Africa for more than half acentury.[70]

Sterile insect technique is emerging as a potential mosquito control method. Progress towards transgenic, orgenetically modified, insects suggest that wild mosquito populations could be made malaria-resistant. Researchers atImperial College London created the world's first transgenic malaria mosquito,[71] with the firstplasmodium-resistant species announced by a team at Case Western Reserve University in Ohio in 2002.[72]

Successful replacement of current populations with a new genetically modified population, relies upon a drivemechanism, 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.[73] An even more futuristic method ofvector control is the idea that lasers could be used to kill flying mosquitoes.[74]

Indoor residual sprayingIndoor residual spraying (IRS) is the practice of spraying insecticides on the interior walls of homes in malariaaffected areas. After feeding, many mosquito species rest on a nearby surface while digesting the bloodmeal, so ifthe walls of dwellings have been coated with insecticides, the resting mosquitos will be killed before they can biteanother victim, transferring the malaria parasite.The first pesticide used for IRS was DDT.[69] 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

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1970s. Since the use of DDT has been limited or banned for agricultural use for some time, DDT may now be moreeffective as a method of disease-control.Although DDT has never been banned for use in malaria control and there are several other insecticides suitable forIRS, some advocates have claimed that bans are responsible for tens of millions of deaths in tropical countries whereDDT had once been effective in controlling malaria. Furthermore, most of the problems associated with DDT usestem specifically from its industrial-scale application in agriculture, rather than its use in public health.[75]

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 and deltamethrin).[76] Thispublic health use of small amounts of DDT is permitted under the Stockholm Convention on Persistent OrganicPollutants (POPs), which prohibits the agricultural use of DDT.[77] However, because of its legacy, many developedcountries previously discouraged DDT use even in small quantities.[78]

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 IRSare endophilic species (species that tend to rest and live indoors), and due to the irritation caused by spraying, theirevolutionary 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 defensemechanism.[79]

Mosquito nets and bedclothes

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 ithas time to search for a way past the net. Insecticide-treated nets (ITNs) are estimated to be twice as effective asuntreated nets and offer greater than 70% protection compared with no net.[80] Although ITNs are proven to be veryeffective against malaria, less than 2% of children in urban areas in Sub-Saharan Africa are protected by ITNs. Sincethe Anopheles mosquitoes feed at night, the preferred method is to hang a large "bed net" above the center of a bedsuch that it drapes down and covers the bed completely.

VaccinationImmunity (or, more accurately, tolerance) does occur naturally, but only in response to repeated infection withmultiple strains of malaria.[81] Vaccines for malaria are under development, with no completely effective vaccine yetavailable. The first promising studies demonstrating the potential for a malaria vaccine were performed in 1967 byimmunizing mice with live, radiation-attenuated sporozoites, providing protection to about 60% of the mice uponsubsequent injection with normal, viable sporozoites.[82] Since the 1970s, there has been a considerable effort todevelop 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.[83]

Other methodsEducation in recognizing the symptoms of malaria has reduced the number of cases in some areas of the developingworld by as much as 20%. Recognizing the disease in the early stages can also stop the disease from becoming akiller. Education can also inform people to cover over areas of stagnant, still water e.g. Water Tanks which are idealbreeding grounds for the parasite and mosquito, thus cutting down the risk of the transmission between people. Thisis most put in practice in urban areas where there are large centers of population in a confined space andtransmission 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

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intensive due to the simulations of large human populations with a vast range of parameters related to biological andsocial factors that influence the spread of the disease. It is expected to take a few months using volunteeredcomputing power compared to the 40 years it would have taken with the current resources available to the scientistswho developed the program.[84]

An example of the importance of computer modeling in planning malaria eradication programs is shown in the paperby Águas and others. They showed that eradication of malaria is crucially dependent on finding and treating the largenumber of people in endemic areas with asymptomatic malaria, who act as a reservoir for infection.[85] The malariaparasites do not affect animal species and therefore eradication of the disease from the human population would beexpected 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, orphotonic fence, which identifies female mosquitoes and shoots them using a medium-powered laser.[86] The deviceis currently undergoing commercial development, although instructions for a DIY version of the photonic fence havealso been published.[87]

Another way of reducing the malaria transmitted to humans from mosquitoes has been developed by the Universityof Arizona. They have engineered a mosquito to become resistant to malaria. This was reported on the 16 July 2010in the journal PLoS Pathogens.[88] With the ultimate end being that the release of this GM mosquito into theenvironment, Gareth Lycett, a malaria researcher from Liverpool School of Tropical Medicine told the BBC that "Itis another step on the journey towards potentially assisting malaria control through GM mosquito release."[89]

TreatmentWhen properly treated, a patient with malaria can expect a complete recovery.[90] The treatment of malaria dependson the severity of the disease; whether patients who can take oral drugs have to be admitted depends on theassessment and the experience of the clinician. Uncomplicated malaria is treated with oral drugs. The most effectivestrategy for P. falciparum infection recommended by WHO is the use of artemisinins in combination with otherantimalarials artemisinin-combination therapy, ACT, in order to avoid the development of drug resistance againstartemisinin-based therapies.Severe malaria requires the parenteral administration of antimalarial drugs. Until recently the most used treatmentfor severe malaria was quinine but artesunate has been shown to be superior to quinine in both children [91] andadults [92] . 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. vivaxrequires both treatment of blood stages (with chloroquine or ACT) as well as clearance of liver forms withprimaquine.

Epidemiology

Countries which have regions where malaria isendemic as of 2003 (coloured yellow).[93]

Countries in green are free of indigenous cases ofmalaria in all areas.

It is estimated that malaria causes 250 million cases of

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Disability-adjusted life year for malaria per 100,000 inhabitants in 2002.  nodata  ≤10  10–50  50–100  100–250  250–500  500–1000  1000–1500  1500–2000  2000–2500  2500–3000  3000–3500  ≥3500

feverandapproximatelyonemilliondeathsannually.[94]

The vastmajority of cases occur in children under 5 years old;[95] pregnant women are also especially vulnerable. Despiteefforts to reduce transmission and increase treatment, there has been little change in which areas are at risk of thisdisease since 1992.[96] Indeed, if the prevalence of malaria stays on its present upwards course, the death rate coulddouble in the next twenty years.[97] Precise statistics are unknown because many cases occur in rural areas wherepeople do not have access to hospitals or the means to afford health care. As a consequence, the majority of cases areundocumented.[97]

Although co-infection with HIV and malaria does cause increased mortality, this is less of a problem than withHIV/tuberculosis co-infection, due to the two diseases usually attacking different age-ranges, with malaria beingmost common in the young and active tuberculosis most common in the old.[98] Although HIV/malaria co-infectionproduces less severe symptoms than the interaction between HIV and TB, HIV and malaria do contribute to eachother's spread. This effect comes from malaria increasing viral load and HIV infection increasing a person'ssusceptibility to malaria infection.[99]

Malaria is presently endemic in a broad band around the equator, in areas of the Americas, many parts of Asia, andmuch of Africa; however, it is in sub-Saharan Africa where 85– 90% of malaria fatalities occur.[100] The geographicdistribution of malaria within large regions is complex, and malaria-afflicted and malaria-free areas are often foundclose to each other.[101] In drier areas, outbreaks of malaria can be predicted with reasonable accuracy by mappingrainfall.[102] Malaria is more common in rural areas than in cities; this is in contrast to dengue fever where urbanareas present the greater risk.[103] For example, several cities in Vietnam, Laos and Cambodia are essentiallymalaria-free, but the disease is present in many rural regions.[104] By contrast, in Africa malaria is present in bothrural and urban areas, though the risk is lower in the larger cities.[105] The global endemic levels of malaria have notbeen mapped since the 1960s. However, the Wellcome Trust, UK, has funded the Malaria Atlas Project[106] to rectifythis, providing a more contemporary and robust means with which to assess current and future malaria diseaseburden.

HistoryMalaria has infected humans for over 50,000 years, and Plasmodium may have been a human pathogen for the entirehistory of the species.[107] Close relatives of the human malaria parasites remain common in chimpanzees.[108] Somenew evidence suggests that the most virulent strain of human malaria may have originated in gorillas.[109]

References to the unique periodic fevers of malaria are found throughout recorded history, beginning in 2700 BC inChina.[110] Malaria may have contributed to the decline of the Roman Empire,[111] and was so pervasive in Romethat it was known as the "Roman fever".[112] The term malaria originates from Medieval Italian: mala aria — "badair"; the disease was formerly called ague or marsh fever due to its association with swamps and marshland.[113]

Malaria was once common in most of Europe and North America,[114] where it is no longer endemic,[115] thoughimported cases do occur.[116]

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.[117] According to Joseph Patrick Byrne, "Sixty thousand American soldiersdied of malaria during the African and South Pacific campaigns."[118]

Malaria 12

PreventionAn early effort at malaria prevention occurred in 1896, just before the mosquito malaria link was confirmed in Indiaby a British physician, Ronald Ross. An 1896 Uxbridge malaria outbreak prompted health officer, Dr. LeonardWhite, 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.[119] Massachusetts State pathologist Theobald Smith, asked that White'sson collect mosquito specimens for further analysis, and that citizens 1) add screens to windows, and 2) draincollections of water.[119] Carlos Finlay was also engaged in mosquito related research, and mosquito borne diseasetheory, in the 1880s in Cuba, basing his work on the study of Yellow Fever.

Discovery of the malaria parasite

Dr. Probert's Malarial Remedy,"Will cure chills and fever, dyspepsia & c. Willcure bilious fever, liver complaint & c.", c.1881,

New York

A continuous P. falciparum culture wasestablished in 1976

Scientific studies on malaria made their first significant advance in1880, when a French army doctor working in the military hospital ofConstantine in Algeria named Charles Louis Alphonse Laveranobserved parasites for the first time, inside the red blood cells of peoplesuffering from malaria. He, therefore, proposed that malaria is causedby this organism, the first time a protist was identified as causingdisease.[120] For this and later discoveries, he was awarded the 1907Nobel Prize for Physiology or Medicine. The malarial parasite wascalled Plasmodium by the Italian scientists Ettore Marchiafava andAngelo Celli.[121]

Discovery of mosquito transmission

A year later, Carlos Finlay, a Cuban doctor treating patients withyellow fever in Havana, provided strong evidence that mosquitoeswere transmitting disease to and from humans.[122] This work followedearlier suggestions by Josiah C. Nott,[123] and work by Patrick Mansonon the transmission of filariasis.[124]

It was Britain's Sir Ronald Ross, working in the Presidency GeneralHospital in Calcutta, who finally proved in 1898 that malaria istransmitted by mosquitoes. He did this by showing that certainmosquito species transmit malaria to birds. He isolated malariaparasites from the salivary glands of mosquitoes that had fed oninfected birds.[125] For this work, Ross received the 1902 Nobel Prizein Medicine. After resigning from the Indian Medical Service, Rossworked at the newly established Liverpool School of TropicalMedicine and directed malaria-control efforts in Egypt, Panama,Greece and Mauritius.[126] The findings of Finlay and Ross were laterconfirmed by a medical board headed by Walter Reed in 1900. Its recommendations were implemented by WilliamC. Gorgas in the health measures undertaken during construction of the Panama Canal. This public-health worksaved the lives of thousands of workers and helped develop the methods used in future public-health campaignsagainst the disease.

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Discovery of the liver stageShortt and Garnham discovered the pre-erythrocytic liver stage, first in the primate parasite P. cynomolgi andsubsequently the human malarias P. vivax [127] and P. falciparum [128] . Further work confirmed the transformationof sporozoites from mosquitoes into liver forms, essentially completing documentation of the lifecycle [129] .

In vitro cultureThe 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.[130]

[131]

History of treatmentThe first effective treatment for malaria came from the bark of cinchona tree, which contains quinine. This treegrows on the slopes of the Andes, mainly in Peru. The indigenous peoples of Peru made a tincture of cinchona tocontrol malaria. The Jesuits noted the efficacy of the practice and introduced the treatment to Europe during the1640s, where it was rapidly accepted.[132] It was not until 1820 that the active ingredient, quinine, was extractedfrom the bark, isolated and named by the French chemists Pierre Joseph Pelletier and Joseph BienaiméCaventou.[133] . In the 20th century, chloroquine replaced quinine as treatment of both uncomplicated and severefalciparum malaria until resistance supervened. Artemisinins, discovered by Chinese scientists in the 1970s, are nowrecommended treatment for falciparum malaria, administered in combination with other antimalarials as well as insevere disease.

Society and cultureMalaria is not just a disease commonly associated with poverty but also a cause of poverty and a major hindrance toeconomic development. Tropical regions are affected most, however malaria’s furthest extent reaches into sometemperate zones with extreme seasonal changes. The disease has been associated with major negative economiceffects on regions where it is widespread. During the late 19th and early 20th centuries, it was a major factor in theslow economic development of the American southern states.[134] A comparison of average per capita GDP in 1995,adjusted for parity of purchasing power, between countries with malaria and countries without malaria gives afivefold difference ($1,526 USD versus $8,268 USD). In countries where malaria is common, average per capitaGDP has risen (between 1965 and 1990) only 0.4% per year, compared to 2.4% per year in other countries.[135]

Poverty is both cause and effect, however, since the poor do not have the financial capacities to prevent or treat thedisease. The lowest income group in Malawi carries (1994) the burden of having 32% of their annual income usedon this disease compared with the 4% of household incomes from low-to-high groups.[136] In its entirety, theeconomic impact of malaria has been estimated to cost Africa $12 billion USD every year. The economic impactincludes costs of health care, working days lost due to sickness, days lost in education, decreased productivity due tobrain damage from cerebral malaria, and loss of investment and tourism.[95] In some countries with a heavy malariaburden, 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.[137]

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.[138] 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

Malaria 14

impaired school performance and cognitive abilities even after recovery. Malaria prophylaxis was shown to improvecognitive function and school performance in clinical trials when compared to placebo groups.[139]

Counterfeit drugsSophisticated counterfeits have been found in several Asian countries such as Cambodia,[140] China,[141] Indonesia,Laos, Thailand, Vietnam and are an important cause of avoidable death in those countries.[142] WHO have said thatstudies indicate that up to 40% of artesunate based malaria medications are counterfeit, especially in the GreaterMekong region and have established a rapid alert system to enable information about counterfeit drugs to be rapidlyreported to the relevant authorities in participating countries.[143] There is no reliable way for doctors or lay people todetect counterfeit drugs without help from a laboratory. Companies are attempting to combat the persistence ofcounterfeit drugs by using new technology to provide security from source to distribution.

WarThroughout history, the contraction of malaria (via natural outbreaks as well as via infliction of the disease as abiological warfare agent) has played a prominent role in the fortunes of government rulers, nation-states, militarypersonnel, and military actions. "Malaria Site: History of Malaria During Wars" addresses the devastating impact ofmalaria in numerous well-known conflicts, beginning in June 323 B.C. That site's authors note: "Many great warriorssuccumbed to malaria after returning from the warfront and advance of armies into continents was prevented bymalaria. In many conflicts, more troops were killed by malaria than in combat."[144] The Centers for Disease Control("CDC") traces the history of malaria and its impacts farther back, to 2700 BCE.[145]

In 1910, Nobel Prize in Medicine-winner Ronald Ross (himself a malaria survivor), published a book titled ThePrevention of Malaria that included the chapter: "The Prevention of Malaria in War." The chapter's author, ColonelC. H. Melville, Professor of Hygiene at Royal Army Medical College in London, addressed the prominent role thatmalaria has historically played during wars and advised: "A specially selected medical officer should be placed incharge 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 anddevelopment of other drugs and vaccines. American military organizations conducting such research initiativesinclude the Navy Medical Research Center, Walter Reed Army Institute of Research, and the U.S. Army MedicalResearch Institute of Infectious Diseases of the US Armed Forces.[144]

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 in1946. According to the CDC, MCWA "was established to control malaria around military training bases in thesouthern United States and its territories, where malaria was still problematic" and, during these activities, to "trainstate and local health department officials in malaria control techniques and strategies." The CDC's Malaria Divisioncontinued that mission, successfully reducing malaria in the United States, after which the organization expanded itsfocus to include "prevention, surveillance, and technical support both domestically and internationally."[145]

Malaria 15

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.[146] One character inthe book, an ivory trader named Kurtz, dies from the disease[146] and the novella's narrator, Charles Marlow, isweakened by it.

• In making the movie The African Queen (1951), most of the crew and the leading lady, Katharine Hepburn,endured malaria.[147] [148] [149]

• In the movie Apocalypse Now (1979), Captain Benjamin L. Willard is a special operations veteran stationed inSoutheast 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 inneutral 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."[150]

• In Barbara Kingsolver's novel, The Poisonwood Bible (1998), Ruth May – the youngest daughter of an AmericanChristian missionary who brings his family to live in the Belgian Congo of the late 1950s – stops taking herquinine tablets and contracts malaria.[151]

ResearchWith 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 theparasite. Thus, trapped upon phosphorylation by plasmodial PdxK (pyridoxine/pyridoxal kinase), the proliferation ofPlasmodium parasites is effectively hindered by a novel compound, PT3, a cyclic pyridoxyl-tryptophan methyl ester,without harming human cells.[152]

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External links• WHO site on malaria (http:/ / www. who. int/ malaria/ )• Global Malaria action Plan (http:/ / www. rollbackmalaria. org/ gmap/ )• Malaria Atlas Project (http:/ / www. map. ox. ac. uk/ )• Medicines for Malaria Venture (MMV) (http:/ / www. mmv. org)• World Malaria Report 2005 (http:/ / www. rollbackmalaria. org/ wmr2005/ )• Doctors Without Borders/Médecins Sans Frontières – Malaria (http:/ / doctorswithoutborders. org/ news/ issue.

cfm?id=2395) information pages• Medline Plus – Malaria (http:/ / www. nlm. nih. gov/ medlineplus/ malaria. html)• Who/TDR Malaria Database (http:/ / www. wehi. edu. au/ other_domains/ MalDB/ who. html)• Anti malaria and sustainable development (http:/ / www. antimalariaomd. org/ en/ index. php)• Worldwide Antimalarial Resistance Network (WWARN) (http:/ / www. wwarn. org)• Malaria (http:/ / www. dmoz. org/ Health/ Conditions_and_Diseases/ Infectious_Diseases/ Parasitic/ Malaria/ ) at

the Open Directory Project

Article Sources and Contributors 22

Article Sources and ContributorsMalaria  Source: http://en.wikipedia.org/w/index.php?oldid=417462218  Contributors: .V., 100110100, 141.236.82.xxx, 62.253.64.xxx, A4, Abanima, Abendroth85, Acalamari, AccursedOne,Adacus12, Adhib, Ahoerstemeier, Ajrodriguezm, Akamad, Alan.ca, Alex.tan, Alexius08, AlexiusHoratius, Alexsautographs, Alfie66, Algebraist, Allmightyduck, Alphax, AlwaysOnion,Amaraiel, Amit0108, Ancient Apparition, Anclation, AndTheCrowdGoesWild, Andrew Benton, Andrew Hartford, Andrew Levine, AndrewDressel, AndrewLeeson, Andries, Andy tatem, AngusLepper, Angusmclellan, Aniram21, Antandrus, Apha, Apliu, Applejack4180, Aranherunar, Arcadian, Arch dude, Archer3, Arcot, Aristiana, AubreyEllenShomo, AvicAWB, Avicennasis,Awolf002, AxelBoldt, Axlq, Azhyd, BJRD, Bachrach44, Baldyshaw, BanyanTree, Barak89, Basil II, Bassbonerocks, Bckirkup, Beaumont, Becksguy, Bejnar, Belovedfreak, Ben Ben,BenJWoodcroft, Bento00, Betacommand, BhagyaMani, Bibliomaniac15, BillC, Billjefferys, Billy64k, BillyGambela, Billypilgrim37, BirgitteSB, Blathnaid, Bletch, Bob Moffatt, Bobo192,Bogey97, Bongwarrior, Boris van Praag, Borisblue, Brady8, Brian the Editor, Brian0918, BridgetEM2008, Brownie96, Brusegadi, Bschnitzel, Bskhaira55, Bunchofgrapes, C6541, CART fan,CDN99, CO, Cacaman, Cactus.man, Caliga10, Caltas, Can't sleep, clown will eat me, CanOfWorms, CanadianCaesar, CanadianLinuxUser, Cantiorix, Capricorn42, Carey Evans, Carlymoy,CattleGirl, Ccevo2010, Cdc, Cessator, Charles Matthews, Charlesbridge, CheesusChrist, Chowbok, Chris 73, Chris Capoccia, Christopher Parham, Chriswaterguy, Chun-hian, Cireshoe,Citanuleht, Ckl16, Clarkzz1234, Clemwang, Closetcloe, Cls micronerd, Colonel Warden, Colonies Chris, CommonsDelinker, Conversion script, Coq Rouge, Corrector6879, Costyn, Cressmj,Ctbolt, Cteaton, Curps, Cwolz, Cynical, Czyrko, D6, DO11.10, Damonhater42, Danny, Davedash, Davemcarlson, David Edgar, David.scully93, Daviddragon96, Davidr222, Davidruben,Daygum, Dbtfz, Ddroar, DeadLeafEcho, Delldot, Demicx, DerHexer, Derekristow, Destroyer2000, Diberri, Diderot, Diggerdude1993, Dixonsej, Dksahu, Dmoskva, DocWatson42, Doctorfluffy,Dodo bird, Dooblegoo, Doseiai2, Doubletrouble50, Dr4chess, DrGaellon, DrMicro, DragonflySixtyseven, Drbaker48, Drmies, Drphilharmonic, Dsreyn, Dudewheresmywallet, Dupz, Dwa 21,ESkog, Ed Poor, EdGl, Edgar181, Eequor, Eleassar, Elliskev, Emperor Banh, Epbr123, Erianna, Eric Kvaalen, Erina17, Eugene van der Pijll, Euryalus, Evil Monkey, Ewlloyd, Excirial, Ezrakilty,Faithbco, Fan-1967, Fconaway, FilippoSidoti, Finavon, Flatterworld, Fleester, Florentino floro, Flubbit, Folkrockprincess, Fram, Frankenpuppy, Frans Fowler, Freakofnurture, Fred Bauder,Fredbauder, Fresheneesz, Froid, Fvasconcellos, Fæ, GT5162, Gabbe, Gaius Cornelius, Gak, GeeSharpMinor, Geeteshgadkari, Gerbilfyed4, Giftlite, Gigemag76, Gil Gamesh, Gilliam, Ginkgo100,Glacialfury, Glass Sword, Gogo Dodo, Goodnightmush, GraemeL, Graham87, GregorB, Guanaco, Gurch, GuustFlater, Gzuckier, Gökhan, HJ Mitchell, HLGallon, Hagerman, Hakufu Sonsaku,HalfShadow, Hashar, Hcps-knachelsa, Hempelmann, HenkBouwman, Henrik, Heron, Hmains, Hmrox, Hockeytaav, Hoeale, Horoporo, Ht686rg90, Hu12, Hugo Merck, Hunter1084, Huntthetroll,Husond, Hydrargyrum, I dream of horses, Ianavelon, IceHorse, Igno2, Imnotminkus, ImperatorExercitus, Indium, InnocentPikachu, InvictaHOG, Iridescent, IstvanWolf, Iwilker, Ixfd64,J.delanoy, JForget, JLM, JLaTondre, JMK, Jackhynes, Jackingram, Jaganath, James logan, Jarbru, Jauhienij, Jeff G., Jennavecia, Jerry2112, Jfdwolff, Jhwang333, Jic, Jimfbleak, Jimmy01,Jmh649, Jnoodle, JoanneB, JoeSmack, John Quiggin, JohnOwens, Johnson aj, JonHarder, Jons63, Josh Grosse, Jpgordon, Jtoomim, Julesd, Junglecat, JustinBlank, Jéské Couriano, KC Panchal,KVDP, Kandar, KarlM, Kazikameuk, Kazvorpal, Kcordina, Kelapstick, Kerowyn, Kevin, Kevinz, Kip2001, Kipala, KnowledgeOfSelf, Knutknatter, Koavf, KojieroSaske, Kosebamse, Kostisl,Kozuch, Kpjas, Kragen, Kralizec!, Ksherin, Kungfuadam, Kurtrik, Kurykh, Kweedado eng, Kymacpherson, Kyoko, L Kensington, L33tminion, LADave, LOL, La Pianista, LaggedOnUser,Lancethex, Larry R. Holmgren, Larry V, LarryBH, Latka, LearnedPingu, Lee, Leevanjackson, Leofer, Leon Byford, LeonardoRob0t, Lexi Marie, Lgh, Liam Skoda, Lidiastarling, Lightdarkness,Lightmouse, Lights, LilHelpa, Lilonstitch, Linnell, Lisasmall, Litobro, LittleT889, Lollerskates, Lollipopisj, Lord Emsworth, Lradrama, Lseidlein, Lucifer86, Lukas.S, Luna Santin, Lupin,Lvalero, M5a63, MC MasterChef, MER-C, Macrakis, Madscientist2212, Maelnuneb, Malarial, Malariaman, Malcolm Farmer, Malleus Fatuorum, Malor, Mambuto omalley, Marasama, MarcoKrohn, MarcoTolo, Marj Tiefert, Mark-shea, Marknash, Martinp, Martylunsford, Marvinandmilo, Massimo Macconi, Master of Puppets, Materialscientist, Matonen, Matt Crypto, MattEvans16,Mattbr, Matthewsimmons95, Mauler90, MaxSem, Maximecaffarel, Mbc362, McDogm, Medicus quisnam, Megfrey, Mesoderm, Metallion, Mets501, Metsavend, Mgiganteus1, Michael Hardy,Michael Zimmermann, Michael.burleigh, Mikael Häggström, Mike6271, Mikiemike, Millahnna, Mintleaf, Miradre, Misza13, Mitchellp27, Mixer98, Mkpumphrey, Monteitho, Mor, Mortense,Moumine, Mpradeep, Mr Adequate, Mradigan, Mrfish777, Mrh30, Mschel, Munita Prasad, Muntuwandi, Muxxa, Mytchill, Naddy, Nbauman, Neelix, Neutrality, NewEnglandYankee,Nhsnoboarder17, Nick C, Nick ostan, NickGorton, Nikitab, Nolelover, Nopetro, Northumbrian, Nunh-huh, Nunocordeiro, Nunquam Dormio, OVERM1ND, Obli, Odea, Ohnoitsjamie,Omicronpersei8, Omls2, Ondenc, Onkelschark, Optigan13, Osterluzei, Ottre, PDH, PMLawrence, Pahari Sahib, PaleWhaleGail, Papa Lima Whiskey, Parkwells, Pascal.Tesson, Paulkappelle,Petekmit, Peter Shearan, Petersam, Pethr, Pharos, Phfung, Phil Boswell, Phorteetoo, Piast93, Pibws001, Picaroon, Picstloup, PierreAbbat, Pigman, Pinethicket, Pingku, Pixma123, Plasticup,Plcoffey, Plumbago, PoliticalJunkie, Polkadot2479, Pracepig, Prashanthns, Precious Roy, PrestonH, PreventMalaria, Procrastinator supreme, Psb313, Pseudomonas, Pulsemeat, Q.manaan,Quadell, Quebec99, Quig, Qxz, RDBrown, RDT2, Radagast83, RandomP, Randywombat, Raph, RasputinAXP, Rbrwr, Rd232, RedGav, Rees11, Res2216firestar, RexNL, Rexparry sydney, RichFarmbrough, Richard Keatinge, Richard Taylor, Risker, Rivertorch, Rjensen, Rjm656s, Rjwellings, Rjwilmsi, Rmky87, Road Doc, Robert Merkel, RockMFR, Rockawares, Romanm, RoyBoy,Rror, Rsabbatini, Rsheridan6, Rtyq2, Russianrevolutionary, RyanGerbil10, Ryulong, S, SDY, SH84, ST47, SYTYCSM, Sagredo, Salseradoctora, Sangak, Santryl, Saravask, Sardar1875,Sasquatch, Savedor, Sayden, ScaldingHotSoup, ScarletLetterer, Scientist2, Scwlong, Sean.hoyland, Seb az86556, Seth Bresnett, Shadow007, Shadwstalkr, Shaq141, Shardulkoza, Shotwell,Shureg, Shushruth, Shyamdash, SidP, Silent SAM, Silivrenion, SimDarthMaul, Simpsone4, Sionus, Siwardio, Slothman32, Smellyk, Snowmanradio, Solace098, Someguy1221, Sonicology,Sonicwave, Sophos II, Spark.1.4, Speakalotash, Spenceju, Spencer, SpuriousQ, Squandermania, Stemonitis, Stephen G. Brown, Stevenfruitsmaak, Stevieg143, Stink weasel, Studerby,Supertommykniba, Svm2, Sw258, Swj1sfu, Syneil, TK111, Tassedethe, TastyPoutine, Taxman, TedErnst, Teles, Tfcoates, Thanol, The Sanctuary Sparrow, The-G-Unit-Boss, TheArchitect,TheOneIsis, Thecathedral, Thecrampton, Theofenton, Theratedrsuperstar36, Thingg, This lousy T-shirt, Thisisbossi, ThoHug, Thomas Blomberg, Tide rolls, TimR, TimVickers, Timoluege,Timwi, Tkn20, Tlotoxl, Tobby72, Tomtefarbror, Topnaman, Touchatou, Tpbradbury, Trainthh, Traveliter, Treisijs, Tremblay, Trevor MacInnis, Trfasulo, Trojancowboy, Troy paulamalu,Trusilver, Ttlymate, Tunatunatunatuna, Twas Now, Twinkling, Tyrol5, Ulflarsen, Ultramarine, Umdreslifesuc, Unmitigated Success, Unyoyega, Uruiamme, User27091, VRCOutreach, ValeriusTygart, Vanderesch, Velella, Velterop, Vespertine27, Vgy7ujm, Violask81976, Vmoses, Vrenator, WLU, WWARN, Wafulz, Wagon weel, Wainstead, Wantok, Wavelength, Wayne Slam,Wayward, Wechselstrom, Wednesday101, Werlop, Wetman, Wharris65, Wikieditor06, Wikipelli, Wikiscribe, Wildnox, William.temperley, WillowW, Wimt, Wizardman, Wk muriithi, Wmahan,Woer$, Wolfrock, Woohookitty, World affairs, Wouterstomp, Wryandwatchful, Wtmitchell, XLerate, Xaosflux, Xenobiologista, Xompanthy, Xtremerandomness, Xyzzyplugh, YellowFives,Yersinia, Yilloslime, Yom, ZL47, Zachary1555, Zadcat, Zashaw, Zeamays, Zyncodex, Ævar Arnfjörð Bjarmason, Јованвб, 1436 ,55דוד anonymous edits

Image Sources, Licenses and ContributorsFile:Plasmodium.jpg  Source: http://en.wikipedia.org/w/index.php?title=File:Plasmodium.jpg  License: Public Domain  Contributors: Original uploader was TimVickers at en.wikipediaFile:Symptoms of Malaria.png  Source: http://en.wikipedia.org/w/index.php?title=File:Symptoms_of_Malaria.png  License: Public Domain  Contributors: Mikael HäggströmFile:Malaria fever.svg  Source: http://en.wikipedia.org/w/index.php?title=File:Malaria_fever.svg  License: Creative Commons Attribution-Sharealike 3.0  Contributors: User:Brady8Image:Malaria.jpg  Source: http://en.wikipedia.org/w/index.php?title=File:Malaria.jpg  License: unknown  Contributors: Abanima, Cdc, ComputerHotline, Juliancolton, Masur, Oks, Thuresson,Wlodzimierz, Überraschungsbilder, 3 anonymous editsImage:MalariacycleBig.jpg  Source: http://en.wikipedia.org/w/index.php?title=File:MalariacycleBig.jpg  License: Public Domain  Contributors: Original uploader was TimVickers aten.wikipediaImage:Plasmodium vivax 01.png  Source: http://en.wikipedia.org/w/index.php?title=File:Plasmodium_vivax_01.png  License: Public Domain  Contributors: Photo Credit: Content Providers(s):CDC/ Steven Glenn, Laboratory & Consultation Division Transwiki approved by: w:en:User:DmcdevitImage:Plasmodium ovale 01.png  Source: http://en.wikipedia.org/w/index.php?title=File:Plasmodium_ovale_01.png  License: Public Domain  Contributors: CopydaysImage:Plasmodium falciparum 01.png  Source: http://en.wikipedia.org/w/index.php?title=File:Plasmodium_falciparum_01.png  License: Public Domain  Contributors: Photo Credit: ContentProviders(s): CDC/Dr. Mae Melvin Transwiki approved by: w:en:User:DmcdevitImage:Mature Plasmodium malariae schizont PHIL 2715 lores.jpg  Source: http://en.wikipedia.org/w/index.php?title=File:Mature_Plasmodium_malariae_schizont_PHIL_2715_lores.jpg License: Public Domain  Contributors: Photo Credit: Content Providers: CDC/Dr. Mae MelvinImage:Anopheles albimanus mosquito.jpg  Source: http://en.wikipedia.org/w/index.php?title=File:Anopheles_albimanus_mosquito.jpg  License: Public Domain  Contributors: Photo Credit:James Gathany Content Providers(s): CDC Original uploader was: TimVickers at en.wikipediaImage:Malaria geographic distribution 2003.png  Source: http://en.wikipedia.org/w/index.php?title=File:Malaria_geographic_distribution_2003.png  License: Public Domain  Contributors:DO11.10, Mysid, Optigan13, 1 anonymous editsImage:Malaria world map - DALY - WHO2002.svg  Source: http://en.wikipedia.org/w/index.php?title=File:Malaria_world_map_-_DALY_-_WHO2002.svg  License: Creative CommonsAttribution-Sharealike 2.5  Contributors: User:Lokal_ProfilFile:Dr Proberts Malarial Remedy c1881.jpg  Source: http://en.wikipedia.org/w/index.php?title=File:Dr_Proberts_Malarial_Remedy_c1881.jpg  License: Public Domain  Contributors: Dr.Robert's Malarial RemedyFile:P.falciparum Gelatine enrichment.jpg  Source: http://en.wikipedia.org/w/index.php?title=File:P.falciparum_Gelatine_enrichment.jpg  License: Creative Commons Zero  Contributors:Ernst Hempelmann

License 23

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