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Malaria
Classification and external resources
Ring-forms and gametocytes of Plasmodium falciparum in human blood.
ICD-10 B50.
ICD-9 084
OMIM 248310
DiseasesDB 7728
MedlinePlus 000621
eMedicine med/1385 emerg/305 ped/1357
MeSH C03.752.250.552
Malaria is a mosquito-borne infectious disease of humans caused by eukaryotic protists of the genus Plasmodium. It is widespread in tropical and subtropical regions, including much of Sub-Saharan Africa, Asia and the Americas. The disease results from the multiplication of malaria parasites within red blood cells, causing symptoms that typically include fever and headache, in severe cases progressing to coma, and death.
Four species of Plasmodium can infect and be transmitted by humans. Severe disease is largely caused by Plasmodium falciparum. Malaria caused by Plasmodium vivax, Plasmodium ovale and Plasmodium malariae is generally a milder disease that is rarely fatal. A fifth species, Plasmodium knowlesi, is a zoonosis that causes malaria in macaques but can also infect humans.[1][2]
Malaria transmission can be reduced by preventing mosquito bites by distribution of inexpensive mosquito nets and insect repellents, or by mosquito-control measures such as spraying insecticides inside houses and draining standing water where mosquitoes lay their eggs. Although many are under development, the challenge of producing a widely available vaccine that provides a high level of protection for a sustained period is still to be met.[3] Two drugs are also available to prevent malaria in travellers to malaria-endemic countries (prophylaxis).
A variety of antimalarial medications are available. In the last 5 years, treatment of P. falciparum infections in endemic countries has been transformed by the use of combinations of drugs containing an artemisinin derivative. Severe malaria is treated with intravenous or intramuscular quinine or, increasingly, the artemisinin derivative artesunate [4] which is superior to quinine in both children and adults.[5] Resistance has developed to several antimalarial drugs, most notably chloroquine.[6]
Each year, there are more than 225 million cases of malaria,[7] killing around 781,000 people each year according to the World Health Organisation's 2010 World Malaria Report [8], 2.23% of deaths worldwide. The majority of deaths are of young children in sub-Saharan Africa.[9] 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[10] and a major hindrance to economic development.
Contents [hide]
1 Signs and symptoms
2 Cause
2.1 Life cycle
2.1.1 Recurrent malaria
3 Pathogenesis
3.1 Genetic resistance
4 Diagnosis
4.1 Blood films
4.2 Antigen tests
4.3 Molecular methods
4.4 Differential
5 Prevention
5.1 Medications
5.2 Vector control
5.3 Indoor residual spraying
5.3.1 Mosquito nets and bedclothes
5.4 Vaccination
5.5 Other methods
6 Treatment
7 Epidemiology
8 History
8.1 Prevention
8.2 Discovery of the parasite
8.3 Discovery of mosquito transmission
8.4 The liver stage
8.5 In vitro culture
8.6 History of treatment
9 Society and culture
9.1 Counterfeit drugs
9.2 War
10 Research
11 References
12 Further reading
13 External links
[edit] Signs and symptoms
Main symptoms of malaria.[11]
Typical fever patterns of malariaSymptoms of malaria include fever, shivering, arthralgia (joint pain), vomiting, anemia (caused by hemolysis), hemoglobinuria, retinal damage,[12] and convulsions. 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.[13] 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.[14] 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.[15][16] Cerebral malaria is associated with retinal whitening,[17] which may be a useful clinical sign in distinguishing malaria from other causes of fever.[18]
Severe malaria is almost exclusively caused by P. falciparum infection, and usually arises 6–14 days after infection.[19] Consequences of severe malaria include coma and death if untreated—young children and pregnant women are especially vulnerable. Splenomegaly (enlarged spleen), severe headache, cerebral ischemia, hepatomegaly (enlarged liver), hypoglycemia, and hemoglobinuria with renal failure may occur. Renal failure is a feature of blackwater fever, where hemoglobin from lysed red blood cells leaks into the urine. Severe malaria can progress extremely rapidly and cause death within hours or days.[19] In the most severe cases of the disease, fatality rates can exceed 20%, even with intensive care and treatment.[20] 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.[21] Over the longer term, developmental impairments have been documented in children who have suffered episodes of severe malaria.[22]
[edit] Cause
A Plasmodium sporozoite traverses the cytoplasm of a mosquito midgut epithelial cell in this false-color electron micrograph.Malaria parasites are members of the genus Plasmodium (phylum Apicomplexa). In humans malaria is caused by P. falciparum, P. malariae, P. ovale, P. vivax and P. knowlesi.[23][24] P. falciparum is the most common cause of infection, and is also responsible for about 90% of the deaths from malaria.[25] Parasitic Plasmodium species also infect birds, reptiles, monkeys, chimpanzees and rodents.[26] There have been documented human infections with several simian species of malaria, namely P. knowlesi, P. inui, P. cynomolgi,[27] P. simiovale, P. brazilianum, P. schwetzi and P. simium; however, with the exception of P. knowlesi, these are mostly of limited public health importance.[28]
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[29] and play a crucial role in various aspects of parasite metabolism e.g. fatty acid bio-synthesis.[30] To date, 466 proteins have been found to be produced by apicoplasts[31] and these are now being looked at as possible targets for novel anti-malarial drugs.
[edit] Life cycleThe parasite's secondary (intermediate) hosts are humans and other vertebrates. Female mosquitoes of the Anopheles genus are primary hosts and transmission vectors. Young mosquitoes first ingest the malaria parasite by feeding on an infected human carrier and the infected Anopheles mosquitoes carry Plasmodium sporozoites in their salivary glands. A mosquito becomes infected when it takes a blood meal from an infected human. Once ingested, the parasite gametocytes taken up in the blood will further differentiate into male or female gametes and then fuse in the mosquito's gut. This produces an ookinete that penetrates the gut lining and produces an oocyst in the gut wall. When the oocyst ruptures, it releases sporozoites that migrate through the mosquito's body to the salivary glands, where they are then ready to infect a new human host. This type of transmission is occasionally referred to as anterior station transfer.[32] The sporozoites are injected into the skin, alongside saliva, when the mosquito takes a subsequent blood meal.
Only female mosquitoes feed on blood while male mosquitoes feed on plant nectar,[33] 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.[34]
[edit] Recurrent malariaMalaria recurs after treatment for three reasons. Recrudescence occurs when parasites are not cleared by treatment, whereas reinfection indicates complete clearance with new infection established from a separate infective mosquito bite; both can occur with any malaria parasite species. Relapse is specific to P. vivax and P. ovale and involves re-emergence of blood-stage parasites from latent parasites (hypnozoites) in the liver. Describing a case of malaria as cured by observing the disappearance of parasites from the bloodstream can, therefore, be deceptive. The longest incubation period reported for a P. vivax infection is 30 years.[19] 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).[35]
[edit] PathogenesisFurther information: Plasmodium falciparum biology
The life cycle of malaria parasites in the human body. A mosquito infects a person by taking a blood meal. First, sporozoites enter the bloodstream, and migrate to the liver. They infect liver cells (hepatocytes), where they multiply into merozoites, rupture the liver cells, and escape back into the bloodstream. Then, the merozoites infect red blood cells, where they develop into ring forms, trophozoites and schizonts which in turn produce further merozoites. Sexual forms (gametocytes) are also produced, which, if taken up by a mosquito, will infect the insect and continue the life cycle.Malaria develops via two phases: an exoerythrocytic and an erythrocytic phase. The exoerythrocytic phase involves infection of the hepatic system, or liver, whereas the erythrocytic phase involves infection of the erythrocytes, or red blood cells. When an infected mosquito pierces a person's skin to take a blood meal, sporozoites in the mosquito's saliva enter the bloodstream and migrate to the liver. Within minutes of being introduced into the human host, the sporozoites infect hepatocytes, multiplying asexually and asymptomatically for a period of 8–30 days.[36] 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.[36] The parasite escapes from the liver undetected by wrapping itself in the cell membrane of the infected host liver cell.[37]
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.[38]
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.[39] This "stickiness" is the main factor giving rise to hemorrhagic 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.[40]
Although the white blood cell surface adhesive proteins (called PfEMP1, for Plasmodium falciparum erythrocyte membrane protein 1) are exposed to the immune system, they do not serve as good immune targets, because of their extreme diversity; there are at least 60 variations of the protein within a single parasite and effectively limitless versions within parasite populations.[39] The parasite switches between a broad repertoire of PfEMP17 surface proteins, thus staying one step ahead of the pursuing immune system.
Some merozoites turn into male and female gametocytes. Since the gametocytes are formed in the blood of the vertebrate host, the vertebrate host is the definitive host of the disease. If a mosquito pierces the skin of an infected person, it potentially picks up gametocytes within the blood. Fertilization and sexual recombination of the parasite occurs in the mosquito's gut. New sporozoites develop and travel to the mosquito's salivary gland, completing the cycle. Pregnant women are especially attractive to the mosquitoes,[41] and malaria in pregnant women is an important cause of stillbirths, infant mortality and low birth weight,[42] particularly in P. falciparum infection, but also in other species infection, such as P. vivax.[43]
[edit] Genetic resistanceMain article: Genetic resistance to malaria
Malaria is thought to have been the greatest selective pressure on the human genome in recent history.[44] This is due to the high levels of mortality and morbidity caused by malaria, especially the P. falciparum species. A number of diseases may provide some resistance to it including sickle cell disease, thalassaemias, glucose-6-phosphate dehydrogenase, Duffy antigens, and possibly others.
[edit] DiagnosisThe mainstay of malaria diagnosis has been the microscopic examination of blood.[45] Although blood is the sample most frequently used to make a diagnosis, both saliva and urine have been investigated as alternative, less invasive specimens.[46]
Areas that cannot afford laboratory diagnostic tests often use only a history of subjective fever as the indication to treat for malaria. Using Giemsa-stained blood smears from children in Malawi, one study showed that when clinical predictors (rectal temperature, nailbed pallor, and splenomegaly) were used as treatment indications, rather than using only a history of subjective fevers, a correct diagnosis increased from 2% to 41% of cases, and unnecessary treatment for malaria was significantly decreased.[47]
[edit] Blood filmsSpecies 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 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.[48]
From the thick film, an experienced microscopist can detect parasite levels (or parasitemia) down to as low as 0.0000001% of red blood cells[citation needed]. Diagnosis of species can be difficult because the early trophozoites ("ring form") of all four species look identical and it is never possible to diagnose species on the basis of a single ring form; species identification is always based on several trophozoites.
One important thing to note is that P. malariae and P. knowlesi (which is the most common cause of malaria in South-east Asia) look very similar under the microscope. However, P. knowlesi parasitemia increases very fast and causes more severe disease than P. malariae, so it is important to identify and treat infections quickly. Therefore modern methods such as PCR (see "Molecular methods" below) or monoclonal antibody panels that can distinguish between the two should be used in this part of the world.[49]
[edit] Antigen testsSee also: Malaria antigen detection tests
For areas where microscopy is not available, or where laboratory staff are not experienced at malaria diagnosis, there are commercial antigen detection tests that require only a drop of blood.[50] 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.[51] 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 methodsMolecular methods are available in some clinical laboratories and rapid real-time assays (for example, QT-NASBA based on the polymerase chain reaction)[52] 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.[53]
[edit] DifferentialFever 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.[54]
[edit] Prevention
Anopheles albimanus mosquito feeding on a human arm. This mosquito is a vector of malaria and mosquito control is a very effective way of reducing the incidence of malaria.Methods used in order to prevent the spread of disease, or to protect individuals in areas where malaria is endemic, include prophylactic drugs, mosquito eradication and the prevention of mosquito bites.
The continued existence of malaria in an area requires a combination of high human population density, high mosquito population density and high rates of transmission from humans to mosquitoes and from mosquitoes to humans. If any of these is lowered sufficiently, the parasite will sooner or later disappear from that area, as happened in North America, Europe and much of Middle East. However, unless the parasite is eliminated from the whole world, it could become re-established if conditions revert to a combination that favours the parasite's reproduction.[citation needed] Many countries are seeing an increasing number of imported malaria cases owing to extensive travel and migration.
Many researchers argue that prevention of malaria may be more cost-effective than treatment of the disease in the long run, but the capital costs required are out of reach of many of the world's poorest people. Economic adviser Jeffrey Sachs estimates that malaria can be controlled for US$3 billion in aid per year.[55]
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).[56]
Brazil, Eritrea, India, and Vietnam, unlike many other developing nations, have successfully reduced the malaria burden. Common success factors have included conducive country conditions, a targeted technical approach using a package of effective tools, data-driven decision-making, active leadership at all levels of government, involvement of communities, decentralized implementation and control of finances, skilled technical and managerial capacity at national and sub-national levels, hands-on technical and programmatic support from partner agencies, and sufficient and flexible financing.[57]
[edit] MedicationsMain 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.[58] 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.[59]
[edit] Vector controlFurther 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[60] (see National Malaria Eradication Program). In 2002, there were 1,059 cases of malaria reported in the US, including eight deaths, but in only five of those cases was the disease contracted in the United States.
Before DDT, malaria was successfully eradicated or controlled also in several tropical areas by removing or poisoning the breeding grounds of the mosquitoes or the aquatic habitats of the larva stages, for example by filling or applying oil to places with standing water. These methods have seen little application in Africa for more than half a century.[61]
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,[62] with the first plasmodium-resistant species announced by a team at Case Western Reserve University in Ohio in 2002.[63] 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.[64] An even more futuristic method of vector control is the idea that lasers could be used to kill flying mosquitoes.[65]
[edit] Indoor residual sprayingMain 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.[60] 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.[66]
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).[67] 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.[68] However, because of its legacy, many developed countries previously discouraged DDT use even in small quantities.[69]
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.[70]
[edit] Mosquito nets and bedclothesMain 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.[71] 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 the Anopheles mosquitoes feed at night, the preferred method is to hang a large "bed net" above the center of a bed such that it drapes down and covers the bed completely.
[edit] VaccinationMain article: Malaria vaccine
Immunity (or, more accurately, tolerance) does occur naturally, but only in response to repeated infection with multiple strains of malaria.[72] 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.[73] Since the 1970s, there has been a considerable effort to develop similar vaccination strategies within humans. It was determined that an individual can be protected from a P. falciparum infection if they receive over 1,000 bites from infected yet irradiated mosquitoes.[74]
[edit] Other methodsEducation 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.[75]
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.[76] 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.[77] The device is currently undergoing commercial development, although instructions for a DIY version of the photonic fence have also been published.[78]
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.[79] 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."[80]
[edit] TreatmentFurther information: Antimalarial drug
When properly treated, a patient with malaria can expect a complete recovery.[81] The treatment of malaria depends on the severity of the disease; whether patients who can take oral drugs have to be admitted depends on the assessment and the experience of the clinician. Uncomplicated malaria is treated with oral drugs. The most effective strategy for P. falciparum infection recommended by WHO is the use of artemisinins in combination with other antimalarials artemisinin-combination therapy, ACT, in order to avoid the development of drug resistance against artemisinin-based therapies.
Severe malaria requires the parenteral administration of antimalarial drugs. Until recently the most used treatment for severe malaria was quinine but artesunate has been shown to be superior to quinine in both children [82] and adults.[83] Treatment of severe malaria also involves supportive measures.
Infection with P. vivax, P. ovale or P. malariae is usually treated on an outpatient basis. Treatment of P. vivax requires both treatment of blood stages (with chloroquine or ACT) as well as clearance of liver forms with primaquine.
[edit] Epidemiology
Malaria
Classification and external resources
Ring-forms and gametocytes of Plasmodium falciparum in human blood.
ICD-10 B50.
ICD-9 084
OMIM 248310
DiseasesDB 7728
MedlinePlus 000621
eMedicine med/1385 emerg/305 ped/1357
MeSH C03.752.250.552
Malaria is a mosquito-borne infectious disease of humans caused by eukaryotic protists of the genus Plasmodium. It is widespread in tropical and subtropical regions, including much of Sub-Saharan Africa, Asia and the Americas. The disease results from the multiplication of malaria parasites within red blood cells, causing symptoms that typically include fever and headache, in severe cases progressing to coma, and death.
Four species of Plasmodium can infect and be transmitted by humans. Severe disease is largely caused by Plasmodium falciparum. Malaria caused by Plasmodium vivax, Plasmodium ovale and Plasmodium malariae is generally a milder disease that is rarely fatal. A fifth species, Plasmodium knowlesi, is a zoonosis that causes malaria in macaques but can also infect humans.[1][2]
Malaria transmission can be reduced by preventing mosquito bites by distribution of inexpensive mosquito nets and insect repellents, or by mosquito-control measures such as spraying insecticides inside houses and draining standing water where mosquitoes lay their eggs. Although many are under development, the challenge of producing a widely available vaccine that provides a high level of protection for a sustained period is still to be met.[3] Two drugs are also available to prevent malaria in travellers to malaria-endemic countries (prophylaxis).
A variety of antimalarial medications are available. In the last 5 years, treatment of P. falciparum infections in endemic countries has been transformed by the use of combinations of drugs containing an artemisinin derivative. Severe malaria is treated with intravenous or intramuscular quinine or, increasingly, the artemisinin derivative artesunate [4] which is superior to quinine in both children and adults.[5] Resistance has developed to several antimalarial drugs, most notably chloroquine.[6]
Each year, there are more than 225 million cases of malaria,[7] killing around 781,000 people each year according to the World Health Organisation's 2010 World Malaria Report [8], 2.23% of deaths worldwide. The majority of deaths are of young children in sub-Saharan Africa.[9] 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[10] and a major hindrance to economic development.
Contents [hide]
1 Signs and symptoms
2 Cause
2.1 Life cycle
2.1.1 Recurrent malaria
3 Pathogenesis
3.1 Genetic resistance
4 Diagnosis
4.1 Blood films
4.2 Antigen tests
4.3 Molecular methods
4.4 Differential
5 Prevention
5.1 Medications
5.2 Vector control
5.3 Indoor residual spraying
5.3.1 Mosquito nets and bedclothes
5.4 Vaccination
5.5 Other methods
6 Treatment
7 Epidemiology
8 History
8.1 Prevention
8.2 Discovery of the parasite
8.3 Discovery of mosquito transmission
8.4 The liver stage
8.5 In vitro culture
8.6 History of treatment
9 Society and culture
9.1 Counterfeit drugs
9.2 War
10 Research
11 References
12 Further reading
13 External links
[edit] Signs and symptoms
Main symptoms of malaria.[11]
Typical fever patterns of malariaSymptoms of malaria include fever, shivering, arthralgia (joint pain), vomiting, anemia (caused by hemolysis), hemoglobinuria, retinal damage,[12] and convulsions. 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.[13] 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.[14] 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.[15][16] Cerebral malaria is associated with retinal whitening,[17] which may be a useful clinical sign in distinguishing malaria from other causes of fever.[18]
Severe malaria is almost exclusively caused by P. falciparum infection, and usually arises 6–14 days after infection.[19] Consequences of severe malaria include coma and death if untreated—young children and pregnant women are especially vulnerable. Splenomegaly (enlarged spleen), severe headache, cerebral ischemia, hepatomegaly (enlarged liver), hypoglycemia, and hemoglobinuria with renal failure may occur. Renal failure is a feature of blackwater fever, where hemoglobin from lysed red blood cells leaks into the urine. Severe malaria can progress extremely rapidly and cause death within hours or days.[19] In the most severe cases of the disease, fatality rates can exceed 20%, even with intensive care and treatment.[20] 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.[21] Over the longer term, developmental impairments have been documented in children who have suffered episodes of severe malaria.[22]
[edit] Cause
A Plasmodium sporozoite traverses the cytoplasm of a mosquito midgut epithelial cell in this false-color electron micrograph.Malaria parasites are members of the genus Plasmodium (phylum Apicomplexa). In humans malaria is caused by P. falciparum, P. malariae, P. ovale, P. vivax and P. knowlesi.[23][24] P. falciparum is the most common cause of infection, and is also responsible for about 90% of the deaths from malaria.[25] Parasitic Plasmodium species also infect birds, reptiles, monkeys, chimpanzees and rodents.[26] There have been documented human infections with several simian species of malaria, namely P. knowlesi, P. inui, P. cynomolgi,[27] P. simiovale, P. brazilianum, P. schwetzi and P. simium; however, with the exception of P. knowlesi, these are mostly of limited public health importance.[28]
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[29] and play a crucial role in various aspects of parasite metabolism e.g. fatty acid bio-synthesis.[30] To date, 466 proteins have been found to be produced by apicoplasts[31] and these are now being looked at as possible targets for novel anti-malarial drugs.
[edit] Life cycleThe parasite's secondary (intermediate) hosts are humans and other vertebrates. Female mosquitoes of the Anopheles genus are primary hosts and transmission vectors. Young mosquitoes first ingest the malaria parasite by feeding on an infected human carrier and the infected Anopheles mosquitoes carry Plasmodium sporozoites in their salivary glands. A mosquito becomes infected when it takes a blood meal from an infected human. Once ingested, the parasite gametocytes taken up in the blood will further differentiate into male or female gametes and then fuse in the mosquito's gut. This produces an ookinete that penetrates the gut lining and produces an oocyst in the gut wall. When the oocyst ruptures, it releases sporozoites that migrate through the mosquito's body to the salivary glands, where they are then ready to infect a new human host. This type of transmission is occasionally referred to as anterior station transfer.[32] The sporozoites are injected into the skin, alongside saliva, when the mosquito takes a subsequent blood meal.
Only female mosquitoes feed on blood while male mosquitoes feed on plant nectar,[33] 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.[34]
[edit] Recurrent malariaMalaria recurs after treatment for three reasons. Recrudescence occurs when parasites are not cleared by treatment, whereas reinfection indicates complete clearance with new infection established from a separate infective mosquito bite; both can occur with any malaria parasite species. Relapse is specific to P. vivax and P. ovale and involves re-emergence of blood-stage parasites from latent parasites (hypnozoites) in the liver. Describing a case of malaria as cured by observing the disappearance of parasites from the bloodstream can, therefore, be deceptive. The longest incubation period reported for a P. vivax infection is 30 years.[19] 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).[35]
[edit] PathogenesisFurther information: Plasmodium falciparum biology
The life cycle of malaria parasites in the human body. A mosquito infects a person by taking a blood meal. First, sporozoites enter the bloodstream, and migrate to the liver. They infect liver cells (hepatocytes), where they multiply into merozoites, rupture the liver cells, and escape back into the bloodstream. Then, the merozoites infect red blood cells, where they develop into ring forms, trophozoites and schizonts which in turn produce further merozoites. Sexual forms (gametocytes) are also produced, which, if taken up by a mosquito, will infect the insect and continue the life cycle.Malaria develops via two phases: an exoerythrocytic and an erythrocytic phase. The exoerythrocytic phase involves infection of the hepatic system, or liver, whereas the erythrocytic phase involves infection of the erythrocytes, or red blood cells. When an infected mosquito pierces a person's skin to take a blood meal, sporozoites in the mosquito's saliva enter the bloodstream and migrate to the liver. Within minutes of being introduced into the human host, the sporozoites infect hepatocytes, multiplying asexually and asymptomatically for a period of 8–30 days.[36] 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.[36] The parasite escapes from the liver undetected by wrapping itself in the cell membrane of the infected host liver cell.[37]
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.[38]
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.[39] This "stickiness" is the main factor giving rise to hemorrhagic 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.[40]
Although the white blood cell surface adhesive proteins (called PfEMP1, for Plasmodium falciparum erythrocyte membrane protein 1) are exposed to the immune system, they do not serve as good immune targets, because of their extreme diversity; there are at least 60 variations of the protein within a single parasite and effectively limitless versions within parasite populations.[39] The parasite switches between a broad repertoire of PfEMP17 surface proteins, thus staying one step ahead of the pursuing immune system.
Some merozoites turn into male and female gametocytes. Since the gametocytes are formed in the blood of the vertebrate host, the vertebrate host is the definitive host of the disease. If a mosquito pierces the skin of an infected person, it potentially picks up gametocytes within the blood. Fertilization and sexual recombination of the parasite occurs in the mosquito's gut. New sporozoites develop and travel to the mosquito's salivary gland, completing the cycle. Pregnant women are especially attractive to the mosquitoes,[41] and malaria in pregnant women is an important cause of stillbirths, infant mortality and low birth weight,[42] particularly in P. falciparum infection, but also in other species infection, such as P. vivax.[43]
[edit] Genetic resistanceMain article: Genetic resistance to malaria
Malaria is thought to have been the greatest selective pressure on the human genome in recent history.[44] This is due to the high levels of mortality and morbidity caused by malaria, especially the P. falciparum species. A number of diseases may provide some resistance to it including sickle cell disease, thalassaemias, glucose-6-phosphate dehydrogenase, Duffy antigens, and possibly others.
[edit] DiagnosisThe mainstay of malaria diagnosis has been the microscopic examination of blood.[45] Although blood is the sample most frequently used to make a diagnosis, both saliva and urine have been investigated as alternative, less invasive specimens.[46]
Areas that cannot afford laboratory diagnostic tests often use only a history of subjective fever as the indication to treat for malaria. Using Giemsa-stained blood smears from children in Malawi, one study showed that when clinical predictors (rectal temperature, nailbed pallor, and splenomegaly) were used as treatment indications, rather than using only a history of subjective fevers, a correct diagnosis increased from 2% to 41% of cases, and unnecessary treatment for malaria was significantly decreased.[47]
[edit] Blood filmsSpecies 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 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.[48]
From the thick film, an experienced microscopist can detect parasite levels (or parasitemia) down to as low as 0.0000001% of red blood cells[citation needed]. Diagnosis of species can be difficult because the early trophozoites ("ring form") of all four species look identical and it is never possible to diagnose species on the basis of a single ring form; species identification is always based on several trophozoites.
One important thing to note is that P. malariae and P. knowlesi (which is the most common cause of malaria in South-east Asia) look very similar under the microscope. However, P. knowlesi parasitemia increases very fast and causes more severe disease than P. malariae, so it is important to identify and treat infections quickly. Therefore modern methods such as PCR (see "Molecular methods" below) or monoclonal antibody panels that can distinguish between the two should be used in this part of the world.[49]
[edit] Antigen testsSee also: Malaria antigen detection tests
For areas where microscopy is not available, or where laboratory staff are not experienced at malaria diagnosis, there are commercial antigen detection tests that require only a drop of blood.[50] 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.[51] 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 methodsMolecular methods are available in some clinical laboratories and rapid real-time assays (for example, QT-NASBA based on the polymerase chain reaction)[52] 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.[53]
[edit] DifferentialFever 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.[54]
[edit] Prevention
Anopheles albimanus mosquito feeding on a human arm. This mosquito is a vector of malaria and mosquito control is a very effective way of reducing the incidence of malaria.Methods used in order to prevent the spread of disease, or to protect individuals in areas where malaria is endemic, include prophylactic drugs, mosquito eradication and the prevention of mosquito bites.
The continued existence of malaria in an area requires a combination of high human population density, high mosquito population density and high rates of transmission from humans to mosquitoes and from mosquitoes to humans. If any of these is lowered sufficiently, the parasite will sooner or later disappear from that area, as happened in North America, Europe and much of Middle East. However, unless the parasite is eliminated from the whole world, it could become re-established if conditions revert to a combination that favours the parasite's reproduction.[citation needed] Many countries are seeing an increasing number of imported malaria cases owing to extensive travel and migration.
Many researchers argue that prevention of malaria may be more cost-effective than treatment of the disease in the long run, but the capital costs required are out of reach of many of the world's poorest people. Economic adviser Jeffrey Sachs estimates that malaria can be controlled for US$3 billion in aid per year.[55]
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).[56]
Brazil, Eritrea, India, and Vietnam, unlike many other developing nations, have successfully reduced the malaria burden. Common success factors have included conducive country conditions, a targeted technical approach using a package of effective tools, data-driven decision-making, active leadership at all levels of government, involvement of communities, decentralized implementation and control of finances, skilled technical and managerial capacity at national and sub-national levels, hands-on technical and programmatic support from partner agencies, and sufficient and flexible financing.[57]
[edit] MedicationsMain 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.[58] 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.[59]
[edit] Vector controlFurther 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[60] (see National Malaria Eradication Program). In 2002, there were 1,059 cases of malaria reported in the US, including eight deaths, but in only five of those cases was the disease contracted in the United States.
Before DDT, malaria was successfully eradicated or controlled also in several tropical areas by removing or poisoning the breeding grounds of the mosquitoes or the aquatic habitats of the larva stages, for example by filling or applying oil to places with standing water. These methods have seen little application in Africa for more than half a century.[61]
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,[62] with the first plasmodium-resistant species announced by a team at Case Western Reserve University in Ohio in 2002.[63] 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.[64] An even more futuristic method of vector control is the idea that lasers could be used to kill flying mosquitoes.[65]
[edit] Indoor residual sprayingMain 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.[60] 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.[66]
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).[67] 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.[68] However, because of its legacy, many developed countries previously discouraged DDT use even in small quantities.[69]
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.[70]
[edit] Mosquito nets and bedclothesMain 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.[71] 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 the Anopheles mosquitoes feed at night, the preferred method is to hang a large "bed net" above the center of a bed such that it drapes down and covers the bed completely.
[edit] VaccinationMain article: Malaria vaccine
Immunity (or, more accurately, tolerance) does occur naturally, but only in response to repeated infection with multiple strains of malaria.[72] 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.[73] Since the 1970s, there has been a considerable effort to develop similar vaccination strategies within humans. It was determined that an individual can be protected from a P. falciparum infection if they receive over 1,000 bites from infected yet irradiated mosquitoes.[74]
[edit] Other methodsEducation 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.[75]
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.[76] 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.[77] The device is currently undergoing commercial development, although instructions for a DIY version of the photonic fence have also been published.[78]
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.[79] 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."[80]
[edit] TreatmentFurther information: Antimalarial drug
When properly treated, a patient with malaria can expect a complete recovery.[81] The treatment of malaria depends on the severity of the disease; whether patients who can take oral drugs have to be admitted depends on the assessment and the experience of the clinician. Uncomplicated malaria is treated with oral drugs. The most effective strategy for P. falciparum infection recommended by WHO is the use of artemisinins in combination with other antimalarials artemisinin-combination therapy, ACT, in order to avoid the development of drug resistance against artemisinin-based therapies.
Severe malaria requires the parenteral administration of antimalarial drugs. Until recently the most used treatment for severe malaria was quinine but artesunate has been shown to be superior to quinine in both children [82] and adults.[83] Treatment of severe malaria also involves supportive measures.
Infection with P. vivax, P. ovale or P. malariae is usually treated on an outpatient basis. Treatment of P. vivax requires both treatment of blood stages (with chloroquine or ACT) as well as clearance of liver forms with primaquine.
[edit] Epidemiology
