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Malaria

2007 Schools Wikipedia Selection. Related subjects: Health and medicine

   CAPTION: Malaria
   Classifications and external resources

   Plasmodium falciparum ring-forms and gametocytes in human blood.
     ICD- 10   B 50.
     ICD- 9    084
      OMIM     248310
   DiseasesDB  7728
   MedlinePlus 000621
    eMedicine  med/1385  emerg/305 ped/1357
   MeSH        C03.752.250.552

   Malaria is an infectious disease that is widespread in tropical and
   subtropical regions. It infects between 300 and 500 million people
   every year and causes between one and three million deaths annually,
   mostly among young children in Sub-Saharan Africa.

   Malaria is one of the most common infectious diseases and an enormous
   public-health problem. The disease is caused by protozoan parasites of
   the genus Plasmodium. The most serious forms of the disease are caused
   by Plasmodium falciparum and Plasmodium vivax, but other related
   species ( Plasmodium ovale and Plasmodium malariae) can also infect
   humans. This group of human-pathogenic Plasmodium species are usually
   referred to as malaria parasites.

   Malaria parasites are transmitted by female Anopheles mosquitoes. The
   parasites multiply within red blood cells, causing symptoms that
   include fever, anaemia, chills, flu-like illness, and in severe cases,
   coma and death. Malaria transmission can be reduced by preventing
   mosquito bites with mosquito nets and insect repellents, or by mosquito
   control by spraying insecticides inside houses and draining standing
   water where mosquitoes lay their eggs.

   Unfortunately, no vaccine is currently available for malaria. Instead
   preventative drugs must be taken continuously to reduce the risk of
   infection. These prophylactic drug treatments are simply too expensive
   for most people living in endemic areas. Malaria infections are treated
   through the use of antimalarial drugs, such as chloroquine or
   pyrimethamine, although drug resistance is increasingly common.

History

   Charles Louis Alphonse Laveran
   Enlarge
   Charles Louis Alphonse Laveran

   Malaria has probably infected humans for over 50,000 years, and may
   have been a human pathogen for the entire history of our species.
   Indeed, close relatives of the human malaria parasites remain common in
   chimpanzees, our closest relatives. References to the unique periodic
   fevers of malaria are found throughout recorded history, beginning in
   2700 BC in China during the Xia Dynasty. The term malaria originates
   from Medieval Italian: mala aria — " bad air"; and the disease was
   formerly called ague or marsh fever due to its association with swamps.

   Scientific studies on malaria made their first significant advance in
   1880, when a French army doctor working in Algeria named Charles Louis
   Alphonse Laveran observed parasites inside the red blood cells of
   people suffering from malaria. He therefore proposed that malaria was
   caused by this protozoan, the first time protozoa were identified as
   causing disease. For this and later discoveries, he was awarded the
   1907 Nobel Prize for Physiology or Medicine. The protozoan was called
   Plasmodium by the Italian scientists Ettore Marchiafava and Angelo
   Celli. A year later, Carlos Finlay, a Cuban doctor treating patients
   with yellow fever in Havana, first suggested that mosquitoes were
   transmitting disease to humans. However, it was Britain's Sir Ronald
   Ross working in India who finally proved in 1898 that malaria is
   transmitted by mosquitoes. He did this by showing that certain mosquito
   species transmit malaria to birds and isolating malaria parasites from
   the salivary glands of mosquitoes that had fed on infected birds. For
   this work Ross received the 1902 Nobel Prize in Medicine. After
   resigning from the Indian Medical Service, Ross worked at the
   newly-established Liverpool School of Tropical Medicine and directed
   malaria-control efforts in Egypt, Panama, Greece and Mauritius. The
   findings of Finlay and Ross were later confirmed by a medical board
   headed by Walter Reed in 1900, and its recommendations implemented by
   William C. Gorgas in the health measures undertaken during construction
   of the Panama Canal. This public-health work saved the lives of
   thousands of workers and helped develop the methods used in future
   public-health campaigns against this disease.

   The first effective treatment for malaria was the bark of cinchona
   tree, which contains quinine. This tree grows on the slopes of the
   Andes, mainly in Peru. This natural product was used by the inhabitants
   of Peru to control malaria, and the Jesuits introduced this practice to
   Europe during the 1640s where it was rapidly accepted. However, it was
   not until 1820 that the active ingredient quinine was extracted from
   the bark, isolated and named by the French chemists Pierre Joseph
   Pelletier and Joseph Caventou.

   In the early twentieth century, before antibiotics, patients with
   syphilis were intentionally infected with malaria to create a fever. By
   accurately controlling the fever with quinine, the effects of both
   syphilis and malaria could be minimised. Although some patients died
   from malaria, this was preferable than the almost-certain death from
   syphilis.

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

Distribution and impact

   Areas of the world where malaria is endemic (coloured blue).
   Enlarge
   Areas of the world where malaria is endemic (coloured blue).

   Malaria causes about 350–500 million infections in humans and
   approximately one to three million deaths annually — this represents at
   least one death every 30 seconds. The vast majority of cases occur in
   children under the age of 5 years; pregnant women are also especially
   vulnerable. Despite efforts to reduce transmission and increase
   treatment, there has been little change in which areas are at risk of
   this disease since 1992. Indeed, if the prevalence of malaria stays on
   its present upwards course, the death rate could double in the next
   twenty years. Precise statistics are unknown because many cases occur
   in rural areas where people do not have access to hospitals or the
   means to afford health care. Consequently, the majority of cases are
   undocumented.

   Although co-infection with HIV and malaria does cause increased
   mortality, this is less of a problem than with HIV/tuberculosis
   co-infection, due to the two diseases usually attacking different
   age-ranges, with malaria being most common in the young and
   tuberculosis most common in the old. However, in areas of unstable
   malaria transmission, HIV does contribute to the incidence of severe
   malaria in adults during malaria outbreaks.

   Malaria is presently endemic in a broad band around the equator, in
   northern South America, South and Southeast Asia, and much of Africa;
   however, it is in sub-Saharan Africa where 85–90% of malaria fatalities
   occur. The geographic distribution of malaria within large regions is
   complex, and malarial and malaria-free areas are often found close to
   each other. In drier areas, outbreaks of malaria can be predicted with
   reasonable accuracy by mapping rainfall. Malaria is more common in
   rural areas than in cities; this is in contrast to dengue fever where
   urban areas present the greater risk. For example, the cities of the
   Philippines, Thailand and Sri Lanka are essentially malaria-free, but
   the disease is present in many rural regions. By contrast, in West
   Africa, Ghana and Nigeria have malaria throughout the entire country,
   though the risk is lower in the larger cities.

Symptoms

   Symptoms of malaria include fever, shivering, arthralgia (joint pain),
   vomiting, anaemia caused by hemolysis, hemoglobinuria, and convulsions.
   There may be the feeling of tingling in the skin, particularly with
   malaria caused by P. falciparum. The classical symptom of malaria is
   cyclical fevers, occurring every two days in P. falciparum, P. vivax
   and P. ovale infections, while every three for P. malariae.

   Severe malaria is almost exclusively caused by P. falciparum infection
   and usually arises 6-14 days after infection. 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), and
   hemoglobinuria with renal failure may occur. Renal failure may cause
   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. In the most severe cases of the disease
   fatality rates can exceed 20%, even with intensive care and treatment.
   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.
   Over the longer term, developmental impairments have been documented in
   children who have suffered episodes of severe malaria.

   Chronic malaria is seen in both P. vivax and P. ovale, but not in P.
   falciparum. Here, the disease can relapse months or years after
   exposure, due to the presence of latent parasites in the liver.
   Describing a case of malaria as cured by observing the disappearance of
   parasites from the bloodstream can therefore be deceptive. The longest
   incubation period reported for a P. vivax infection is 30 years.
   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).

Causes

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

Malaria parasites

   Malaria is caused by protozoan parasites of the genus Plasmodium
   (phylum Apicomplexa). In humans malaria is caused by P. falciparum, P.
   malariae, P. ovale, and P. vivax. However, P. falciparum is the most
   important cause of disease and responsible for about 80% of infections
   and 90% of deaths. Parasitic Plasmodium species also infect birds,
   reptiles, monkeys, chimpanzees and rodents. There has been documented
   human infections with several simian species of malaria, namely P.
   knowlesi, P. inui, P. cynomolgi and P. simiovale; however these are
   mostly of limited public health importance. Although avian malaria can
   kill chickens and turkeys, this disease does not cause serious economic
   losses to poultry farmers.

Mosquito vectors and the Plasmodium life cycle

   The parasite's primary (definitive) hosts and transmission vectors are
   female mosquitoes of the Anopheles genus. 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 gut. This produces an ookinete that
   penetrates the gut lining and produces a 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. The sporozoites are injected into the skin,
   alongside saliva, when the mosquito takes a subsequent blood meal.

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

Pathogenesis

   The life cycle of malaria parasites in the human body. The various
   stages in this process are discussed in the text.
   Enlarge
   The life cycle of malaria parasites in the human body. The various
   stages in this process are discussed in the text.

   Malaria in humans develops via two phases: an exoerythrocytic (hepatic)
   and an erythrocytic phase. When an infected mosquito pierces a person's
   skin to take a blood meal, sporozoites in the mosquito's saliva enter
   the bloodstream and migrate to the liver. Within 30 minutes of being
   introduced into the human host, they infect hepatocytes, multiplying
   asexually and asymptomatically for a period of 6–15 days. During this
   so-called dormant time in the liver the sporozoites are often referred
   to as hypnozoites. In the liver they 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 its life cycle. The parasite escapes from the liver undetected
   by wrapping itself in the cell membrane of the infected host liver
   cell.

   Within the red blood cells the parasites multiply further, again
   asexually, periodically breaking out of their hosts to invade fresh red
   blood cells. Several of 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.

   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. 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.

   Although the red blood cell surface adhesive proteins (called PfEMP1,
   for Plasmodium falciparum erythrocyte membrane protein 1) are exposed
   to the immune system they do not serve as good immune targets because
   of their extreme diversity; there are at least 60 variations of the
   protein within a single parasite and perhaps limitless versions within
   parasite populations. Like a thief changing disguises or a spy with
   multiple passports, the parasite switches between a broad repertoire of
   PfEMP1 surface proteins, thus staying one step ahead of the pursuing
   immune system.

   Some merozoites turn into male and female gametocytes. If a mosquito
   pierces the skin of an infected person, it potentially picks up
   gametocytes within the blood. Fertilization and sexual recombination of
   the parasite occurs in the mosquito's gut, thereby defining the
   mosquito as the definitive host of the disease. New sporozoites develop
   and travel to the mosquito's salivary gland, completing the cycle.
   Pregnant women are especially attractive to the mosquitoes, and malaria
   in pregnant women is an important cause of stillbirths, infant
   mortality and low birth weight.

Diagnosis

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

   The preferred and most 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.

   From the thick film, an experienced microscopist can detect parasite
   levels (or parasitemia) down to as low as 0.0000001% of red blood
   cells. Microscopic diagnosis 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. Please
   refer to the chapters on each parasite for their microscopic
   appearances: P. falciparum, P. vivax, P. ovale, P. malariae.

   In areas where microscopy is not available, there are antigen detection
   tests that require only a drop of blood. OptiMAL-IT® will reliably
   detect falciparum down to 0.01% parasitemia and non-falciparum down to
   0.1%. Paracheck-Pf® will detect parasitemias down to 0.002% but will
   not distinguish between falciparum and non-falciparum malaria. Parasite
   nucleic acids are detected using polymerase chain reaction. This
   technique 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
   for in order to detect low levels of parasitaemia in the field.

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

Treatment

   An active malaria infection (especially Falciparum malaria) is a
   medical emergency requiring hospitalization. When properly treated,
   someone with malaria can be completely cured.

Antimalarial drugs

   There are several families of drugs used to treat malaria. As it was
   cheap and effective, chloroquine was the antimalarial drug of choice
   for many years in most parts of the world. However, resistance of
   Plasmodium falciparum to chloroquine has spread recently from Asia to
   Africa, making the drug ineffective against the most dangerous
   Plasmodium strain in many affected regions of the world.

   There are several other substances which are used for treatment and,
   partially, for prevention (prophylaxis). Many drugs can be used for
   both purposes; larger doses are used to treat cases of malaria. Their
   deployment depends mainly on the frequency of resistant parasites in
   the area where the drug is used.

   Currently available anti-malarial drugs include:
     * Artemether- lumefantrine (Therapy only, commercial name Coartem)
     * Artesunate- amodiaquine (Therapy only)
     * Artesunate- mefloquine (Therapy only)
     * Artesunate- Sulfadoxine/ pyrimethamine (Therapy only)
     * Atovaquone- proguanil, trade name Malarone (Therapy and
       prophylaxis)
     * Quinine (Therapy only)
     * Chloroquine (Therapy and prophylaxis; usefulness now reduced due to
       resistance)
     * Cotrifazid (Therapy and prophylaxis)
     * Doxycycline (Therapy and prophylaxis)
     * Mefloquine, trade name Lariam (Therapy and prophylaxis)
     * Primaquine (Therapy in P. vivax and P. ovale only; not for
       prophylaxis)
     * Proguanil (Prophylaxis only)
     * Sulfadoxine- pyrimethamine (Therapy; prophylaxis for semi-immune
       pregnant women in endemic countries as "Intermittent Preventive
       Treatment" - IPT)
     * Hydroxychloroquine, trade name Plaquenil (Therapy and prophylaxis)

   The development of drugs was facilitated when Plasmodium falciparum was
   successfully cultured. This allowed in vitro testing of new drug
   candidates.

   Extracts of the plant Artemisia annua, containing the compound
   artemisinin or semi-synthetic derivatives (a substance unrelated to
   quinine), offer over 90% efficacy rates, but their supply is not
   meeting demand. Since 2001 the World Health Organization has
   recommended using artemisinin-based combination therapy (ACT) as
   first-line treatment for uncomplicated malaria in areas experiencing
   resistance to older medications. The most recent WHO treatment
   guidelines for malaria recommend four different ACTs. While numerous
   countries, including most African nations, have adopted the change in
   their official malaria treatment policies, cost remains a major barrier
   to ACT implementation. Because ACTs cost up to twenty times as much as
   older medications, they remain unaffordable in many malaria-endemic
   countries. The molecular target of artemisinin is controversial,
   although recent studies suggest that SERCA, a calcium pump in the
   endoplasmic reticulum may be associated with artemisinin resistance.
   Malaria parasites can develop resistance to artemisinin and resistance
   can be produced by mutation of SERCA. However, other studies suggest
   the mitochondria is the major target for artemisinin and its analogs.

   In February 2002, the journal Science and other press outlets announced
   progress on a new treatment for infected individuals. A team of French
   and South African researchers had identified a new drug they were
   calling "G25." It cured malaria in test primates by blocking the
   ability of the parasite to copy itself within the red blood cells of
   its victims. In 2005 the same team of researchers published their
   research on achieving an oral form, which they refer to as "TE3" or
   "te3." As of early 2006, there is no information in the mainstream
   press as to when this family of drugs will become commercially
   available.

   Although effective anti-malarial drugs are on the market, the disease
   remains a threat to people living in endemic areas who have no proper
   and prompt access to effective drugs. Access to pharmacies and health
   facilities, as well as drug costs, are major obstacles. Médecins Sans
   Frontières estimates that the cost to treat a malaria-infected person
   in an endemic country is between US$0.25 and $2.40.

Counterfeit drugs

   Sophisticated counterfeits have been found in Thailand, Vietnam,
   Cambodia and China, and are an important cause of avoidable death in
   these countries. There is no reliable way for doctors or lay people to
   detect counterfeit drugs without help from a laboratory.

Prevention and disease control

   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.
   Enlarge
   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 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.
   There is currently no vaccine that will prevent malaria, but this is an
   active field of research.

   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. It has been argued that,
   in order to meet the Millennium Development Goals, money should be
   redirected from HIV/AIDS treatment to malaria prevention, which for the
   same amount of money would provide greater benefit to African
   economies.

   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 the draining of wetland breeding grounds and
   better sanitation, in conjunction with the monitoring and treatment of
   infected humans, eliminated it from affluent regions. In 2002, there
   were 1,059 cases of malaria reported in the US, including eight deaths.
   In five of those cases, the disease was contracted in the United
   States. Malaria was eliminated from the northern parts of the USA in
   the early twentieth century, and the use of the pesticide DDT
   eliminated it from the South by 1951. In the 1950s and 1960s, there was
   a major public health effort to eradicate malaria worldwide by
   selectively targeting mosquitoes in areas where malaria was rampant.
   However, these efforts have so far failed to eradicate malaria in many
   parts of the developing world - the problem is most prevalent in
   Africa.

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

Prophylactic drugs

   Several drugs, most of which are also used for treatment of malaria,
   can be taken preventively. 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 starting in the seventeenth century as a prophylactic
   against malaria. The development of more effective alternatives such as
   quinacrine, chloroquine, and primaquine in the twentieth century
   reduced the reliance on quinine. Today, quinine is still used to treat
   chloroquine resistant Plasmodium falciparum, as well as severe and
   cerebral stages of malaria, but is not generally used for prophylaxis.

   Modern drugs used preventively include mefloquine (Lariam®),
   doxycycline (available generically), and atovaquone proguanil
   hydrochloride ( Malarone®). 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).

Indoor residual spraying

   DDT was developed as the first of the modern insecticides early in
   World War II. While it was initially used to combat malaria, its use
   spread to agriculture where it was used to eliminate insect pests. In
   time, pest-control, rather than disease-control, came to dominate DDT
   use, particularly in the developed world. During the 1960s, awareness
   of the negative consequences of its indiscriminate use increased, and
   ultimately led to bans in many countries in the 1970s. By this time,
   its large-scale use had already led to the evolution of resistant
   mosquitos in many regions.

   However, given the continuing toll to malaria, particularly in
   developing countries, there is considerable controversy regarding the
   restrictions placed on the use of DDT. Some advocates claim that bans
   are responsible for tens of millions of deaths in tropical countries
   where previously DDT was 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.

   The World Health Organization (WHO) currently advises the use of DDT to
   combat malaria in endemic areas. For instance, DDT-spraying the
   interior walls of living spaces, where mosquitoes land, is an effective
   control. The WHO also recommends a series of alternative insecticides
   to both combat malaria in areas where mosquitos are DDT-resistant, and
   to slow the evolution of resistance. 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 for large-scale field spraying. However, because of its
   legacy, many developed countries discourage DDT use even in small
   quantities.

Mosquito nets and bedclothes

   Mosquito nets help keep mosquitoes away from people, and thus greatly
   reduce the infection and transmission of malaria. The nets are not a
   perfect barrier, so 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 (ITN) are estimated to be twice as
   effective as untreated nets, and a offers greater than 70% protection
   compared with no net. Since the Anopheles mosquitoes feed at night, the
   preferred method is to hang a large "bed net" above the centre of a bed
   such that it drapes down and covers the bed completely. .

   The distribution of mosquito nets impregnated with insecticide (often
   permethrin) has been shown to be an extremely effective method of
   malaria prevention, and it is also one of the most cost-effective
   methods of prevention. These nets can often be obtained for around
   US$2.50 - $3.50 (2-3 euros) from the United Nations, the World Health
   Organization, and others.

   For maximum effectiveness, the nets should be re-impregnated with
   insecticide every six months. This process poses a significant
   logistical problem in rural areas. A new type of impregnated net,
   called Olyset, releases insecticide for approximately 5 years, and
   costs about US$5.50. ITN's have the advantage of protecting people
   sleeping under the net and simultaneously killing mosquitoes that
   contact the net. This has the effect of killing the most dangerous
   mosquitoes. Some protection is also provided to others, including
   people sleeping in the same room but not under the net.

   Unfortunately, the cost of treating malaria is high relative to income,
   and the illness results in lost wages. Consequently, the financial
   burden means that the cost of a mosquito net is often unaffordable to
   people in developing countries, especially for those most at risk. Only
   1 out of 20 people in Africa own a bed net.

   A study among Afghan refugees in Pakistan found that treating
   top-sheets and chaddars (head coverings) with permethrin has similar
   effectiveness to using a treated net, but is much cheaper.

   A new approach, announced in Science on June 10, 2005, uses spores of
   the fungus Beauveria bassiana, sprayed on walls and bed nets, to kill
   mosquitoes. While some mosquitoes have developed resistance to
   chemicals, they have not been found to develop a resistance to fungal
   infections.

Vaccination

   Vaccines for malaria are under development, with no completely
   effective vaccine yet available (as of June 2006). A team backed by the
   PATH Malaria Vaccine Initiative, a grantee of the Gates Foundation, and
   the pharmaceutical company GlaxoSmithKline have announced results of a
   Phase IIb trial for RTS,S/ AS02A, a vaccine which reduces infection
   risk by approximately 30% and severity of infection by over 50%. The
   study looked at over 2000 Mozambican children. Further research will
   delay this vaccine from commercial release until around 2011.

   In January 2005, University of Edinburgh scientists announced the
   discovery of an antibody which protects against the disease. The
   scientists will lead a £17m European consortium of malaria researchers.
   It is hoped that the genome sequences of the most deadly agent of
   malaria, Plasmodium falciparum will provide targets for new drugs or
   vaccines.

Other methods

   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, with the first plasmodium-resistant
   species announced by a team at Case Western Reserve University in Ohio
   in 2002.

   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.

Social and economic effects

   Malaria is not just a disease common associated with poverty, but is
   also a cause of poverty and a major hindrance to economic development.
   The disease has been associated with major negative economic effects on
   regions where it is widespread. A comparison of average per capita GDP
   in 1995, adjusted to give parity of purchasing power, between malarious
   and non-malarious countries demonstrate a five-fold difference
   (US$1,526 versus US$8,268). Moreover, in countries where malaria is
   common, average per capita GDP has risen (between 1965 and 1990) only
   0.4% per year, compared to 2.4% per year in other countries. In its
   entirety, the economic impact of malaria has been estimated to cost
   Africa US$12 billion every year. The economic impact includes costs of
   health care, working days lost due to sickness, days lost in education,
   decreased productivity due to brain damage from cerebral malaria, and
   loss of investment and tourism. In some countries with a heavy malaria
   burden, the disease may account for as much as 40% of public health
   expenditure, 30-50% of inpatient admissions, and up to 50% of
   outpatient visits.

Evolutionary pressure of malaria on human genes

   Malaria is thought to have been the greatest selective pressure on the
   human genome in recent history. This is due to the high levels of
   mortality and morbidity caused by malaria, especially the P. falciparum
   species.

Sickle-cell anaemia

   The best-studied influence of the malaria parasite upon the human
   genome is the blood disease, sickle-cell anaemia. In sickle-cell
   anaemia, there is a mutation in the HBB gene which codes for a
   haemoglobin subunit. The normal allele is HbA, but the sickle-cell
   allele, HbS, has a mutation from Glutamic Acid to Valine at amino acid
   6. This change from a hydrophilic to a hydrophobic residue encourages
   binding between haemoglobin molecules, with polymerization of
   haemoglobin deforming red blood cells into a sickle shape.

   Individuals homozygous for HbS have full sickle-cell anaemia and rarely
   live beyond adolescence. However, this allele has sustained gene
   frequencies in populations where malaria is endemic of around 10%. This
   is because individuals heterozygous for the mutated allele (HbA/HbS),
   known as Sickle-cell trait, have a low level of anaemia but also have a
   greatly reduced chance of malaria infection. The existence of four
   haplotypes of HbS suggests that this mutation has emerged independently
   at least four times in malaria-endemic areas, further demonstrating its
   evolutionary advantage in such affected regions.

   There are also other mutations of the HBB gene which appear to confer
   similar resistance to malaria infection. These are HbE and HbC which
   are common in Southeast Asia and Western Africa respectively.

Thalassaemias

   Another well documented set of mutations found in the human genome
   associated with malaria are those involved in causing blood disorders
   known as thalassaemias. Studies in Sardinia and Papua New Guinea have
   found that the gene frequency of β-thalassaemias is related to the
   level of endemicity in a given population. A study on more than 500
   children in Liberia found that those with β-thalassaemia had a 50%
   decreased chance of getting clinical malaria. Similar studies have
   found links between gene frequency and malaria endemicity in the α+
   form of α-thalassaemia.

Duffy antigens

   The Duffy antigens are antigens expressed on red blood cells and other
   cells in the body acting as a chemokine receptor. The expression of
   Duffy antigens on blood cells is encoded by Fy genes (Fya, Fyb, Fyc
   etc.). Plasmodium vivax malaria uses the Duffy antigen to enter blood
   cells. However, it is possible to express no Duffy antigen on red blood
   cells (Fy-/Fy-). This genotype confers complete resistance to P. vivax
   infection. The genotype has not been found in Chinese populations, has
   rarely been found in white populations, but is found in 68% of black
   people. This is thought to be due to very high exposure to P. vivax in
   Africa in the past.

G6PD

   Glucose-6-phosphate dehydrogenase (G6PD) is an enzyme which normally
   protects from the effects of oxidative stress in red blood cells.
   However, a genetic deficiency in this enzyme results in increased
   protection against severe malaria.
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