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Malaria
Classification and external resources
Template:Px
Plasmodium falciparum ring-forms and gametocytes 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 vector-borne infectious disease caused by protozoan parasites. It is widespread in tropical and subtropical regions, including parts of the Americas, Asia, and Africa. Each year, there are approximately 350–500 million cases of malaria,[1] killing between one and three million people, the majority of whom are young children in Sub-Saharan Africa.[2] Ninety percent of malaria-related deaths occur in Sub-Saharan Africa. Malaria is commonly associated with poverty, but is also a cause of poverty[3] and a major hindrance to economic development.

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. Five species of the plasmodium parasite can infect humans; the most serious forms of the disease are caused by Plasmodium falciparum. Malaria caused by Plasmodium vivax, Plasmodium ovale and Plasmodium malariae causes milder disease in humans that is not generally fatal. A fifth species, Plasmodium knowlesi, causes malaria in macaques but can also infect humans. This group of human-pathogenic Plasmodium species is usually referred to as malaria parasites.

Usually, people get malaria by being bitten by an infective female Anopheles mosquito. Only Anopheles mosquitoes can transmit malaria, and they must have been infected through a previous blood meal taken on an infected person. When a mosquito bites an infected person, a small amount of blood is taken, which contains microscopic malaria parasites. About one week later, when the mosquito takes its next blood meal, these parasites mix with the mosquito's saliva and are injected into the person being bitten. The parasites multiply within red blood cells, causing symptoms that include symptoms of anemia (light-headedness, shortness of breath, tachycardia, etc.), as well as other general symptoms such as fever, chills, nausea, 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 measures such as spraying insecticides inside houses and draining standing water where mosquitoes lay their eggs. Work has been done on malaria vaccines with limited success and more exotic controls, such as genetic manipulation of mosquitoes to make them resistant to the parasite have also been considered. [4]

Although some are under development, no vaccine is currently available for malaria that provides a high level of protection[5]; preventive drugs must be taken continuously to reduce the risk of infection. These prophylactic drug treatments are often too expensive for most people living in endemic areas. Most adults from endemic areas have a degree of long-term infection, which tends to recur, and also possess partial immunity (resistance); the resistance reduces with time, and such adults may become susceptible to severe malaria if they have spent a significant amount of time in non-endemic areas. They are strongly recommended to take full precautions if they return to an endemic area. Malaria infections are treated through the use of antimalarial drugs, such as quinine or artemisinin derivatives. However, parasites have evolved to be resistant to many of these drugs. Therefore, in some areas of the world, only a few drugs remain as effective treatments for malaria.

Symptoms

File:Symptoms of Malaria.png

Symptoms of malaria include fever, shivering, arthralgia (joint pain), vomiting, anemia (caused by hemolysis), hemoglobinuria, retinal damage,[7] 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 for P. malariae.[8] 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.[9] 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.[10][11] Cerebral malaria is associated with retinal whitening,[12] which may be a useful clinical sign in distinguishing it from other causes of fever.[13]

Species Appearance Periodicity Persistent in liver?
Plasmodium vivax tertian yes
Plasmodium ovale tertian yes
Plasmodium falciparum tertian no
Plasmodium malariae quartan no

Severe malaria is almost exclusively caused by P. falciparum infection and usually arises 6–14 days after infection.[14] 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 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.[14] In the most severe cases of the disease fatality rates can exceed 20%, even with intensive care and treatment.[15] 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.[16] Over the longer term, developmental impairments have been documented in children who have suffered episodes of severe malaria.[17]

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.[14] 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).[18]

Causes

Malaria

A Plasmodium sporozoite traverses the cytoplasm of a mosquito midgut epithelial cell in this false-color 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, P. vivax and P. knowlesi.[19][20] P. falciparum is the most common cause of infection and is responsible for about 80% of all malaria cases, and is also responsible for about 90% of the deaths from malaria.[21] Parasitic Plasmodium species also infect birds, reptiles, monkeys, chimpanzees and rodents.[22] There have been documented human infections with several simian species of malaria, namely P. knowlesi, P. inui, P. cynomolgi,[23] P. simiovale, P. brazilianum, P. schwetzi and P. simium; however, with the exception of P. knowlesi, these are mostly of limited public health importance.[24] Although avian malaria can kill chickens and turkeys, this disease does not cause serious economic losses to poultry farmers.[25] However, since being accidentally introduced by humans it has decimated the endemic birds of Hawaii, which evolved in its absence and lack any resistance to it.[26]

Mechanism

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 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.[27] 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.[28]

Pathogenesis

File:MalariacycleBig.jpg

Malaria in humans develops via two phases: an exoerythrocytic and an erythrocytic phase. The exoerythrocytic phase involves infection of the hepatic system, or liver, whereas the erythrocytic phase involves infection of the erythrocytes, or red blood cells. When an infected mosquito pierces a person's skin to take a blood meal, sporozoites in the mosquito's saliva enter the bloodstream and migrate to the liver. Within 30 minutes of being introduced into the human host, the sporozoites infect hepatocytes, multiplying asexually and asymptomatically for a period of 6–15 days. 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.[29] The parasite escapes from the liver undetected by wrapping itself in the cell membrane of the infected host liver cell.[30]

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.[31]

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.[32] 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.[33]

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.[32] 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,[34] and malaria in pregnant women is an important cause of stillbirths, infant mortality and low birth weight,[35] particularly in P. falciparum infection, but also in other species infection, such as P. vivax.[36]

Diagnosis

File:Plasmodium falciparum 02.jpg

Since Charles Laveran first visualised the malaria parasite in blood in 1880,[37] the mainstay of malaria diagnosis has been the microscopic examination of blood.

Fever and septic shock are commonly misdiagnosed as severe malaria in Africa, leading to a failure to treat other life-threatening illnesses. In malaria-endemic areas, parasitemia does not ensure a diagnosis of severe malaria because parasitemia can be incidental to other concurrent disease. Recent investigations suggest that malarial retinopathy is better (collective sensitivity of 95% and specificity of 90%) than any other clinical or laboratory feature in distinguishing malarial from non-malarial coma.[38]

Although blood is the sample most frequently used to make a diagnosis, both saliva and urine have been investigated as alternative, less invasive specimens.[37]

Symptomatic diagnosis

Areas that cannot afford even simple laboratory diagnostic tests often use only a history of subjective fever as the indication to treat for malaria. Using Giemsa-stained blood smears from children in Malawi, one study showed that unnecessary treatment for malaria was significantly decreased when clinical predictors (rectal temperature, nailbed pallor, and splenomegaly) were used as treatment indications, rather than the current national policy of using only a history of subjective fevers (sensitivity increased from 21% to 41%).[39]


Prevention

File:Anopheles albimanus mosquito.jpg

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. The continued existence of malaria in an area requires a combination of high human population density, high mosquito population density, and high rates of transmission from humans to mosquitoes and from mosquitoes to humans. If any of these is lowered sufficiently, the parasite will sooner or later disappear from that area, as happened in North America, Europe and much of Middle East. However, unless the parasite is eliminated from the whole world, it could become re-established if conditions revert to a combination that favors the parasite's reproduction. Many countries are seeing an increasing number of imported malaria cases due to extensive travel and migration. (See Anopheles.)

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.[40]

The distribution of funding varies among countries. Countries with large populations do not receive the same amount of support. The 34 countries that received a per capita annual support of less than $1 included some of the poorest countries 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.[41]

Vector control

Further information: Mosquito control

Efforts to eradicate malaria by eliminating mosquitoes have been successful in some areas. Malaria was once common in the United States and southern Europe, but vector control programs, in conjunction with the monitoring and treatment of infected humans, eliminated it from affluent regions. In some areas, the draining of wetland breeding grounds and better sanitation were adequate. Malaria was eliminated from the northern parts of the USA in the early twentieth century by such methods, and the use of the pesticide DDT eliminated it from the South by 1951.[42] 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.[43] 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.[44] However, these efforts have so far failed to eradicate malaria in many parts of the developing world - the problem is most prevalent in Africa.

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,[45] with the first plasmodium-resistant species announced by a team at Case Western Reserve University in Ohio in 2002.[46] Successful replacement of existent populations with genetically modified populations, 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 34% of the malaria research and control community say that such an approach “will never fly” [47]. Furthermore, such an approach is at least 5 to 10 years away from introduction and the progress which has been made in developing a vaccine could influence further research in genetic modification of malaria mosquitoes negatively [48].

On December 21, 2007, a study published in PLoS Pathogens found that the hemolytic C-type lectin CEL-III from Cucumaria echinata, a sea cucumber found in the Bay of Bengal, impaired the development of the malaria parasite when produced by transgenic mosquitoes.[49][50] This could potentially be used one day to control malaria by using genetically modified mosquitoes refractory to the parasites, although the authors of the study recognize that there are numerous scientific and ethical problems to be overcome before such a control strategy could be implemented.

Prophylactic drugs

Main article: Malaria prophylaxis

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. Samuel Hahnemann in the late 18th century noted that over-dosing of quinine leads to a symptomatic state very similar to that of malaria. This led him to develop the Law of Similars and homeopathy.

Modern drugs used preventively include mefloquine (Lariam), doxycycline (available generically), and the combination of atovaquone and 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

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 and historically most effective insecticide used for IRS was DDT.[42] While 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.

Though 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.[51]

The World Health Organization (WHO) currently advises the use of 12 different insecticides in IRS operations. These include DDT and a series of alternative insecticides (such as the pyrethroids permethrin and deltamethrin) to both combat malaria in areas where mosquitoes are DDT-resistant, and to slow the evolution of resistance.[52] 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.[53] However, because of its legacy, many developed countries discourage DDT use even in small quantities.[54][55]

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 breeds that are affected by IRS are endophilic species(Species which tend to rest and live indoors), and due to the irritation caused by spraying, their evolutionary descendants are trending towards becoming exophilic(Species which 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 [56].

Mosquito nets and bedclothes

Mosquito nets help keep mosquitoes away from people and greatly reduce the infection and transmission of malaria. The nets are not a perfect barrier and they are often treated with an insecticide designed to kill the mosquito before 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,[40] and offer greater than 70% protection compared with no net.[57]. Although ITN 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.

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

For maximum effectiveness, the nets should be re-impregnated with insecticide every six months. This process poses a significant logistical problem in rural areas. New technologies like Olyset or DawaPlus allow for production of long-lasting insecticidal mosquito nets (LLINs), which release insecticide for approximately 5 years,[58] and cost about US$5.50. ITNs protect people sleeping under the net and simultaneously kill mosquitoes that contact the net. Some protection is also provided to others by this method, including people sleeping in the same room but not under the net.

While distributing mosquito nets is a major component of malaria prevention, community education and awareness on the dangers of malaria are associated with distribution campaigns to make sure people who receive a net know how to use it. "Hang Up" campaigns such as the ones conducted by volunteers of the International Red Cross and Red Crescent Movement consist of visiting households that received a net at the end of the campaign or just before the rainy season, ensuring that the net is being used properly and that the people most vulnerable to malaria, such as young children and the elderly, sleep under it. A study conducted by the CDC in Sierra Leone showed a 22 percent increase in net utilization following a personal visit from a volunteer living in the same community promoting net usage. A study in Togo showed similar improvements.[59]

The cost of treating malaria is high relative to income and the illness results in lost wages. Mosquito nets are often unaffordable to people in developing countries, especially for those most at risk. Only 1 out of 20 people in Africa own a bed net.[40] Although shipped into Africa mainly from Europe as free development help, the nets quickly become expensive trade goods. They are mainly used for fishing, and by combining hundreds of donated mosquito nets, whole river sections can be completely shut off, catching even the smallest fish.[60] Nets are also often distributed though vaccine campaigns using voucher subsidies, such as the measles campaign for children.

A study among Afghan refugees in Pakistan found that treating top-sheets and chaddars (head coverings) with permethrin has similar effectiveness to using a treated net, but is much cheaper.[61] Another alternative approach uses spores of the fungus Beauveria bassiana, sprayed on walls and bed nets, to kill mosquitoes. While some mosquitoes have developed resistance to chemicals, they have not been found to develop a resistance to fungal infections.[62]

Vaccination

Further information: Malaria vaccine

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.[63] 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 1000 bites from infected, irradiated mosquitoes.[64]

It has been generally accepted that it is impractical to provide at-risk individuals with this vaccination strategy, but that has been recently challenged with work being done by Dr. Stephen Hoffman of Sanaria, one of the key researchers who originally sequenced the genome of Plasmodium falciparum. His work most recently has revolved around solving the logistical problem of isolating and preparing the parasites equivalent to 1000 irradiated mosquitoes for mass storage and inoculation of human beings. The company has recently received several multi-million dollar grants from the Bill & Melinda Gates Foundation and the U.S. government to begin early clinical studies in 2007 and 2008.[65] The Seattle Biomedical Research Institute (SBRI), funded by the Malaria Vaccine Initiative, assures potential volunteers that "the [2009] clinical trials won't be a life-threatening experience. While many volunteers [in Seattle] will actually contract malaria, the cloned strain used in the experiments can be quickly cured, and does not cause a recurring form of the disease." "Some participants will get experimental drugs or vaccines, while others will get placebo."[66]

Instead, much work has been performed to try and understand the immunological processes that provide protection after immunization with irradiated sporozoites. After the mouse vaccination study in 1967,[63] it was hypothesized that the injected sporozoites themselves were being recognized by the immune system, which was in turn creating antibodies against the parasite. It was determined that the immune system was creating antibodies against the circumsporozoite protein (CSP) which coated the sporozoite.[67] Moreover, antibodies against CSP prevented the sporozoite from invading hepatocytes.[68] CSP was therefore chosen as the most promising protein on which to develop a vaccine against the malaria sporozoite. It is for these historical reasons that vaccines based on CSP are the most numerous of all malaria vaccines.

Presently, there is a huge variety of vaccine candidates on the table. Pre-erythrocytic vaccines (vaccines that target the parasite before it reaches the blood), in particular vaccines based on CSP, make up the largest group of research for the malaria vaccine. Other vaccine candidates include: those that seek to induce immunity to the blood stages of the infection; those that seek to avoid more severe pathologies of malaria by preventing adherence of the parasite to blood venules and placenta; and transmission-blocking vaccines that would stop the development of the parasite in the mosquito right after the mosquito has taken a bloodmeal from an infected person.[69] It is hoped that the sequencing of the P. falciparum genome will provide targets for new drugs or vaccines.[70]

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

The efficacy of Patarroyo's vaccine has been disputed with some US scientists concluding in The Lancet (1997) that "the vaccine was not effective and should be dropped" while the Colombian accused them of "arrogance" putting down their assertions to the fact that he came from a developing country.

The RTS,S/AS02A vaccine is the candidate furthest along in vaccine trials. It is being developed by a partnership between the PATH Malaria Vaccine Initiative (a grantee of the Gates Foundation), the pharmaceutical company, GlaxoSmithKline, and the Walter Reed Army Institute of Research[71] In the vaccine, a portion of CSP has been fused to the immunogenic "S antigen" of the hepatitis B virus; this recombinant protein is injected alongside the potent AS02A adjuvant.[69] In October 2004, the RTS,S/AS02A researchers announced results of a Phase IIb trial, indicating the vaccine reduced infection risk by approximately 30% and severity of infection by over 50%. The study looked at over 2,000 Mozambican children.[72] More recent testing of the RTS,S/AS02A vaccine has focused on the safety and efficacy of administering it earlier in infancy: In October 2007, the researchers announced results of a phase I/IIb trial conducted on 214 Mozambican infants between the ages of 10 and 18 months in which the full three-dose course of the vaccine led to a 62% reduction of infection with no serious side-effects save some pain at the point of injection.[73] Further research will delay this vaccine from commercial release until around 2011.[74]

Other methods

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

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

Treatment

Active malaria infection with P. falciparum is a medical emergency requiring hospitalization. Infection with P. vivax, P. ovale or P. malariae can often be treated on an outpatient basis. Treatment of malaria involves supportive measures as well as specific antimalarial drugs. When properly treated, someone with malaria can expect a complete recovery.[77]

Antimalarial drugs

Further information: Antimalarial drugs

There are several families of drugs used to treat malaria. Chloroquine is very cheap and, until recently, was very effective, which made it 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.[78] In those areas where chloroquine is still effective it remains the first choice. Unfortunately, chloroquine-resistance is associated with reduced sensitivity to other drugs such as quinine and amodiaquine.[79]

There are several other substances that are used for treatment and, partially, for prevention (prophylaxis). Many drugs may 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. One drug currentlyTemplate:Dated maintenance category being investigated for possible use as an anti-malarial, especially for treatment of drug-resistant strains, is the beta blocker propranolol. Propranolol has been shown to block both Plasmodium's ability to enter red blood cell and establish an infection, as well as parasite replication. A December 2006 study by Northwestern University researchers suggested that propranolol may reduce the dosages required for existing drugs to be effective against P. falciparum by 5- to 10-fold, suggesting a role in combination therapies.[80]

Currently available anti-malarial drugs include:[81]

The development of drugs was facilitated when Plasmodium falciparum was successfully cultured.[82] 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.[83] One study in Rwanda showed that children with uncomplicated P. falciparum malaria demonstrated fewer clinical and parasitological failures on post-treatment day 28 when amodiaquine was combined with artesunate, rather than administered alone (OR = 0.34). However, increased resistance to amodiaquine during this study period was also noted.[84] 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.[85] Malaria parasites can develop resistance to artemisinin and resistance can be produced by mutation of SERCA.[86] However, other studies suggest the mitochondrion is the major target for artemisinin and its analogs.[87]

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 of treating a malaria-infected person in an endemic country was between US$0.25 and $2.40 per dose in 2002.[88]

Counterfeit drugs

Sophisticated counterfeits have been found in several Asian countries such as Cambodia,[89] China,[90] Indonesia, Laos, Thailand, Vietnam and are an important cause of avoidable death in these countries.[91] WHO have said that studies indicate that up to 40% of artesunate based malaria medications are counterfeit, especially in the Greater Mekong region and have established a rapid alert system to enable information about counterfeit drugs to be rapidly reported to the relevant authorities in participating countries.[92] There is no reliable way for doctors or lay people to detect counterfeit drugs without help from a laboratory. Companies are attempting to combat the persistence of counterfeit drugs by using new technology to provide security from source to distribution.

History

Further information: History of malaria

Malaria has infected humans for over 50,000 years, and malarial protozoa may have been a human pathogen for the entire history of the species.[93] Close relatives of the human malaria parasites remain common in chimpanzees.[94] References to the unique periodic fevers of malaria are found throughout recorded history, beginning in 2700 BC in China.[95] 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 and marshland.[96] Malaria was once common in most of Europe and North America, where it is no longer endemic[97], though imported cases do occur.

Scientific studies on malaria made their first significant advance in 1880, when a French army doctor working in the military hospital of Constantine in Algeria named Charles Louis Alphonse Laveran observed parasites for the first time, inside the red blood cells of people suffering from malaria. He, therefore, proposed that malaria is caused by this protozoan, the first time protozoa were identified as causing disease.[98] 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.[99] A year later, Carlos Finlay, a Cuban doctor treating patients with yellow fever in Havana, provided strong evidence that mosquitoes were transmitting disease to and from humans.[100] This work followed earlier suggestions by Josiah C. Nott,[101] and work by Patrick Manson on the transmission of filariasis.[102]

However, it was Britain's Sir Ronald Ross working in the Presidency General Hospital in Calcutta who finally proved in 1898 that malaria is transmitted by mosquitoes. He did this by showing that certain mosquito species transmit malaria to birds and isolating malaria parasites from the salivary glands of mosquitoes that had fed on infected birds.[103] 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.[104] 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 came from the bark of cinchona tree, which contains quinine. This tree grows on the slopes of the Andes, mainly in Peru. A tincture made of 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.[105] 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 Bienaimé Caventou.[106]

In the early twentieth century, before antibiotics, patients with syphilis were intentionally infected with malaria to create a fever, following the work of Julius Wagner-Jauregg. By accurately controlling the fever with quinine, the effects of both syphilis and malaria could be minimized. Although some patients died from malaria, this was preferable to the almost-certain death from syphilis.[107]

Although the blood stage and mosquito stages of the malaria life cycle were identified in the 19th and early 20th centuries, it was not until the 1980s that the latent liver form of the parasite was observed.[108][109] 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.

Evolutionary pressure of malaria on human genes

Further information: Evolution, Natural selection

Malaria is thought to have been the greatest selective pressure on the human genome in recent history.[110] This is due to the high levels of mortality and morbidity caused by malaria, especially the P. falciparum species.

Sickle-cell disease

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The most-studied influence of the malaria parasite upon the human genome is a hereditary blood disease, sickle-cell disease. The sickle-cell trait causes disease, but even those only partially affected by sickle-cell have substantial protection against malaria.

In sickle-cell disease, there is a mutation in the HBB gene, which encodes the beta-globin subunit of haemoglobin. The normal allele encodes a glutamate at position six of the beta-globin protein, whereas the sickle-cell allele encodes a valine. This change from a hydrophilic to a hydrophobic amino acid encourages binding between haemoglobin molecules, with polymerization of haemoglobin deforming red blood cells into a "sickle" shape. Such deformed cells are cleared rapidly from the blood, mainly in the spleen, for destruction and recycling.

In the merozoite stage of its life cycle, the malaria parasite lives inside red blood cells, and its metabolism changes the internal chemistry of the red blood cell. Infected cells normally survive until the parasite reproduces, but, if the red cell contains a mixture of sickle and normal haemoglobin, it is likely to become deformed and be destroyed before the daughter parasites emerge. Thus, individuals heterozygous for the mutated allele, known as sickle-cell trait, may have a low and usually-unimportant level of anaemia, but also have a greatly reduced chance of serious malaria infection. This is a classic example of heterozygote advantage.

Individuals homozygous for the mutation have full sickle-cell disease and in traditional societies rarely live beyond adolescence. However, in populations where malaria is endemic, the frequency of sickle-cell genes is around 10%. The existence of four haplotypes of sickle-type hemoglobin 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 that produce haemoglobin molecules capable of conferring similar resistance to malaria infection. These mutations produce haemoglobin types 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 malarial 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. Presumably these genes have also been selected in the course of human evolution.

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 is very rare in European, Asian and American populations, but is found in almost all of the indigenous population of West and Central Africa.[112] This is thought to be due to very high exposure to P. vivax in Africa in the last few thousand years.

G6PD

Glucose-6-phosphate dehydrogenase (G6PD) is an enzyme that 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.

HLA and interleukin-4

HLA-B53 is associated with low risk of severe malaria. This MHC class I molecule presents liver stage and sporozoite antigens to T-Cells. Interleukin-4, encoded by IL4, is produced by activated T cells and promotes proliferation and differentiation of antibody-producing B cells. A study of the Fulani of Burkina Faso, who have both fewer malaria attacks and higher levels of antimalarial antibodies than do neighboring ethnic groups, found that the IL4-524 T allele was associated with elevated antibody levels against malaria antigens, which raises the possibility that this might be a factor in increased resistance to malaria.[113]

Society and culture

Further information: Diseases of poverty, Tropical disease
File:Malaria geographic distribution 2003.png

Malaria causes about 250 million cases of fever and approximately one million deaths annually.[115] The vast majority of cases occur in children under 5 years old;[116] 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.[117] Indeed, if the prevalence of malaria stays on its present upwards course, the death rate could double in the next twenty years.[118] Precise statistics are unknown because many cases occur in rural areas where people do not have access to hospitals or the means to afford health care. As a consequence, the majority of cases are undocumented.[118]

Although co-infection with HIV and malaria does cause increased mortality, this is less of a problem than with HIV/tuberculosis co-infection, due to the two diseases usually attacking different age-ranges, with malaria being most common in the young and active tuberculosis most common in the old.[119] Although HIV/malaria co-infection produces less severe symptoms than the interaction between HIV and TB, HIV and malaria do contribute to each other's spread. This effect comes from malaria increasing viral load and HIV infection increasing a person's susceptibility to malaria infection.[120]

Malaria is presently endemic in a broad band around the equator, in areas of the Americas, many parts of Asia, and much of Africa; however, it is in sub-Saharan Africa where 85– 90% of malaria fatalities occur.[121] The geographic distribution of malaria within large regions is complex, and malaria-afflicted and malaria-free areas are often found close to each other.[122] In drier areas, outbreaks of malaria can be predicted with reasonable accuracy by mapping rainfall.[123] Malaria is more common in rural areas than in cities; this is in contrast to dengue fever where urban areas present the greater risk.[124] For example, the cities of Vietnam, Laos and Cambodia are essentially malaria-free, but the disease is present in many rural regions.[125] By contrast, in Africa malaria is present in both rural and urban areas, though the risk is lower in the larger cities.[126] The global endemic levels of malaria have not been mapped since the 1960s. However, the Wellcome Trust, UK, has funded the Malaria Atlas Project[127] to rectify this, providing a more contemporary and robust means with which to assess current and future malaria disease burden.

Socio-economic effects

Malaria is not just a disease commonly associated with poverty but also a cause of poverty and a major hindrance to economic development. Tropical regions are affected most, however malaria’s furthest extent reaches into some temperate zones with extreme seasonal changes. The disease has been associated with major negative economic effects on regions where it is widespread. During the late 19th and early 20th centuries, it was a major factor in the slow economic development of the American southern states.[128]. A comparison of average per capita GDP in 1995, adjusted for parity of purchasing power, between countries with malaria and countries without malaria gives a fivefold difference ($1,526 USD versus $8,268 USD). In countries where malaria is common, average per capita GDP has risen (between 1965 and 1990) only 0.4% per year, compared to 2.4% per year in other countries.[129] Poverty is both cause and effect, however, since the poor do not have the financial capacities to prevent or treat the disease. The lowest income group in Malawi carries the burden of having 32% of their annual income used on this disease compared with the 4% of household incomes from low-to-high groups.[How to reference and link to summary or text] In its entirety, the economic impact of malaria has been estimated to cost Africa $12 billion USD every year. The economic impact includes costs of health care, working days lost due to sickness, days lost in education, decreased productivity due to brain damage from cerebral malaria, and loss of investment and tourism.[116] 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.[130]

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Further reading

Books

  • Mills, A., & Shillcutt, S. (2006). Communicable Diseases. New York, NY: Cambridge University Press.

Papers

  • Abraham, C., Clift, S., & Grabowski, P. (1999). Cognitive predictors of adherence to malaria prophylaxis regimens on return from a malarious region: A prospective study: Social Science & Medicine Vol 48(11) Jun 1999, 1641-1654.
  • Abubakar, A., Van De Vijver, F. J. R., Mithwani, S., Obiero, E., Lewa, N., Kenga, S., et al. (2007). Assessing developmental outcomes in children from Kilifi, Kenya, following prophylaxis for seizures in cerebral malaria: Journal of Health Psychology Vol 12(3) May 2007, 417-430.
  • Adam, I., Omer, E. s. M., Salih, A., Khamis, A. H., & Malik, E. M. (2008). Perceptions of the causes of malaria and of its complications, treatment and prevention among midwives and pregnant women of Eastern Sudan: Journal of Public Health Vol 16(2) Apr 2008, 129-132.
  • Agyepong, I. A. (1992). Malaria: Ethnomedical perceptions and practice in an Adangbe farming community and implications for control: Social Science & Medicine Vol 35(2) Jul 1992, 131-137.
  • Agyepong, I. A., Ansah, E., Gyapong, M., Adjei, S., Barnish, G., & Evans, D. (2002). Strategies to improve adherence to recommended chloroquine treatment regimes: A quasi-experimental in the context of integrated primary health care delivery in Ghana: Social Science & Medicine Vol 55(12) Dec 2002, 2215-2226.
  • Ahorlu, C. K., Koram, K. A., & Weiss, M. G. (2007). Children, pregnant women and the culture of malaria in two rural communities of Ghana: Anthropology & Medicine Vol 14(2) Aug 2007, 167-181.
  • Ajayi, I. O., Falade, C. O., Adeniyi, J. D., & Bolaji, M. O. (2002). The role of patent medicine sellers in home management of childhood malaria: A situational analysis of experience in rural Nigeria: International Quarterly of Community Health Education Vol 21(3) 2002-2003, 271-281.
  • Ajayi, I. O., Kale, O. O., Oladepo, O., & Bamgboye, E. A. (2006). Using "mother trainers" for malaria control: The Nigerian experience: International Quarterly of Community Health Education Vol 27(4) 2006, 351-369.
  • Alao, A. O., & Dewan, M. J. (2001). Psychiatric complications of malaria: A case report: International Journal of Psychiatry in Medicine Vol 31(2) 2001, 217-223.
  • Alilio, M. S., Eversole, H., & Bammek, J. (1998). A KAP study on malaria in Zanzibar: Implications for prevention and control. A study conducted for UNICEF sub-office Zanzibar: Evaluation and Program Planning Vol 21(4) Nov 1998, 409-413.
  • Amin, A. A., Walley, T., Kokwaro, G. O., Winstanley, P. A., & Snow, R. W. (2007). Reconciling national treatment policies and drug regulation in Kenya: Health Policy and Planning Vol 22(2) Mar 2007, 111-112.
  • Anyanwu, E. C., Kanu, I., & Merrick, J. (2007). Impact of malaria infectious pathways on disability and child development in endemic regions: International Journal on Disability and Human Development Vol 6(3) Jul-Sep 2007, 253-258.
  • Asa, A., Adegbenro, C. A., Dare, F. O., Adeniyi, J. D., Osowole, O. S., & Oladepo, O. (2003). Enhancing Treatment Compliance in the Home Management of Childhood Malaria: The Use of a Participatory Approach in Ensuring Intervention Appropriateness: International Quarterly of Community Health Education Vol 22(4) 2003-2004, 239-248.
  • Asa, O. O., Onayade, A. A., Fatusi, A. O., Ijadunola, K. T., & Abiona, T. C. (2008). Efficacy of intermittent preventive treatment of malaria with sulphadoxine-pyrimethamine in preventing anaemia in pregnancy among Nigerian women: Maternal & Child Health Journal Vol 12(6) Nov 2008, 692-698.
  • Ayouba, A., Badaut, C., Kfutwah, A., Cannou, C., Juillerat, A., Gangnard, S., et al. (2008). Specific stimulation of HIV-1 replication in human placental trophoblasts by an antigen of Plasmodium falciparum: AIDS Vol 22(6) Mar 2008, 785-787.
  • Babalola, O. O., & Lamikanra, A. (2007). The response of students to malaria and malaria therapy in a university in southwest Nigeria: Research in Social & Administrative Pharmacy Vol 3(3) Sep 2007, 351-362.
  • Betanzos-Reyes, A. F., Rodriguez, M. H., Duran-Arenas, L. G., Hernandez-Avila, J. E., Mendez-Galvan, J. F., Monroy, O. J. V., et al. (2007). Comparative analysis of two alternative models for epidemiological surveillance in the Mexican Malaria Control Program: Health Policy Vol 80(3) Mar 2007, 465-482.
  • Boivin, M. J. (2002). Effects of early cerebral malaria on cognitive ability in Senegalese children: Journal of Developmental & Behavioral Pediatrics Vol 23(5) Oct 2002, 353-364.
  • Boivin, M. J., Giordani, B., Ndanga, K., Maky, M. M., Manzeki, K. M., Ngunu, N., et al. (1993). Effects of treatment for intestinal parasites and malaria on the cognitive abilities of schoolchildren in Zaire, Africa: Health Psychology Vol 12(3) May 1993, 220-226.
  • Brieger, W. R., Nwankwo, E., Ezike, V. I., Sexton, J. D., & et al. (1996). Social and behavioural baseline for guiding implementation of an efficacy trial of insecticide impregnated bed nets for malaria control at Nsukka, Nigeria: International Quarterly of Community Health Education Vol 16(1) 1996, 47-61.
  • Caillon, E., Schmitt, L., & Moron, P. (1992). Acute depressive symptoms after mefloquine treatment: American Journal of Psychiatry Vol 149(5) May 1992, 712.
  • Carter, J. A., Lees, J. A., Gona, J. K., Murira, G., Rimba, K., Neville, B. G. R., et al. (2006). Severe falciparum malaria and acquired childhood language disorder: Developmental Medicine & Child Neurology Vol 48(1) Jan 2006, 51-57.
  • Carter, J. A., Mung'ala-Odera, V., Neville, B. G. R., Murira, G., Mturi, N., Musumba, C., et al. (2005). Persistent neurocognitive impairments associated with severe falciparum malaria in Kenyan children: Journal of Neurology, Neurosurgery & Psychiatry Vol 76(4) Apr 2005, 476-481.
  • Carter, J. A., Murira, G. M., Ross, A. J., Mung'ala-Odera, V., & Newton, C. R. J. C. (2003). Speech and language sequelae of severe malaria in Kenyan children: Brain Injury Vol 17(3) 2003, 217-224.
  • Casals-Pascual, C., Idro, R., Gicheru, N., Gwer, S., Kitsao, B., Gitau, E., et al. (2008). High levels of erythropoietin are associated with protection against neurological sequelae in African children with cerebral malaria: PNAS Proceedings of the National Academy of Sciences of the United States of America Vol 105(7) Feb 2008, 2634-2639.
  • Chahad-Ehlers, S., Lozovei, A. L., & Marques, M. D. (2007). Reproductive and post-embryonic daily rhythm patterns of the malaria vector Anopheles (Kerteszia) Cruzii: Aspects of the life cycle: Chronobiology International Vol 24(2) Apr 2007, 289-304.
  • Chandler, C. I. R., Mwangi, R., Mbakilwa, H., Olomi, R., Whitty, C. J. M., & Reyburn, H. (2008). Malaria overdiagnosis: Is patient pressure the problem? : Health Policy and Planning Vol 23(3) May 2008, 170-178.
  • Clarke, S. E., Jukes, M. C. H., Njagi, J. K., Khasakhala, L., Cundill, B., Otido, J., et al. (2008). Effect of intermittent preventive treatment of malaria on health and education in schoolchildren: A cluster-randomised, double-blind, placebo-controlled trial: Lancet Vol 372(9633) Jul 2008, 127-138.
  • Clattenburg, R. N., & Donnelly, C. L. (1997). Case study: Neuropsychiatric symptoms associated with the antimalarial agent mefloquine: Journal of the American Academy of Child & Adolescent Psychiatry Vol 36(11) Nov 1997, 1606-1608.
  • Cropley, L. (2003). Malaria Treatment Seeking Practices among Mothers in Rural Refugee Villages in Belize, Central America: A Qualitative Study: International Quarterly of Community Health Education Vol22(1-2) 2003-2004, 3-16.
  • Cropley, L. (2004). The effect of health education interventions on child malaria treatment-seeking practices among mothers in rural refugee villages in Belize, Central America: Health Promotion International Vol 19(4) Dec 2004, 445-452.
  • Dare, O. O., & Badru, O. B. (2000). Promoting the use of insecticide treated materials at the community level: Experience from the ITN-ORIADE initiative: International Quarterly of Community Health Education Vol 20(3) 2000-2001, 281-295.
  • Dawson, A., & Joof, B. M. (2005). Seeing, thinking and acting against Malaria--A new approach to health worker training in rural Gambia: Education for Health: Change in Learning & Practice Vol 18(3) Nov 2005, 387-394.
  • Denic, S., Nagelkerke, N., & Agarwal, M. M. (2008). Consanguineous marriages: Do genetic benefits outweigh its costs in populations with alpha -super(+)-thalassemia, hemoglobin S, and malaria? : Evolution and Human Behavior Vol 29(5) Sep 2008, 364-369.
  • Deressa, W., Ali, A., & Hailemariam, D. (2008). Malaria-related health seeking-behaviour and challenges for care providers in rural Ethiopia: Implications for control: Journal of Biosocial Science Vol 40(1) Jan 2008, 115-135.
  • Dietz, A., & Frolich, L. (2002). Mefloquine-induced paranoid psychosis and subsequent major depression in a 25-year-old student: Pharmacopsychiatry Vol 35(5) Sep 2002, 200-202.
  • Dike, N., Onwujekwe, O., Ojukwu, J., Ikeme, A., Uzochukwu, B., & Shu, E. (2006). Influence of education and knowledge on perceptions and practices to control malaria in Southeast Nigeria: Social Science & Medicine Vol 63(1) Jul 2006, 103-106.
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  • Ehigie, B. O. (2003). Comparative analysis of the psychological consequences of the traumatic experiences of cancer HIV/AIDS, and sickle-cell anemia patients: IFE Psychologia: An International Journal Vol 11(3) 2003, 34-54.
  • Eisenhut, M. (2007). Factors influencing capillary refill time: The Journal of Pediatrics Vol 151(5) Nov 2007, e17.
  • Espino, F., & Manderson, L. (2000). Treatment seeking for malaria in Morong, Bataan, The Philippines: Social Science & Medicine Vol 50(9) May 2000, 1309-1316.
  • Evans, J. (2007). "Factors influencing capillary refill time": Reply: The Journal of Pediatrics Vol 151(5) Nov 2007, e17.
  • Falade, C. O., Ogundiran, M. O., Bolaji, M. O., Ajayi, I. O., Akinboye, D. O., Oladepo, O., et al. (2005). The Influence of Cultural Perception of Causation, Complications, and Severity of Childhood Malaria on Determinants of Treatment and Preventive Pathways: International Quarterly of Community Health Education Vol 24(4) 2005-2006, 347-363.
  • Falade, C. O., Osowole, O. S., Adeniyi, J. D., Oladepo, O., & Oduola, A. M. J. (2004). Attitude of Health Care Workers to the Involvement of Alternative Healthcare Providers in the Home Management of Childhood Malaria: International Quarterly of Community Health Education Vol 23(2) 2004-2005, 169-180.
  • Farquharson, L., Noble, L. M., Barker, C., & Behrens, R. H. (2004). Health beliefs and communication in the travel clinic consultation as predictors of adherence to malaria chemoprophylaxis: British Journal of Health Psychology Vol 9(2) May 2004, 201-217.
  • Fawole, O. I., Onadeko, M. O., & Oyejide, C. O. (2003). Knowledge of Malaria and Management Practices of Primary Health Care Workers Treating Children with Malaria in Ibadan, Nigeria: International Quarterly of Community Health Education Vol22(1-2) 2003-2004, 95-109.
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Dissertations

  • Abimbola, T. (2008). Malaria, labor supply, and schooling in Sub-Sahara Africa. Dissertation Abstracts International Section A: Humanities and Social Sciences.
  • Bangs, M. J. (1999). The susceptibility and behavioral response of Anopheles albimanus weidemann and Anopheles vestitipennis dyar and knap (Diptera: Culicidae) to insecticides in Northern Belize, Central America. Dissertation Abstracts International: Section B: The Sciences and Engineering.
  • Cohen, J. L. (2008). Essays on the economics of education and health. Dissertation Abstracts International Section A: Humanities and Social Sciences.
  • Cohen, J. M. (2008). The landscape epidemiology of malaria within two communities in a highland region of Kenya. Dissertation Abstracts International: Section B: The Sciences and Engineering.
  • Dugbartey, A. T. (1997). The neuropsychology of cerebral malaria. Dissertation Abstracts International: Section B: The Sciences and Engineering.
  • Ellis, A. A. (2008). Intra-household dynamics and treatment responses to severe febrile illness in children in Koulikoro region, Mali. Dissertation Abstracts International: Section B: The Sciences and Engineering.
  • Hong, S. C. (2007). The health and economic burdens of malaria: The American case. Dissertation Abstracts International Section A: Humanities and Social Sciences.
  • Li, L. (2009). Spatial distribution of mosquitoes: The context of malaria outbreaks in Western Kenya highlands. Dissertation Abstracts International Section A: Humanities and Social Sciences.
  • Nyunt, M. M. (2008). Experimental approaches to rational strategies for the prophylaxis and treatment of Falciparum malaria. Dissertation Abstracts International: Section B: The Sciences and Engineering.
  • Richardson, E. D. (1990). Long-term neuropsychological, psychiatric and psychosocial sequelae of cerebral malaria: Dissertation Abstracts International.
  • Szlezak, N. A. B. (2008). Global health in the making: China, HIV/AIDs, and the global fund to fight AIDs, tuberculosis and malaria. Dissertation Abstracts International: Section B: The Sciences and Engineering.
  • Yatich, N. J. (2008). The effect of malaria and intestinal helminth coinfection on birth outcomes in Ghana. Dissertation Abstracts International: Section B: The Sciences and Engineering.

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