A disease, endemic in tropical countries, caused by infection with one of four species of Plasmodium, a parasite transmitted by Anopheles mosquitoes. The parasites multiply in the liver and in red blood cells, which are destroyed with each life cycle, producing characteristic symptoms of high fever, shaking, and aches. Plasmodium vivax and ovale produce symptoms on alternate days; Plasmodium malariae produces symptoms every three days, associated with an enlarged spleen. Plasmodium falciparum infection is the most serious, giving rise to more continuous symptoms and a range of complications. Parasites and cell debris block capillaries, resulting in organ damage; involvement of the brain can lead to convulsions, coma, and death. Diagnosis is made by observation of the parasite under a microscope. Several drugs are available for treatment, but increasing resistance to these is now being seen, particularly by Plasmodium falciparum. Travellers should consult an expert centre for provision of anti-malarial medication.
MalariaClassifications and external resources
| Plasmodium falciparum ring-forms and gametocytes in human blood. emerg/305 ped/1357 | ||
| MeSH | C03.752.250.552 | |
Malaria is an infectious disease that is widespread in tropical and subtropical regions.
Malaria is one of the most common infectious diseases and an enormous public-health problem. 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.
Malaria parasites are transmitted by female Anopheles mosquitoes. The parasites multiply within red blood cells, causing symptoms that include fever, anemia, 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. Malaria infections are treated through the use of antimalarial drugs, such as chloroquine or pyrimethamine, although drug resistance is increasingly common.
History
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";
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. 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.
The first effective treatment for malaria was the bark of cinchona tree, which contains quinine. 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.
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
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. Indeed, if the prevalence of malaria stays on its present upwards course, the death rate could double in the next twenty years.
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; 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, anemia caused by hemolysis, hemoglobinuria, and convulsions. There may be the feeling of tingling in the skin, particularly with malaria caused by P. The classical symptom of malaria is cyclical fevers, occurring every two days in P.
Severe malaria is almost exclusively caused by P. Consequences of severe malaria include coma and death if untreated—young children and pregnant women are especially vulnerable. Severe malaria can progress extremely rapidly and cause death within hours or days. 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. Describing a case of malaria as cured by observing the disappearance of parasites from the bloodstream can therefore be deceptive. vivax malaria cases in temperate areas involve overwintering by hypnozoites (i.e., relapses begin the year after the mosquito bite).
Causes
Malaria parasites
Malaria is caused by protozoan parasites of the genus Plasmodium (phylum Apicomplexa). In humans malaria is caused by P. There has been documented human infections with several simian species of malaria, namely P. 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.
Only female mosquitoes feed on blood, thus males do not transmit the disease. Malaria parasites can also be transmitted by blood transfusions, although this is rare.
Pathogenesis
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. 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.
Within the red blood cells the parasites multiply further, again asexually, periodically breaking out of their hosts to invade fresh red blood cells.
Some P. 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. 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. 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;
Some merozoites turn into male and female gametocytes. Fertilization and sexual recombination of the parasite occurs in the mosquito's gut, thereby defining the mosquito as the definitive host of the disease. 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
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.
From the thick film, an experienced microscopist can detect parasite levels (or parasitemia) down to as low as 0.0000001% of red blood cells.
In areas where microscopy is not available, there are antigen detection tests that require only a drop of blood. Paracheck-Pf® will detect parasitemias down to 0.002% but will not distinguish between falciparum and non-falciparum malaria.
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.
There are several other substances which are used for treatment and, partially, for prevention (prophylaxis). larger doses are used to treat cases of malaria.
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; 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.
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. Malaria parasites can develop resistance to artemisinin and resistance can be produced by mutation of SERCA.
In February 2002, the journal Science and other press outlets announced progress on a new treatment for infected individuals. It cured malaria in test primates by blocking the ability of the parasite to copy itself within the red blood cells of its victims.
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.
Counterfeit drugs
Sophisticated counterfeits have been found in Thailand, Vietnam, Cambodia and China, and are an important cause of avoidable death in these countries.
Prevention and disease control
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. 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.
Prophylactic drugs
Several drugs, most of which are also used for treatment of malaria, can be taken preventively.
Quinine was used starting in the seventeenth century as a prophylactic against malaria. 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 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.
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.
The World Health Organization (WHO) currently advises the use of DDT to combat malaria in endemic areas. 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.
Mosquito nets and bedclothes
Mosquito nets help keep mosquitoes away from people, and thus greatly reduce the infection and transmission of malaria.
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.
For maximum effectiveness, the nets should be re-impregnated with insecticide every six months.
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.
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 pharma giant 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%.
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 sequence of the most deadly agent of malaria, Plasmodium falciparum, which was completed in 2002, will provide targets for new drugs or vaccines.
Other methods
Sterile insect technique is emerging as a potential mosquito control method. 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.
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. 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.
Sickle-cell anemia
The best-studied influence of the malaria parasite upon the human genome is the blood disease, sickle-cell anaemia.
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.
There are also other mutations of the HBB gene which appear to confer similar resistance to malaria infection.
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. 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. Plasmodium vivax malaria uses the Duffy antigen to enter blood cells.
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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