Malaria
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| ICD-10 | B50 |
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| ICD-9 | 084 |
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| DiseasesDB | {{{DiseasesDB}}} |
Malaria, derived from mala aria ( Italian for "bad air") and formerly called ague or marsh fever in English, is an infectious disease which causes about 350-500 million infections with humans and approximately 1.3 million deaths annually, mainly in the tropics. Sub-Saharan Africa accounts for 85% of these fatalities.
Malaria is caused by the protozoan parasites of the genus Plasmodium (of the phylum Apicomplexa), and the transmission vector for human malarial parasite is the female Anopheles mosquito. The P. falciparum variety of the parasite accounts for 80% of cases and 90% of deaths. Children under the age of five and pregnant women are the most vulnerable to the severe forms of malaria.
For his discovery of the cause of malaria, the French army doctor Charles Louis Alphonse Laveran was awarded the Nobel Prize for Physiology or Medicine in 1907. Britain's Sir Ronald Ross also received a Nobel prize (in 1902) for describing the life cycle stages of the malaria parasite that develop within the mosquito host.
Symptoms
Symptoms of malaria include fever, shivering, arthralgia (joint pain), vomiting, anemia due to hemolysis, hemoglobinuria, and convulsions. There may be the feeling of tingling in the skin, particularly with malaria caused by P. falciparum. Complications of malaria include coma and death if untreated—young children and pregnant women are especially vulnerable. Splenomegaly (enlarged spleen), intense headaches, cerebral ischemia and hemoglobinuria with renal failure may occur.
Mechanism of the disease
Infected female Anopheles mosquitoes carry Plasmodium sporozoites in their salivary glands. Once an infected mosquito pierces a person's skin to take a blood meal, which they usually do starting at dusk and continuing throughout the night, the sporozoites enter the person's body via the mosquito's saliva, migrate to the liver where they multiply within hepatic liver cells asexually. Development in the hepatic cell takes 6 to 15 days depending on the species. Within hepatic cells the parasite replicates to produce hundreds or thousands of merozoites which, following rupture of the hepatic cell, are released into the blood stream and invade red blood cells.
Within the red blood cells they multiply further, again asexually, periodically breaking out of the exploited red blood cells to invade fresh red blood cells and start the amplification cycle anew. The classical description of waves of fever coming every two (Plasmodium falciparum) or three days (Plasmodium vivax) arises from simultaneous waves of merozoites breaking out of red blood cells during the same day.
Some of the sporozoites in vivax and ovale malaria do not develop into hepatic stage merozoites immediately, but produce hypnozoites that remain dormant for several months (typically, from 6 to 12 months, but sometimes up to 3 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. About a half of the cases of vivax infection in temperate areas start after having overwintered, i.e. during the next year after the mosquito bite.
The parasite is relatively protected from attack by the body's immune system because for most of its human life cycle it resides within 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.
Although the red blood cell surface adhesive proteins (called PfEMP1) are exposed to the immune system they do not serve as good immune targets because of their extreme diversity; there are at least 50 variations of PfEMP1 within a single parasite and perhaps limitless versions within parasite populations. Like a thief changing disquises 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.
By the time the human immune system learns to recognize the protein and starts making antibodies against it, the parasite has switched to another form of the protein, making it difficult for the immune system to keep up.
The stickiness of the red blood cells is particularly pronounced in Plasmodium falciparum malaria and this is the main factor giving rise to hemorrhagic complications of malaria.
High endothelial venules (the smallest branches of the circulatory system) can be occluded by the infected red blood cells, such as in placental and cerebral malaria. In cerebral malaria the sequestrated red blood cells affect the integrity of the blood brain barrier possibly leading to reversible coma. Even when treated, serious neurological consequences may result from cerebral malaria, especially in children.
Some merozoites turn into male and female gametocytes. If a mosquito pierces the skin of infected person, it potentially picks up gametocytes with the blood, fertilization occurs in the mosquito's gut which means the mosquito is 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.
The recognized species causing disease in humans are P. falciparum (which alone accounts for 80% of the recognized cases and ~90% of the deaths), P. vivax, P. ovale, and P. malariae. Infections with P. knowlesi and P. semiovale are also known to cause malaria but are of limited public health importance.
Other mammals (bats, rodents, non-human primates) as well as birds and reptiles also suffer from malaria. However, the form of malaria found in animals is usually different than that found in humans. Three human forms (which account for most malaria cases) are completely exclusive to humans. Only one form, P. malariae, can cause malaria in both humans and higher primates. Other animal forms of malaria do not infect humans at all.
Only female mosquitoes are blood-feeders and therefore transmit malaria. Males cannot transmit the disease.
Sickle cell anemia and other genetic effects
Carriers of the sickle cell anemia gene are protected against malaria because of their particular hemoglobin mutation; this explains why sickle cell anemia is particularly common among people of African origin. They have a specific variant of the beta-globin gene. Some scientists hypothesize that another hemoglobin mutation, which causes the genetic disease thalassemia, may also give its carriers an enhanced immunity to malaria.
Another disease which is linked to protection against malaria is glucose-6-phosphate dehydrogenase deficiency (G6PD). It protects against malaria caused by Plasmodium falciparum as the presence of this enzyme is critical to survival of these parasites within red blood cells.
It is thought that humans have been affected by malaria for about 50,000 years, and several human genes responsible for blood cell proteins and the immune system have been shaped by the struggle against the parasite.
Diagnosis
The gold standard for the diagnosis of malaria is microscopic examination of blood films, because each of the four major parasite species has distinguising physical characteristics visible under a microscope. Two sorts of blood films are traditionally used. Thin films are similar to usual blood films and allow the microscopist to tell what species the malaria is, because the appearance of the parasite 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 down to as low as 0.0000001%. Microscopic diagnosis can be difficult because he early trophozoites ("ring form") of all four species look identical. Thus species identification is always done based on several ring forms.
The biggest pitfall in most laboratories in developed countries is leaving too great a delay between taking the blood sample and making the blood films. As blood cools to room temperature, male gametocytes will divide and release microgametes: these are long sinuous filamentous structures that can be mistaken for organisms such as Borrelia. If the blood is kept at warmer temperatures, schizonts will rupture and merozoites invading erythrocytes will mistakenly give the appreance of the accolé form of P. falciparum. If P. vivax or P. ovale is left for several hours in EDTA, the build up of acid in the sample will cause the parasitised erythrocytes to shrink and the parasite will roll up, simulating the appearance of P. malariae. This problem is made worse if anticoagulants such as heparin or citrate are used. The anticoagulant that causes the least problems is EDTA. Romanovski's stain or a variant stain is usually used. Some laboratories mistakenly use the same stain as they do for routine haematology blood films ( pH 6.8): malaria blood films must be stained at pH 7.2, or Schüffner's dots and James's dots will not be seen.
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% parasitaemia and non-falciparum down to 0.1%. Paracheck-Pf® will detect parasitaemias down to 0.002% but will not distinguish between falciparum and non-falciparum malaria.
Treatment
There are several families of drugs used to treat malaria. 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 antimalarial drugs include:
- Artemether- lumefantrine (Therapy only)
- Artesunate- amodiaquine (Therapy only)
- Atovaquone- proguanil, trade name Malarone (Therapy and prophylaxis)
- Quinine (Therapy only)
- Chloroquine (Therapy and prophylaxis; usefulness now reduced due to resistance)
- 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)
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. A 2005 study published in Nature described possible drug resistance, although the finding could help the development of other drugs.
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 antimalarial 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.
There is a problem of availability of effective malaria treatments in the United States. Most hospitals in the United States do not stock intravenous quinine, and with the reduced use of quinidine by cardiologists, many hospitals have no access to intravenous anti-malarial drugs at all.
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.
Prophylactic drugs
Several drugs, most of which are also used for treatment of malaria, can be taken preventatively. 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 travellers to malarial regions. This is due to the potentially high cost of purchasing the drugs, because long-term use of some drugs may have negative side effects, and because some effective antimalarial 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 for malaria prophylaxis.
Modern drugs used preventatively include mefloquine (Lariam®), doxycycline (available generically), and atovaquone proguanil hydrochloride (Malarone®). The choice of which drug to use is usually driven by what 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 malarial areas usually begin taking the drugs one to two weeks before arriving, and continue taking them for a similar amount of time after leaving.
Mosquito eradication
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. Malaria was eliminated from the northern parts of the USA in the early twentieth century, and the use of the pesticide DDT during the 1950s eliminated it from the South. A major public health effort to eradicate malaria worldwide by selectively targeting mosquitoes in areas where malaria was rampant was embarked upon in the 1950s and 1960s. However, these efforts have so far failed to eradicate malaria in many parts of the developing world, with the problem most prevalent in Africa.
DDT was developed as the first of the modern insecticides early in World War II. While it was initially used with great effect to combat mosquitoes spreading malaria, it was banned for use in many countries in the 1970s due to its negative impact in high concentrations. There is great controversy regarding this impact and the use of DDT to fight human diseases. Some claim that the ban is responsible for malaria deaths counted in tens of millions in tropical countries where the disease had been controlled effectively by DDT.
The World Bank estimates that malaria costs Africa $12bn a year in lost productivity. Yet international funding for malaria control is only $100m-$200m a 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 much greater benefit to African economies.[ citation needed]
Prevention of mosquito bites
Since most of the deaths today occur in poor rural areas of Africa that lack proper health care, the distribution of mosquito nets impregnated with insecticide (often permethrin) has been suggested as the most effective and cost-effective prevention method. These nets can often be obtained for less than US$10 or 10 euros when purchased in bulk from the United Nations or other organizations. The nets need to be re-impregnated with the chemical about every six months. Insecticide-treated bednets (ITN) have the advantage of protecting people living under the net and simultaneously killing mosquitoes which get in contact with the net and thus protecting people sleeping in the same room but not under the net.
Spraying interior walls with DDT is also effective in most areas, where the mosquitoes are not DDT-resistant. 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 many developed countries heavily discourage DDT use even in small amounts.
A new approach, announced in Science on June 10, 2005, uses inert 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 January 2006). A team backed by 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%. The study looked at over 2000 Mozambican children. Further research will delay this vaccine from commercial release until around 2010.
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.
Sterile insect technique is emerging as a potential method to control malaria-carrying mosquitoes. Progress towards transgenic, or genetically modified, insects suggests 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.
Social and economic impacts of malaria
The geographic distribution of malaria is complex, and malarial and malaria-free areas are often found very close to each other. In general, though, 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 capital cities of the Philippines, Thailand and Sri Lanka are essentially malaria-free, but the disease is present in many rural parts of those nations. By contrast, in West Africa, Ghana and Nigeria have malaria throughout the entire country, though the risk is lower in the larger cities.