Encyclopedia
Malaria is an infectious disease that is widespread in many
tropical and subtropical regions. It causes between one and three million deaths annually, mostly among young children in
Sub-Saharan Africa. The disease is caused by a
protistan parasite of the genus
Plasmodium is a genus of parasitic protozoa [i], four species of which cause malaria [i] in humans. ...
that is transmitted primarily by female
Anopheles mosquitoes.
Plasmodium invades and consumes the
red blood cells of its host, which leads to symptoms including
fever, anemia, and in severe cases, a coma potentially leading to death. Some techniques used to control the disease include mosquito eradication with insecticides, prevention of mosquito bites, and the use of drugs to prevent and treat infection.
History
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In 1880, French army doctor
Charles Louis Alphonse Laveran proposed that malaria was caused by a protozoan, the first time protozoa was identified as causing a disease. For this and later discoveries, he was awarded the 1907 Nobel Prize for Physiology or Medicine. A year later,
Carlos Finlay, a Cuban doctor treating patients with
yellow fever in
Havana, first suggested that mosquitoes were transmitting disease to humans. Britain's
Sir Ronald Ross showed in 1898 that certain mosquito species transmit malaria to birds and received the 1902 Nobel Prize in Medicine for describing the life cycle of the malarial parasite. The findings of Finlay 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.
Distribution and impact
Malaria causes about 350–500 million infections in humans and approximately 1.3–3 million deaths annually — this represents at least one death every 30 seconds. The vast majority of cases occur in children under the age of 5 years; pregnant women are also especially vulnerable. The death rate is expected to double in the next twenty years. Precise statistics are unknown because many cases occur in rural areas where people do not have access to hospitals and/or the means to afford health care. Consequently, many cases are undocumented.
Malaria is presently endemic 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 generally considered malarial is complex, and malarial and malaria-free areas are often found close to each other. Malaria is more common in rural areas than in cities; this is in contrast to
dengue fever where urban areas present the greater risk. For example, the cities of the
Philippines,
Thailand and
Sri Lanka are essentially malaria-free, but the disease is present in many rural regions. By contrast, in
West Africa,
Ghana and
Nigeria have malaria throughout the entire country, though the risk is lower in the larger cities.
Social and economic effects
The disease has been associated with major negative economic effects on regions where it is widespread. A comparison of average per capita GDP in 1995, adjusted to give parity of purchasing power, between malarious and non-malarious countries demonstrate a five-fold difference . Moreover, in countries where malaria is common, average per capita GDP has risen only 0.4% per year, compared to 2.4% per year in other countries. In its entirely, 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.
Transmission and symptoms
Malaria is caused by protozoan parasites of the genus
Plasmodium is a genus of parasitic protozoa [i], four species of which cause malaria [i] in humans. ...
:
P. falciparum is a protozoan [i] parasite [i], one of the species of Plasmodium [i] ...
,
P. malariae,
P. ovale is a species of parasitic [i] protozoa [i] that causes tertian malaria [i] ...
, and
P. vivax is the most frequent and widely distributed cause of benign, but r...
.
P. falciparum is responsible for about 80% of infections and 90% of deaths. Infections with
P. knowlesi and
P. simiovale are also known to cause malaria but are of limited public health importance.
The parasite's primary hosts and transmission vectors are female
mosquitoes of the Anopheles genus; humans act as intermediate hosts.
Symptoms of malaria include
fever, shivering, arthralgia , vomiting, anemia caused by hemolysis, hemoglobinuria, and convulsions. There may be the feeling of tingling in the skin, particularly with malaria caused by
P. falciparum. Consequences of infection with malaria include coma and death if untreated—young children and pregnant women are especially vulnerable. Splenomegaly , severe headache, cerebral ischemia and hemoglobinuria with renal failure may occur. Over the longer term, developmental impairments have been documented in children who have suffered episodes of severe malaria.
Mosquitoes
Only female mosquitoes feed on blood, thus males do not transmit the disease. The females of the
Anopheles species 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. Young mosquitoes first ingest the malaria parasite by feeding on a human carrier. Infected female
Anopheles mosquitoes carry
Plasmodium sporozoites in their salivary glands.
Pathogenesis
Malaria in humans develops via two phases: an exoerythrocytic and an erythrocytic phase. When an infected mosquito pierces a person's skin to take a blood meal, sporozoites in the mosquito's saliva enter the bloodstream and migrate to the
liver. Within 30 minutes of being introduced into the human host, they infect
hepatocytes, multiplying asexually for a period of 6–15 days. They then differentiate to yield hundreds or thousands of merozoites which, following rupture of their host cells, escape into the blood and infect
red blood cells.
How it escapes undetected has been a mystery until recently. The parasite acts like a
trojan horse in the dead liver cell and releases cloaking chemicals to prevent detection.
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Within the red blood cells they 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 coming every two or three days arises from simultaneous waves of merozoites escaping and infecting red blood cells.
P. falciparum is said to have no such cyclic fever waves.
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 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. Approximately 50% of
P. vivax malaria cases in temperate areas involve overwintering by hypnozoites .
The parasite is relatively protected from attack by the body's
immune system because for most of its human life cycle it resides within the liver and blood cells and is relatively invisible to immune surveillance. However, circulating infected blood cells are destroyed in the
spleen. To avoid this fate, the
P. falciparum parasite displays adhesive
proteins on the surface of the infected blood cells, causing the blood cells to stick to the walls of small blood vessels, thereby sequestering the parasite from passage through the general circulation and the spleen. This "stickiness" is the main factor giving rise to
hemorrhagic complications of malaria.
Although the red blood cell surface adhesive proteins are exposed to the immune system they do not serve as good immune targets because of their extreme diversity; there are at least 60 variations of the protein within a single parasite and perhaps limitless versions within parasite populations. Like a thief changing disguises or a spy with multiple passports, the parasite switches between a broad repertoire of PfEMP1 surface proteins, thus staying one step ahead of the pursuing immune system.
High endothelial venules 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 an 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.
Other mammals as well as
birds and
reptiles also suffer from malaria. However, the species of malaria found in animals is rarely infectious in humans. Three human forms are completely exclusive to humans. Only one form,
P. malariae, can cause malaria in both humans and other higher
primates. Other animal forms of malaria do not infect humans at all.
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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. Two sorts of blood film are traditionally used. Thin films are similar to usual blood films and allow species identification, because the parasite's appearance is best preserved in this preparation. Thick films allow the microscopist to screen a larger volume of blood and are about eleven times more sensitive than the thin film, so picking up low levels of infection is easier on the thick film, but the appearance of the parasite is much more distorted and therefore distinguishing between the different species can be much more difficult. From the thick film, an experienced microscopist can detect parasite levels down to as low as 0.0000001%. Microscopic diagnosis can be difficult because the early trophozoites of all four species look identical and it is never possible to diagnose species on the basis of a single ring form; species identification is always based on several trophozoites. Please refer to the chapters on each parasite for their microscopic appearances:
P. falciparum is a protozoan [i] parasite [i], one of the species of Plasmodium [i] ...
,
P. vivax,
P. ovale,
P. malariae.
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, will rupture and merozoites invading erythrocytes will mistakenly give the appearance 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 : malaria blood films must be stained at pH 6.8, 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. Parasite nucleic acids are detected using polymerase chain reaction. This technique is more accurate than microscopy. However, it is expensive, and requires a specialized laboratory.
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 . 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.
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Currently available anti-malarial drugs include:
Since 2001 the
World Health Organization has recommended using
artemisinin-based combination therapy as first-line treatment for uncomplicated malaria in areas experiencing resistance to older medications. The most recent WHO 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.
Extracts of the plant
Artemisia annua, also known as
Sweet Wormwood,
Sweet Annie, or
Chinese wormwood, i...
, containing the compound
artemisinin or semi-synthetic derivatives , offer over 90% efficacy rates, but their supply is not meeting demand. A 2005 study published in
Nature Structural And Molecular Biology described possible drug resistance, although the finding could help the development of other drugs.. These findings contradict other findings published at Plos Genetics which suggest the mitochondria as the major target of action of artemisinin and its analogs. The paper published at NSMB has gained support from the observation that mutations in the proposed target for artemisinins are associated with decreased sensitivity to artemether in parasites studied in French Guiana by a team based at the Institute Pasteur.
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In February 2002, the journal
Science and other press outlets announced progress on a new treatment for infected individuals. A team of French and South African researchers had identified a new drug they were calling "G25." It cured malaria in test primates by blocking the ability of the parasite to copy itself within the red blood cells of its victims. In 2005 the same team of researchers published their research on achieving an oral form, which they refer to as "TE3" or "te3." As of early 2006, there is no information in the mainstream press as to when this family of drugs will become commercially available.
Although effective anti-malarial drugs are on the market, the disease remains a threat to people living in endemic areas who have no proper and prompt access to effective drugs. Access to pharmacies and health facilities, as well as drug costs, are major obstacles.
Médecins Sans Frontières estimates that the cost to treat a malaria-infected person in an endemic country is between
US$0.25 and $2.40.
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.
Malaria as treatment
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 avoided.
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. In five of those cases, the disease was contracted in the United States. Malaria was eliminated from the northern parts of the USA in the early twentieth century, and the use of the
pesticide DDT eliminated it from the South by 1951. In the 1950s and 1960s, there was a major public health effort to eradicate malaria worldwide by selectively targeting mosquitoes in areas where malaria was rampant. However, these efforts have so far failed to eradicate malaria in many parts of the developing world - the problem is most prevalent in Africa.
Brazil, Eritrea, India, and Vietnam have, unlike many other developing nations, successfully reduced the malaria burden. Common success factors included conducive country conditions, a targeted technical approach using a package of effective tools, data-driven decision-making, active leadership at all levels of government, involvement of communities, decentralized implementation and control of finances, skilled technical and managerial capacity at national and sub-national levels, hands-on technical and programmatic support from partner agencies, and sufficient and flexible financing.
Prophylactic drugs
Several drugs, most of which are also used for treatment of malaria, can be taken preventively. Generally, these drugs are taken daily or weekly, at a lower dose than would be used for treatment of a person who had actually contracted the disease. Use of prophylactic drugs is seldom practical for full-time residents of malaria-endemic areas, and their use is usually restricted to short-term visitors and travelers to malarial regions. This is due to the potentially high cost of purchasing the drugs, because long-term use of some drugs may have negative side effects, 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 for malaria prophylaxis.
Modern drugs used preventively include
mefloquine , doxycycline , and atovaquone proguanil hydrochloride . 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 malaria-endemic areas usually begin taking the drugs one to two weeks before arriving and must continue taking them for 4 weeks after leaving .
Indoor residual spraying
DDT was developed as the first of the modern insecticides early in
World War II. While it was initially used to combat malaria, its use spread to
agriculture where it was used to eliminate insect pests. In time, pest-control, rather than disease-control, came to dominate DDT use, particularly in the developed world. During the 1960s, awareness of the negative consequences of its indiscriminate use increased, and ultimately led to bans in many countries in the 1970s. By this time, its large-scale use had already led to the
evolution of resistant mosquitos in many regions.
However, given the continuing toll to malaria, particularly in developing countries, there is considerable controversy regarding the restrictions placed on the use of DDT. Some advocates claim that bans are responsible for tens of millions of deaths in tropical countries where previously DDT was effective in controlling malaria. Furthermore, most of the problems associated with DDT use stem specifically from its industrial-scale application in agriculture, rather than its use in public health.
The
World Health Organisation currently advises the use of DDT to combat malaria in endemic areas. For instance, DDT-spraying the interior walls of living spaces, where mosquitoes land, is an effective control. The WHO also recommends a series of alternative insecticides to both combat malaria in areas where mosquitos are DDT-resistant, and to slow the evolution of resistance. This public health use of small amounts of DDT is permitted under the Stockholm Convention on persistent organic pollutants , which prohibits the agricultural use of DDT for large-scale field spraying. However, because of its legacy, many developed countries discourage DDT use even in small quantities.
Mosquito nets and bedclothes
Mosquito nets help keep mosquitoes away from people, and thus greatly reduce the infection and transmission of malaria. The nets are not a perfect barrier, so they are often treated with an insecticide designed to kill the mosquito before it has time to search for a way past the net. Insecticide-treated nets are estimated to be twice as effective as untreated nets. 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 insecticide 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 from the
United Nations, the World Health Organization, and others.
For maximum effectiveness, the nets should be re-impregnated with insecticide every six months. This process poses a significant logistical problem in rural areas. A new type of impregnated net, called Olyset, releases insecticide for approximately 5 years, and costs about US$5.50. ITN's have the advantage of protecting people sleeping under the net and simultaneously killing mosquitoes that contact the net. This has the effect of killing the most dangerous mosquitoes. Some protection is also provided to others, including people sleeping in the same room but not under the net.
Unfortunately, the cost of treating malaria is high relative to income, and the illness results in lost wages. Consequently, the financial burden means that the cost of a mosquito net is often unaffordable to people in developing countries, especially for those most at risk. Only 1 out of 20 people in Africa own a bed net.
A study among Afghan refugees in Pakistan found that treating top-sheets and chaddars 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 inert spores of the
fungus Beauveria bassiana is a fungus [i] that grows naturally in soils throughout the world and causes dis ...
, 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 . 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.
Other methods
Sterile insect technique is emerging as a potential mosquito control method. Progress towards transgenic, or
genetically modified, insects suggest that wild mosquito populations could be made malaria-resistant. Researchers at
Imperial College London created the world's first transgenic malaria mosquito, with the first plasmodium-resistant species announced by a team at
Case Western Reserve University in
Ohio in 2002.
Before DDT, malaria was successfully eradicated or controlled also in several tropical areas by removing or poisoning the breeding grounds of the mosquitoes or the aquatic habitats of the larva stages, for example by filling or applying oil to places with standing water. These methods have seen little application in Africa for more than half a century.
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
falciparum form.
Sickle-cell anemia
The best-studied influence of the malaria parasite upon the human genome is the blood disease,
sickle-cell anaemia. In sickle-cell anaemia, there is a mutation in the HBB gene which codes for a
haemoglobin subunit. The normal allele is HbA, but the sickle-cell allele, HbS, has a mutation from
Glutamic Acid to
Valine at
amino acid 6. This change from a hydrophilic to a hydrophobic residue encourages binding between
haemoglobin molecules, with polymerization of haemoglobin deforming
red blood cells into a
sickle shape.
Individuals homozygous for HbS have full sickle-cell anaemia and rarely live beyond
adolescence. However, this allele has sustained gene frequencies in populations where malaria is endemic of around 10%. This is because individuals heterozygous for the mutated allele have a low level of anaemia but also have a greatly reduced chance of malaria infection. The existence of four haplotypes of HbS suggests that this mutation has emerged independently at least four times in malaria-endemic areas, further demonstrating its evolutionary advantage in such affected regions.
There are also other mutations of the HBB
gene which appear to confer similar resistance to malaria infection. These are HbE and HbC which are common in
Southeast Asia and
Western Africa respectively.
Thalassaemias
Another well documented set of mutations found in the human genome associated with malaria are those involved in causing blood disorders known as
thalassaemias. Studies in
Sardinia and
Papua New Guinea have found that the gene frequency of ß-thalassaemias is related to the level of endemicity in a given population. A study on more than 500 children in
Liberia found that those with ß-thalassaemia had a 50% decreased chance of getting clinical malaria. Similar studies have found links between gene frequency and malaria endemicity in the a+ form of a-thalassaemia.
Duffy antigens
The Duffy antigens are antigens expressed on red blood cells and other cells in the body acting as a chemokine receptor. The expression of Duffy antigens on blood cells is encoded by Fy genes .
Plasmodium vivax malaria uses the Duffy antigen to enter blood cells. However, it is possible to express no Duffy antigen on red blood cells . This genotype confers complete resistance to
P. vivax infection. The genotype has not been found in Chinese populations, has rarely been found in white populations, but is found in 68% of black people. This is thought to be due to very high exposure to
P. vivax in
Africa in the past.
G6PD
Glucose-6-phosphate dehydrogenase 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.
Footnotes
External links
General information
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- distributed computing project for the fight against malaria
- information pages
- information pages
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- research and resources on health in developing countries
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- directory category
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- Malaria Cases and Deaths by Country
- home page at The Global Fund
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- Organization dedicated to the distribution of insecticide treated nets for the prevention of malaria
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Vaccine and other research
- 15 October 2004
- 8 April 2005
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- 15 October 2004
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Mosquito Netting as Prevention
DDT
Animations, images and photos
- , BBC pictures relating to malaria in northern Uganda
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