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Malaria
 

Malaria (Medieval Italian: mala aria — "bad air") and formerly called ague or marsh fever in English, is an infectious disease which causes about 350–500 million infections in humans and approximately 1.3–3 million deaths annuallyCampbell, Neil A. et al. "Biology" Seventh edition. Menlo Park, CA: Addison Wesley Longman, Inc. 2005 — at least one death every 30 seconds. Sub-Saharan Africa accounts for 85–90% of these fatalities,Scott P. Layne, M.D. UCLA Department of Epidemiology, "Principles of Infectious Disease Epidemiology / EPI 220" the vast majority of which occur in children under the age of 5 years. The death rate is expected to double in the next 20 years.Hull, Kevin. (2006) "Malaria: Fever Wars". PBS Documentary 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.Hull, Kevin. (2006) "Malaria: Fever Wars". PBS Documentary

Malaria is caused by protozoan parasites of the genus Plasmodium (phylum Apicomplexa): P. falciparum, P. malariae, P. ovale, and P. vivax. Their primary hosts and transmission vectors are female mosquitos of genus Anopheles; humans act as intermediate hosts. 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.

History

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.

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. falciparum. Consequences of infection with malaria include coma and death if untreated—young children and pregnant women are especially vulnerable. Splenomegaly (enlarged spleen), severe headache, cerebral ischemia and hemoglobinuria with renal failure may occur.

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 (hepatic) and an erythrocytic phase. When an infected mosquito pierces a person's skin to take a blood meal, sporozoites in the mosquito's saliva enter the bloodstream and migrate to the liver. Within 30 minutes of being introduced into the human host, they infect hepatocytes, multiplying asexually 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.

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 (P. vivax and P. ovale, Malaria tertiana) or three days (P. malariae, Malaria quartana) 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 (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. Approximately 50% of P. vivax malaria cases in temperate areas involve overwintering by hypnozoites (i.e., relapses begin the 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 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.

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 60 variations of PfEMP1 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.

By the time the human immune system recognizes the protein and develops 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 P. 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 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.

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. simiovale 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 species of malaria found in animals is rarely infectious 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 other higher primates. Other animal forms of malaria do not infect humans at all.

Diagnosis

The gold standard for the 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 ("ring form") of all four species look identical and it is never possible to diagnose species on the basis of a single ring form; species identification is always based on several trophozoites. Please refer to the chapters on each parasite for their microscopic appearances: P. falciparum, P. vivax, P. ovale, P. malariae.

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, schizont 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 (pH 7.2): 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 (prophylaxis). Many drugs can be used for both purposes; larger doses are used to treat cases of malaria. Their deployment depends mainly on the frequency of resistant parasites in the area where the drug is used.

Currently available anti-malarial drugs include:

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 Structural And Molecular Biology (NSMB) described possible drug resistance, although the finding could help the development of other drugs."Malaria drug resistance warning", BBC News, 2005-06-06. 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 is under heavy criticism since they did not perform obvious experiments to conclude to their findings (They did not actually create resistant parasites).

In February 2002, the journal Science and other press outletsMalaria drug offers new hope. BBC News 2002-02-15. 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."One step closer to conquering malaria 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."Salom-Roig, X. et al. (2005) Dual molecules as new antimalarials. Combinatorial Chemistry & High Throughput Screening 8:49-62. 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 States dollar|US$" target="_blank" >*0.25 and $2.40. Medecins Sans Frontieres, "What is the Cost and Who Will Pay?"

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.

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 (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 malaria-endemic areas usually begin taking the drugs one to two weeks before arriving and must continue taking them for 4 weeks after leaving (atovaquone proguanil only needs be started 2 days prior and continued for 7 days afterwards).

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. 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.Gladwell, Malcolm. (2001) "The Mosquito Killer", The New Yorker, 2001-07-02. However, these efforts have so far failed to eradicate malaria in many parts of the developing world - the problem is most prevalent in Africa. The United States itself may face the spread of malaria in the future as climate change (warming) leads to an expansion of the areas in which mosquitoes are active.

DDT insecticide

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 (WHO) currently advises the use of DDT to combat malaria in endemic areasWHO frequently asked questions on DDT use for disease vector control. For instance, DDT-spraying the interior walls of living spaces, where mosquitoes land, is an effective control. The WHO also recommends a series of alternative insecticides to both combat malaria in areas where mosquitos are DDT-resistant, and to slow the evolution of resistance. This public health use of small amounts of DDT is permitted under the Stockholm Convention on persistent organic pollutants (POPs), which prohibits the agricultural use of DDT for large-scale field spraying10 Things You Need to Know about DDT Use under The Stockholm Convention. However, because of its legacy, many developed countries discourage DDT use even in small quantitiesThe Stockholm Convention on persistent organic pollutants.

Economics

Economic adviser Jeffrey Sachs estimates that malaria can be controlled for $3 billion a year. In 2004, the US gave $500 Million in anti-malaria aid.Hull, Kevin. (2006) "Malaria: Fever Wars". PBS Documentary 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.Hull, Kevin. (2006) "Malaria: Fever Wars". PBS Documentary

In the long run, it seems that disease prevention is likely to be more cost-effective than disease treatment; however, disease prevention programs typically require funding for capital costs. A simple mosquito net costing US$2-$5 is effective in preventing malaria for a household; however, this capital cost is often considered unaffordable by a subsistence farmer who may earn ~US$250 per year. In cases where preventative measures exist, appropriate financing may assist in making these solutions more affordable to all.

Mosquito nets and prevention of mosquito bites

Mosquito nets help keep mosquitoes away from people, and thus greatly reduce the infection and transmission of malaria. The nets are not a perfect barrier, so they are often treated with an insecticide designed to kill the mosquito before it has time to search for a way past the net. Insecticide-treated nets (ITN) are estimated to be twice as effective as untreated nets.Hull, Kevin. (2006) "Malaria: Fever Wars". PBS Documentary 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 (often permethrin) has been shown to be an extremely effective method of malaria prevention, and it is also one of the most cost-effective methods of prevention. These nets can often be obtained for around US$2.50 - $3.50 (2-3 euros) from the United Nations, the World Health Organization, and others.

For maximum effectiveness, the nets should be re-impregnated with insecticide every six months. This process poses a significant logistical problem in rural areas. A new type of impregnated net, called Olyset, releases insecticide for approximately 5 yearsNew Mosquito Nets Could Help Fight Malaria in Africa, 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.Hull, Kevin. (2006) "Malaria: Fever Wars". PBS Documentary

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.Permethrin-treated chaddars and top-sheets: appropriate technology for protection against malaria in Afghanistan and other complex emergencies.

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."Fungus 'may help malaria fight'", BBC News, 2005-06-09

Vaccination

Vaccines for malaria are under development, with no completely effective vaccine yet available (as of June 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.Malaria Vaccine Initiative 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.MacGregor, Fiona. (2005) Scots scientists boost malaria vaccine quest. The Scotsman, 2005-01-16. 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.

Transgenic Mosquitoes

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,Imperial College, London, "Scientists create first transgenic malaria mosquito", 2000-06-22. with the first plasmodium-resistant species announced by a team at Case Western Reserve University in Ohio in 2002. Jacobs-Lorena et al, " Researchers genetically alter mosquitoes to impair malaria transmission", Case-Western, 2002.

Social and economic impacts of malaria

The geographic distribution of malaria 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 parts. By contrast, in West Africa, Ghana and Nigeria have malaria throughout the entire country, though the risk is lower in the larger cities.

The economic impacts of malaria, though difficult to quantify, are most certainly real, as the disease can reduce attendance and productivity at both school and work. There has even been demonstration of developmental impairments in children who have suffered episodes of severe malaria. As such, the connection between poverty and malaria cannot be denied. A comparison of average per capita GDP in 1995, adjusted to give parity of purchasing power, between malarious and non-malarious countries demonstrate a five-fold difference (US$1,526 versus US$8,268). Moreover, in countries that are battling malaria, 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 entirely, the economic impact of malaria has been estimated to cost Africa US$12 billion every year.Greenwood B, (2005) Lancet

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 polymerisation of haemoglobin deforming red blood cells into a sickle shape.

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

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

Thalassaemias

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

Duffy antigens

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

G6PD

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

References

External links

Vaccine and other research

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