, derived from ''mala aria'' (.
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 death rate is expected to double in the next 20 years.
Hull, Kevin. (2006) "Malaria: Fever Wars". PBS Documentary The exact 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 the
Protozoa n
Parasite s 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 showed in 1898 that certain mosquito species transmit malaria to birds and received a Nobel prize (in 1902) for describing the life cycle stages that develop within the mosquito.
Juan Carlos Finley , a Cuban doctor, first suggested that mosquitoes could transmit disease to humans, and his work inspired Dr
William C. Gorgas in his effective sanitation work during construction of the
Panama Canal .
Symptoms of malaria include
Fever ,
Shivering ,
Arthralgia (joint pain),
Vomiting ,
Anaemia caused by
Haemolysis ,
Haemoglobinuria , and
Convulsion s. 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.
Only females feed on blood, thus males do not transmit the disease. The ''Anopheles'' species 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''
Sporozoite s in their
Salivary Gland s.
When an infected mosquito pierces a person's skin to take a blood meal, the sporozoites in the mosquito's saliva enter the bloodstream and migrate to the
Liver . There they hide within hepatic liver cells and multiply asexually. Development in the hepatic cell takes 6 to 15 days depending on the species. Within hepatic cells the parasite mutates to produce hundreds or thousands of
Merozoite s which, following rupture of the hepatic cell, are released into the blood stream and invade
Red Blood Cell s.
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 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 50 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 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
Gametocyte s. 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. Semiovale '' are also known to cause malaria but are of limited public health importance.
Other
Mammal s (
Bat s,
Rodent s, non-human
Primates ) as well as
Bird s and
Reptile s 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.
The ,
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, schizonts 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
Anticoagulant s 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.
2 OptiMAL-IT® will reliably detect falciparum down to 0.01% parasitaemia and non-''falciparum'' down to 0.1%. ''Para''check-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.
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 '''',
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 ''. 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
US$ 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.
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.
(USA).]]
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.
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 Effect s, 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).
Efforts to eradicate malaria by eliminating mosquitoes have been successful in some areas. Malaria was once common in the . 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 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. During the 1960s, awareness of the negative consequences of its use ultimately led to bans on its use in many countries in the 1970s. There is still great controversy regarding the impact and the use of DDT to fight human diseases. Some claim that the ban is responsible for tens of millions of deaths in tropical countries where previously, DDT was effective in controlling malaria.
Given the severity of the malaria epidemic, there is renewed interest in the measured use of DDT. Spraying interior walls, where mosquitoes land, with DDT is effective in 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 discourage DDT use even in small amounts.
The Stockholm Convention on persistent organic pollutants
The , 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. The
World Bank estimates that
Malaria costs
Africa millions of lives a year, and $12 billion in lost productivity. 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 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 years
New 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
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.
Malaria Vaccine Initiative Further research will delay this vaccine from commercial release until around 2010.
In January 2005, . 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. Ito J, Ghosh A, Moreira LA, Wimmer EA, Jacobs-Lorena M. (2002) ''Transgenic anopheline mosquitoes impaired in transmission of a malaria parasite''. ''Nature'' 417:387-8. PMID 12024215
. with the first plasmodium-resistant species announced by a team at
Case Western Reserve University in
Ohio in 2002. Jacobs-Lorena et al, "[http://www.cwru.edu/pubaff/univcomm/2002/may/mosquito.htm Researchers genetically alter mosquitoes to impair malaria transmission]", Case-Western, 2002.
The geographic distribution of malaria is complex, and malarial and malaria-free areas are often found close to each other.Greenwood, B. and Mutabingwa, T. (2002) Malaria in 2002. ''Nature'' 415:670-672. 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.
and
Morbidity caused by
Malaria , especially the ''falciparum'' form.
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.
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.
The
Duffy Antigen s 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.
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.
