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| Malaria Classification & external resources | ||
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| Plasmodium falciparum ring-forms and gametocytes in human blood. | ||
| ICD-10 | B50. | |
| ICD-9 | 084 | |
| OMIM | 248310 | |
| DiseasesDB | 7728 | |
| MedlinePlus | 000621 | |
| eMedicine | med/1385 emerg/305 ped/1357 | |
| MeSH | C03.752.250.552 | |
Malaria is a vector-borne infectious disease caused by protozoan parasites. It is widespread in tropical and subtropical regions, including parts of the Americas, Asia, and Africa. Each year, it causes disease in approximately 515 million people and kills between one and three million people, the majority of whom are young children in Sub-Saharan Africa.Snow RW, Guerra CA, Noor AM, Myint HY, Hay SI (2005). "The global distribution of clinical episodes of Plasmodium falciparum malaria". Nature 434 (7030): 214-7. PMID 15759000. Malaria is commonly associated with poverty, but is also a cause of poverty and a major hindrance to economic development.
Malaria is one of the most common infectious diseases and an enormous public health problem. The disease is caused by protozoan parasites of the genus Plasmodium. Only four types of the plasmodium parasite can infect humans; the most serious forms of the disease are caused by Plasmodium falciparum and Plasmodium vivax, but other related species (Plasmodium ovale, Plasmodium malariae) can also affect humans. This group of human-pathogenic Plasmodium species is usually referred to as malaria parasites.
Malaria parasites are transmitted by female Anopheles mosquitoes. The parasites multiply within red blood cells, causing symptoms that include symptoms of anemia (light headedness, shortness of breath, tachycardia etc.), as well as other general symptoms such as fever, chills, nausea, flu-like illness, and in severe cases, coma and death. Malaria transmission can be reduced by preventing mosquito bites with mosquito nets and insect repellents, or by mosquito control measures such as spraying insecticides inside houses and draining standing water where mosquitoes lay their eggs.
Although some are under development, no vaccine is currently available for malaria; preventative drugs must be taken continuously to reduce the risk of infection. These prophylactic drug treatments are often too expensive for most people living in endemic areas. Most adults from endemic areas have a degree of long-term recurrent infection and also of partial resistance; the resistance reduces with time and such adults may become susceptible to severe malaria if they have spent a significant amount of time in non-endemic areas. They are strongly recommended to take full precautions if they return to an endemic area. Malaria infections are treated through the use of antimalarial drugs, such as quinine or artemisinin derivatives, although drug resistance is increasingly common.
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Charles Louis Alphonse Laveran
Malaria has infected humans for over 50,000 years, and may have been a human pathogen for the entire history of our species.Joy D, Feng X, Mu J, et al (2003). "Early origin and recent expansion of Plasmodium falciparum.". Science 300 (5617): 318-21. PMID 12690197. Indeed, close relatives of the human malaria parasites remain common in chimpanzees, our closest relatives.Escalante A, Freeland D, Collins W, Lal A (1998). "The evolution of primate malaria parasites based on the gene encoding cytochrome b from the linear mitochondrial genome.". Proc Natl Acad Sci U S A 95 (14): 8124-9. PMID 9653151. References to the unique periodic fevers of malaria are found throughout recorded history, beginning in 2700 BC in China.Cox F (2002). "History of human parasitology.". Clin Microbiol Rev 15 (4): 595-612. PMID 12364371. The term malaria originates from Medieval Italian: mala aria — "bad air"; and the disease was formerly called ague or marsh fever due to its association with swamps.
Scientific studies on malaria made their first significant advance in 1880, when a French army doctor working in the military hospital of Constantine Algeria named Charles Louis Alphonse Laveran observed parasites for the first time, inside the red blood cells of people suffering from malaria. He therefore proposed that malaria was caused by this protozoan, the first time protozoa were identified as causing disease.Biography of Alphonse Laveran. The Nobel Foundation. Retrieved on 2007-06-15. ] Nobel foundation. Accessed 25 Oct 2006 For this and later discoveries, he was awarded the 1907 Nobel Prize for Physiology or Medicine. The protozoan was called Plasmodium by the Italian scientists Ettore Marchiafava and Angelo Celli.Ettore Marchiafava. Retrieved on 2007-06-15. A year later, Carlos Finlay, a Cuban doctor treating patients with yellow fever in Havana, first suggested that mosquitoes were transmitting disease to and from humans. However, it was Britain\'s Sir Ronald Ross working in India who finally proved in 1898 that malaria is transmitted by mosquitoes. He did this by showing that certain mosquito species transmit malaria to birds and isolating malaria parasites from the salivary glands of mosquitoes that had fed on infected birds.Biography of Ronald Ross. The Nobel Foundation. Retrieved on 2007-06-15. For this work Ross received the 1902 Nobel Prize in Medicine. After resigning from the Indian Medical Service, Ross worked at the newly-established Liverpool School of Tropical Medicine and directed malaria-control efforts in Egypt, Panama, Greece and Mauritius.Ross and the Discovery that Mosquitoes Transmit Malaria Parasites. CDC Malaria website. Retrieved on 2007-06-15. The findings of Finlay and Ross 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. This public-health work saved the lives of thousands of workers and helped develop the methods used in future public-health campaigns against this disease.
The first effective treatment for malaria was the bark of cinchona tree, which contains quinine. This tree grows on the slopes of the Andes, mainly in Peru. This natural product was used by the inhabitants of Peru to control malaria, and the Jesuits introduced this practice to Europe during the 1640s where it was rapidly accepted.Kaufman T, Rúveda E (2005). "The quest for quinine: those who won the battles and those who won the war.". Angew Chem Int Ed Engl 44 (6): 854-85. PMID 15669029. However, it was not until 1820 that the active ingredient quinine was extracted from the bark, isolated and named by the French chemists Pierre Joseph Pelletier and Joseph Bienaimé Caventou.Kyle R, Shampe M (1974). "Discoverers of quinine". JAMA 229 (4): 462. PMID 4600403.
In the early twentieth century, before antibiotics, patients with syphilis were intentionally infected with malaria to create a fever, following the work of Julius Wagner-Jauregg. By accurately controlling the fever with quinine, the effects of both syphilis and malaria could be minimized. Although some patients died from malaria, this was preferable than the almost-certain death from syphilis.Raju T (2006). "Hot brains: manipulating body heat to save the brain.". Pediatrics 117 (2): e320-1. PMID 16452338.
Although the blood stage and mosquito stages of the malaria life cycle were identified in the 19th and early 20th centuries, it was not until the 1980s that the latent liver form of the parasite was observed.Krotoski W, Collins W, Bray R, et al (1982). "Demonstration of hypnozoites in sporozoite-transmitted Plasmodium vivax infection.". Am J Trop Med Hyg 31 (6): 1291-3. PMID 6816080. Meis J, Verhave J, Jap P, Sinden R, Meuwissen J (1983). "Malaria parasites--discovery of the early liver form.". Nature 302 (5907): 424-6. PMID 6339945. The discovery of this latent form of the parasite finally explained why people could appear to be cured of malaria but still relapse years after the parasite had disappeared from their bloodstreams.
Malaria causes about 400–900 million cases of fever and approximately one to three million deaths annuallyBreman J (2001). "The ears of the hippopotamus: manifestations, determinants, and estimates of the malaria burden.". Am J Trop Med Hyg 64 (1-2 Suppl): 1-11. PMID 11425172. USAID’s Malaria Programs — this represents at least one death every 30 seconds. The vast majority of cases occur in children under the age of 5 years;Greenwood BM, Bojang K, Whitty CJ, Targett GA (2005). "Malaria". Lancet 365: 1487-1498. PMID 15850634. pregnant women are also especially vulnerable. Despite efforts to reduce transmission and increase treatment, there has been little change in which areas are at risk of this disease since 1992.Hay S, Guerra C, Tatem A, Noor A, Snow R (2004). "The global distribution and population at risk of malaria: past, present, and future.". Lancet Infect Dis 4 (6): 327-36. PMID 15172341. Indeed, if the prevalence of malaria stays on its present upwards course, the death rate could 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 or the means to afford health care. Consequently, the majority of cases are undocumented.
Although co-infection with HIV and malaria does cause increased mortality, this is less of a problem than with HIV/tuberculosis co-infection, due to the two diseases usually attacking different age-ranges, with malaria being most common in the young and active tuberculosis most common in the old.Korenromp E, Williams B, de Vlas S, Gouws E, Gilks C, Ghys P, Nahlen B (2005). "Malaria attributable to the HIV-1 epidemic, sub-Saharan Africa.". Emerg Infect Dis 11 (9): 1410-9. PMID 16229771. Although HIV/malaria co-infection produces less severe symptoms than the interaction between HIV and TB, HIV and malaria do contribute to each other\'s spread. This effect comes from malaria increasing viral load and HIV infection increasing a person\'s susceptibility to malaria infection.Abu-Raddad L, Patnaik P, Kublin J (2006). "Dual infection with HIV and malaria fuels the spread of both diseases in sub-Saharan Africa". Science 314 (5805): 1603-6. PMID 17158329.
Malaria is presently endemic in a broad band around the equator, in areas of the Americas, many parts of Asia, and much of Africa; however, it is in sub-Saharan Africa where 85– 90% of malaria fatalities occur.Layne SP. Principles of Infectious Disease Epidemiology /. EPI 220. UCLA Department of Epidemiology. Retrieved on 2007-06-15. The geographic distribution of malaria within large regions is complex, and malarial and malaria-free areas are often found close to each other.Greenwood B, Mutabingwa T (2002). "Malaria in 2002". Nature 415: 670–2. PMID 11832954. In drier areas, outbreaks of malaria can be predicted with reasonable accuracy by mapping rainfall.Grover-Kopec E, Kawano M, Klaver R, Blumenthal B, Ceccato P, Connor S (2005). "An online operational rainfall-monitoring resource for epidemic malaria early warning systems in Africa.". Malar J 4: 6. PMID 15663795. Malaria is more common in rural areas than in cities; this is in contrast to dengue fever where urban areas present the greater risk.Van Benthem B, Vanwambeke S, Khantikul N, Burghoorn-Maas C, Panart K, Oskam L, Lambin E, Somboon P (2005). "Spatial patterns of and risk factors for seropositivity for dengue infection". Am J Trop Med Hyg 72 (2): 201-8. PMID 15741558. For example, the cities of the Vietnam, Laos and Cambodia are essentially malaria-free, but the disease is present in many rural regions.Trung H, Van Bortel W, Sochantha T, Keokenchanh K, Quang N, Cong L, Coosemans M (2004). "Malaria transmission and major malaria vectors in different geographical areas of Southeast Asia". Trop Med Int Health 9 (2): 230-7. PMID 15040560. By contrast, in Africa malaria is present in both rural and urban areas, though the risk is lower in the larger cities.Keiser J, Utzinger J, Caldas de Castro M, Smith T, Tanner M, Singer B (2004). "Urbanization in sub-saharan Africa and implication for malaria control". Am J Trop Med Hyg 71 (2 Suppl): 118-27. PMID 15331827. The global endemic levels of malaria have not been mapped since the 1960s, however, the Wellcome Trust, UK, has funded the Malaria Atlas ProjectHay SI, Snow RW (2006). "The Malaria Atlas Project: Developing Global Maps of Malaria Risk.". PLoS Medicine 3 (12): e473. to rectify this, providing a more contemporary and robust means with which to assess current and future malaria disease burden.
Malaria is not just a disease commonly associated with poverty, but is also a cause of poverty and a major hindrance to economic development. 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 demonstrates a fivefold difference ($1,526 USD versus $8,268 USD). Moreover, in countries where malaria is common, average per capita GDP has risen (between 1965 and 1990) only 0.4% per year, compared to 2.4% per year in other countries.Sachs J, Malaney P (2002). "The economic and social burden of malaria". Nature 415: 680-5. PMID 11832956. However, correlation does not demonstrate causation, and the prevalence is at least partly because these regions do not have the financial capacities to prevent malaria. In its entirety, the economic impact of malaria has been estimated to cost Africa $12 billion USD every year. The economic impact includes costs of health care, working days lost due to sickness, days lost in education, decreased productivity due to brain damage from cerebral malaria, and loss of investment and tourism. In some countries with a heavy malaria burden, the disease may account for as much as 40% of public health expenditure, 30-50% of inpatient admissions, and up to 50% of outpatient visits.Roll Back Malaria. Economic costs of malaria. WHO. Retrieved on 2006-09-21.
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. The classical symptom of malaria is cyclical occurrence of sudden coldness followed by rigor and then fever and sweating lasting four to six hours, occurring every two days in P. vivax and P. ovale infections, while every three for P. malariae.Malaria life cycle & pathogenesis. Malaria in Armenia. Accessed October 31, 2006. P. falciparum can have recurrent fever every 36-48 hours or a less pronounced and almost continuous fever. For reasons that are poorly understood, but which may be related to high intracranial pressure, children with malaria frequently exhibit abnormal posturing, a sign indicating severe brain damage.Idro, R; Otieno G, White S, Kahindi A, Fegan G, Ogutu B, Mithwani S, Maitland K, Neville BG, Newton CR. "Decorticate, decerebrate and opisthotonic posturing and seizures in Kenyan children with cerebral malaria". Malaria Journal 4 (57). PMID 16336645. Retrieved on 2007-01-21. Malaria has been found to cause cognitive impairments, especially in children. It causes widespread anemia during a period of rapid brain development and also direct brain damage. This neurologic damage results from cerebral malaria to which children are more vulnerable.Boivin, M.J., "Effects of early cerebral malaria on cognitive ability in Senegalese children," Journal of Developmental and Behavioral Pediatrics 23, no. 5 (October 2002): 353–64. Holding, P.A. and Snow, R.W., "Impact of Plasmodium falciparum malaria on performance and learning: review of the evidence," American Journal of Tropical Medicine and Hygiene 64, suppl. nos. 1–2 (January–February 2001): 68–75.
Severe malaria is almost exclusively caused by P. falciparum infection and usually arises 6-14 days after infection.Trampuz A, Jereb M, Muzlovic I, Prabhu R (2003). "Clinical review: Severe malaria.". Crit Care 7 (4): 315-23. PMID 12930555. Consequences of severe malaria include coma and death if untreated—young children and pregnant women are especially vulnerable. Splenomegaly (enlarged spleen), severe headache, cerebral ischemia, hepatomegaly (enlarged liver), hypoglycemia, and hemoglobinuria with renal failure may occur. Renal failure may cause blackwater fever, where hemoglobin from lysed red blood cells leaks into the urine. Severe malaria can progress extremely rapidly and cause death within hours or days. In the most severe cases of the disease fatality rates can exceed 20%, even with intensive care and treatment.Kain K, Harrington M, Tennyson S, Keystone J (1998). "Imported malaria: prospective analysis of problems in diagnosis and management.". Clin Infect Dis 27 (1): 142-9. PMID 9675468. In endemic areas, treatment is often less satisfactory and the overall fatality rate for all cases of malaria can be as high as one in ten.Mockenhaupt F, Ehrhardt S, Burkhardt J, Bosomtwe S, Laryea S, Anemana S, Otchwemah R, Cramer J, Dietz E, Gellert S, Bienzle U (2004). "Manifestation and outcome of severe malaria in children in northern Ghana.". Am J Trop Med Hyg 71 (2): 167-72. PMID 15306705. Over the longer term, developmental impairments have been documented in children who have suffered episodes of severe malaria.Carter JA, Ross AJ, Neville BG, Obiero E, Katana K, Mung\'ala-Odera V, Lees JA, Newton CR (2005). "Developmental impairments following severe falciparum malaria in children". Trop Med Int Health 10: 3-10. PMID 15655008.
Chronic malaria is seen in both P. vivax and P. ovale, but not in P. falciparum. Here, the disease can relapse months or years after exposure, due to the presence of latent parasites in the liver. Describing a case of malaria as cured by observing the disappearance of parasites from the bloodstream can therefore be deceptive. The longest incubation period reported for a P. vivax infection is 30 years. Approximately one in five of P. vivax malaria cases in temperate areas involve overwintering by hypnozoites (i.e., relapses begin the year after the mosquito bite).Adak T, Sharma V, Orlov V (1998). "Studies on the Plasmodium vivax relapse pattern in Delhi, India.". Am J Trop Med Hyg 59 (1): 175-9. PMID 9684649.
A Plasmodium sporozoite traverses the cytoplasm of a mosquito midgut epithelial cell in this false-color electron micrograph.
Malaria is caused by protozoan parasites of the genus Plasmodium (phylum Apicomplexa). In humans malaria is caused by P. falciparum, P. malariae, P. ovale, and P. vivax. P. falciparum is the most common cause of infection, responsible for about 80 % of all malaria cases. However, P. falciparum is the most important cause of disease, and responsible for about 90% of deaths.Mendis K, Sina B, Marchesini P, Carter R (2001). "The neglected burden of Plasmodium vivax malaria.". Am J Trop Med Hyg 64 (1-2 Suppl): 97-106. PMID 11425182. Parasitic Plasmodium species also infect birds, reptiles, monkeys, chimpanzees and rodents.Escalante A, Ayala F (1994). "Phylogeny of the malarial genus Plasmodium, derived from rRNA gene sequences.". Proc Natl Acad Sci U S A 91 (24): 11373-7. PMID 7972067. There have been documented human infections with several simian species of malaria, namely P. knowlesi, P. inui, P. cynomolgi,Garnham, PCC (1966). Malaria parasites and other haemosporidia. Blackwell Scientific Publications. P. simiovale, P. brazilianum, P. schwetzi and P. simium; however these are mostly of limited public health importance. Although avian malaria can kill chickens and turkeys, this disease does not cause serious economic losses to poultry farmers.Investing in Animal Health Research to Alleviate Poverty. International Livestock Research Institute. Permin A. and Madsen M. (2001) Appendix 2: review on disease occurrence and impact (smallholder poultry). Accessed 29 Oct 2006 However, since being accidentally introduced by humans it has decimated the endemic birds of Hawaii, which evolved in its absence and lack any resistance to it.Atkinson CT, Woods KL, Dusek RJ, Sileo LS, Iko WM (1995). "Wildlife disease and conservation in Hawaii: pathogenicity of avian malaria (Plasmodium relictum) in experimentally infected iiwi (Vestiaria coccinea)". Parasitology 111 Suppl: S59-69. PMID 8632925.
The parasite\'s primary (definitive) hosts and transmission vectors are female mosquitoes of the Anopheles genus. Young mosquitoes first ingest the malaria parasite by feeding on an infected human carrier and the infected Anopheles mosquitoes carry Plasmodium sporozoites in their salivary glands. A mosquito becomes infected when it takes a blood meal from an infected human. Once ingested, the parasite gametocytes taken up in the blood will further differentiate into male or female gametes and then fuse in the mosquito gut. This produces an ookinete that penetrates the gut lining and produces an oocyst in the gut wall. When the oocyst ruptures, it releases sporozoites that migrate through the mosquito\'s body to the salivary glands, where they are then ready to infect a new human host. This type of transmission is occasionally referred to as anterior station transfer.Talman A, Domarle O, McKenzie F, Ariey F, Robert V. "Gametocytogenesis: the puberty of Plasmodium falciparum.". Malar J 3: 24. PMID 15253774. The sporozoites are injected into the skin, alongside saliva, when the mosquito takes a subsequent blood meal.
Only female mosquitoes feed on blood, thus males do not transmit the disease. The females of the Anopheles genus 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. Malaria parasites can also be transmitted by blood transfusions, although this is rare.Marcucci C, Madjdpour C, Spahn D. "Allogeneic blood transfusions: benefit, risks and clinical indications in countries with a low or high human development index.". Br Med Bull 70: 15-28. PMID 15339855.
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 and asymptomatically for a period of 6–15 days. Once in the liver these organisms differentiate to yield thousands of merozoites which, following rupture of their host cells, escape into the blood and infect red blood cells, thus beginning the erythrocytic stage of the life cycle.Bledsoe, G. H. (December 2005) "Malaria primer for clinicians in the United States" Southern Medical Journal 98(12): pp. 1197-204, (PMID: 16440920); The parasite escapes from the liver undetected by wrapping itself in the cell membrane of the infected host liver cell.Sturm A, Amino R, van de Sand C, Regen T, Retzlaff S, Rennenberg A, Krueger A, Pollok JM, Menard R, Heussler VT (2006). "Manipulation of host hepatocytes by the malaria parasite for delivery into liver sinusoids". Science 313: 1287-1490. PMID 16888102.
Within the red blood cells the parasites 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 arise from simultaneous waves of merozoites escaping and infecting red blood cells.
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.Cogswell F (1992). "The hypnozoite and relapse in primate malaria.". Clin Microbiol Rev 5 (1): 26-35. PMID 1735093.
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.Chen Q, Schlichtherle M, Wahlgren M (2000). "Molecular aspects of severe malaria.". Clin Microbiol Rev 13 (3): 439-50. PMID 10885986. This "stickiness" is the main factor giving rise to hemorrhagic complications of malaria. High endothelial venules (the smallest branches of the circulatory system) can be blocked by the attachment of masses of these infected red blood cells. The blockage of these vessels causes symptoms such as in placental and cerebral malaria. In cerebral malaria the sequestrated red blood cells can breach the blood brain barrier possibly leading to coma.Adams S, Brown H, Turner G (2002). "Breaking down the blood-brain barrier: signaling a path to cerebral malaria?". Trends Parasitol 18 (8): 360-6. PMID 12377286.
Although the red blood cell surface adhesive proteins (called PfEMP1, for Plasmodium falciparum erythrocyte membrane protein 1) are exposed to the immune system they do not serve as good immune targets because of their extreme diversity; 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.
Some merozoites turn into male and female gametocytes. If a mosquito pierces the skin of an infected person, it potentially picks up gametocytes within the blood. Fertilization and sexual recombination of the parasite occurs in the mosquito\'s gut, thereby defining the mosquito as 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,Lindsay S, Ansell J, Selman C, Cox V, Hamilton K, Walraven G (2000). "Effect of pregnancy on exposure to malaria mosquitoes.". Lancet 355 (9219): 1972. PMID 10859048. and malaria in pregnant women is an important cause of stillbirths, infant mortality and low birth weight,van Geertruyden J, Thomas F, Erhart A, D\'Alessandro U (2004). "The contribution of malaria in pregnancy to perinatal mortality.". Am J Trop Med Hyg 71 (2 Suppl): 35-40. PMID 15331817. particularly in P. falciparum infection, but also in other species infection, such as P. vivax.Rodriguez-Morales AJ, Sanchez E, Vargas M, Piccolo C, Colina R, Arria M, Franco-Paredes C (2006). "Pregnancy outcomes associated with Plasmodium vivax malaria in northeastern Venezuela". Am J Trop Med Hyg 74: 755-757. PMID 16687675.
Malaria is thought to have been the greatest selective pressure on the human genome in recent history.Kwiatkowski, DP (2005). "How Malaria Has Affected the Human Genome and What Human Genetics Can Teach Us about Malaria". Am J Hum Genet 77: 171-92. PMID 16001361. This is due to the high levels of mortality and morbidity caused by malaria, especially the P. falciparum species.
Distribution of the sickle cell trait.
Distribution of malaria.
The best-studied influence of the malaria parasite upon the human genome is the blood disease, sickle-cell disease. In sickle-cell disease, there is a mutation in the HBB gene, which encodes the beta globin subunit of haemoglobin. The normal allele encodes a glutamate at position six of the beta globin protein, while the sickle-cell allele encodes a valine. This change from a hydrophilic to a hydrophobic amino acid encourages binding between haemoglobin molecules, with polymerization of haemoglobin deforming red blood cells into a "sickle" shape. Such deformed cells are cleared rapidly from the blood, mainly in the spleen, for destruction and recycling.
In the merozoite stage of its life cycle the malaria parasite lives inside red blood cells, and its metabolism changes the internal chemistry of the red blood cell. Infected cells normally survive until the parasite reproduces, but if the red cell contains a mixture of sickle and normal haemoglobin, it is likely to become deformed and be destroyed before the daughter parasites emerge. Thus, individuals heterozygous for the mutated allele, known as sickle-cell trait, may have a low and usually unimportant level of anaemia, but also have a greatly reduced chance of serious malaria infection. This is a classic example of heterozygote advantage.
Individuals homozygous for the mutation have full sickle-cell disease and in traditional societies rarely live beyond adolescence. However, in populations where malaria is endemic, the frequency of sickle-cell genes is around 10%. The existence of four haplotypes of sickle-type hemoglobin 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 that produce haemoglobin molecules capable of conferring similar resistance to malaria infection. These mutations produce haemoglobin types 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 malarial 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. Presumably these genes have also been selected in the course of human evolution.
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 is very rare in European, Asian and American populations, but is found in almost all of the indigenous population of West and Central Africa.Carter R, Mendis KN (2002). "Evolutionary and historical aspects of the burden of malaria". Clin. Microbiol. Rev. 15 (4): 564-94. PMID 12364370. This is thought to be due to very high exposure to P. vivax in Africa in the last few thousand years.
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.
HLA-B53 is associated with low risk of severe malaria. This MHC class I molecule presents liver stage and sporozoite antigens to T-Cells. Interleukin-4, encoded by IL4, is produced by activated T cells and promotes proliferation and differentiation of antibody-producing B cells. A study of the Fulani of Burkina Faso, who have both fewer malaria attacks and higher levels of antimalarial antibodies than do neighboring ethnic groups, found that the IL4-524 T allele was associated with elevated antibody levels against malaria antigens, which raises the possibility that this might be a factor in increased resistance to malaria.Verra F, Luoni G, Calissano C, Troye-Blomberg M, Perlmann P, Perlmann H, Arcà B, Sirima B, Konaté A, Coluzzi M, Kwiatkowski D, Modiano D (2004). "IL4-589C/T polymorphism and IgE levels in severe malaria". Acta Trop. 90 (2): 205-9. PMID 15177147.
The most economic, preferred, and 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. With the pros and cons of both thick and thin smears taken into consideration, it is imperative to utilize both smears while attempting to make a definitive diagnosis.Warhurst DC, Williams JE (1996). "Laboratory diagnosis of malaria". J Clin Pathol 49: 533–38. PMID 8813948.
From the thick film, an experienced microscopist can detect parasite levels (or parasitemia) down to as low as 0.0000001% of red blood cells. 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 articles on each parasite for their microscopic appearances: P. falciparum, P. vivax, P. ovale, P. malariae.
In areas where microscopy is not available, or where laboratory staff are not experienced at malaria diagnosis, there are antigen detection tests that require only a drop of blood.Pattanasin S, Proux S, Chompasuk D, Luwiradaj K, Jacquier P, Looareesuwan S, Nosten F (2003). "Evaluation of a new Plasmodium lactate dehydrogenase assay (OptiMAL-IT®) for the detection of malaria". Transact Royal Soc Trop Med 97: 672–4. PMID 16117960. OptiMAL-IT® will reliably detect falciparum down to 0.01% parasitemia and non-falciparum down to 0.1%. Paracheck-Pf® will detect parasitemias 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. Moreover, levels of parasitemia are not necessarily correlative with the progression of disease, particularly when the parasite is able to adhere to blood vessel walls. Therefore more sensitive, low-tech diagnosis tools need to be developed in order to detect low levels of parasitaemia in the field. Areas that cannot afford even simple laboratory diagnostic tests often use only a history of subjective fever as the indication to treat for malaria. Using Giemsa-stained blood smears from children in Malawi, one study showed that unnecessary treatment for malaria was significantly decreased when clinical predictors (rectal temperature, nailbed pallor, and splenomegaly) were used as treatment indications, rather than the current national policy of using only a history of subjective fevers (sensitivity increased from 21% to 41%).Redd S, Kazembe P, Luby S, Nwanyanwu O, Hightower A, Ziba C, Wirima J, Chitsulo L, Franco C, Olivar M (1996). "Clinical algorithm for treatment of Plasmodium falciparum malaria in children". Lancet 347 (8996): 223-7. PMID 8551881. .
Molecular methods are available in some clinical laboratories and rapid real-time assays (for example, QT-NASBA based on the polymerase chain reaction)Mens PF, Schoone GJ, Kager PA, Schallig HDFH. (2006). "Detection and identification of human Plasmodium species with real-time quantitative nucleic acid sequence-based amplification". Malaria Journal 5 (80). doi:10.1186/1475-2875-5-80. are being developed with the hope of being able to deploy them in endemic areas.
Severe malaria is commonly misdiagnosed in Africa, leading to a failure to treat other life-threatening illnesses. In malaria-endemic areas, parasitemia does not ensure a diagnosis of severe malaria because parasitemia can be incidental to other concurrent disease. Recent investigations suggest that malarial retinopathy is better (collective sensitivity of 95% and specificity of 90%) than any other clinical or laboratory feature in distinguishing malarial from non-malarial coma. Beare NA et al. Am J Trop Med Hyg. 2006 Nov;75(5):790-797.
Active malaria infection with P. falciparum is a medical emergency requiring hospitalization. Infection with P. vivax, P. ovale or P. malariae can often be treated on an outpatient basis. Treatment of malaria involves supportive measures as well as specific antimalarial drugs. When properly treated, someone with malaria can expect a complete cure.If I get malaria, will I have it for the rest of my life? CDC publication, Accessed 14 Nov 2006
There are several families of drugs used to treat malaria. Chloroquine is very cheap and, until recently, was very effective, which made it 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. In those areas where chloroquine is still effective it remains the first choice. Unfortunately, chloroquine-resistance is associated with reduced sensitivity to other drugs such as quinine and amodiaquine.Tinto H, Rwagacondo C, Karema C, et al.. "In-vitro susceptibility of Plasmodium falciparum to monodesethylamodiaquine, dihydroartemsinin and quinine in an area of high chloroquine resistance in Rwanda". Trans R Soc Trop Med Hyg 100 (6): 509–14. doi:10.1016/j.trstmh.2005.09.018.
There are several other substances which are used for treatment and, partially, for prevention (prophylaxis). Many drugs may 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. One drug currently being investigated for possible use as an anti-malarial, especially for treatment of drug-resistant strains, is the beta blocker propranolol. Propranolol has been shown to block both Plasmodium\'s ability to enter red blood cell and establish an infection, as well as parasite replication. A December 2006 study by Northwestern University researchers suggested that propranolol may reduce the dosages required for existing drugs to be effective against P. falciparum by 5- to 10-fold, suggesting a role in combination therapies.Murphy S, Harrison T, Hamm H, Lomasney J, Mohandas N, Haldar K (Dec 2006). "Erythrocyte G protein as a novel target for malarial chemotherapy". PLoS Med 3 (12): e528. PMID 17194200.
Currently available anti-malarial drugs include:Prescription drugs for malaria Retrieved February 27, 2007.
The development of drugs was facilitated when Plasmodium falciparum was successfully cultured.Trager W, Jensen JB. (1976). "Human malaria parasites in continuous culture". Science 193(4254): 673–5. PMID 781840. This allowed in vitro testing of new drug candidates.
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.Senior K (2005). "Shortfall in front-line antimalarial drug likely in 2005". Lancet Infect Dis 5 (2): 75. PMID 15702504. One study in Rwanda showed that children with uncomplicated P. falciparum malaria demonstrated fewer clinical and parasitological failures on post-treatment day 28 when amodiaquine was combined with artesunate, rather than administered alone (OR = 0.34). However, increased resistance to amodiaquine during this study period was also noted.Rwagacondo C, Karema C, Mugisha V, Erhart A, Dujardin J, Van Overmeir C, Ringwald P, D\'Alessandro U (2004). "Is amodiaquine failing in Rwanda? Efficacy of amodiaquine alone and combined with artesunate in children with uncomplicated malaria". Trop Med Int Health 9 (10): 1091-8. PMID 15482401.
