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{{Infobox_Disease
__NOTOC__
| Name          = Malaria
{{About1|Plasmodium}}
| ICD10          = {{ICD10|B|50||b|50}}
'''For patient information click [[{{PAGENAME}} (patient information)|here]]'''
| ICD9          = {{ICD9|084}}
| Image          = Plasmodium.jpg
| Caption        = ''Plasmodium falciparum'' ring-forms and gametocytes in human blood.
| DiseasesDB    = 7728
| MedlinePlus    = 000621
| OMIM          = 248310
| eMedicineSubj  = med
| eMedicineTopic = 1385
| eMedicine_mult = {{eMedicine2|emerg|305}} {{eMedicine2|ped|1357}}
| MeshName      = Malaria
| MeshNumber    = C03.752.250.552 |
}}


{{SI}}
{{Malaria}}
{{CMG}}


{{Editor Help}}
{{CMG}}; {{AE}}{{USAMA}}


'''Malaria''' is a [[Vector (biology)|vector]]-borne [[infectious disease]] caused by [[protozoan]] [[parasite]]s. It is widespread in tropical and subtropical regions, including parts of the Americas, Asia, and Africa. Each year, it causes disease in approximately 650 million people and kills between one and three million, most of them young children in Sub-Saharan Africa. Malaria is commonly associated with poverty, but is also a cause of poverty and a major hindrance to economic development.
== [[Malaria overview|Overview]] ==


Malaria is one of the most common infectious diseases and an enormous public-health problem. The disease is caused by [[protozoan]] [[parasite]]s of the [[genus]] ''[[Plasmodium]]''. The most serious forms of the disease are caused by ''[[Plasmodium falciparum]]'' and ''[[Plasmodium vivax]]'', but other related species (''[[Plasmodium ovale]]'', ''[[Plasmodium malariae]]'', and sometimes ''[[Plasmodium knowlesi]]'') can also infect humans. This group of human-pathogenic ''Plasmodium'' species is usually referred to as ''malaria parasites''.
== [[Malaria historical perspective|Historical Perspective]] ==


Malaria parasites are transmitted by female ''[[Anopheles]]'' [[mosquito]]es. The parasites multiply within [[red blood cell]]s, 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]], [[influenza|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 [[insecticide]]s inside houses and draining standing water where mosquitoes lay their eggs.
== [[Malaria classification|Classification]]==


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 [[Prophylaxis|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 drug]]s, such as [[quinine]] or [[artemisinin]] derivatives, although [[drug resistance]] is increasingly common.
== [[Malaria pathophysiology|Pathophysiology]] ==


==History ==
== [[Malaria causes|Causes]] ==
{{further|[[Jesuit's bark]]}}
Malaria has infected humans for over 50,000 years, and may have been a human [[pathogen]] for the entire history of our species.<ref>{{cite journal | author = Joy D, Feng X, Mu J, ''et al'' | title = Early origin and recent expansion of Plasmodium falciparum. | journal = Science | volume = 300 | issue = 5617 | pages = 318-21 | year = 2003 | pmid = 12690197}}</ref> Indeed, close relatives of the human malaria parasites remain common in chimpanzees, our closest relatives.<ref>{{cite journal | author = Escalante A, Freeland D, Collins W, Lal A | title = The evolution of primate malaria parasites based on the gene encoding cytochrome b from the linear mitochondrial genome. | url=http://www.pnas.org/cgi/content/full/95/14/8124 | journal = Proc Natl Acad Sci U S A | volume = 95 | issue = 14 | pages = 8124-9 | year = 1998 | pmid = 9653151}}</ref> References to the unique periodic fevers of malaria are found throughout recorded history, beginning in 2700 BC in China.<ref>{{cite journal | author = Cox F | title = History of human parasitology. | url=http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=12364371 | journal = Clin Microbiol Rev | volume = 15 | issue = 4 | pages = 595-612 | year = 2002 | pmid = 12364371}}</ref> The term malaria originates from Medieval [[Italian language|Italian]]: ''mala aria'' &mdash; "[[miasma theory of disease|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 Algeria named [[Charles Louis Alphonse Laveran]] observed parasites inside the [[red blood cell]]s of people suffering from malaria. He therefore proposed that malaria was caused by this [[protozoa]]n, the first time protozoa were identified as causing disease.<ref>{{cite web | title = Biography of Alphonse Laveran | publisher = The Nobel Foundation | url = http://nobelprize.org/nobel_prizes/medicine/laureates/1907/laveran-bio.html | accessdate = 2007-06-15}} ] Nobel foundation. Accessed 25 Oct 2006</ref> 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.<ref>{{cite web | title =  Ettore Marchiafava| work = | url = http://www.whonamedit.com/doctor.cfm/2478.html | accessdate = 2007-06-15}}</ref> 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.<ref>{{cite web | title = Biography of Ronald Ross | publisher = The Nobel Foundation | url = http://nobelprize.org/nobel_prizes/medicine/laureates/1902/ross-bio.html | accessdate = 2007-06-15}}</ref> 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.<ref>{{cite web | title = Ross and the Discovery that Mosquitoes Transmit Malaria Parasites| work = CDC Malaria website | url = http://www.cdc.gov/malaria/history/ross.htm | accessdate = 2007-06-15}}</ref> 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 [[Health measures during the construction of the Panama Canal|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.
== [[Malaria differential diagnosis|Differentiating Malaria from other Diseases]]==


The first effective treatment for malaria was the bark of [[Cinchona|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.<ref>{{cite journal | author = Kaufman T, Rúveda E | title = The quest for quinine: those who won the battles and those who won the war. | journal = Angew Chem Int Ed Engl | volume = 44 | issue = 6 | pages = 854-85 | year = 2005 | pmid = 15669029}}</ref> 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 Jean Bienaime Caventou.<ref>{{cite journal |author=Kyle R, Shampe M |title=Discoverers of quinine |journal=JAMA |volume=229 |issue=4 |pages=462 |year=1974 |pmid=4600403}}</ref>
== [[Malaria epidemiology and demographics|Epidemiology and Demographics]] ==


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.<ref>{{cite journal | author = Raju T | title = Hot brains: manipulating body heat to save the brain. | url=http://pediatrics.aappublications.org/cgi/content/full/117/2/e320 | journal = Pediatrics | volume = 117 | issue = 2 | pages = e320-1 | year = 2006 | pmid = 16452338}}</ref>
== [[Malaria risk factors|Risk Factors]]==


Although the blood stage and mosquito stages of the malaria life cycle were established in the 19<sup>th</sup> and early 20<sup>th</sup> centuries, it was not until the 1980s that the latent liver form of the parasite was observed.<ref>{{cite journal | author = Krotoski W, Collins W, Bray R, ''et al'' | title = Demonstration of hypnozoites in sporozoite-transmitted Plasmodium vivax infection. | journal = Am J Trop Med Hyg | volume = 31 | issue = 6 | pages = 1291-3 | year = 1982 | pmid = 6816080}}</ref><ref>{{cite journal | author = Meis J, Verhave J, Jap P, Sinden R, Meuwissen J | title = Malaria parasites--discovery of the early liver form. | journal = Nature | volume = 302 | issue = 5907 | pages = 424-6 | year =1983 | pmid = 6339945}}</ref> 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 screening|Screening]]==


==Distribution and impact==
== [[Malaria natural history, complications, and prognosis|Natural History, Complications and Prognosis]]==
{{further|[[Diseases of poverty]], [[Tropical disease]]}}
[[Image:Malariageodistribution.png|350px|thumb|Areas of the world where malaria is [[Endemic (epidemiology)|endemic]] in the 21st Century (coloured blue).<ref>{{cite web | title = Malaria: Geographic Distribution | work = CDC Malaria website | url = http://www.cdc.gov/malaria/distribution_epi/distribution.htm | accessdate = 2007-06-15}}</ref>]]
Malaria causes about 400&ndash;900 million cases of fever and approximately one to three million deaths annually <ref name=Breman>{{cite journal | author = Breman J | title = The ears of the hippopotamus: manifestations, determinants, and estimates of the malaria burden. | url=http://www.ajtmh.org/cgi/reprint/64/1_suppl/1-c | journal = Am J Trop Med Hyg | year=2001 | volume = 64 | issue = 1-2 Suppl | pages = 1-11 | year = 2001 | pmid = 11425172}}</ref> &mdash; this represents at least one death every 30 seconds.  The vast majority of cases occur in children under the age of 5 years;<ref name="greenwood2005">{{cite journal | author=Greenwood BM, Bojang K, Whitty CJ, Targett GA | title=Malaria | journal=Lancet | year=2005 | volume=365 | pages=1487-1498  | pmid = 15850634}}</ref> 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.<ref>{{cite journal | author = Hay S, Guerra C, Tatem A, Noor A, Snow R | title = The global distribution and population at risk of malaria: past, present, and future. | journal = Lancet Infect Dis | volume = 4 | issue = 6 | pages = 327-36 | year = 2004 | pmid = 15172341}}</ref> Indeed, if the prevalence of malaria stays on its present upwards course, the death rate could double in the next twenty years.<ref name=Breman/> 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.<ref name=Breman/>
 
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.<ref>{{cite journal | author = Korenromp E, Williams B, de Vlas S, Gouws E, Gilks C, Ghys P, Nahlen B | title = Malaria attributable to the HIV-1 epidemic, sub-Saharan Africa. | url=http://www.cdc.gov/ncidod/EID/vol11no09/05-0337.htm | journal = Emerg Infect Dis | volume = 11 | issue = 9 | pages = 1410-9 | year = 2005 | pmid = 16229771}}</ref> 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.<ref>{{cite journal |author=Abu-Raddad L, Patnaik P, Kublin J |title=Dual infection with HIV and malaria fuels the spread of both diseases in sub-Saharan Africa |journal=Science |volume=314 |issue=5805 |pages=1603-6 |year=2006 | pmid = 17158329}}</ref>
 
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&ndash; 90% of malaria fatalities occur.<ref>{{cite web | author = Layne SP | title = Principles of Infectious Disease Epidemiology /| work =  EPI 220 | publisher = UCLA Department of Epidemiology | url = http://web.archive.org/web/20060220083223/http://www.ph.ucla.edu/epi/layne/Epidemiology+220/07.malaria.pdf | accessdate = 2007-06-15}}</ref> The geographic distribution of malaria within large regions is complex, and malarial and malaria-free areas are often found close to each other.<ref name="greenwood2002">{{cite journal | author=Greenwood B, Mutabingwa T | title=Malaria in 2002 | journal=Nature | year=2002 | volume=415 | pages=670–2  | pmid = 11832954}}</ref> In drier areas, outbreaks of malaria can be predicted with reasonable accuracy by mapping rainfall.<ref>{{cite journal | author = Grover-Kopec E, Kawano M, Klaver R, Blumenthal B, Ceccato P, Connor S | title = An online operational rainfall-monitoring resource for epidemic malaria early warning systems in Africa. | url=http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=15663795 | journal = Malar J | volume = 4 | issue = | pages = 6 | year = 2005 | pmid = 15663795}}</ref> Malaria is more common in rural areas than in cities; this is in contrast to [[dengue fever]] where urban areas present the greater risk.<ref>{{cite journal |author=Van Benthem B, Vanwambeke S, Khantikul N, Burghoorn-Maas C, Panart K, Oskam L, Lambin E, Somboon P |title=Spatial patterns of and risk factors for seropositivity for dengue infection | url=http://www.ajtmh.org/cgi/content/full/72/2/201 |journal=Am J Trop Med Hyg |volume=72 |issue=2 |pages=201-8 |year=2005 | pmid = 15741558}}</ref> For example, the cities of the Vietnam, Laos and Cambodia are essentially malaria-free, but the disease is present in many rural regions.<ref>{{cite journal |author=Trung H, Van Bortel W, Sochantha T, Keokenchanh K, Quang N, Cong L, Coosemans M |title=Malaria transmission and major malaria vectors in different geographical areas of Southeast Asia |journal=Trop Med Int Health |volume=9 |issue=2 |pages=230-7 |year=2004 | pmid = 15040560}}</ref> By contrast, in Africa malaria is present in both rural and urban areas, though the risk is lower in the larger cities.<ref>{{cite journal |author=Keiser J, Utzinger J, Caldas de Castro M, Smith T, Tanner M, Singer B |title=Urbanization in sub-saharan Africa and implication for malaria control | url=http://www.ajtmh.org/cgi/content/full/71/2_suppl/118 |journal=Am J Trop Med Hyg |volume=71 |issue=2 Suppl |pages=118-27 |year=2004 |id=PMID 15331827}}</ref> The global [[Endemic (epidemiology)|endemic]] levels of malaria have not been mapped since the 1960s, however, the [[Wellcome Trust]], UK, has funded the [[Malaria Atlas Project]]<ref>{{cite journal | author = Hay SI, Snow RW | title = The Malaria Atlas Project: Developing Global Maps of Malaria Risk. | url = http://medicine.plosjournals.org/perlserv/?request=get-document&doi=10.1371/journal.pmed.0030473 | journal = PLoS Medicine | volume = 3 | issue = 12 | pages = e473 | year = 2006 }}</ref> to rectify this, providing a more contemporary and robust means with which to assess current and future malaria [[disease burden]].
 
===Socio-economic effects===
 
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 (US$1,526 versus US$8,268).  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.<ref name="sachs2002">{{cite journal | author=Sachs J, Malaney P | title=The economic and social burden of malaria | journal=Nature | year=2002 | volume=415 | pages=680-5 | pmid = 11832956}}</ref> However, correlation does not imply 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 US$12 billion every year.  The economic impact includes costs of health care, working days lost due to sickness, days lost in education, decreased productivity due to brain damage from cerebral malaria, and loss of investment and tourism.<ref name="greenwood2005"/>  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.<ref>{{cite web | author=Roll Back Malaria | title=Economic costs of malaria | url=http://www.rbm.who.int/cmc_upload/0/000/015/363/RBMInfosheet_10.htm|publisher=[[World Health Organization|WHO]] | accessdate=2006-09-21}}</ref>
 
==Symptoms==
Symptoms of malaria include [[fever]], [[shivering]], [[arthralgia]] (joint pain), [[vomiting]], [[anemia]] caused by [[hemolysis]], [[hemoglobinuria]], and [[convulsion]]s. 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''.<ref name=RBMarmenia>[http://www.malaria.am/eng/pathogenesis.php Malaria life cycle & pathogenesis]. Malaria in Armenia. Accessed October 31, 2006.</ref> ''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.<ref name="Idro ">{{cite journal | last =Idro  | first =R | authorlink = | coauthors =Otieno G, White S, Kahindi A, Fegan G, Ogutu B, Mithwani S, Maitland K, Neville BG, Newton CR | title = Decorticate, decerebrate and opisthotonic posturing and seizures in Kenyan children with cerebral malaria| journal =Malaria Journal | volume =4 | issue =57 | pages = | publisher = | date = | url =http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=16336645 | doi = | id =PMID 16336645 | accessdate =2007-01-21 }} </ref>  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.<ref>Boivin, M.J., "[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12394524&dopt=Citation Effects of early cerebral malaria on cognitive ability in Senegalese children]," ''Journal of Developmental and Behavioral Pediatrics'' 23, no. 5 (October 2002): 353&ndash;64. Holding, P.A. and Snow, R.W., "[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11425179&dopt=Citation Impact of Plasmodium falciparum malaria on performance and learning: review of the evidence]," ''American Journal of Tropical Medicine and Hygiene'' 64, suppl. nos. 1&ndash;2 (January&ndash;February 2001): 68&ndash;75.</ref>
 
Severe malaria is almost exclusively caused by ''P. falciparum'' infection and usually arises 6-14 days after infection.<ref name=Trampuz>{{cite journal | author = Trampuz A, Jereb M, Muzlovic I, Prabhu R | title = Clinical review: Severe malaria. | url=http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=12930555 | journal = Crit Care | volume = 7 | issue = 4 | pages = 315-23 | year = 2003 | id = PMID 12930555}}</ref> Consequences of severe malaria include [[coma]] and death if untreated&mdash;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.<ref name=Trampuz/> In the most severe cases of the disease fatality rates can exceed 20%, even with intensive care and treatment.<ref>{{cite journal | author = Kain K, Harrington M, Tennyson S, Keystone J | title = Imported malaria: prospective analysis of problems in diagnosis and management. | journal = Clin Infect Dis | volume = 27 | issue = 1 | pages = 142-9 | year = 1998 | id = PMID 9675468}}</ref> 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.<ref>{{cite journal | author = Mockenhaupt F, Ehrhardt S, Burkhardt J, Bosomtwe S, Laryea S, Anemana S, Otchwemah R, Cramer J, Dietz E, Gellert S, Bienzle U | title = Manifestation and outcome of severe malaria in children in northern Ghana. | journal = Am J Trop Med Hyg | volume = 71 | issue = 2 | pages = 167-72 | year = 2004 | id = PMID 15306705}}</ref> Over the longer term, developmental impairments have been documented in children who have suffered episodes of severe malaria.<ref name="carter2005">{{cite journal | author=Carter JA, Ross AJ, Neville BG, Obiero E, Katana K, Mung'ala-Odera V, Lees JA, Newton CR | title=Developmental impairments following severe falciparum malaria in children | journal=Trop Med Int Health | year=2005 | volume=10 | pages=3-10  | id=PMID 15655008}}</ref>
 
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.<ref name=Trampuz/> 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).<ref>{{cite journal | author = Adak T, Sharma V, Orlov V | title = Studies on the Plasmodium vivax relapse pattern in Delhi, India. | journal = Am J Trop Med Hyg | volume = 59 | issue = 1 | pages = 175-9 | year = 1998 | id = PMID 9684649}}</ref>
 
==Causes==
[[Image:Malaria.jpg|thumb|left|250px|A ''Plasmodium'' sporozoite traverses the cytoplasm of a mosquito midgut epithelial cell in this false-color [[electron micrograph]].]]
 
=== Malaria parasites ===
 
Malaria is caused by [[protozoa]]n [[parasite]]s of the genus ''[[Plasmodium]]'' (phylum [[Apicomplexa]]). In humans malaria is caused by ''[[Plasmodium falciparum|P. falciparum]]'', ''[[Plasmodium malariae|P. malariae]]'', ''[[Plasmodium ovale|P. ovale]]'', and ''[[Plasmodium vivax|P. vivax]]''. '' P. vivax'' 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 15% of infections and 90% of deaths.<ref>{{cite journal | author = Mendis K, Sina B, Marchesini P, Carter R | title = The neglected burden of Plasmodium vivax malaria. | url=http://www.ajtmh.org/cgi/reprint/64/1_suppl/97.pdf | journal = Am J Trop Med Hyg | volume = 64 | issue = 1-2 Suppl | pages = 97-106 | year = 2001 | pmid = 11425182}}</ref> Parasitic ''Plasmodium'' species also infect birds, reptiles, monkeys, chimpanzees and rodents.<ref>{{cite journal | author = Escalante A, Ayala F | title = Phylogeny of the malarial genus Plasmodium, derived from rRNA gene sequences. | url=http://www.pnas.org/cgi/reprint/91/24/11373 | journal = Proc Natl Acad Sci U S A | volume = 91 | issue = 24 | pages = 11373-7 | year = 1994 | pmid = 7972067}}</ref> There have been documented human infections with several [[Wiktionary:simian|simian]] species of malaria, namely ''[[Plasmodium knowlesi|P. knowlesi]]'', ''P. inui'', ''P. cynomolgi''<ref>{{cite book | last=Garnham | first=PCC | date=1966 | title=Malaria parasites and other haemosporidia | publisher=Blackwell Scientific Publications|Location=Oxford }}</ref>, ''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.<ref>Investing in Animal Health Research to Alleviate Poverty. International Livestock Research Institute. Permin A. and Madsen M. (2001) [http://www.ilri.cgiar.org/InfoServ/Webpub/fulldocs/investinginanimal/Book1/media/PDF_Appendix/Appendix8.pdfLiterature Appendix 2: review on disease occurrence and impact (smallholder poultry)]. Accessed 29 Oct 2006</ref> 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.<ref>{{cite journal |author=Atkinson CT, Woods KL, Dusek RJ, Sileo LS, Iko WM |title=Wildlife disease and conservation in Hawaii: pathogenicity of avian malaria (''Plasmodium relictum'') in experimentally infected iiwi (''Vestiaria coccinea'') |journal=Parasitology |volume=111 Suppl |issue= |pages=S59-69 |year=1995 |pmid=8632925 |doi=}}</ref>
 
== Mosquito vectors and the ''Plasmodium'' life cycle ==
 
The parasite's primary (definitive) hosts and transmission [[vector (biology)|vector]]s are female [[mosquito]]es 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'' [[sporozoite]]s in their [[salivary gland]]s. 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.<ref>{{cite journal | author = Talman A, Domarle O, McKenzie F, Ariey F, Robert V | title = Gametocytogenesis: the puberty of Plasmodium falciparum. | journal = Malar J | volume = 3 | issue = | pages = 24 | year = | id = PMID 15253774}}</ref> 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 transfusion]]s, although this is rare.<ref>{{cite journal | author = Marcucci C, Madjdpour C, Spahn D | title = Allogeneic blood transfusions: benefit, risks and clinical indications in countries with a low or high human development index. | journal = Br Med Bull | volume = 70 | issue = | pages = 15-28 | year = | id = PMID 15339855}}</ref>
 
== Pathogenesis ==
[[Image:MalariacycleBig.jpg|thumb|right|400px|The life cycle of malaria parasites in the human body. The various stages in this process are discussed in the text.]]
 
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, [[sporozoite]]s 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 [[hepatocyte]]s, multiplying asexually and asymptomatically for a period of 6&ndash;15 days. Once in the liver these organisms differentiate to yield thousands of [[merozoite]]s which, following rupture of their host cells, escape into the blood and infect [[red blood cell]]s, thus beginning the erythrocytic stage of the life cycle.<ref>[http://www.sma.org/pdfs/objecttypes/smj/91C48D32-BCD4-FF25-565C69314AF7EB48/1196.pdf Bledsoe, G. H. (December 2005) "Malaria primer for clinicians in the United States"  ''Southern Medical Journal'' 98(12): pp. 1197-204, (PMID: 16440920)];</ref> The parasite escapes from the liver undetected by wrapping itself in the cell membrane of the infected host liver cell.<ref name="sturm2006">{{cite journal | author=Sturm A,
Amino R, van de Sand C, Regen T, Retzlaff S, Rennenberg A, Krueger A, Pollok JM, Menard R, Heussler VT | title=Manipulation of host hepatocytes by the malaria parasite for delivery into liver sinusoids | journal=Science | year=2006 | volume=313 | pages=1287-1490  | id=PMID 16888102}}</ref>
 
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&ndash;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.<ref>{{cite journal | author = Cogswell F | title = The hypnozoite and relapse in primate malaria. | url=http://www.pubmedcentral.nih.gov/picrender.fcgi?artid=358221&blobtype=pdf | journal = Clin Microbiol Rev | volume = 5 | issue = 1 | pages = 26-35 | year = 1992 | id = PMID 1735093}}</ref>
 
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 [[protein]]s 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.<ref name=Chen>{{cite journal | author = Chen Q, Schlichtherle M, Wahlgren M | title = Molecular aspects of severe malaria. | url=http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=10885986 | journal = Clin Microbiol Rev | volume = 13 | issue = 3 | pages = 439-50 | year = 2000 | id = PMID 10885986}}</ref>  This "stickiness"  is the main factor giving rise to [[hemorrhage|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|blood brain barrier]] possibly leading to coma.<ref>{{cite journal | author = Adams S, Brown H, Turner G | title = Breaking down the blood-brain barrier: signaling a path to cerebral malaria? | journal = Trends Parasitol | volume = 18 | issue = 8 | pages = 360-6 | year = 2002 | id = PMID 12377286}}</ref>
 
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.<ref name=Chen/>  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 [[gametocyte]]s. 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,<ref>{{cite journal | author = Lindsay S, Ansell J, Selman C, Cox V, Hamilton K, Walraven G | title = Effect of pregnancy on exposure to malaria mosquitoes. | journal = Lancet | volume = 355 | issue = 9219 | pages = 1972 | year = 2000 | id = PMID 10859048}}</ref> and malaria in pregnant women is an important cause of [[stillbirth]]s, infant mortality and low birth weight.<ref>{{cite journal | author = van Geertruyden J, Thomas F, Erhart A, D'Alessandro U | title = The contribution of malaria in pregnancy to perinatal mortality. | url=http://www.ajtmh.org/cgi/content/full/71/2_suppl/35 | journal = Am J Trop Med Hyg | volume = 71 | issue = 2 Suppl | pages = 35-40 | year = 2004 | id = PMID 15331817}}</ref>
 
==Evolutionary pressure of malaria on human genes==
{{further|[[Evolution]], [[Natural selection]]}}
Malaria is thought to have been the greatest [[selection|selective pressure]] on the [[human genome]] in recent history.<ref name=Kwiatkowski_2005>{{cite journal | author=Kwiatkowski, DP | title=How Malaria Has Affected the Human Genome and What Human Genetics Can Teach Us about Malaria| journal=Am J Hum Genet | year=2005 | volume=77 | pages=171-92 |url=http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=16001361 |id=PMID 16001361}}</ref> This is due to the high levels of [[death|mortality]] and [[morbidity]] caused by malaria, especially the ''[[Plasmodium falciparum|P. falciparum]]'' species.
 
===Sickle-cell disease===
[[Image:Sickle cell distribution.jpg|thumb|right|Distribution of the sickle cell trait.]]
[[Image:Malaria distribution.jpg|thumb|right|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 (epidemiology)|endemic]], the [[gene frequencies|frequency]] of sickle-cell genes is around 10%. The existence of four [[haplotype]]s 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.
 
===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 [[Thalassemia#Beta (β) thalassemias|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 [[natural selection|selected]] in the course of human evolution.
 
===Duffy antigens===
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 is very rare in European, Asian and American populations, but is found in almost all of the indigenous population of West and Central Africa.<ref>{{cite journal |author=Carter R, Mendis KN |title=Evolutionary and historical aspects of the burden of malaria |url=http://cmr.asm.org/cgi/content/full/15/4/564?view=long&pmid=12364370#RBC%20Duffy%20Negativity |journal=Clin. Microbiol. Rev. |volume=15 |issue=4 |pages=564-94 |year=2002 |pmid=12364370}}</ref> This is thought to be due to very high exposure to ''P. vivax'' in Africa in the last few thousand years.
 
===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.
 
===HLA and interleukin-4===
[[Human leukocyte antigen|HLA-B53]] is associated with low risk of severe malaria. This [[Major histocompatibility complex|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.<ref>{{cite journal |author=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 |title=IL4-589C/T polymorphism and IgE levels in severe malaria |journal=Acta Trop. |volume=90 |issue=2 |pages=205-9 |year=2004 |pmid=15177147}}</ref>


== Diagnosis ==
== Diagnosis ==
{{further|[[Blood film]]}}
[[Malaria history and symptoms|History and Symptoms]] | [[Malaria physical examination|Physical Examination]] | [[Malaria laboratory findings|Laboratory Findings]] | [[Malaria xray|X rays]] | [[Malaria ultrasound|Ultrasound]] | [[Malaria ct scan|CT scan]] | [[Malaria mri|MRI]]
 
[[Image:Malaria 0001.jpg|thumb|350px|left|Malaria]]
 
The most economic, preferred, and reliable diagnosis of malaria is microscopic examination of [[blood film]]s 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.<ref name="warhurst1996">{{cite journal | author=Warhurst DC, Williams JE | title=Laboratory diagnosis of malaria | journal=J Clin Pathol | year=1996 | volume=49 | pages=533–38 |id=PMID 8813948}}</ref>
 
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: ''[[Plasmodium falciparum|P. falciparum]], [[Plasmodium vivax|P. vivax]], [[Plasmodium ovale|P. ovale]], [[Plasmodium malariae|P. malariae]]''. 
 
In areas where microscopy is not available, or where laboratory staff are not experienced at malaria diagnosis, there are [[Malaria antigen detection tests|antigen detection tests]] that require only a drop of blood.<ref>{{cite journal | author=Pattanasin S, Proux S, Chompasuk D, Luwiradaj K, Jacquier P, Looareesuwan S, Nosten F | title=Evaluation of a new Plasmodium lactate dehydrogenase assay (OptiMAL-IT®) for the detection of malaria | journal=Transact Royal Soc Trop Med | year=2003 | volume=97 | pages=672–4  | id=PMID 16117960}}</ref>  OptiMAL-IT® will reliably detect ''falciparum'' down to 0.01% [[parasitemia]] and non-''falciparum'' down to 0.1%.  ''Para''check-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%).  <ref>{{cite journal |author=Redd S, Kazembe P, Luby S, Nwanyanwu O, Hightower A, Ziba C, Wirima J, Chitsulo L, Franco C, Olivar M |title=Clinical algorithm for treatment of Plasmodium falciparum malaria in children |journal=Lancet |volume=347 |issue=8996 |pages=223-7 |year=1996 |pmid=8551881}}.</ref>
 
Molecular methods are available in some clinical laboratories and rapid real-time assays (for example, [[Real-time polymerase chain reaction|QT-NASBA]] based on the polymerase chain reaction)<ref>{{cite journal | title=Detection and identification of human Plasmodium species with real-time quantitative nucleic acid sequence-based amplification | author=Mens PF, Schoone GJ, Kager PA, Schallig HDFH. | journal=Malaria Journal | year=2006 | volume=5 | issue=80 | doi=10.1186/1475-2875-5-80 }}</ref> 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]].<ref> Beare NA et al. ''Am J Trop Med Hyg.'' 2006 Nov;75(5):790-797.</ref>
 
<div align="center">
<gallery heights="175" widths="175">
Image:Plasmodium falciparum 02.jpg|Blood smear from a ''P. falciparum'' [[Malaria culture|culture]] (K1 strain). Several red blood cells have ring stages inside them. Close to the center there is a schizont and on the left a trophozoite.
Image:Malaria2.jpg|Malaria (organisms in cells)
</gallery>
</div>


== Treatment ==
== Treatment ==
Active malaria infection with ''P. falciparum'' is a [[medical emergency]] requiring [[hospital]]ization. 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.<ref>[http://www.cdc.gov/malaria/faq.htm#treatment If I get malaria, will I have it for the rest of my life?] CDC publication, Accessed 14 Nov 2006</ref>
===Antimalarial drugs===
{{further|[[Antimalarial drug]]s}}
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]].<ref>{{cite journal | author=Tinto H, Rwagacondo C, Karema C, ''et al.'' | title=In-vitro susceptibility of ''Plasmodium falciparum'' to monodesethylamodiaquine, dihydroartemsinin and quinine in an area of high chloroquine resistance in Rwanda | journal=Trans R Soc Trop Med Hyg | volume=100 | issue=6 | pages=509&ndash;14 | doi=10.1016/j.trstmh.2005.09.018 }}</ref>
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.<ref>{{cite journal |author=Murphy S, Harrison T, Hamm H, Lomasney J, Mohandas N, Haldar K |title=Erythrocyte G protein as a novel target for malarial chemotherapy |journal=PLoS Med |volume=3 |issue=12 |pages=e528 |year=2006 | month=Dec | id=PMID 17194200 | url=http://medicine.plosjournals.org/perlserv/?request=get-document&doi=10.1371/journal.pmed.0030528}}</ref>
 
Currently available anti-malarial drugs include:<ref>[http://www.cdc.gov/travel/malariadrugs.htm Prescription drugs for malaria] Retrieved [[February 27]], [[2007]].</ref>
* [[Artemether]]-[[lumefantrine]] (Therapy only, commercial names ''Coartem''® and ''Riamet''®)
* [[Artesunate]]-[[amodiaquine]] (Therapy only)
* [[Artesunate]]-[[mefloquine]] (Therapy only)
* [[Artesunate]]-[[sulfonamide (medicine)|Sulfadoxine]]/[[pyrimethamine]] (Therapy only)
* [[Atovaquone]]-[[proguanil]], trade name [[Malarone]] (Therapy and prophylaxis)
* [[Quinine]] (Therapy only)
* [[Chloroquine]] (Therapy and prophylaxis; usefulness now reduced due to resistance)
* [[Cotrifazid]] (Therapy and prophylaxis)
* [[Doxycycline]] (Therapy and prophylaxis)
* [[Mefloquine]], trade name Lariam (Therapy and prophylaxis)
* [[Primaquine]] (Therapy in ''P. vivax'' and ''P. ovale'' only; not for prophylaxis)
* [[Proguanil]] (Prophylaxis only)
* [[Sulfonamide (medicine)|Sulfadoxine]]-[[pyrimethamine]] (Therapy; prophylaxis for semi-immune pregnant women in endemic countries as "Intermittent Preventive Treatment" - IPT)
*[[Hydroxychloroquine]], trade name Plaquenil (Therapy and prophylaxis)
The development of drugs was facilitated when ''Plasmodium falciparum'' was successfully [[Malaria culture|cultured]].<ref name="Trager1976">{{cite journal | author= Trager W, Jensen JB.| title=Human malaria parasites in continuous culture | journal=Science| year=1976| volume=193(4254)| pages=673&ndash;5  | id=PMID 781840}}</ref> 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.<ref>{{cite journal | author = Senior K | title = Shortfall in front-line antimalarial drug likely in 2005 | journal = Lancet Infect Dis | volume = 5 | issue = 2 | pages = 75 | year = 2005 | id = PMID 15702504}}</ref> 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.  <ref>{{cite journal |author=Rwagacondo C, Karema C, Mugisha V, Erhart A, Dujardin J, Van Overmeir C, Ringwald P, D'Alessandro U |title=Is amodiaquine failing in Rwanda? Efficacy of amodiaquine alone and combined with artesunate in children with uncomplicated malaria |journal=Trop Med Int Health |volume=9 |issue=10 |pages=1091-8 |year=2004 |pmid=15482401}}.</ref>
Since 2001 the [[World Health Organization]] has recommended using [[artemisinin]]-based combination therapy (ACT) as first-line treatment for uncomplicated malaria in areas experiencing resistance to older medications. The most recent [[WHO]] [http://www.who.int/malaria/docs/TreatmentGuidelines2006.pdf treatment guidelines for malaria] recommend four different ACTs. While numerous countries, including most African nations, have adopted the change in their official malaria treatment policies, cost remains a major barrier to ACT implementation. Because ACTs cost up to twenty times as much as older medications, they remain unaffordable in many malaria-endemic countries. The molecular target of artemisinin is controversial, although recent studies suggest that [[SERCA]], a calcium pump in the [[endoplasmic reticulum]] may be associated with artemisinin resistance.<ref>{{cite journal | author = Eckstein-Ludwig U, Webb R, Van Goethem I, East J, Lee A, Kimura M, O'Neill P, Bray P, Ward S, Krishna S | title = Artemisinins target the SERCA of Plasmodium falciparum. | journal = Nature | volume = 424 | issue = 6951 | pages = 957-61 | year = 2003 | id = PMID 12931192}}</ref> Malaria parasites can develop resistance to artemisinin and resistance can be produced by mutation of SERCA.<ref>{{cite journal | author = Uhlemann A, Cameron A, Eckstein-Ludwig U, Fischbarg J, Iserovich P, Zuniga F, East M, Lee A, Brady L, Haynes R, Krishna S | title = A single amino acid residue may determine the sensitivity of SER`CAs to artemisinins. | journal = Nat Struct Mol Biol | volume = 12 | issue = 7 | pages = 628-9 | year = 2005 | id = PMID 15937493}}</ref> However, other studies suggest the mitochondrion is the major target for artemisinin and its analogs.<ref>{{cite journal | author = Li W, Mo W, Shen D, Sun L, Wang J, Lu S, Gitschier J, Zhou B | title = Yeast model uncovers dual roles of mitochondria in action of artemisinin. | journal = PLoS Genet | volume = 1 | issue = 3 | pages = e36 | year = 2005 | id = PMID 16170412}}</ref>
 
In February 2002, the journal ''[[Science (journal)|Science]]'' and other press outlets<ref name="bbcnewdrug2002">[http://news.bbc.co.uk/1/hi/health/1821686.stm Malaria drug offers new hope]. ''BBC News'' 2002-02-15.</ref> 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".<ref>[http://www.forumlabo.com/anglais/actus/actus/cnrs/0302onestep.htm One step closer to conquering malaria]</ref> 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".<ref>Salom-Roig, X. ''et al''. (2005) [http://www.bentham.org/cchts/samples/cchts8-1/0007A.pdf Dual molecules as new antimalarials]. ''Combinatorial Chemistry & High Throughput Screening'' 8:49-62.</ref> As of early 2006, there is no information in the mainstream press as to when this family of drugs will become commercially available.
In 1996, Professor Geoff McFadden stumbled upon the work of British biologist Ian Wilson, who had discovered that the plasmodia responsible for causing malaria retained parts of chloroplasts<ref>{{cite web |url=http://www.abc.net.au/rn/scienceshow/stories/2007/1902657.htm |title=Herbicides as a treatment for malaria|accessdate=2007-09-25 |format= |work= }}</ref>, an organelle usually found in plants, complete with their own functioning genomes. This led Professor McFadden to the realisation that any number of herbicides may in fact be successful in the fight against malaria, and so he set about trialing large numbers of them, and enjoyed a 75% success rate.
These "[[apicoplast]]s" are thought to have originated through the endosymbiosis of algae<ref>{{cite journal |last=Khöler |first=Sabine |authorlink= |coauthors= |year=1997 |month=March |title=A Plastid of Probable Green Algal Origin in Apicomplexan Parasites |journal=Science |volume=275 |issue=5305 |pages=1485-1489 |id= |url=http://www.sciencemag.org/cgi/content/abstract/275/5305/1485?maxtoshow=&HITS=10&hits=10&RESULTFORMAT=&fulltext=apicoplast&searchid=1&FIRSTINDEX=0&resourcetype=HWCIT |accessdate= |quote= }}</ref> and play a crucial role in fatty acid bio-synthesis in plasmodia<ref>{{cite journal |last=Gardner |first=Malcom |authorlink= |coauthors= |year=1998 |month=November |title=Chromosome 2 Sequence of the Human Malaria Parasite Plasmodium falciparum  |journal=Science |volume=282 |issue=5391 |pages=1126-1132 |id= |url=http://www.sciencemag.org/cgi/content/abstract/282/5391/1126?maxtoshow=&HITS=10&hits=10&RESULTFORMAT=&fulltext=apicoplast+fatty+acid+plasmodia&searchid=1&FIRSTINDEX=0&resourcetype=HWCIT |accessdate= |quote= }}</ref>. To date, 466 proteins have been found to be produced by apicoplasts<ref>{{cite journal |last=Foth |first=Bernado |authorlink= |coauthors= |year=2003 |month=January |title=Dissecting Apicoplast Targeting in the Malaria Parasite Plasmodium falciparum  |journal=Science |volume=299 |issue=5607 |pages=705-708 |id= |url=http://www.sciencemag.org/cgi/content/abstract/299/5607/705?maxtoshow=&HITS=10&hits=10&RESULTFORMAT=&fulltext=apicoplast&searchid=1&FIRSTINDEX=0&resourcetype=HWCIT |accessdate= |quote= }}</ref> and these are now being looked at as possible targets for novel anti-malarial drugs.
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 of treating a malaria-infected person in an endemic country was between US$0.25 and $2.40 per dose in 2002.<ref name="msf">Medecins Sans Frontieres, "[http://www.msf.org/content/page.cfm?articleid=44247857-6A39-4D9C-8FA7E54299FF1D4D What is the Cost and Who Will Pay?]"</ref>
===Counterfeit drugs===
Sophisticated [[counterfeit drugs|counterfeits]] have been found in Thailand, Vietnam, Cambodia<ref>{{cite journal | author=Lon CT, Tsuyuoka R, Phanouvong S, ''et al.'' | title=Counterfeit and substandard antimalarial drugs in Cambodia | year=2006 | journal=Trans R Soc Trop Med Hyg | volume=100 | issue=11 | pages=1019&ndash;24 | doi=10.1016/j.trstmh.2006.01.003 }}</ref> and China,<ref>{{cite web | author=U. S. Pharmacopeia | title=Fake antimalarials found in Yunan province, China | url=http://www.uspdqi.org/pubs/other/FakeAntimalarialsinChina.pdf | accessdate=2006-10-06 | year=2004 }}</ref> and are an important cause of avoidable death in these countries.<ref>{{cite journal | author=Newton PN, Green MD, Fernández FM, Day NPJ, White NJ. | title=Counterfeit anti-infective drugs | journal=Lancet Infect Dis | year=2006 | volume=6 | issue=9 | pages=602&ndash;13 | id=PMID 16931411 }}</ref>  There is no reliable way for doctors or lay people to detect counterfeit drugs without help from a laboratory.  Companies are attempting to combat the persistence of counterfeit drugs by using new technology to provide security from source to distribution.
==Prevention and disease control==
{{further|[[Mosquito control]]}}
[[Image:Anopheles albimanus mosquito.jpg|400px|thumb|''[[Anopheles]] albimanus'' mosquito feeding on a human arm. This mosquito is a vector of malaria and mosquito control is a very effective way of reducing the incidence of malaria.]]
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 [[vaccination|vaccine]] that will prevent malaria, but this is an active field of research. 
Many researchers argue that prevention of malaria may be more cost-effective than treatment of the disease in the long run, but the capital costs required are out of reach of many of the world's poorest people.  Economic adviser Jeffrey Sachs estimates that malaria can be controlled for US$3 billion in aid per year.  It has been argued that, in order to meet the [[Millennium Development Goals]], money should be redirected from [[HIV]]/[[AIDS]] treatment to malaria prevention, which for the same amount of money would provide greater benefit to African economies.<ref name="hull2006">[http://www.wgbh.org:81/cgi-bin/nph-algs.cgi/000000A/http/www.wgbh.org/schedules/program-info?program_id=2682027&episode_id=2682029 Hull, Kevin. (2006) "Malaria: Fever Wars". PBS Documentary]</ref>
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.<ref>{{cite news | author=Gladwell, Malcolm.|date=[[2001-07-02]] | title=The Mosquito Killer | url=http://www.gladwell.com/2001/2001_07_02_a_ddt.htm | publisher=The New Yorker}}</ref> However, these efforts have so far failed to eradicate malaria in many parts of the developing world - the problem is most prevalent in Africa.
Brazil, Eritrea, India, and Vietnam have, unlike many other developing nations, successfully reduced the malaria burden. Common success factors included conducive country conditions, a targeted technical approach using a package of effective tools, data-driven decision-making, active leadership at all levels of government, involvement of communities, decentralized implementation and control of finances, skilled technical and managerial capacity at national and sub-national levels, hands-on technical and programmatic support from partner agencies, and sufficient and flexible financing.<ref>{{cite journal | author = Barat L | title = Four malaria success stories: how malaria burden was successfully reduced in Brazil, Eritrea, India, and Vietnam. | journal = Am J Trop Med Hyg | volume = 74 | issue = 1 | pages = 12-6 | year = 2006 | id = PMID 16407339}}</ref>
The [[Malaria Control Project]] is currently using downtime computing power donated by individual volunteers around the world (see Volunteer computing and BOINC) to simulate models of the health effects and transmission dynamics in order to find the best method or combination of methods for malaria control. This modeling is extremely computer intensive due to the simulations of large human populations with a vast range of parameters related to biological and social factors that influence the spread of the disease. It is expected to take a few months using volunteered computing power compared to the 40 years it would have taken with the current resources available to the scientists who developed the program.<ref>{{cite web | title=What is Malariacontrol.net |publisher=AFRICA@home | url=http://africa-at-home.web.cern.ch/africa%2Dat%2Dhome/malariacontrol.html |accessdate=2007-03-11}}</ref>
===Prophylactic drugs===
{{Main|Malaria prophylaxis}}
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 cost of purchasing the drugs, negative [[adverse effect (medicine)|side effect]]s from long-term use, 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 used for prophylaxis.  Of interesting historical note is the observation by Samuel Hahnemann in the late 18th Century that over-dosing of quinine leads to a symptomatic state very similar to that of malaria itself.  This lead Hahnemann to develop the medical [[Law of Similars]], and the subsequent medical system of [[Homeopathy]].
Modern drugs used preventively include [[mefloquine]] ('''Lariam®'''), [[doxycycline]] (available generically), and the combination of [[atovaquone]] and [[proguanil]] hydrochloride ('''Malarone®'''). The choice of which drug to use depends on which drugs the parasites in the area are [[drug resistance|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 (with the exception of atovaquone proguanil that only needs be started 2 days prior and continued for 7 days afterwards).
===Indoor residual spraying===
[[DDT]] was developed as the first of the modern [[insecticide]]s 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 mosquitoes 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.  Though DDT has never been banned for use in malaria control, some advocates claim that bans are responsible for tens of millions of deaths in tropical countries where DDT had previously been 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]].<ref name="pmid17111979">{{cite journal |author=Tia E, Akogbeto M, Koffi A, ''et al'' |title=[Pyrethroid and DDT resistance of Anopheles gambiae s.s. (Diptera: Culicidae) in five agricultural ecosystems from Côte-d'Ivoire] |language=French |journal=Bulletin de la Société de pathologie exotique (1990) |volume=99 |issue=4 |pages=278-82 |year=2006 |pmid=17111979 |doi=}}</ref>


The [[World Health Organization]] (WHO) currently advises the use of DDT to combat malaria in endemic areas.<ref>{{cite web | title=WHO frequently asked questions on DDT use for disease vector control | url=http://www.who.int/malaria/docs/FAQonDDT.pdf | format=PDF|publisher=[[World Health Organization|WHO]]}}</ref>  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 (such as the pyrethroids [[permethrin]] and [[deltamethrin]]) to both combat malaria in areas where mosquitoes 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 spraying.<ref>[http://www.who.int/malaria/docs/10thingsonDDT.pdf 10 Things You Need to Know about DDT Use under The Stockholm Convention]</ref>  However, because of its legacy, many developed countries discourage DDT use even in small quantities.<ref>[http://www.pops.int/ The Stockholm Convention on persistent organic pollutants]</ref>
[[Malaria medical therapy|Medical Therapy]] | [[Malaria prevention|Prevention]] | [[Malaria cost-effectiveness of therapy|Cost-Effectiveness of Therapy]] | [[Malaria future or investigational therapies|Future or Investigational Therapies]]


===Mosquito nets and bedclothes===
== Case Studies ==
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,<ref name="hull2006">[http://www.wgbh.org:81/cgi-bin/nph-algs.cgi/000000A/http/www.wgbh.org/schedules/program-info?program_id=2682027&episode_id=2682029 Hull, Kevin. (2006) "Malaria: Fever Wars". PBS Documentary]</ref> and offer greater than 70% protection compared with no net.<ref>{{cite journal | title=Bacteraemia among severely malnourished children infected and uninfected with the human immunodeficiency virus-1 in Kampala, Uganda | author=Bachou H, Tylleskar T, Kaddu-Mulindwa DH, Tumwine JK. | journal=BMC Infect Dis | year=2006 | volume=6 | pages=160 | doi=10.1186/1471-2334-6-160 }}</ref>  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]] or deltamethrin) 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. 
[[Malaria case study one|Case #1]]


For maximum effectiveness, the nets should be re-impregnated with insecticide every six months.  This process poses a significant logistical problem in rural areas.  New technologies like Olyset or DawaPlus allow for production of long-lasting insecticidal mosquito nets (LLINs), which release insecticide for approximately 5 years,<ref>[http://www.voanews.com/english/archive/2004-11/2004-11-23-voa30.cfm?CFID=15461499&CFTOKEN=28007413 New Mosquito Nets Could Help Fight Malaria in Africa]</ref> and cost 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.<ref name="hull2006">{{cite news | author=Hull, Kevin | title=Malaria: Fever Wars | url=http://www.wgbh.org:81/cgi-bin/nph-algs.cgi/000000A/http/www.wgbh.org/schedules/program-info?program_id=2682027&episode_id=2682029 | date=2006 | publisher=PBS Documentary}}</ref> Although shipped into Africa mainly from Europe as free development help, the nets quickly become expensive trade goods. They are mainly used for fishing, and by combining hundreds of donated mosquito nets, whole river sections can be completely shut off, catching even the smallest fish. <ref name="Economist">{{cite news | author=The Economist | title=Traditional Economy of the Kavango | url=http://www.economist.com.na/2002/15mar/03-15-22.htm | date=2007 | publisher=Economist Documentary}}</ref>
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.<ref>{{cite journal | author = Rowland M, Durrani N, Hewitt S, Mohammed N, Bouma M, Carneiro I, Rozendaal J, Schapira A | title = Permethrin-treated chaddars and top-sheets: appropriate technology for protection against malaria in Afghanistan and other complex emergencies. | journal = Trans R Soc Trop Med Hyg | volume = 93 | issue = 5 | pages = 465-72 | year = | id = PMID 10696399}}</ref>
A new approach, announced in ''Science'' on June 10, 2005, uses 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.<ref name="bbcfungus">"[http://news.bbc.co.uk/1/hi/health/4074212.stm Fungus 'may help malaria fight']", ''BBC News'', [[2005-06-09]]</ref>
===Vaccination===
{{further|[[Malaria vaccine]]}}
[[Vaccination|Vaccines]] for malaria are under development, with no completely effective vaccine yet available. The first promising studies demonstrating the potential for a malaria vaccine were performed in 1967 by immunizing mice with live, radiation-[[Attenuator (genetics)|attenuated]] [[sporozoite]]s, providing protection to about 60% of the mice upon subsequent injection with normal, viable sporozoites.<ref name="Nussenzweig1967">{{cite journal |author=Nussenzweig R, Vanderberg J, Most H, Orton C |title=Protective immunity produced by the injection of x-irradiated sporozoites of plasmodium berghei |journal=Nature |volume=216 |issue=5111 |pages=160-2 |year=1967 | pmid = 6057225}}</ref>  Since the 1970s, there has been a considerable effort to develop similar vaccination strategies within humans.  It was determined that an individual can be protected from a ''P. falciparum'' infection if they receive over 1000 bites from infected, irradiated mosquitoes.<ref name="Hoffman2002">{{cite journal |author=Hoffman SL, Goh LM, Luke TC, ''et al'' |title=Protection of humans against malaria by immunization with radiation-attenuated Plasmodium falciparum sporozoites |journal=J. Infect. Dis. |volume=185 |issue=8 |pages=1155-64 |year=2002 |pmid=11930326 |doi=}}</ref>
It has been generally accepted that it is impractical to provide at-risk individuals with this vaccination strategy, but that has been recently challenged with work being done by Dr. Stephen Hoffman of [http://www.sanaria.com Sanaria], one of the key researchers who originally sequenced the genome of ''[[Plasmodium falciparum]]''.  His work most recently has revolved around solving the logistical problem of isolating and preparing the parasites equivalent to a 1000 irradiated mosquitoes for mass storage and inoculation of human beings. The company has recently received several multi-million dollar grants from the Bill & Melinda Gates Foundation and the U.S. government to begin early clinical studies in 2007 and 2008.<ref name="Sanaria studies">[http://www.sanaria.com/presspublications.html Sanaria Press and Publications]</ref>
Instead, much work has been performed to try and understand the [[immune system|immunological]] processes that provide protection after immunization with irradiated sporozoites.  After the mouse vaccination study in 1967,<ref name="Nussenzweig1967"/> it was hypothesized that the injected sporozoites themselves were being recognized by the immune system, which was in turn creating [[antibody|antibodies]] against the parasite.  It was determined that the immune system was creating antibodies against the circumsporozoite protein (CSP) which coated the sporozoite.<ref>{{cite journal |author=Zavala F, Cochrane A, Nardin E, Nussenzweig R, Nussenzweig V |title=Circumsporozoite proteins of malaria parasites contain a single immunodominant region with two or more identical epitopes |journal=J Exp Med |volume=157 |issue=6 |pages=1947-57 |year=1983 |i pmid = 6189951}}</ref>  Moreover, antibodies against CSP prevented the sporozoite from invading hepatocytes.<ref>{{cite journal |author=Hollingdale M, Nardin E, Tharavanij S, Schwartz A, Nussenzweig R |title=Inhibition of entry of Plasmodium falciparum and P. vivax sporozoites into cultured cells; an in vitro assay of protective antibodies |journal=J Immunol |volume=132 |issue=2 |pages=909-13 |year=1984 | pmid =  6317752}}</ref> CSP was therefore chosen as the most promising protein on which to develop a vaccine against the malaria sporozoite.  It is for these historical reasons that vaccines based on CSP are the most numerous of all malaria vaccines.
Presently, there is a huge variety of vaccine candidates on the table.  Pre-erythrocytic vaccines (vaccines that target the parasite before it reaches the blood), in particular vaccines based on CSP, make up the largest group of research for the malaria vaccine.  Other vaccine candidates include: those that seek to induce immunity to the blood stages of the infection; those that seek to avoid more severe pathologies of malaria by preventing adherence of the parasite to blood [[venules]] and [[placenta]]; and [[transmission (medicine)|transmission]]-blocking vaccines that would stop the development of the parasite in the mosquito right after the mosquito has taken a bloodmeal from an infected person.<ref name="Matuschewski2006">{{cite journal |author=Matuschewski K |title=Vaccine development against malaria |journal=Curr Opin Immunol |volume=18 |issue=4 |pages=449-57 |year=2006 | pmid = 16765576}}</ref> It is hoped that the sequencing of the ''P. falciparum'' [[genome]] will provide targets for new drugs or vaccines.<ref>{{cite journal | author = Gardner M, Hall N, Fung E, ''et al'' | title = Genome sequence of the human malaria parasite Plasmodium falciparum. | journal = Nature | volume = 419 | issue = 6906 | pages = 498-511 | year = 2002 | pmid = 12368864}}</ref>
The first vaccine developed that has undergone field trials, is the SPf66, developed by [[Manuel Elkin Patarroyo]] in 1987. It presents a combination of antigens from the sporozoite (using CS repeats) and merozoite parasites. During phase I trials a 75% efficacy rate was demonstrated and the vaccine appeared to be well tolerated by subjects and immunogenic. The phase IIb and III trials were less promising, with the efficacy falling to between 38.8% and 60.2%. A trial was carried out in Tanzania in 1993 demonstrating the efficacy to be 31% after a years follow up, however the most recent (though controversial) study in the Gambia did not show any effect. Despite the relatively long trial periods and the number of studies carried out, it is still not known how the SPf66 vaccine confers immunity; it therefore remains an unlikely solution to malaria.
The CSP was the next vaccine developed that initially appeared promising enough to undergo trials. It is also based on the circumsporoziote protein, but additionally has the recombinant (Asn-Ala-Pro15Asn-Val-Asp-Pro)2-Leu-Arg(R32LR) protein covalently bound to a purified ''[[Pseudomonas aeruginosa]]'' toxin (A9). However at an early stage a complete lack of protective immunity was demonstrated in those inoculated. The study group used in Kenya had an 82% incidence of parasitaemia whilst the control group only had an 89% incidence. The vaccine intended to cause an increased T-lymphocyte response in those exposed, this was also not observed.
The efficacy of Patarroyo's vaccine has been disputed with some US scientists concluding in [[The Lancet]] (1997) that "the vaccine was not effective and should be dropped" while the Colombian accused them of "arrogance" putting down their assertions to the fact that he came from a developing country.
The RTS,S/AS02A vaccine is the candidate furthest along in vaccine trials.  It is being developed by a partnership between the PATH Malaria Vaccine Initiative (a grantee of the Gates Foundation), the [[pharmaceutical company]], [[GlaxoSmithKline]], and the Walter Reed Army Institute of Research<ref>{{cite journal |author=Heppner DG, Kester KE, Ockenhouse CF, ''et al'' |title=Towards an RTS,S-based, multi-stage, multi-antigen vaccine against falciparum malaria: progress at the Walter Reed Army Institute of Research |journal=Vaccine |volume=23 |issue=17-18 |pages=2243-50 |year=2005 |pmid=15755604 |doi=10.1016/j.vaccine.2005.01.142}}</ref>  In the vaccine, a portion of CSP has been fused to the [[immunogenicity|immunogenic]] "S [[antigen]]" of the [[hepatitis B]] virus; this [[recombinant]] protein is injected alongside the potent AS02A [[adjuvant]].<ref name="Matuschewski2006"/> In October 2004, the RTS,S/AS02A researchers announced results of a [[clinical trial|Phase IIb trial]], indicating the vaccine reduced infection risk by approximately 30% and severity of infection by over 50%.  The study looked at over 2,000 Mozambican children.<ref>{{cite journal |author=Alonso PL, Sacarlal J, Aponte JJ, ''et al'' |title=Efficacy of the RTS,S/AS02A vaccine against Plasmodium falciparum infection and disease in young African children: randomised controlled trial |journal=Lancet |volume=364 |issue=9443 |pages=1411-20 |year=2004 |pmid=15488216 |doi=10.1016/S0140-6736(04)17223-1}}</ref> More recent testing of the RTS,S/AS02A vaccine has focused on the safety and efficacy of administering it earlier in infancy: In October 2007, the researchers announced results of a [[clinical trial|phase I/IIb trial]] conducted on 214 Mozambican infants between the ages of 10 and 18 months in which the full three-dose course of the vaccine led to a 62% reduction of infection with no serious side-effects save some pain at the point of injection.<ref>{{cite journal |author=Aponte JJ, Aide P, Renom M ''et al'' |title=Safety of the RTS,S/AS02D candidate malaria vaccine in infants living in a highly endemic area of Mozambique: a double blind randomised controlled phase I/IIb trial |journal=Lancet |year=2007 |doi=10.1016/S0140-6736(07)61542-6}}</ref> Further research will delay this vaccine from commercial release until around 2011.<ref>[http://allafrica.com/stories/200701090730.html Africa: Malaria - Vaccine Expected in 2011.] ''[http://www.accra-mail.com Accra Mail.]'' 9 January 2007. Accessed 15 January 2007.</ref>
===Other methods===
[[Sterile insect technique]] is emerging as a potential mosquito control method.  Progress towards transgenic, or [[genetically modified organism|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,<ref>Imperial College, London, "[http://www.ic.ac.uk/templates/text_3.asp?P=1911 Scientists create first transgenic malaria mosquito]", [[2000-06-22]].</ref> with the first plasmodium-resistant species announced by a team at Case Western Reserve University in Ohio in 2002.<ref name="ito2002"> {{cite journal | author=Ito J, Ghosh A, Moreira LA, Wimmer EA, Jacobs-Lorena M | title=Transgenic anopheline mosquitoes impaired in transmission of a malaria parasite | journal=Nature | year=2002 | volume=417 | pages=387-8  | id=PMID 12024215}}</ref> Successful replacement of existent populations with genetically modified populations, relies upon a drive mechanism, such as [[transposable elements]] to allow for non-Mendelian inheritance of the gene of interest.
Education in recognising the symptoms of Malaria has reduced the number of cases in some areas of the developing world by as much as 20%.  Recognising the disease in the early stages can also stop the disease from becoming a killer.  Education can also inform people to cover over areas of stangnant, still water eg Water Tanks which are ideal breeding grounds for the parastie and mosquito thus, cutting down the risk of the transmission between people.  This is most put in practice in urban areas where there is large centres of population in a confined space and transmission would be most likely in these areas.
Before DDT, malaria was successfully eradicated or controlled also in several tropical areas by removing or poisoning the breeding grounds of the mosquitoes or the aquatic habitats of the larva stages, for example by filling or applying oil to places with standing water. These methods have seen little application in Africa for more than half a century.<ref>{{cite journal | author = Killeen G, Fillinger U, Kiche I, Gouagna L, Knols B | title = Eradication of Anopheles gambiae from Brazil: lessons for malaria control in Africa? | journal = Lancet Infect Dis | volume = 2 | issue = 10 | pages = 618-27 | year = 2002 | id = PMID 12383612}}</ref>
==Policy implementation and access to anti-malarial drugs in developing countries==
The introduction of any anti-malarial therapy requires policies to regulate local distribution, access and guidelines for usage. There are many considerations when implementing the use a newly developed drug.
These include:
* the known efficacy of the treatment and the adherence levels likely within the constraints of the local health system;
* the economic resources necessary to implement the policy by the health care sector;
* the human and technical resources and the basic primary health care infrastructure;
* education;
* training and health promotion schemes for staff and the general population;
* successful interactions between the public and private sector to ensure that sufficient drugs are supplied;
* regulation over quality control;
* distribution and pricing;
* regular monitoring and a system enabling alteration of the policy.
One of the major problems associated with anti-malarial therapy is the inadequate primary health care infrastructure in many of the countries where malaria is endemic. It is estimated that one third of the population at risk of developing the infection has no access to therapy. Access is defined as the availability to pharmaceuticals of quality and can be subdivided in to physical, financial (affordability and equity) and rational-use access. The level of access is determined by many factors from the appropriate knowledge to use the drug effectively, supply management, basic infrastructure for delivery, economic and legislative issues. This is affected by the participation and support of all the stakeholders involved from the government to local private companies. In many countries access is prevented by poor political will and interest, low levels of economic growth and the investment of the majority of financial resources in secondary or tertiary health care.
The level of quality control over anti-malarials provided is a key problem in many areas of the world. Poor quality and counterfeit drugs can lead to an increase in the rate of resistance development due to incorrect dosing and can pose a fatal risk if given in acute cases where little or no drug is contained within the given dose. This issue is thought to account, to an unknown degree, to the perceived resistance and treatment failure rates seen. The percentage failure rates in sub-Saharan Africa vary from 20 to 67%. Random content testing has been carried out and demonstrated that, in certain areas up to 100% of this failure is due to poor content. This poses a serious danger to the international campaigns against malaria and therefore cannot be ignored. Suggestions to overcome such problems include international surveillance systems within drug regulatory authorities and supporting pharmaceutical manufacturers.
==References==
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==<font color=#FFFFFF>External links</font>==
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<div style="background: #ccddcc; text-align: center; border: 1px solid #667766" class="NavHead">'''External links'''
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'''General information'''
* [http://www7.nationalgeographic.com/ngm/0707/index.html National Geographic July 2007 Issue on Malaria]
* [http://www.who.int/malaria/ WHO site on malaria]
** [http://www.who.int/malaria/docs/TreatmentGuidelines2006.pdf 2006 WHO Guidelines for the Treatment of Malaria]
* {{McGrawHillAnimation|microbiology|Malaria}}
* [http://ocw.jhsph.edu/courses/malariology/lectureNotes.cfm Johns Hopkins Malariology Open Courseware]
** [http://www.rollbackmalaria.org/wmr2005/ World Malaria Report 2005]
* [http://www.malariacontrol.net/ www.malariacontrol.net] distributed computing project for the fight against malaria
* [http://www.cdc.gov/malaria/ United States Centers for Disease Control - ''Malaria''] information pages
* [http://www.doctorswithoutborders.org/news/malaria/index.cfm Doctors Without Borders/Medecins Sans Frontieres - ''Malaria''] information pages
* [http://www.eldis.org/go/topics/resource-guides/health/malaria HRC/Eldis Health Resource Guide - ''Malaria''] research and resources on health in developing countries
* [http://www.nlm.nih.gov/medlineplus/malaria.html Medline Plus - ''Malaria'']
* [http://www.vega.org.uk/video/programme/87 Interview with Dr Andrew Speilman, Harvard malaria specialist]
* [http://www.malariaconsortium.org/ Malaria Consortium website]
* [http://www.globalhealthfacts.org/topic.jsp?i=20 GlobalHealthFacts.org] Malaria Cases and Deaths by Country
* [http://www.xs4all.nl/~ottoknot/werk/Malaria.html Survey article: History of malaria around the North Sea]
* [http://www.driveagainstmalaria.org DriveAgainstMalaria.org], "World's longest journey to fight the biggest killer of children"
* [http://ocw.jhsph.edu/courses/malariology/ Malaria on JHSPH OpenCourseWare]
* [http://www.malaria.org/ Malaria Foundation International]
* [http://www.map.ox.ac.uk Malaria Atlas Project]
* [http://www.unitaid.eu UNITAID, International Facility for the Purchase of Drugs] ([[UNITAID|Wikipedia Article]])
'''Vaccine and other research'''
* [http://news.bbc.co.uk/2/hi/health/3742876.stm BBC - ''Hopes of Malaria Vaccine by 2010''] 15 October 2004
* [http://news.bbc.co.uk/1/hi/health/4419835.stm BBC - ''Science shows how malaria hides''] 8 April 2005
* [http://www.malariasite.com/malaria/History.htm History of discoveries in malaria]
* [http://www.who.int/tdr/diseases/malaria/default.htm Malaria. The UNICEF-UNDP-World Bank-WHO Special Programme for Research and Training in Tropical Diseases]
* [http://www.malariavaccine.org Malaria Vaccine Initiative]
* [http://stevenlehrer.com/explorers/chapter_6-5.htm Story of the discovery of the vector of the malarial parasite]
* [http://www.wellcome.ac.uk/en/malaria/ Wellcome Trust against Malaria]
* [http://blogs.cgdev.org/vaccine/ "Vaccines for Development" - Blog on vaccine research and production for developing countries]
* [http://www.mmv.org/index.php Medicines for Malaria Venture]
* [http://www.allmosquitos.com/deseases/mosquito-transmitted-human-diseases/malaria.html Malaria and Mosquitos - questions and answers]
'''Mosquito Netting as Prevention'''
* [http://www.hisnets.org Hisnets] - Fighting Malaria: One Net At A Time
* [http://www.unicef.org/media/media_23447.html Call for Increased Production of Long-Lasting Insecticidal Nets as Part of the U.N. Millenium Campaign]
* [http://www.gmin.org/m3s1.html Providing everyone with a LLIN in Sahn Malen, a small village in Sierra Leone]
'''DDT'''
* [http://www.who.int/malaria/ddtandmalariavectorcontrol.html DDT and malaria vector control]
* [http://www.who.int/malaria/stockholmconventiononpops.html WHO Position on DDT Use]
* [http://info-pollution.com/ddtban.htm The DDT Ban Myth]
'''Animations, images and photos'''
* [http://news.bbc.co.uk/2/shared/spl/hi/picture_gallery/05/world_burden_of_malaria/html/1.stm Burden of Malaria], BBC pictures relating to malaria in northern Uganda
* [http://www.sumanasinc.com/scienceinfocus/sif_malaria.html Malaria: Cooperation among Parasite, Vector, and Host (Animation)]
*[http://www.malariafreefuture.org/blog/ Malaria Blog from the Johns Hopkins Bloomberg School of Public Health Center for Communications Programs]
|}
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Latest revision as of 22:37, 29 July 2020

This page is about clinical aspects of the disease.  For microbiologic aspects of the causative organism(s), see Plasmodium.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Usama Talib, BSc, MD [2]

Overview

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