View source for Malaria

{{Infobox disease
 | Name           = Malaria
 | ICD10          = {{ICD10|B|50||b|50}}
 | ICD9           = {{ICD9|084}}
 | Image          = Plasmodium.jpg
 | Caption        = Ring-forms and [[gametocyte]]s of ''Plasmodium falciparum'' 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 |
 }}
'''Malaria''' is a [[mosquito]]-borne [[infectious disease]] of humans caused by [[eukaryotic]] [[protists]] of the genus ''[[Plasmodium]]''. It is widespread in [[Tropics|tropical]] and subtropical regions, including much of [[Sub-Saharan Africa]], [[Asia]] and the [[Americas]]. Malaria is very prevalent in these regions because they have significant amounts of rain fall and consistent hot temperatures. These warm, consistent temperatures and moisture provide mosquitos with the environment they need to breed continuously.<ref>Prothero, R. Mansell. "Malaria, Forests and People in Southeast Asia." Singapore Journal of Tropical Geography 20.1</ref> The disease results from the multiplication of malaria parasites within [[red blood cell]]s, causing symptoms that typically include [[fever]] and [[headache]], in severe cases progressing to [[coma]], and death.

<!--Cause  -->
Four species of ''Plasmodium'' can infect and be transmitted by humans. Severe disease is largely caused by ''[[Plasmodium falciparum]]''. Malaria caused by ''[[Plasmodium vivax]]'', ''[[Plasmodium ovale]]'' and ''[[Plasmodium malariae]]'' is generally a milder disease that is rarely fatal. A fifth species, ''[[Plasmodium knowlesi]]'', is a [[zoonosis]] that causes malaria in [[macaques]] but can also infect humans.<ref>{{Cite journal|author=Fong YL, Cadigan FC, Coatney GR |title=A presumptive case of naturally occurring Plasmodium knowlesi malaria in man in Malaysia |journal=Trans. R. Soc. Trop. Med. Hyg. |volume=65 |issue=6 |pages=839–40 |year=1971 |pmid=5003320 |doi= 10.1016/0035-9203(71)90103-9|url=}}</ref><ref>{{Cite journal|author=Singh B, Kim Sung L, Matusop A, ''et al.'' |title=A large focus of naturally acquired Plasmodium knowlesi infections in human beings |journal=Lancet |volume=363 |issue=9414 |pages=1017–24 |year=2004 |month=March |pmid=15051281 |doi=10.1016/S0140-6736(04)15836-4 |url=http://linkinghub.elsevier.com/retrieve/pii/S0140673604158364}}</ref>

<!--Prevention  -->
Malaria transmission can be reduced by preventing mosquito bites by distribution of inexpensive [[mosquito net]]s and [[insect repellent]]s, or by mosquito-control measures such as spraying [[insecticide]]s inside houses and draining standing water where mosquitoes lay their eggs. Although many are under development, the challenge of producing a widely available [[vaccine]] that provides a high level of protection for a sustained period is still to be met.<ref>{{Cite journal|author=Kilama W, Ntoumi F |title=Malaria: a research agenda for the eradication era |journal=Lancet |volume=374 |issue=9700 |pages=1480–2 |year=2009 |month=October |pmid=19880004 |doi=10.1016/S0140-6736(09)61884-5 |url=http://linkinghub.elsevier.com/retrieve/pii/S0140-6736(09)61884-5}}</ref> Two drugs are also available to prevent malaria in travellers to malaria-[[Endemic (epidemiology)|endemic]] countries ([[malaria prophylaxis|prophylaxis]]).

<!-- Treatment -->
A variety of [[antimalarial medication]]s are available. In the last 5 years, treatment of ''P. falciparum'' infections in [[Endemism|endemic]] countries has been transformed by the use of combinations of drugs containing an [[artemisinin]] derivative.  Severe malaria is treated with intravenous or intramuscular quinine or, increasingly, the [[artemisinin]] derivative [[artesunate]] <ref>{{Cite journal|author=Dondorp AM, Day NP |title=The treatment of severe malaria. |journal=Trans. R. Soc. Trop. Med. Hyg. |volume=101 |issue=7 |pages=633–4 |year=2007 |month=July |pmid=17434195 |doi=10.1016/j.trstmh.2007.03.011 |url=http://linkinghub.elsevier.com/retrieve/pii/S0035-9203(07)00093-4}}</ref> which is superior to quinine in both children and adults.<ref>{{cite journal |author=Dondorp AM, Fanello CI, Hendriksen IC, ''et al.'' |title=Artesunate versus quinine in the treatment of severe falciparum malaria in African children (AQUAMAT): an open-label, randomised trial |journal=Lancet |volume=376 |issue=9753 |pages=1647–57 |year=2010 |month=November |pmid=21062666 |doi=10.1016/S0140-6736(10)61924-1 |url= |pmc=3033534}}</ref>  Resistance has developed to several antimalarial drugs, most notably [[chloroquine]].<ref>{{Cite journal|author=Wellems TE |title=Plasmodium chloroquine resistance and the search for a replacement antimalarial drug |journal=Science |volume=298 |issue=5591 |pages=124–6 |year=2002 |month=October |pmid=12364789 |doi=10.1126/science.1078167 |url=http://www.sciencemag.org/cgi/pmidlookup?view=long&pmid=12364789}}</ref>

<!--Epidemiology  -->
Each year, there are more than 225 million cases of malaria,<ref>{{Cite news| url=http://www.smh.com.au/environment/conservation/gorillas-in-midst-of-malaria-mystery-20100925-15rlm.html | work=Sydney Morning Hearld | title=Gorillas in midst of malaria mystery | date=September 26, 2010 | accessdate=September 28, 2010 | first=Nicky | last=Phillips}}</ref> killing around 781,000 people each year according to the World Health Organisation's 2010 World Malaria Report,<ref>http://www.who.int/malaria/world_malaria_report_2010/en/index.html WHO Report</ref> 2.23% of deaths worldwide. The majority of deaths are of young children in [[sub-Saharan Africa]].<ref>{{Cite journal| author = Snow RW, Guerra CA, Noor AM, Myint HY, Hay SI| title = The global distribution of clinical episodes of Plasmodium falciparum malaria | journal = Nature | volume = 434 | issue = 7030 | pages = 214–7 | year = 2005 | pmid = 15759000  | doi = 10.1038/nature03342}}</ref> Ninety percent of malaria-related deaths occur in sub-Saharan Africa. Malaria is commonly associated with poverty, and can indeed be a cause of poverty<ref>{{Cite web|url=http://ftp.iza.org/dp2997.pdf|format=PDF|title=Malaria: Disease Impacts and Long-Run Income Differences|publisher=[[Institute for the Study of Labor]]|accessdate=2008-12-10}}</ref> and a major hindrance to [[economic development]].
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==Signs and symptoms==
[[File:Symptoms of Malaria.png|thumb|Main symptoms of malaria.<ref>[http://www.webmd.com/a-to-z-guides/malaria-symptoms WebMD > Malaria symptoms] Last Updated: May 16, 2007</ref>]]

[[File:Malaria fever.svg|thumb|Typical fever patterns of malaria]]

Symptoms of malaria include [[fever]], [[shivering]], [[arthralgia]] (joint pain), [[vomiting]], [[anemia]] (caused by [[hemolysis]]), [[hemoglobinuria]], [[Retinopathy|retinal damage]],<ref>{{Cite journal|author=Beare NA, Taylor TE, Harding SP, Lewallen S, Molyneux ME |title=Malarial retinopathy: a newly established diagnostic sign in severe malaria |journal=Am. J. Trop. Med. Hyg. |volume=75 |issue=5 |pages=790–7 |pmid=17123967 |pmc=2367432 |url=http://www.ajtmh.org/cgi/pmidlookup?view=long&pmid=17123967 |date= November 1, 2006 }}</ref> and [[convulsion]]s. The classic symptom of malaria is cyclical occurrence of sudden coldness followed by [[Rigor (medicine)|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 days for ''P. malariae''.<ref name=RBMarmenia>[http://www.malaria.am/eng/pathogenesis.php Malaria life cycle & pathogenesis]. Malaria in Armenia. Retrieved 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 that 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  | page = 57| publisher = | date = | url = | pmc = 1326205 | doi = 10.1186/1475-2875-4-57| 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>{{Cite journal|author=Boivin MJ |title=Effects of early cerebral malaria on cognitive ability in Senegalese children |journal=J Dev Behav Pediatr |volume=23 |issue=5 |pages=353–64 |year=2002 |month=October |pmid=12394524 |doi= |url=http://meta.wkhealth.com/pt/pt-core/template-journal/lwwgateway/media/landingpage.htm?issn=0196-206X&volume=23&issue=5&spage=353}}</ref><ref>{{Cite journal|author=Holding PA, Snow RW |title=Impact of Plasmodium falciparum malaria on performance and learning: review of the evidence |journal=Am. J. Trop. Med. Hyg. |volume=64 |issue=1–2 Suppl |pages=68–75 |year=2001 |pmid=11425179 |doi= |url=http://www.ajtmh.org/cgi/content/abstract/64/1_suppl/68 }} <sup>[http://scholar.google.co.uk/scholar?hl=en&lr=&q=intitle%3AImpact+of+Plasmodium+falciparum+malaria+on+performance+and+learning%3A+review+of+the+evidence&as_publication=Am.+J.+Trop.+Med.+Hyg.&as_ylo=2001&as_yhi=2001&btnG=Search Scholar search]</sup></ref>  Cerebral malaria is associated with retinal whitening,<ref>{{Cite journal|unused_data=DUPLICATE DATA: page=881|author=Maude RJ, Hassan MU, Beare NAV|title=Severe retinal whitening in an adult with cerebral malaria|journal=Am J Trop Med Hyg|volume=80|issue=6|date= June 1, 2009 |page=881|url=http://www.ajtmh.org/cgi/content/full/80/6/881|pmid=19478242|pmc=2843443}}</ref> which may be a useful clinical sign in distinguishing malaria from other causes of fever.<ref>{{Cite journal|author=Beare NAV, Taylor TE, Harding SP, Lewallen S, Molyneux ME|year=2006|title=Malarial retinopathy: a newly established diagnostic sign in severe malaria|journal=Am J Trop Med Hyg|volume=75|pages=790–797|pmid=17123967|issue=5|pmc=2367432}}</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= | pmc=270697 | journal = Crit Care | volume = 7 | issue = 4 | pages = 315–23 | year = 2003 | pmid = 12930555 | doi = 10.1186/cc2183}}</ref> Consequences of severe malaria include [[coma]] and death if untreated—young children and pregnant women are especially vulnerable. [[Splenomegaly]] (enlarged spleen), severe [[headache]], cerebral [[ischemia]], [[hepatomegaly]] (enlarged liver), [[hypoglycemia]], and hemoglobinuria with [[renal failure]] may occur. Renal failure is a feature of [[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 | pmid = 9675468 | doi = 10.1086/514616}}</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 | 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  | pmid=15655008 | doi = 10.1111/j.1365-3156.2004.01345.x | issue=1}}</ref>

==Cause==
[[Image:Malaria.jpg|thumb|A ''Plasmodium'' sporozoite traverses the cytoplasm of a mosquito midgut epithelial cell in this false-color [[electron micrograph]].]]

Malaria [[parasite]]s are members of the genus ''[[Plasmodium]]'' (phylum [[Apicomplexa]]). In humans malaria is caused by ''[[Plasmodium falciparum|P. falciparum]]'', ''[[Plasmodium malariae|P. malariae]]'', ''[[Plasmodium ovale|P. ovale]]'', ''[[Plasmodium vivax|P. vivax]]'' and ''[[Plasmodium knowlesi|P. knowlesi]]''.<ref>{{Cite journal|author=Mueller I, Zimmerman PA, Reeder JC |title=Plasmodium malariae and Plasmodium ovale—the "bashful" malaria parasites |journal=Trends Parasitol. |volume=23 |issue=6 |pages=278–83 |year=2007 |month=June |pmid=17459775 |doi=10.1016/j.pt.2007.04.009}}</ref><ref>{{Cite journal|author=Singh B, Kim Sung L, Matusop A, ''et al.'' |title=A large focus of naturally acquired Plasmodium knowlesi infections in human beings |journal=Lancet |volume=363 |issue=9414 |pages=1017–24 |year=2004 |month=March |pmid=15051281 |doi=10.1016/S0140-6736(04)15836-4}}</ref> '' P. falciparum'' is the most common cause of infection, and is also responsible for about 90% of the deaths from malaria.<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|format=PDF}}</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 | doi= 10.1073/pnas.91.24.11373 | journal = Proc Natl Acad Sci USA | volume = 91 | issue = 24 | pages = 11373–7 | year = 1994 | pmid = 7972067 | pmc = 45233}}</ref> There have been documented human infections with several [[Wiktionary:simian|simian]] species of malaria, namely ''P. knowlesi'', ''[[Plasmodium inui|P. inui]]'', ''[[Plasmodium cynomolgi|P. cynomolgi]]'',<ref>{{Cite book| last=Garnham | first=PCC | year=1966 | title=Malaria parasites and other haemosporidia | publisher=Blackwell Scientific Publications|location=Oxford | isbn=186983500X }}</ref> ''[[Plasmodium simiovale|P. simiovale]]'', ''[[P. brazilianum]]'', ''[[P. schwetzi]]'' and ''[[P. simium]]''; however, with the exception of ''P. knowlesi'', these are mostly of limited public health importance.<ref>{{Cite journal|title=''Plasmodium knowlesi:'' Finally being recognized|journal=J Infect Dis|year=2009|volume=199|pages=1107–1108|doi=10.1086/597415|pmid=19284287|last1=Collins|first1=WE|last2=Barnwell|first2=JW|issue=8|author1=&Amp, Collins W.E.|author2=Barnwell, J.W.}}</ref>

Malaria parasites contain [[apicoplast]]s, an organelle usually found in plants, complete with their own functioning genomes. These apicoplast are thought to have originated through the [[Endosymbiont|endosymbiosis]] of algae<ref>{{Cite journal|last=Köhler |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 |url= |accessdate= |quote= |doi=10.1126/science.275.5305.1485 |pmid=9045615 |last2=Delwiche |first2=CF |last3=Denny |first3=PW |last4=Tilney |first4=LG |last5=Webster |first5=P |last6=Wilson |first6=RJ |last7=Palmer |first7=JD |last8=Roos |first8=DS }}</ref> and play a crucial role in various aspects of parasite metabolism e.g. fatty acid bio-synthesis.<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 |url= |accessdate= |quote= |doi=10.1126/science.282.5391.1126 |pmid=9804551 |last2=Tettelin |first2=H |last3=Carucci |first3=DJ |last4=Cummings |first4=LM |last5=Aravind |first5=L |last6=Koonin |first6=EV |last7=Shallom |first7=S |last8=Mason |first8=T |last9=Yu |first9=K }}</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= |doi=10.1126/science.1078599 |pmid=12560551 |last2=Ralph |first2=SA |last3=Tonkin |first3=CJ |last4=Struck |first4=NS |last5=Fraunholz |first5=M |last6=Roos |first6=DS |last7=Cowman |first7=AF |last8=McFadden |first8=GI }}</ref> and these are now being looked at as possible targets for novel anti-malarial drugs.

===Life cycle===
The parasite's secondary (intermediate) [[host (biology)|hosts]] are humans and other vertebrates. Female [[mosquito]]es of the ''[[Anopheles]]'' genus are primary hosts and transmission [[Vector (epidemiology)|vector]]s. 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's 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 = | page = 24 | year = 2004| pmid = 15253774 | doi = 10.1186/1475-2875-3-24 | pmc = 497046}}</ref> The sporozoites are injected into the skin, alongside saliva, when the mosquito takes a subsequent blood meal.

Only female mosquitoes feed on blood while male mosquitoes feed on plant nectar,<ref>[http://www.mosquitoes.org/downloads/MosqFacts.pdf Mosquitoe Facts]</ref> 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 = 2004| pmid = 15339855 | doi = 10.1093/bmb/ldh023}}</ref>

====Recurrent malaria====
Malaria recurs after treatment for three reasons. Recrudescence occurs when parasites are not cleared by treatment, whereas reinfection indicates complete clearance with new infection established from a separate infective mosquito bite; both can occur with any malaria parasite species. Relapse is specific to ''P. vivax'' and ''P. ovale'' and involves re-emergence of blood-stage parasites from latent parasites (hypnozoites) 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 | pmid = 9684649}}</ref>

==Pathogenesis==
{{further|[[Plasmodium falciparum biology]]}}
[[Image:MalariacycleBig.jpg|thumb|right|The life cycle of malaria parasites in the human body. A mosquito infects a person by taking a blood meal. First, sporozoites enter the bloodstream, and migrate to the liver. They infect liver cells (hepatocytes), where they multiply into merozoites, rupture the liver cells, and escape back into the bloodstream. Then, the merozoites infect red blood cells, where they develop into ring forms, trophozoites and schizonts which in turn produce further merozoites. Sexual forms (gametocytes) are also produced, which, if taken up by a mosquito, will infect the insect and continue the life cycle.]]
Malaria develops via two phases: an exoerythrocytic and an erythrocytic phase. The exoerythrocytic phase involves infection of the hepatic system, or liver, whereas the erythrocytic phase involves infection of the erythrocytes, or red blood cells. 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 minutes of being introduced into the human host, the sporozoites infect [[hepatocyte]]s, multiplying asexually and asymptomatically for a period of 8–30 days.<ref name="Bledsoe"/> 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 name="Bledsoe">{{Cite journal|doi=10.1097/01.smj.0000189904.50838.eb |author=Bledsoe GH |title=Malaria primer for clinicians in the United States |journal=South. Med. J. |volume=98 |issue=12 |pages=1197–204; quiz 1205, 1230 |year=2005 |month=December |pmid=16440920 |url=http://journals.lww.com/smajournalonline/Fulltext/2005/12000/Malaria_Primer_for_Clinicians_in_the_United_States.12.aspx}}</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  | pmid=16888102 | doi = 10.1126/science.1129720 | issue=5791
}}</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 (6–12 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 FB |title=The hypnozoite and relapse in primate malaria |journal=Clin. Microbiol. Rev. |volume=5 |issue=1 |pages=26–35 |year=1992 |month=January |pmid=1735093 |pmc=358221 |doi= |url=http://cmr.asm.org/cgi/pmidlookup?view=long&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 |journal=Clin. Microbiol. Rev. |volume=13 |issue=3 |pages=439–50 |year=2000 |month=July |pmid=10885986 |pmc=88942 |doi=10.1128/CMR.13.3.439-450.2000 |url=http://cmr.asm.org/cgi/pmidlookup?view=long&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 | pmid = 12377286 | doi = 10.1016/S1471-4922(02)02353-X}}</ref>

Although the white 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 effectively limitless versions within parasite populations.<ref name=Chen/>  The parasite switches between a broad repertoire of PfEMP17 surface proteins, thus staying one step ahead of the pursuing immune system.

Some merozoites turn into male and female [[gametocyte]]s. Since the gametocytes are formed in the blood of the vertebrate host, the vertebrate host is the [[definitive host]] of the disease. 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. 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 | page = 1972 | year = 2000 | pmid = 10859048 | doi = 10.1016/S0140-6736(00)02334-5}}</ref> and [[pregnancy-associated malaria|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 | date =  August 1, 2004 | pmid = 15331817 }}</ref> particularly in ''P. falciparum'' infection, but also in other species infection, such as ''P. vivax''.<ref name="rodriguezmorales2006">{{Cite journal| author=Rodriguez-Morales AJ, Sanchez E, Vargas M, Piccolo C, Colina R, Arria M, Franco-Paredes C | title=Pregnancy outcomes associated with Plasmodium vivax malaria in northeastern Venezuela | journal=Am J Trop Med Hyg | year=2006 | volume=74 | pages=755–757  | pmid = 16687675 | issue=5}}</ref>

===Genetic resistance===
{{Main|Genetic resistance to malaria}}
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. |volume=77 |issue=2 |pages=171–92 |year=2005 |month=August |pmid=16001361 |pmc=1224522 |doi=10.1086/432519 }}</ref> This is due to the high levels of [[death|mortality]] and [[morbidity]] caused by malaria, especially the ''[[Plasmodium falciparum|P. falciparum]]'' species. A number of diseases may provide some resistance to it including [[sickle cell disease]], [[thalassaemias]], [[glucose-6-phosphate dehydrogenase]], [[Duffy antigen]]s, and possibly others.

==Diagnosis==
The mainstay of malaria diagnosis has been the microscopic examination of blood.<ref>{{cite journal |author=Krafts K, Hempelmann E, Oleksyn B |title=The color purple: from royalty to laboratory, with apologies to Malachowski |journal= Biotech Histochem |volume=86 |pages=7–35|year=2011|pmid= 21235291| doi = 10.3109/10520295.2010.515490}}</ref> Although blood is the sample most frequently used to make a diagnosis, both saliva and urine have been investigated as alternative, less invasive specimens.<ref name="Sutherland2009">{{Cite journal|author=Sutherland CJ, Hallett R|title=Detecting malaria parasites outside the blood|journal=J Infect Dis|year=2009|volume=199|issue=11|pages=1561–1563|doi=10.1086/598857|pmid=19432543|last1=Sutherland|first1=CJ|last2=Hallett|first2=R}}</ref>

Areas that cannot afford 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 when clinical predictors (rectal temperature, nailbed pallor, and splenomegaly) were used as treatment indications, rather than using only a history of subjective fevers, a correct diagnosis increased from 2% to 41% of cases, and unnecessary treatment for malaria was significantly decreased.<ref name="Redd S, Kazembe P, Luby S, Nwanyanwu O, Hightower A, Ziba C, Wirima J, Chitsulo L, Franco C, Olivar M 2006 80">{{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 | page = 80 | year = 2006 |pmid=8551881 | doi = 10.1016/S0140-6736(96)90404-3}}</ref>
</br>

===Blood films===
{| class="wikitable" style = "float: right; margin-left:15px; text-align:center"
|-
! Species
! Appearance
! Periodicity
! Liver persistent
|-
| ''[[Plasmodium vivax]]''
| [[Image:Plasmodium vivax 01.png|center|100px]]
| tertian
| yes
|-
| ''[[Plasmodium ovale]]''
| [[Image:Plasmodium ovale 01.png|center|100px]]
| tertian
| yes
|-
| ''[[Plasmodium falciparum]]''
| [[Image:Plasmodium falciparum 01.png|center|100px]]
| tertian
| no
|-
| ''[[Plasmodium malariae]]''
| [[Image:Mature Plasmodium malariae schizont PHIL 2715 lores.jpg|center|100px]]
| quartan
| no
|}

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 |pmid=8813948 |doi = 10.1136/jcp.49.7.533 |issue=7 | pmc=500564}}</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 {{Citation needed|date=April 2011}}. Diagnosis of species 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.

One important thing to note is that ''P. malariae'' and ''P. knowlesi'' (which is the most common cause of malaria in [[South-east Asia]]) look very similar under the microscope. However, ''P. knowlesi'' parasitemia increases very fast and causes more severe disease than ''P. malariae'', so it is important to identify and treat infections quickly. Therefore modern methods such as PCR (see "Molecular methods" below) or [[monoclonal antibody]] panels that can distinguish between the two should be used in this part of the world.<ref>{{Cite journal
|last = McCutchan
|first = Thomas F.
|authorlink =
|coauthors = Robert C. Piper, and Michael T. Makler
|title = Use of Malaria Rapid Diagnostic Test to Identify Plasmodium knowlesi Infection
|journal = Emerging Infectious Disease
|volume = 14
|issue = 11
|pages = 1750–1752
|publisher = Centers for Disease Control
|location =
|year = 2008 |month = November
|pmc=2630758
|issn =
|doi = 10.3201/eid1411.080840
|accessdate =
|pmid=18976561}}</ref>

===Antigen tests===
{{see also|Malaria antigen detection tests}}
For areas where microscopy is not available, or where laboratory staff are not experienced at malaria diagnosis, there are commercial 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  | pmid=16117960 | doi=10.1016/S0035-9203(03)80100-1 | issue=6}}</ref>  Immunochromatographic tests (also called: [[Malaria antigen detection tests|Malaria Rapid Diagnostic Tests]], Antigen-Capture Assay or "[[Dipsticks]]") have been developed, distributed and fieldtested. These tests use finger-stick or venous blood, the completed test takes a total of 15–20 minutes, and the results are read visually as the presence or absence of colored stripes on the dipstick, so they are suitable for use in the field. The threshold of detection by these rapid diagnostic tests is in the range of 100 parasites/µl of blood (commercial kits can range from about 0.002% to 0.1% parasitemia) compared to 5 by thick film microscopy. One disadvantage is that dipstick tests are qualitative but not quantitative – they can determine if parasites are present in the blood, but not how many.

The first rapid diagnostic tests were using ''P. falciparum'' [[glutamate dehydrogenase]] as antigen.<ref>{{Cite journal| author=Ling IT., Cooksley S., Bates PA., Hempelmann E., Wilson RJM.
| title=Antibodies to the glutamate dehydrogenase of Plasmodium falciparum
| journal=Parasitology | year=1986 | volume=92 | pages=313–24  | pmid=3086819 | doi=10.1017/S0031182000064088 }}</ref>
PGluDH was soon replaced by ''P.falciparum'' [[lactate dehydrogenase]], a 33 kDa [[oxidoreductase]] [EC 1.1.1.27]. It is the last enzyme of the [[glycolysis|glycolytic]] pathway, essential for [[adenosine triphosphate|ATP]] generation and one of the most abundant enzymes expressed by ''P.falciparum''. PLDH does not persist in the blood but clears about the same time as the parasites following successful treatment. The lack of antigen persistence after treatment makes the pLDH test useful in predicting treatment failure. In this respect, pLDH is similar to pGluDH. Depending on which [[monoclonal antibodies]] are used, this type of assay can distinguish between all five different species of human malaria parasites, because of antigenic differences between their pLDH isoenzymes.

===Molecular methods===
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 |page=80 |pmid=17018138 |last1=Mens |first1=PF |last2=Schoone |first2=GJ |last3=Kager |first3=PA |last4=Schallig |first4=HD |pmc=1592503 }}</ref> are being developed with the hope of being able to deploy them in endemic areas.

PCR (and other molecular methods) 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 parasitemia in the field.<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 |page=80 |year=2006 |pmid=8551881 |doi=10.1016/S0140-6736(96)90404-3}}</ref>

===Differential===
Fever and septic shock are commonly misdiagnosed as severe malaria 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>{{Cite journal|author=Beare NA, Taylor TE, Harding SP, Lewallen S, Molyneux ME |title=Malarial retinopathy: a newly established diagnostic sign in severe malaria |journal=Am. J. Trop. Med. Hyg. |volume=75 |issue=5 |pages=790–7 |year=2006 |month=November |pmid=17123967 |pmc=2367432 |doi= |url=http://www.ajtmh.org/cgi/pmidlookup?view=long&pmid=17123967}}</ref>

==Prevention==
<!-- The list of methods seems to put the least cost-effective first. What's the reason for that? -->
[[Image:Anopheles albimanus mosquito.jpg|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 in order 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.

The continued existence of malaria in an area requires a combination of high human population density, high mosquito population density and high rates of transmission from humans to mosquitoes and from mosquitoes to humans. If any of these is lowered sufficiently, the parasite will sooner or later disappear from that area, as happened in [[North America]], [[Europe]] and much of [[Middle East]]. However, unless the parasite is eliminated from the whole world, it could become re-established if conditions revert to a combination that favours the parasite's reproduction.{{citation needed|date=October 2010}} Many countries are seeing an increasing number of imported malaria cases owing to extensive travel and migration.

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.<ref name="Medical News Today">{{Cite web|url=http://www.medicalnewstoday.com/articles/74907.php |title=Medical News Today, 2007 |publisher=Medicalnewstoday.com |date= |accessdate=2010-08-24}}</ref>

A 2008 study that examined international financing of malaria control found large regional variations in the levels of average annual per capita funding ranging from US$0.01 in Myanmar to US$147 in Suriname. The study found 34 countries where the funding was less than US$1 per capita, including 16 countries where annual malaria support was less than US$0.5. The 16 countries included 710 million people or 50% of the global population exposed to the risks of malaria transmission, including seven of the poorest countries in Africa (Côte d'Ivoire, Republic of the Congo, Chad, Mali, Democratic Republic of the Congo, Somalia, and Guinea) and two of the most densely populated stable endemic countries in the world (Indonesia and India).<ref name="plos-snow">{{cite journal|last=Snow|first=Robert W.|coauthors=Carlos A. Guerra, Juliette J. Mutheu, Simon I. Hay|year=2008|title=International Funding for Malaria Control in Relation to Populations at Risk of Stable Plasmodium falciparum Transmission|journal=PLoS Medicine|pmid=18651785|publisher=Public Library of Science|pages=e142|volume=5|pmc=2488181|issue=7|doi=10.1371/journal.pmed.0050142}}</ref>

[[Brazil]], [[Eritrea]], [[India]], and [[Vietnam]], unlike many other developing nations, have  successfully reduced the malaria burden. Common success factors have 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 | pmid = 16407339}}</ref>

===Medications===
{{Main|Malaria prophylaxis}}

Several drugs, most of which are also used for treatment of malaria, can be taken preventively.  Modern drugs used include [[mefloquine]] (''Lariam''), [[doxycycline]] (available generically), and the combination of [[atovaquone]] and [[proguanil]] hydrochloride (''Malarone''). Doxycycline and the atovaquone and proguanil combination are the best tolerated with mefloquine associated with higher rates of neurological and psychiatric symptoms.<ref>{{Cite journal|author=Jacquerioz FA, Croft AM |title=Drugs for preventing malaria in travellers |journal=Cochrane Database Syst Rev |volume= |issue=4 |pages=CD006491 |year=2009 |pmid=19821371 |doi=10.1002/14651858.CD006491.pub2 |url=}}</ref> 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).  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 historically, however the development of more effective alternatives such as [[quinacrine]], [[chloroquine]], and [[primaquine]] in the 20th century reduced its use. Today, quinine is not generally used for prophylaxis.  The use of prophylactic drugs where malaria-bearing mosquitoes are present may encourage the development of partial immunity.<ref>{{Cite journal|author=Roestenberg M, McCall M, Hopman J, ''et al.'' |title=Protection against a malaria challenge by sporozoite inoculation |journal=N. Engl. J. Med. |volume=361 |issue=5 |pages=468–77 |year=2009 |month=July |pmid=19641203 |doi=10.1056/NEJMoa0805832}}</ref>

===Vector control===
{{further|[[Mosquito control]]}}

Efforts to [[Eradication of infectious diseases|eradicate]] malaria by eliminating mosquitoes have been successful in some areas.  Malaria was once common in the [[United States]] and southern [[Europe]], but vector control programs, in conjunction with the monitoring and treatment of infected humans, eliminated it from those regions. In some areas, the draining of wetland breeding grounds and better sanitation were adequate. Malaria was eliminated from most parts of the USA in the early 20th century by such methods, and the use of the [[pesticide]] [[DDT]] and other means eliminated it from the remaining pockets in the South by 1951<ref name=CDChistory>http://www.cdc.gov/malaria/history/eradication_us.htm Centers for Disease Control. ''Eradication of Malaria in the United States (1947–1951)'' 2004.</ref> (see [[National Malaria Eradication Program]]).  In 2002, there were 1,059 cases of malaria reported in the US, including eight deaths, but in only five of those cases was the disease contracted in the United States.

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 = e192 | year = 2002 | pmid = 12383612 | doi = 10.1016/S1473-3099(02)00397-3}}</ref>

[[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  | pmid=12024215 | doi = 10.1038/417452a | issue=6887}}</ref> Successful replacement of current populations with a new genetically modified population, relies upon a drive mechanism, such as [[transposable elements]] to allow for non-Mendelian inheritance of the gene of interest. However, this approach contains many difficulties and success is a distant prospect.<ref>Knols et al., 2007</ref> An even more futuristic method of vector control is the idea that [[laser]]s could be used to kill flying mosquitoes.<ref>{{Cite news|url=http://online.wsj.com/article/SB123680870885500701.html |title=Rocket Scientists Shoot Down Mosquitoes With Lasers |publisher=WSJ.com |author=Robert Guth |accessdate=8 July 2009 | date=2009-03-14}}</ref>

===Indoor residual spraying===
{{Main|Indoor residual spraying|DDT use against malaria}}
Indoor residual spraying (IRS) is the practice of spraying insecticides on the interior walls of homes in malaria affected areas. After feeding, many mosquito species rest on a nearby surface while digesting the bloodmeal, so if the walls of dwellings have been coated with insecticides, the resting mosquitos will be killed before they can bite another victim, transferring the malaria parasite.

The first pesticide used for IRS was [[DDT]].<ref name=CDChistory/> Although it was initially used exclusively to combat malaria, its use quickly spread to [[agriculture]]. In time, pest-control, rather than disease-control, came to dominate DDT use, and this large-scale agricultural use led to the [[evolution]] of resistant mosquitoes in many regions. The DDT resistance shown by Anopheles mosquitoes can be compared to antibiotic resistance shown by bacteria. The overuse of anti-bacterial soaps and antibiotics led to antibiotic resistance in bacteria, similar to how overspraying of DDT on crops led to DDT resistance in Anopheles mosquitoes.  During the 1960s, awareness of the negative consequences of its indiscriminate use increased, ultimately leading to bans on agricultural applications of DDT in many countries in the 1970s.  Since the use of DDT has been limited or banned for agricultural use for some time, DDT may now be more effective as a method of disease-control.

Although DDT has never been banned for use in malaria control and there are several other insecticides suitable for IRS, some advocates have claimed that bans are responsible for tens of millions of deaths in tropical countries where DDT had once been effective in controlling malaria.<!-- these claims seem less and less notable -->  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 12 different insecticides in IRS operations, including DDT as well as alternative insecticides (such as the pyrethroids [[permethrin]] and [[deltamethrin]]).<ref>[http://whqlibdoc.who.int/hq/2006/WHO_HTM_MAL_2006.1112_eng.pdf Indoor Residual Spraying: Use of Indoor Residual Spraying for Scaling Up Global Malaria Control and Elimination.] World Health Organization, 2006.</ref> This public health use of small amounts of DDT is permitted under the [[Stockholm Convention]] on [[Persistent Organic Pollutant]]s (POPs), which prohibits the agricultural use of DDT.<ref name="van den Berg2009">{{Cite journal|last=van den Berg|first=Henk|year=2009|title=Global Status of DDT and Its Alternatives for Use in Vector Control to Prevent Disease|journal=Environmental Health Perspectives|volume=117|issue=11|pages=1656–1663|issn=0091-6765|pmid=20049114|pmc=2801202|doi=10.1289/ehp.0900785}}</ref>  However, because of its legacy, many developed countries previously discouraged DDT use even in small quantities.<ref>{{Cite news| last= Rosenberg | first= Tina |title= What the world needs now is DDT | publisher= New York Times |date=   April 11, 2004 | url= http://query.nytimes.com/gst/fullpage.html?sec=health&res=9F0DEEDA1738F932A25757C0A9629C8B63 | accessdate= 2008-11-03}}</ref>

One problem with all forms of Indoor Residual Spraying is insecticide [[Pesticide resistance|resistance]] via evolution of mosquitos. According to a study published on Mosquito Behavior and Vector Control, mosquito species that are affected by IRS are endophilic species (species that tend to rest and live indoors), and due to the irritation caused by spraying, their evolutionary descendants are trending towards becoming exophilic (species that tend to rest and live out of doors), meaning that they are not as affected—if affected at all—by the IRS, rendering it somewhat useless as a defense mechanism.<ref>Pates, H & Curtis, C.:"Mosquito behaviour and vector control", page 53-70. Annual Review on Entomology, 50, 2005.</ref>

====Mosquito nets and bedclothes====
{{Main|Mosquito net}}
Mosquito nets help keep mosquitoes away from people and greatly reduce the infection and transmission of malaria.  The nets are not a perfect barrier and 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 (ITNs) are estimated to be twice as effective as untreated nets and offer greater than 70% protection compared with no net.<ref>{{Cite journal|author=Bachou H, Tylleskär T, Kaddu-Mulindwa DH, Tumwine JK |title=Bacteraemia among severely malnourished children infected and uninfected with the human immunodeficiency virus-1 in Kampala, Uganda |journal=BMC Infect. Dis. |volume=6 |issue= |page=160 |year=2006 |pmid=17090299 |pmc=1660577 |doi=10.1186/1471-2334-6-160 |url=}}</ref> Although ITNs are proven to be very effective against malaria, less than 2% of children in urban areas in Sub-Saharan Africa are protected by ITNs.  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.

===Vaccination===
{{Main|Malaria vaccine}}

Immunity (or, more accurately, tolerance) does occur naturally, but only in response to repeated infection with multiple strains of malaria.<ref>{{Cite journal|author=Färnert A, Williams TN, Mwangi TW, ''et al.''|title=Transmission‐dependent tolerance to multiclonal ''Plasmodium falciparum'' infection|journal=J Infect Dis|year=2009|volume=200|issue=7|pages=1166–1175|doi=10.1086/605652|pmid=19702508|last1=Färnert|first1=A|last2=Williams|first2=TN|last3=Mwangi|first3=TW|last4=Ehlin|first4=A|last5=Fegan|first5=G|last6=Macharia|first6=A|last7=Lowe|first7=BS|last8=Montgomery|first8=SM|last9=Marsh|first9=K|pmc=2741682}}</ref> [[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 | doi = 10.1038/216160a0}}</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 1,000 bites from infected yet 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 = 10.1086/339409 |last12=Stoute |first12=JA |last13=Church |first13=LW |last14=Sedegah |first14=M |last15=Heppner |first15=DG |last16=Ballou |first16=WR |last17=Richie |first17=TL}}</ref>

===Other methods===
Education in recognizing the symptoms of malaria has reduced the number of cases in some areas of the developing world by as much as 20%.  Recognizing 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 stagnant, still water e.g. Water Tanks which are ideal breeding grounds for the parasite and mosquito, thus cutting down the risk of the transmission between people.  This is most put in practice in urban areas where there are large centers of population in a confined space and transmission would be most likely in these areas.

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>

An example of the importance of computer modeling in planning malaria [[Eradication of infectious diseases|eradication]] programs is shown in the paper by Águas and others.  They showed that eradication of malaria is crucially dependent on finding and treating the large number of people in endemic areas with asymptomatic malaria, who act as a reservoir for infection.<ref>{{Cite journal|author=Águas R, White LJ, Snow RW, Gomes MG |title=Prospects for malaria eradication in sub-Saharan Africa |journal=PLoS ONE |volume=3 |issue=3 |pages=e1767 |year=2008 |pmid=18335042 |pmc=2262141 |doi=10.1371/journal.pone.0001767 |url=}}</ref>  The malaria parasites do not affect animal species and therefore eradication of the disease from the human population would be expected to be effective.

Other interventions for the control of  malaria include [[mass drug administration]]s and [[intermittent preventive therapy]].

Furthering attempts to reduce transmission rates, a proposed alternative to mosquito nets is the [[mosquito laser]], or photonic fence, which identifies female mosquitoes and shoots them using a medium-powered [[laser]].<ref>[http://www.physics.org/featuredetail.asp?id=48 Laser pest control] physics.org, May 2010</ref> The device is currently undergoing commercial development, although instructions for a [[do it yourself|DIY]] version of the photonic fence have also been published.<ref>Kare, Jordin. [http://spectrum.ieee.org/consumer-electronics/gadgets/backyard-star-wars "Backyard Star Wars: Build your own photonic fence to zap mosquitoes midflight"]. [http://spectrum.ieee.org IEEE Spectrum] (2010 May).</ref>

Another way of reducing the malaria transmitted to humans from mosquitoes has been developed by the University of Arizona. They have engineered a mosquito to become resistant to malaria. This was reported on the 16 July 2010 in the journal ''[[PLoS Pathogens]]''.<ref>{{Cite journal|author=Corby-Harris V, Drexler A, Watkins de Jong L, Antonova Y, Pakpour N, ''et al.'' |year=2010 |title=Activation of ''Akt'' Signaling Reduces the Prevalence and Intensity of Malaria Parasite Infection and Lifespan in ''Anopheles stephensi'' Mosquitoes |journal=PLoS Pathog |pmid=20664791 |volume=6 |issue=7 |pmc=2904800 |pages=e1001003 |doi=10.1371/journal.ppat.1001003}}</ref> With the ultimate end being that the release of this GM mosquito into the environment,  Gareth Lycett, a malaria researcher from Liverpool School of Tropical Medicine told the BBC that "It is another step on the journey towards potentially assisting malaria control through GM mosquito release."<ref>{{Cite news|url=http://www.bbc.co.uk/news/science-environment-10654599 |title=Malaria-proof mosquito engineered |date=16 July 2010 |first=Victoria |last=Gill |newspaper=[[BBC News Online]]}}</ref>

==Treatment==
{{See|Antimalarial drug}}
When properly treated, a patient with malaria can expect a complete recovery.<ref>[http://www.cdc.gov/malaria/about/faqs.html#treatment If I get malaria, will I have it for the rest of my life?] CDC publication, Accessed 14 November 2006.</ref> The treatment of malaria depends on the severity of the disease; whether patients who can take oral drugs have to be admitted depends on the assessment and the experience of the clinician. Uncomplicated malaria is treated with oral drugs. The most effective strategy for ''P. falciparum'' infection recommended by [[WHO]] is the use of artemisinins in combination with other antimalarials artemisinin-combination therapy, ACT, in order to avoid the development of drug resistance against [[artemisinin]]-based therapies.

Severe malaria requires the [[parenteral administration]] of antimalarial drugs. Until recently the most used treatment for severe malaria was [[quinine]] but [[artesunate]] has been shown to be superior to quinine in both children <ref>{{cite journal |author=Dondorp AM, Fanello CI, Hendriksen IC, ''et al.'' |title=Artesunate versus quinine in the treatment of severe falciparum malaria in African children (AQUAMAT): an open-label, randomised trial |journal=Lancet |volume=376 |issue=9753 |pages=1647–57 |year=2010 |month=November |pmid=21062666 |pmc=3033534 |doi=10.1016/S0140-6736(10)61924-1 |url=}}</ref> and adults.<ref>{{cite journal |author=Dondorp A, Nosten F, Stepniewska K, Day N, White N |title=Artesunate versus quinine for treatment of severe falciparum malaria: a randomised trial |journal=Lancet |volume=366 |issue=9487 |pages=717–25 |year=2005 |pmid=16125588 |doi=10.1016/S0140-6736(05)67176-0 |url=}}</ref> Treatment of severe malaria also involves supportive measures.

Infection with ''P. vivax'', ''P. ovale'' or ''P. malariae'' is usually treated on an outpatient basis. Treatment of ''P. vivax'' requires both treatment of blood stages (with chloroquine or ACT) as well as clearance of liver forms with [[primaquine]].

It is advised to be cautious diagnosing and treating without the presence of a headache, as it is possible that the patient has [[dengue]]; not malaria.<ref>http://books.google.com/books?id=tYJV5_zchjcC&pg=PA262&dq=night+sweats&hl=en&ei=TerPTc_6JOnL0AGHq7yXCg&sa=X&oi=book_result&ct=result&resnum=3&ved=0CGoQ6AEwAjgU#v=onepage&q=night%20sweats&f=false</ref>

==Epidemiology==
[[Image:Malaria geographic distribution 2003.png|thumb|Countries which have regions where malaria is [[Endemic (epidemiology)|endemic]] as of 2003 (coloured yellow).<ref name='CDC Malaria distribution'>{{Cite web|url=http://www.dpd.cdc.gov/dpdx/HTML/ImageLibrary/Malaria_il.htm |title=Malaria |accessdate=2008-07-20 |year=2003 |publisher=[[US Centers for Disease Control and Prevention]] }}</ref> Countries in green are free of indigenous cases of malaria in all areas.]]
[[Image:Malaria world map - DALY - WHO2002.svg|thumb|[[Disability-adjusted life year]] for malaria per 100,000&nbsp;inhabitants in 2002.<div class="references-small" style="-moz-column-count:2; column-count:2;">
{{legend|#b3b3b3|no data}}
{{legend|#ffff65|≤10}}
{{legend|#fff200|10–50}}
{{legend|#ffdc00|50–100}}
{{legend|#ffc600|100–250}}
{{legend|#ffb000|250–500}}
{{legend|#ff9a00|500–1000}}
{{legend|#ff8400|1000–1500}}
{{legend|#ff6e00|1500–2000}}
{{legend|#ff5800|2000–2500}}
{{legend|#ff4200|2500–3000}}
{{legend|#ff2c00|3000–3500}}
{{legend|#cb0000|≥3500}}
</div>]]
It is estimated that malaria causes 250 million cases of fever and approximately one million deaths annually.<ref name=wmr08>2005 WHO [http://www.who.int/entity/pmnch/topics/add_publications/2008_worldmalariarep/en/ World Malaria Report 2008]</ref> The vast majority of cases occur in children under 5 years old;<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 | doi = 10.1016/S0140-6736(05)66420-3 | issue=9469}}</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 | doi = 10.1016/S1473-3099(04)01043-6}}</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. As a consequence, the majority of cases are undocumented.<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/content/abstract/64/1_suppl/1 | journal = Am J Trop Med Hyg | date =  January 1, 2001 | volume = 64 | issue = 1–2 Suppl | pages = 1–11 | pmid = 11425172 }}</ref>

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 | doi = 10.1126/science.1132338}}</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– 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://www.ph.ucla.edu/epi/layne/Epidemiology+220/07.malaria.pdf | archiveurl = http://web.archive.org/web/20060220083223/http://www.ph.ucla.edu/epi/layne/Epidemiology+220/07.malaria.pdf | archivedate = 2006-02-20 | accessdate = 2007-06-15|format=PDF}}</ref> The geographic distribution of malaria within large regions is complex, and malaria-afflicted 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 | doi = 10.1038/415670a | issue=6872}}</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= | journal = Malar J | volume = 4 | issue = | page = 6 | year = 2005 | pmc = 548290 | pmid = 15663795 | doi = 10.1186/1475-2875-4-6}}</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 |date= February 1, 2005 | pmid = 15741558 }}</ref> For example, several cities in [[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 = e473 |year=2004 | pmid = 15040560 | doi = 10.1046/j.1365-3156.2003.01179.x}}</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 |date= August 1, 2004 |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 | doi =  10.1371/journal.pmed.0030473 | journal = PLoS Medicine | volume = 3 | issue = 12 | pages = e473 | year = 2006 |pmid=17147467 |pmc=1762059 }}</ref> to rectify this, providing a more contemporary and robust means with which to assess current and future malaria [[disease burden]].

By 2010 countries with the highest death rate per 100,000 population are [[Cote d'Ivoire]] with (86.15), [[Angola]] (56.93) and [[Burkina Faso]] (50.66) - all in Africa.<ref>http://www.guardian.co.uk/global-development/datablog/2011/apr/25/world-malaria-day-data#data</ref>

==History==
{{Main|History of malaria}}

Malaria has infected humans for over 50,000 years, and ''Plasmodium'' may have been a human [[pathogen]] for the entire history of the 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 | doi = 10.1126/science.1081449 | last12 = Su | first12 = XZ}}</ref> Close relatives of the human malaria parasites remain common in chimpanzees.<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 | doi= 10.1073/pnas.95.14.8124 | journal = Proc Natl Acad Sci USA | volume = 95 | issue = 14 | pages = 8124–9 | year = 1998 | pmid = 9653151 | pmc = 20940}}</ref>  Some new evidence suggests that the most virulent strain of human malaria may have originated in gorillas.<ref name="Liu et al., 2010">{{Cite journal| volume = 467| last = Liu| first = W| coauthors = Y Li, GH Learn, RS Rudicell, JD Robertson, BF Keele, JN Ndjango, CM Sanz, DB Morgan, S Locatelli, MK Gonder, PJ Kranzusch, PD Walsh, E Delaporte, E Mpoudi-Ngole, AV Georgiev, MN Muller, GM Shaw, M Peeters, PM Sharp, JC Rayner, BH Hahn | title = Origin of the human malaria parasite ''Plasmodium falciparum'' in gorillas.| journal = Nature| year = 2010}}</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= | pmc = 126866 | journal = Clin Microbiol Rev | volume = 15 | issue = 4 | pages = 595–612 | year = 2002 | pmid = 12364371 | doi = 10.1128/CMR.15.4.595-612.2002}}</ref> Malaria may have contributed to the decline of the [[Roman Empire]],<ref>[http://news.bbc.co.uk/2/hi/science/nature/1180469.stm DNA clues to malaria in ancient Rome]. ''BBC News.'' February 20, 2001.</ref> and was so pervasive in Rome that it was known as the "[[Roman Fever (disease)|Roman fever]]".<ref>[http://www.abc.net.au/rn/talks/perspective/stories/s776423.htm "Malaria and Rome"]. Robert Sallares. ''ABC.net.au.'' January  29, 2003.</ref> The term malaria originates from [[Middle Ages|Medieval]] {{lang-it|mala aria}}&nbsp;— "[[miasma theory of disease|bad air]]"; the disease was formerly called ''ague'' or ''marsh fever'' due to its association with swamps and marshland.<ref>[http://www.cdc.gov/ncidod/EID/vol6no1/reiter.htm From Shakespeare to Defoe: Malaria in England in the Little Ice Age]. Paul Reiter. ''Centers for Disease Control and Prevention, San Juan, Puerto Rico.''</ref> Malaria was once common in most of Europe and North America,<ref>"''[http://books.google.com/books?id=fQxAkrbksTEC&pg=PA62&dq&hl=en#v=onepage&q=&f=false Medicine and society in early modern Europe]''". Mary Lindemann (1999). [[Cambridge University Press]]. p.62. ISBN 0521423546</ref> where it is no longer [[Endemic (epidemiology)|endemic]],<ref>[http://www.cambridge.org/catalogue/catalogue.asp?isbn=9780511254819&ss=exc Vector- and Rodent-Borne Diseases in Europe and North America]. Norman G. Gratz. ''World Health Organization, Geneva.''</ref> though imported cases do occur.<ref>James L. A. Webb, Jr., ''Humanity’s Burden: A Global History of Malaria'' (Cambridge University Press, 2009)</ref>

Malaria was the most important health hazard encountered by U.S. troops in the South Pacific during [[World War II]], where about 500,000 men were infected.<ref>"''[http://books.google.com/books?id=djPWGnvBm08C&pg=PA102&dq&hl=en#v=onepage&q=&f=false Armies of pestilence: the effects of pandemics on history]''". James Clarke & Co. (2004). p.102. ISBN 022717240X</ref> According to Joseph Patrick Byrne, "Sixty thousand American soldiers died of malaria during the African and South Pacific campaigns."<ref>"''[http://books.google.com/books?id=5Pvi-ksuKFIC&pg=PA383&dq&hl=en#v=onepage&q=&f=false Encyclopedia of Pestilence, Pandemics, and Plagues: A-M]''". Joseph Patrick Byrne (2008). p.383. ISBN 0313341028</ref>

===Prevention===
An early effort at malaria prevention occurred in 1896, just before the mosquito malaria link was confirmed in India by a British physician, [[Ronald Ross]]. An 1896 [[Uxbridge, Massachusetts|Uxbridge]] malaria outbreak prompted health officer, [[Leonard White (physician)|Dr. Leonard White]], to write a report to the [[Massachusetts]] State Board of Health, which led to study of mosquito-malaria links, and the first efforts for malaria [[preventive medicine|prevention]].<ref name="malaria"/> [[Massachusetts]] State [[pathologist]] Theobald Smith, asked that White's son collect mosquito specimens for further analysis, and that citizens 1) add screens to windows, and 2) drain collections of water.<ref name="malaria">{{cite web |title=A History of Mosquitoes in Massachusetts, by Curtis R. Best |publisher=Northeast Mosquito Control Association |url=http://www.nmca.org/Nmca93-4.htm |accessdate=2008-03-31}}</ref> [[Carlos Finlay]] was also engaged in mosquito related research, and mosquito borne disease theory, in the 1880s in [[Cuba]], basing his work on the study of [[Yellow Fever]].

===Discovery of the parasite===
[[File:Dr Proberts Malarial Remedy c1881.jpg|thumb|Dr. Probert's Malarial Remedy,<br>"Will cure chills and fever, dyspepsia & c. Will cure bilious fever, liver complaint & c.", c.1881, New York]]

[[File:P.falciparum Gelatine enrichment.jpg|thumb|A continuous ''[[Malaria culture|P. falciparum]]'' culture was established in 1976]]
Scientific studies on malaria made their first significant advance in 1880, when a French army doctor working in the military hospital of [[Constantine, Algeria|Constantine]] in [[Algeria]] named [[Charles Louis Alphonse Laveran]] observed parasites for the first time, inside the [[red blood cell]]s of people suffering from malaria. He, therefore, proposed that malaria is caused by this organism, the first time a protist was 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 October 2006</ref> For this and later discoveries, he was awarded the 1907 [[Nobel Prize for Physiology or Medicine]]. The malarial parasite 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>

===Discovery of mosquito transmission===
A year later, [[Carlos Finlay]], a Cuban doctor treating patients with [[yellow fever]] in [[Havana]], provided strong evidence that mosquitoes were transmitting disease to and from humans.<ref>{{Cite journal|author=Tan SY, Sung H |title=Carlos Juan Finlay (1833–1915): of mosquitoes and yellow fever |journal=Singapore Med J |volume=49 |issue=5 |pages=370–1 |year=2008 |month=May |pmid=18465043 |url=http://smj.sma.org.sg/4905/4905ms1.pdf|format=PDF}}</ref> This work followed earlier suggestions by [[Josiah C. Nott]],<ref>{{Cite journal|author=Chernin E |title=Josiah Clark Nott, insects, and yellow fever |journal=Bull N Y Acad Med |volume=59 |issue=9 |pages=790–802 |year=1983 |month=November |pmid=6140039 |pmc=1911699 |url=}}</ref> and work by [[Patrick Manson]] on the transmission of [[filariasis]].<ref>{{Cite journal|author=Chernin E |title=Patrick Manson (1844–1922) and the transmission of filariasis |journal=Am. J. Trop. Med. Hyg. |volume=26 |issue=5 Pt 2 Suppl |pages=1065–70 |year=1977 |month=September |pmid=20786 |doi= |url=http://www.ajtmh.org/cgi/pmidlookup?view=long&pmid=20786}}</ref>

It was Britain's [[Ronald Ross|Sir Ronald Ross]], working in the [[Presidency General Hospital]] in [[Kolkata|Calcutta]], who finally proved in 1898 that malaria is transmitted by mosquitoes. He did this by showing that certain mosquito species transmit malaria to birds. He isolated 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 |archiveurl = http://web.archive.org/web/20070602185153/http://www.cdc.gov/malaria/history/ross.htm |archivedate = June 2, 2007}}</ref> The findings of Finlay and Ross were later confirmed by a medical board headed by [[Walter Reed]] in 1900.  Its recommendations were 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 the  disease.

===The liver stage===
Shortt and Garnham discovered the pre-erythrocytic liver stage, first in the primate parasite ''P. cynomolgi'' and subsequently the human malarias ''P. vivax'' <ref>{{cite journal |author=SHORTT HE, GARNHAM PC |title=The pre-erythrocytic stage of human malaria, Plasmodium vivax |journal=Br Med J |volume=1 |issue=4550 |pages=547 |year=1948 |month=March |pmid=18909485 |pmc=2090089 |doi= |url=}}</ref> and ''P. falciparum''.<ref>{{cite journal |author=SHORTT HE, FAIRLEY NH, COVELL G, SHUTE PG, GARNHAM PC |title=The pre-erythrocytic stage of Plasmodium falciparum |journal=Trans. R. Soc. Trop. Med. Hyg. |volume=44 |issue=4 |pages=405–19 |year=1951 |month=February |pmid=14817818 |doi= |url=}}</ref> Further work confirmed the transformation of sporozoites from mosquitoes into liver forms, essentially completing documentation of the lifecycle.<ref>{{cite journal |author=Meis JF, Verhave JP, Jap PH, Sinden RE, Meuwissen JH |title=Malaria parasites--discovery of the early liver form |journal=Nature |volume=302 |issue=5907 |pages=424–6 |year=1983 |pmid=6339945 |doi= |url=}}</ref>

===In vitro culture===
The first successful continuous in vitro [[malaria culture]] was established in 1976 by William Trager and James B. Jensen, which facilitated research into the molecular biology of the parasite and the development of new drugs.<ref>{{Cite journal| author = Trager W, Jensen JB | title = Human malaria parasites in continuous culture.| journal = Science| volume = 193 | issue = 4254 | pages = 673–675 | year = 1976 | pmid = 781840| doi=10.1126/science.781840}}</ref><ref>{{Cite journal| author = Schuster FL | title = Cultivation of plasmodium spp | journal = Clin Microbiol Rev.| volume = 15 | issue = 3 | pages = 355–364 | year = 2002 | pmid = 12097244 | url = http://cmr.asm.org/cgi/reprint/15/3/355 | doi = 10.1128/CMR.15.3.355-364.2002 | pmc = 118084 }}</ref>

===History of treatment===
The first effective treatment for malaria came from the bark of [[Cinchona|cinchona tree]], which contains [[quinine]]. This tree grows on the slopes of the [[Andes]], mainly in [[Peru]]. The [[indigenous peoples]] of Peru made a tincture of cinchona to control malaria.  The [[Jesuit]]s noted the efficacy of the practice and introduced the treatment 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 | doi = 10.1002/anie.200400663}}</ref> It was not until 1820 that the active ingredient, quinine, was extracted from the bark, isolated and named by the French chemists [[Pierre Joseph Pelletier]] and [[Joseph Bienaimé Caventou]].<ref>{{Cite journal|author=Kyle R, Shampe M |title=Discoverers of quinine |journal=JAMA |volume=229 |issue=4 | pages = e320 |year=1974 |pmid=4600403 | doi = 10.1001/jama.229.4.462}}</ref> In the 20th century, chloroquine replaced quinine as treatment of both uncomplicated and severe falciparum malaria until resistance supervened. [[Artemisinins]], discovered by Chinese scientists in the 1970s, are now recommended treatment for falciparum malaria, administered in combination with other antimalarials as well as in severe disease.

==Society and culture==
Malaria is not just a disease commonly associated with poverty but also a cause of poverty and a major hindrance to [[economic development]]. Tropical regions are affected most, however malaria’s furthest extent reaches into some temperate zones with extreme seasonal changes.  The disease has been associated with major negative economic effects on regions where it is widespread. During the late 19th and early 20th centuries, it was a major factor in the slow economic development of the American southern states.<ref name="humphreys">{{Cite book|last=Humphreys|first=M|title=Malaria: Poverty, Race, and Public Health in the United States|publisher=Johns Hopkins University Press|year=2001|page=256|isbn=0-8018-6637-5}}</ref> A comparison of average per capita GDP in 1995, adjusted for [[purchasing power parity|parity of purchasing power]], between countries with malaria and countries without malaria gives a fivefold difference ($1,526 USD versus $8,268 USD).  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 | doi = 10.1038/415680a | issue=6872}}</ref>

Poverty is both cause and effect, however, since the poor do not have the financial capacities to prevent or treat the disease. The lowest income group in Malawi carries (1994) the burden of having 32% of their annual income used on this disease compared with the 4% of household incomes from low-to-high groups.<ref>{{Cite journal|author=Ettling M, McFarland DA, Schultz LJ, Chitsulo L |title=Economic impact of malaria in Malawian households |journal=Trop. Med. Parasitol. |volume=45 |issue=1 |pages=74–9 |year=1994 |month=March |pmid=8066390}}</ref> In its entirety, the economic impact of malaria has been estimated to cost Africa $12 billion USD every year.  The economic impact includes costs of health care, working days lost due to sickness, days lost in education, decreased productivity due to brain damage from cerebral malaria, and loss of investment and tourism.<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 WHO partnership| title=Economic costs of malaria | url=http://www.rollbackmalaria.org/cmc_upload/0/000/015/363/RBMInfosheet_10.pdf|format=PDF|publisher=[[World Health Organization|WHO]] | accessdate=2009-09-18}}</ref>

A study on the effect of malaria on [[IQ]] in a sample of Mexicans found that exposure during the birth year to malaria eradication was associated with increases in IQ. It also increased the probability of employment in a skilled occupation. The author suggests that this may be one explanation for the [[Flynn effect]] and that this may be an important explanation for the link between national malaria burden and economic development.<ref>Venkataramani, Atheendar, Early Life Exposure to Malaria and Cognition and Skills in Adulthood: Evidence from Mexico (September 18, 2010). Available at SSRN: http://ssrn.com/abstract=1679164</ref> A literature review of 44 papers states that cognitive abilities and school performance were shown to be impaired in sub-groups of patients (with either cerebral malaria or uncomplicated malaria) when compared with healthy controls. Studies comparing cognitive functions before and after treatment for acute malarial illness continued to show significantly impaired school performance and cognitive abilities even after recovery. Malaria prophylaxis was shown to improve cognitive function and school performance in clinical trials when compared to placebo groups.<ref>The ‘hidden’ burden of malaria: cognitive
impairment following infection. Sumadhya D Fernando, Chaturaka Rodrigo, and Senaka Rajapakse. Malaria Journal 2010, 9:366. http://preview.malariajournal.com/content/pdf/1475-2875-9-366.pdf</ref> April 25 is [[World Malaria Day]].<ref>http://www.guardian.co.uk/global-development/datablog/2011/apr/25/world-malaria-day-data</ref>

===Counterfeit drugs===
Sophisticated [[counterfeit drugs|counterfeits]] have been found in several Asian countries such as [[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=1019–24
| doi=10.1016/j.trstmh.2006.01.003
| pmid=16765399
}}</ref> [[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 |format=PDF}}</ref> [[Indonesia]], [[Laos]], [[Thailand]], [[Vietnam]] and are an important cause of avoidable death in those 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=602–13
| pmid=16931411
| doi = 10.1016/S1473-3099(06)70581-3}}</ref>
[[WHO]] said that studies indicate that up to 40% of [[artesunate]] based malaria medications are counterfeit, especially in the Greater [[Mekong]] region and have established a rapid alert system to enable information about counterfeit drugs to be rapidly reported to the relevant authorities in participating countries.<ref>{{Cite web
| author=Jane Parry
| title=WHO combats counterfeit malaria drugs in Asia
| url=http://www.bmj.com/cgi/content/full/330/7499/1044-d
| accessdate=2008-07-19 | year=2005}}</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.

===War===
Throughout history, the contraction of malaria (via natural outbreaks as well as via infliction of the disease as a biological warfare agent) has played a prominent role in the fortunes of government rulers, nation-states, military personnel, and military actions. "Malaria Site: History of Malaria During Wars" addresses the devastating impact of malaria in numerous well-known conflicts, beginning in June 323 B.C. That site's authors note: "Many great warriors succumbed to malaria after returning from the warfront and advance of armies into continents was prevented by malaria. In many conflicts, more troops were killed by malaria than in combat."<ref name="malariasite1">http://www.malariasite.com/malaria/history_wars.htm</ref>  The [[Centers for Disease Control]] ("CDC") traces the history of malaria and its impacts farther back, to 2700 BCE.<ref name="autogenerated1">{{Cite web|url=http://www.cdc.gov/malaria/history/index.htm#mcwa |title=History &#124; CDC Malaria |publisher=Cdc.gov |date=2004-04-23 |accessdate=2010-08-24}}</ref>

In 1910, [[Nobel Prize in Medicine]]-winner [[Ronald Ross]] (himself a malaria survivor), published a book titled ''The Prevention of Malaria'' that included the chapter: "The Prevention of Malaria in War." The chapter's author, Colonel C. H. Melville, Professor of Hygiene at Royal Army Medical College in London, addressed the prominent role that malaria has historically played during wars and advised: "A specially selected medical officer should be placed in charge of these operations with executive and disciplinary powers [...]."

Significant financial investments have been made to fund procure existing and create new anti-malarial agents. During [[World War I]] and [[World War II]], the supplies of the natural anti-malaria drugs, [[cinchona bark]] and [[quinine]], proved to be inadequate to supply military personnel and substantial funding was funnelled into [[research and development]] of other drugs and vaccines.  American military organizations conducting such research initiatives include the Navy Medical Research Center, [[Walter Reed Army Institute of Research]], and the U.S. Army Medical Research Institute of Infectious Diseases of the US Armed Forces.<ref name="malariasite1"/>

Additionally, initiatives have been founded such as Malaria Control in War Areas (MCWA), established in 1942, and its successor, the Communicable Disease Center (now known as the Centers for Disease Control) established in 1946.  According to the CDC, MCWA "was established to control malaria around military training bases in the southern United States and its territories, where malaria was still problematic" and, during these activities, to "train state and local health department officials in malaria control techniques and strategies." The CDC's Malaria Division continued that mission, successfully reducing malaria in the United States, after which the organization expanded its focus to include "prevention, surveillance, and technical support both domestically and internationally."<ref name="autogenerated1"/>

==Research==
With the onset of drug resistant [[Plasmodium]] parasites, new strategies are required to combat the widespread disease. One such approach lies in the introduction of synthetic [[pyridoxal]]-amino acid adducts, which are channelled into the parasite. Thus, trapped upon [[phosphorylation]] by plasmodial PdxK (pyridoxine/[[pyridoxal kinase]]), the proliferation of Plasmodium parasites is effectively hindered by a novel compound, PT3, a cyclic pyridoxyl-tryptophan methyl ester, without harming human cells.<ref>{{cite journal |author=Müller IB, Wu F, Bergmann B, ''et al.'' |title=Poisoning pyridoxal 5-phosphate-dependent enzymes: a new strategy to target the malaria parasite Plasmodium falciparum |journal=PLoS ONE |volume=4 |issue=2 |pages=e4406 |year=2009 |pmid=19197387 |pmc=2634962 |doi=10.1371/journal.pone.0004406 |url=}}</ref>

==References==
{{Reflist|colwidth=35em}}

==Further reading==
* Packard, Randall M. ''The Making of a Tropical Disease: A Short History of Malaria'' (Johns Hopkins Biographies of Disease)  (2007)
* Shah, Sonia. ''The Fever: How Malaria Has Ruled Humankind for 500,000 Years'' (2010) [http://www.amazon.com/Fever-Malaria-Ruled-Humankind-Years/dp/0374230013/ excerpt and text search]
* Webb, Jr., James L. A. ''Humanity's Burden: A Global History of Malaria'' (Cambridge University Press, 2008) 236 pp.&nbsp;ISBN 978-0-521-67012-8 [http://www.amazon.com/Humanitys-Burden-History-Malaria-Environment/dp/0521670128/ excerpt and text search]

==External links==
{{commons category}}
* [http://www.who.int/malaria/ WHO site on malaria]
* [http://www.rollbackmalaria.org/gmap/ Global Malaria action Plan]
* [http://www.map.ox.ac.uk/ Malaria Atlas Project]
* [http://www.mmv.org Medicines for Malaria Venture (MMV)]
* [http://www.rollbackmalaria.org/wmr2005/ World Malaria Report 2005]
* [http://doctorswithoutborders.org/news/issue.cfm?id=2395 Doctors Without Borders/Médecins Sans Frontières – ''Malaria''] information pages
* [http://www.nlm.nih.gov/medlineplus/malaria.html Medline Plus – ''Malaria'']
* [http://www.wehi.edu.au/other_domains/MalDB/who.html Who/TDR Malaria Database]
* [http://www.antimalariaomd.org/en/index.php Anti malaria and sustainable development]
* [http://www.wwarn.org Worldwide Antimalarial Resistance Network (WWARN)]
* {{dmoz|Health/Conditions_and_Diseases/Infectious_Diseases/Parasitic/Malaria}}

{{Diseases of Poverty}}
{{Chromalveolate diseases}}

[[Category:Apicomplexa]]
[[Category:Insect-borne diseases]]
[[Category:Malaria]]
[[Category:Medical emergencies]]
[[Category:Protozoal diseases]]
[[Category:Tropical diseases]]
[[Category:Deaths from malaria]]
[[Category:Millennium Development Goals]]

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