“疟疾”:修订间差异

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除了蚊蟲感染之外,瘧原蟲也有可能藉由[[輸血]]感染,但此情況相當罕見。<ref name="Owusu-Ofori 2010"/>2006年,[[台北榮民總醫院]]發生了一起嚴重的[[院內感染]]案例,造成4名病患感染惡性瘧疾死亡,即因輸血方式不當。<ref name="Taipei">{{cite doi|10.1086/501557}}</ref>
除了蚊蟲感染之外,瘧原蟲也有可能藉由[[輸血]]感染,但此情況相當罕見。<ref name="Owusu-Ofori 2010"/>2006年,[[台北榮民總醫院]]發生了一起嚴重的[[院內感染]]案例,造成4名病患感染惡性瘧疾死亡,即因輸血方式不當。<ref name="Taipei">{{cite doi|10.1086/501557}}</ref>


{{TransH}}


===Recurrent malaria===
Symptoms of malaria can recur after varying symptom-free periods. Depending upon the cause, recurrence can be classified as either [[recrudescence]], [[relapse]], or reinfection. Recrudescence is when symptoms return after a symptom-free period. It is caused by parasites surviving in the blood as a result of inadequate or ineffective treatment.<ref>{{harvnb|WHO|2010|p=vi}}</ref> Relapse is when symptoms reappear after the parasites have been eliminated from blood but persist as dormant hypnozoites in liver cells. Relapse commonly occurs between 8–24 weeks and is commonly seen with ''P.&nbsp;vivax'' and ''P.&nbsp;ovale'' infections.<ref name="Nadjm 2012"/> ''P.&nbsp;vivax'' malaria cases in [[temperate]] areas often involve [[overwintering]] by hypnozoites, with relapses beginning the year after the mosquito bite.<ref name="White 2011"/> Reinfection means the parasite that caused the past infection was eliminated from the body but a new parasite was introduced. Reinfection cannot readily be distinguished from recrudescence, although recurrence of infection within two weeks of treatment for the initial infection is typically attributed to treatment failure.<ref>{{harvnb|WHO|2010|p=17}}</ref> People may develop some [[premunity|immunity]] when exposed to frequent infections.<ref name="Tran 2012"/>

==Pathophysiology==
{{further2|[[Plasmodium falciparum biology|''Plasmodium falciparum'' biology]]}}
[[File:Maternal malaria placenta - cropped - very high mag.jpg|thumb|right|[[Micrograph]] of a [[placenta]] from a [[stillbirth]] due to maternal malaria. [[H&E stain]]. Red blood cells are anuclear; blue/black staining in bright red structures (red blood cells) indicate foreign nuclei from the parasites.]]

Malaria infection develops via two phases: one that involves the [[liver]] (exoerythrocytic phase), and one that involves red blood cells, or [[erythrocyte]]s (erythrocytic phase). When an infected mosquito pierces a person's skin to take a blood meal, sporozoites in the mosquito's saliva enter the bloodstream and migrate to the liver where they infect hepatocytes, multiplying asexually and asymptomatically for a period of 8–30 days.<ref name="Bledsoe 2005"/>

After a potential dormant period in the liver, these organisms [[cellular differentiation|differentiate]] to yield thousands of merozoites, which, following rupture of their host cells, escape into the blood and infect red blood cells to begin the erythrocytic stage of the life cycle.<ref name="Bledsoe 2005"/> The parasite escapes from the liver undetected by wrapping itself in the [[cell membrane]] of the infected host liver cell.<ref name="Vaughan 2008"/>

Within the red blood cells, the parasites multiply further, again asexually, periodically breaking out of their host cells 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.<ref name="Bledsoe 2005"/>

Some ''P.&nbsp;vivax'' sporozoites do not immediately develop into exoerythrocytic-phase merozoites, but instead produce hypnozoites that remain dormant for periods ranging from several months (7–10 months is typical) to several years. After a period of dormancy, they reactivate and produce merozoites. Hypnozoites are responsible for long incubation and late relapses in ''P.&nbsp;vivax'' infections,<ref name="White 2011"/> although their existence in ''P.&nbsp;ovale'' is uncertain.<ref name="Richter 2010"/>

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.&nbsp;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="Tilley 2011"/> The blockage of the microvasculature causes symptoms such as in placental malaria.<ref name="Mens 2010"/> Sequestered red blood cells can breach the [[blood–brain barrier]] and cause cerebral malaria.<ref name="Rénia 2012"/>

===Genetic resistance===
{{Main|Genetic resistance to malaria}}
According to a 2005 review, due to the high levels of [[death|mortality]] and [[morbidity]] caused by malaria—especially the ''P.&nbsp;falciparum'' species—it has placed the greatest [[selection|selective pressure]] on the [[human genome]] in recent history. Several genetic factors provide some resistance to it including [[sickle cell trait]], [[thalassaemia]] traits, [[glucose-6-phosphate dehydrogenase deficiency]], and the absence of [[Duffy antigen]]s on red blood cells.<ref name="Kwiatkowski 2005"/><ref name="Hedrick 2011"/>

The impact of sickle cell trait on malaria immunity illustrates some evolutionary trade-offs that have occurred because of endemic malaria. Sickle cell trait causes a defect in the hemoglobin molecule in the blood. Instead of retaining the biconcave shape of a normal red blood cell, the modified [[hemoglobin S|hemoglobin&nbsp;S]] molecule causes the cell to sickle or distort into a curved shape. Due to the sickle shape, the molecule is not as effective in taking or releasing oxygen. Infection causes red cells to sickle more, and so they are removed from circulation sooner. This reduces the frequency with which malaria parasites complete their life cycle in the cell. Individuals who are [[homozygous]] (with two copies of the abnormal hemoglobin beta [[allele]]) have [[sickle-cell anaemia]], while those who are heterozygous (with one abnormal allele and one normal allele) experience resistance to malaria. Although the shorter life expectancy for those with the homozygous condition would not sustain the trait's survival, the trait is preserved because of the [[heterozygote advantage|benefits]] provided by the heterozygous form.<ref name="Hedrick 2011"/><ref name="Weatherall 2008"/>

===Liver dysfunction===
Liver dysfunction as a result of malaria is uncommon and usually only occurs in those with other liver condition such as [[viral hepatitis]] or [[chronic liver disease]]. The syndrome is sometimes called ''malarial hepatitis''.<ref name="Bhalla 2006"/> While it has been considered a rare occurrence, malarial hepatopathy has seen an increase, particularly in Southeast Asia and India. Liver compromise in people with malaria correlates with a greater likelihood of complications and death.<ref name="Bhalla 2006"/>

==Diagnosis==
{{Main|Diagnosis of malaria}}
[[File:5901 lores.jpg|thumb|The blood film is the [[gold standard (test)|gold standard]] for malaria diagnosis.]]
[[File:Plasmodium.jpg|thumb|Ring-forms and [[gametocyte]]s of ''Plasmodium falciparum'' in human blood]]
Owing to the non-specific nature of the presentation of symptoms, diagnosis of malaria in non-endemic areas requires a high degree of suspicion, which might be elicited by any of the following: recent travel history, [[splenomegaly|enlarged spleen]], fever, [[thrombocytopenia|low number of platelets]] in the blood, and [[hyperbilirubinemia|higher-than-normal levels of bilirubin]] in the blood combined with a normal level of [[white blood cells]].<ref name="Nadjm 2012"/>

Malaria is usually confirmed by the microscopic examination of [[blood film]]s or by [[antigen]]-based [[Malaria antigen detection tests|rapid diagnostic tests]] (RDT).<ref name="Abba 2011"/><ref name="Kattenberg 2011"/> Microscopy is the most commonly used method to detect the malarial parasite—about 165 million blood films were examined for malaria in 2010.<ref name="Wilson 2012"/> Despite its widespread usage, diagnosis by microscopy suffers from two main drawbacks: many settings (especially rural) are not equipped to perform the test, and the accuracy of the results depends on both the skill of the person examining the blood film and the levels of the parasite in the blood. The [[Sensitivity and specificity|sensitivity]] of blood films ranges from 75–90% in optimum conditions, to as low as 50%. Commercially available RDTs are often more accurate than blood films at predicting the presence of malaria parasites, but they are widely variable in diagnostic sensitivity and specificity depending on manufacturer, and are unable to tell how many parasites are present.<ref name="Wilson 2012"/>

In regions where laboratory tests are readily available, malaria should be suspected, and tested for, in any unwell person who has been in an area where malaria is endemic. In areas that cannot afford laboratory diagnostic tests, it has become common to use only a history of fever as the indication to treat for malaria—thus the common teaching "fever equals malaria unless proven otherwise". A drawback of this practice is [[overdiagnosis]] of malaria and mismanagement of non-malarial fever, which wastes limited resources, erodes confidence in the health care system, and contributes to drug resistance.<ref name="Perkins 2008"/> Although [[polymerase chain reaction]]-based tests have been developed, they are not widely used in areas where malaria is common as of 2012, due to their complexity.<ref name="Nadjm 2012"/>

===Classification===
Malaria is classified into either "severe" or "uncomplicated" by the [[World Health Organization]] (WHO).<ref name="Nadjm 2012"/> It is deemed severe when ''any'' of the following criteria are present, otherwise it is considered uncomplicated.<ref>{{harvnb|WHO|2010|p=35}}</ref>
* Decreased consciousness
* Significant weakness such that the person is unable to walk
* Inability to feed
* Two or more [[convulsions]]
* [[Low blood pressure]] (less than 70&nbsp;[[mmHg]] in adults and 50&nbsp;mmHg in children)
* [[respiratory distress|Breathing problems]]
* [[Circulatory shock]]
* [[Kidney failure]] or [[hemoglobin]] in the urine
* Bleeding problems, or hemoglobin less than 50&nbsp;g/L (5&nbsp;g/dL)
* [[Pulmonary oedema]]
* [[Blood glucose]] less than 2.2&nbsp;mmol/L (40&nbsp;mg/dL)
* [[Acidosis]] or [[lactic acid|lactate]] levels of greater than 5&nbsp;mmol/L
* A parasite level in the blood of greater than 100,000 per [[microlitre]] (µL) in low-intensity transmission areas, or 250,000 per µL in high-intensity transmission areas

Cerebral malaria is defined as a severe ''P.&nbsp;falciparum''-malaria presenting with neurological symptoms, including coma (with a [[Glasgow coma scale]] less than 11, or a [[Blantyre coma scale]] greater than 3), or with a coma that lasts longer than 30 minutes after a seizure.<ref>{{harvnb|WHO|2010|p=v}}</ref>

==Prevention==
<!-- The list of methods seems to put the least cost-effective first. What's the reason for that? -->
[[File:Anopheles stephensi.jpeg|thumb|An ''[[Anopheles stephensi]]'' mosquito shortly after obtaining blood from a human (the droplet of blood is expelled as a surplus). This mosquito is a vector of malaria, and mosquito control is an effective way of reducing its incidence.]]

Methods used to prevent malaria include medications, mosquito elimination and the prevention of bites. There is no [[malaria vaccine|vaccine for malaria]]. The presence of malaria in an area requires a combination of high human population density, high anopheles 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 eventually disappear from that area, as happened in North America, Europe and parts of the 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. Furthermore, the cost per person of eliminating anopheles mosquitoes rises with decreasing population density, making it economically unfeasible in some areas.<ref name="whqlibdoc"/>

Prevention of malaria may be more cost-effective than treatment of the disease in the long run, but the [[capital cost|initial costs]] required are out of reach of many of the world's poorest people. There is a wide difference in the costs of control (i.e. maintenance of low endemicity) and elimination programs between countries. For example, in China—whose government in 2010 announced a strategy to pursue malaria elimination in the [[Chinese province]]s—the required investment is a small proportion of public expenditure on health. In contrast, a similar program in Tanzania would cost an estimated one-fifth of the public health budget.<ref name="Sabot 2010"/>

===Mosquito control===
{{further2|[[Mosquito control]]}}
[[File:Mansprayingkeroseneoil.jpg|thumb|left|Man spraying kerosene oil in standing water, [[Panama Canal Zone]] 1912]]
[[Vector control]] refers to methods used to decrease malaria by reducing the levels of transmission by mosquitoes. For individual protection, the most effective [[insect repellent]]s are based on [[DEET]] or [[picaridin]].<ref name="Kajfasz 2009"/> Insecticide-treated [[mosquito net]]s (ITNs) and [[indoor residual spraying]] (IRS) have been shown to be highly effective in preventing malaria among children in areas where malaria is common.<ref name="Lengeler 2004"/><ref name="Pluess 2010"/> Prompt treatment of confirmed cases with artemisinin-based combination therapies (ACTs) may also reduce transmission.<ref>{{cite web|last=Palmer|first=J.|title=WHO gives indoor use of DDT a clean bill of health for controlling malaria|url=http://www.who.int/mediacentre/news/releases/2006/pr50/en/|publisher=WHO}}</ref>
[[File:Mosquitoes-Killedy-By-DDT-Lake-Victoria.JPG|thumb|right|Walls where indoor residual spraying of DDT has been applied. The mosquitoes remain on the wall until they fall down dead on the floor.]]

<!-- Bet nets -->
[[File:Mosquitonet149.jpg|thumb|A mosquito net in use.]]
Mosquito nets help keep mosquitoes away from people and reduce infection rates and transmission of malaria. Nets are not a perfect barrier and are often treated with an insecticide designed to kill the mosquito before it has time to find a way past the net. Insecticide-treated nets are estimated to be twice as effective as untreated nets and offer greater than 70% protection compared with no net.<ref name="Raghavendra 2011"/> Between 2000 and 2008, the use of ITNs saved the lives of an estimated 250,000 infants in Sub-Saharan Africa.<ref name="Howitt 2012"/> About 13% of households in Sub-Saharan countries own ITNs.<ref name="Miller 2007"/> In 2000, 1.7 million (1.8%) African children living in areas of the world where malaria is common were protected by an ITN. That number increased to 20.3 million (18.5%) African children using ITNs in 2007, leaving 89.6 million children unprotected.<ref name="Noor 2009"/> An increased percentage of African households (31%) are estimated to own at least one ITN in 2008. Most nets are impregnated with [[pyrethroid]]s, a class of insecticides with low [[toxicity]]. They are most effective when used from dusk to dawn.<ref>{{harvnb|Schlagenhauf-Lawlor|2008|pp=[http://books.google.com/books?id=54Dza0UHyngC&pg=PA215 215]}}</ref> It is recommended to hang a large "bed net" above the center of a bed and either tuck the edges under the mattress or make sure it is large enough such that it touches the ground.<ref>{{cite book|title=Instructions for treatment and use of insecticide-treated mosquito nets|date=2002|publisher=World Health Organization|page=34|url=http://whqlibdoc.who.int/hq/2002/WHO_CDS_RBM_2002.41.pdf|format=pdf}}</ref>

<!-- Indoor residual spraying -->
Indoor residual spraying is the spraying of insecticides on the walls inside a home. After feeding, many mosquitoes rest on a nearby surface while digesting the bloodmeal, so if the walls of houses have been coated with insecticides, the resting mosquitoes can be killed before they can bite another person and transfer the malaria parasite.<ref name="Enayati 2010"/> As of 2006, the [[World Health Organization]] recommends 12 insecticides in IRS operations, including [[DDT#Use against malaria|DDT]] and the pyrethroids [[cyfluthrin]] and [[deltamethrin]].<ref name="WHO Indoor Residual Spraying"/> This public health use of small amounts of DDT is permitted under the [[Stockholm Convention]], which prohibits its agricultural use.<ref name="van den Berg 2009"/> One problem with all forms of IRS is [[insecticide resistance]]. Mosquitoes affected by IRS tend to rest and live indoors, and due to the irritation caused by spraying, their descendants tend to rest and live outdoors, meaning that they are less affected by the IRS.<ref name="Pates 2005"/>

<!-- Other -->
There are a number of other methods to reduce mosquito bites and slow the spread of malaria. Efforts to decrease mosquito larva by decreasing the availability of open water in which they develop or by adding substances to decrease their development is effective in some locations.<ref name="Tusting 2013"/> Electronic mosquito repellent devices which make very high frequency sounds that are supposed to keep female mosquitoes away, do not have supporting evidence.<ref name="Enayati 2007"/>

===Other methods===
Community participation and [[health education]] strategies promoting awareness of malaria and the importance of control measures have been successfully used to reduce the incidence of malaria in some areas of the developing world.<ref name="Lalloo 2006"/> Recognizing the disease in the early stages can stop the disease from becoming fatal. Education can also inform people to cover over areas of stagnant, still water, such as water tanks that are ideal breeding grounds for the parasite and mosquito, thus cutting down the risk of the transmission between people. This is generally used in urban areas where there are large centers of population in a confined space and transmission would be most likely in these areas.<ref name="Mehlhorn 2008"/> [[Intermittent preventive therapy]] is another intervention that has been used successfully to control malaria in pregnant women and infants,<ref name="Bardají 2012"/> and in preschool children where transmission is seasonal.<ref name="Meremikwu 2012"/>

===Medications===
{{Main|Malaria prophylaxis}}
There are a number of drugs that can help prevent malaria while travelling in areas where it exists. Most of these drugs are also sometimes used in treatment. [[Chloroquine]] may be used where the parasite is still sensitive.<ref name="Jacquerioz 2009"/> Because most ''Plasmodium'' is resistant to one or more medications, one of three medications—[[mefloquine]] (''Lariam''), [[doxycycline]] (available generically), or the combination of [[atovaquone]] and [[proguanil]] hydrochloride (''Malarone'')—is frequently needed.<ref name="Jacquerioz 2009"/> Doxycycline and the atovaquone and proguanil combination are the best tolerated; mefloquine is associated with death, suicide, and neurological and psychiatric symptoms.<ref name="Jacquerioz 2009"/>

The protective effect does not begin immediately, and people visiting areas where malaria exists usually start taking the drugs one to two weeks before arriving and continue taking them for four weeks after leaving (except for atovaquone/proguanil, which only needs to be started two days before and continued for seven days afterward).<ref name="Freedman 2008"/> The use of preventative drugs is often not practical for those who live in areas where malaria exists, and their use is usually only in short-term visitors and travellers. This is due to the cost of the drugs, [[adverse effect (medicine)|side effects]] from long-term use, and the difficulty in obtaining anti-malarial drugs outside of wealthy nations.<ref name="Fernando 2011"/> The use of preventative drugs where malaria-bearing mosquitoes are present may encourage the development of partial resistance.<ref name="Turschner 2009"/> An exception to this is during pregnancy when taking medication to prevent malaria has been found to improve the weight of the baby at birth and decrease the risk of [[anemia]] in the mother.<ref>{{cite journal|last1=Radeva-Petrova|first1=D|last2=Kayentao|first2=K|last3=Ter Kuile|first3=FO|last4=Sinclair|first4=D|last5=Garner|first5=P|title=Drugs for preventing malaria in pregnant women in endemic areas: any drug regimen versus placebo or no treatment.|journal=The Cochrane database of systematic reviews|date=Oct 10, 2014|volume=10|pages=CD000169|pmid=25300703|doi=10.1002/14651858.CD000169.pub3}}</ref>

==Treatment==
Malaria is treated with [[antimalarial medication]]s; the ones used depends on the type and severity of the disease. While [[antipyretics|medications against fever]] are commonly used, their effects on outcomes are not clear.<ref name="Meremikwu 2012b"/>

<!--Uncomplicated -->
Uncomplicated malaria may be treated with oral medications. The most effective treatment for ''P.&nbsp;falciparum'' infection is the use of [[artemisinin]]s in combination with other antimalarials (known as [[artemisinin-combination therapy]], or ACT), which decreases resistance to any single drug component.<ref name="Kokwaro 2009"/> These additional antimalarials include: [[amodiaquine]], [[lumefantrine]], mefloquine or [[sulfadoxine/pyrimethamine]].<ref>{{harnvb|WHO|2010|pp=75–86}}</ref> Another recommended combination is [[dihydroartemisinin]] and [[piperaquine]].<ref>{{harvnb|WHO|2010|p=21}}</ref><ref name="Keating 2012"/> ACT is about 90% effective when used to treat uncomplicated malaria.<ref name="Howitt 2012"/> To treat malaria during pregnancy, the WHO recommends the use of quinine plus [[clindamycin]] early in the pregnancy (1st trimester), and ACT in later stages (2nd and 3rd trimesters).<ref name="Manyando 2012"/> In the 2000s (decade), malaria with partial resistance to artemisins emerged in Southeast Asia.<ref name="O'Brien 2011"/><ref name="Fairhurst 2012"/>

Infection with ''P.&nbsp;vivax'', ''P.&nbsp;ovale'' or ''P.&nbsp;malariae'' is usually treated without the need for hospitalization. Treatment of ''P.&nbsp;vivax'' requires both treatment of blood stages (with chloroquine or ACT) and clearance of liver forms with [[primaquine]].<ref name="Waters 2012"/>

<!--Severe -->
Recommended treatment for severe malaria is the [[parenteral administration|intravenous]] use of antimalarial drugs. For severe malaria, artesunate is superior to quinine in both children and adults.<ref name="Sinclair 2012"/> Treatment of severe malaria involves supportive measures that are best done in a [[critical care unit]]. This includes the management of [[hyperpyrexia|high fevers]] and the seizures that may result from it. It also includes monitoring for [[respiratory depression|poor breathing effort]], low blood sugar, and [[hypokalemia|low blood potassium]].<ref name="Sarkar 2009"/>

===Resistance===
[[Drug resistance]] poses a growing problem in 21st-century malaria treatment.<ref name="SinhaMedhi2014"/> Resistance is now common against all classes of antimalarial drugs save the artemisinins. Treatment of resistant strains became increasingly dependent on this class of drugs. The cost of artemisinins limits their use in the developing world.<ref name="White 2008"/> Malaria strains found on the Cambodia–Thailand border are resistant to combination therapies that include artemisinins, and may therefore be untreatable.<ref name="Wongsrichanalai 2008"/> Exposure of the parasite population to artemisinin monotherapies in subtherapeutic doses for over 30 years and the availability of substandard artemisinins likely drove the selection of the resistant phenotype.<ref name="Dondorp 2010"/> Resistance to artemisinin has been detected in Cambodia, Myanmar, Thailand, and Vietnam,<ref>{{cite journal |author= World Health Organization |title=Q&A on artemisinin resistance|journal= WHO malaria publications|year=2013|url=http://www.who.int/malaria/media/artemisinin_resistance_qa/en/index.html}}</ref> and there has been emerging resistance in Laos.<ref name = Briggs>Briggs, Helen (30 July 2014) [http://www.bbc.co.uk/news/health-28569966 Call for 'radical action' on drug-resistant malaria] BBC News, health, Retrieved 30 July 2013</ref><ref name="Ashley 2014"/>

==Prognosis==
[[File:Malaria world map - DALY - WHO2004.svg|thumb|upright=1.2|[[Disability-adjusted life year]] for malaria per 100,000 inhabitants in 2004{{Multicol}}
{{legend|#b3b3b3| no data}}
{{legend|#ffff65| <10}}
{{legend|#fff200| 0–100}}
{{legend|#ffdc00| 100–500}}
{{legend|#ffc600| 500–1000}}
{{legend|#ffb000|1000–1500}}
{{legend|#ff9a00|1500–2000}}
{{Multicol-break}}
{{legend|#ff8400|2000–2500}}
{{legend|#ff6e00|2500–2750}}
{{legend|#ff5800|2750–3000}}
{{legend|#ff4200|3000–3250}}
{{legend|#ff2c00|3250–3500}}
{{legend|#cb0000| ≥3500}}
{{Multicol-end}}]]
When properly treated, people with malaria can usually expect a complete recovery.<ref name="CDC Malaria"/> However, severe malaria can progress extremely rapidly and cause death within hours or days.<ref name="Trampuz 2003"/> In the most severe cases of the disease, [[fatality rate]]s can reach 20%, even with intensive care and treatment.<ref name="Nadjm 2012"/> Over the longer term, developmental impairments have been documented in children who have suffered episodes of severe malaria.<ref name="Fernando 2010"/> [[chronic (medicine)|Chronic]] infection without severe disease can occur in an immune-deficiency syndrome associated with a decreased responsiveness to ''[[Salmonella]]'' bacteria and the [[Epstein–Barr virus]].<ref name="Riley 2013"/>

During childhood, malaria causes anemia during a period of rapid brain development, and also direct brain damage resulting from cerebral malaria.<ref name="Fernando 2010"/> Some survivors of cerebral malaria have an increased risk of neurological and cognitive deficits, [[Emotional and behavioral disorders|behavioural disorders]], and [[epilepsy]].<ref name="Idro 2010"/> Malaria prophylaxis was shown to improve cognitive function and school performance in [[clinical trial]]s when compared to [[placebo]] groups.<ref name="Fernando 2010"/>

==Epidemiology==
[[File:Paludisme.png|thumb|left|Distribution of malaria in the world:<ref name="CDC Malaria distribution"/>
<span style="color:#7e0000; font-size:120%;">♦</span>&nbsp;Elevated occurrence of chloroquine- or multi-resistant malaria
<br> <span style="color:#f00; font-size:120%;">♦</span>&nbsp;Occurrence of chloroquine-resistant malaria
<br> <span style="color:#e08040; font-size:120%;">♦</span>&nbsp;No ''Plasmodium falciparum'' or chloroquine-resistance
<br> <span style="color:silver; font-size:120%;">♦</span>&nbsp;No malaria
]]
The WHO estimates that in 2010 there were 219 million cases of malaria resulting in 660,000 deaths.<ref name="Nadjm 2012"/><ref name="World Malaria Report 2012"/> Others have estimated the number of cases at between 350 and 550 million for falciparum malaria<ref name="Olu 2013"/> and deaths in 2010 at 1.24 million<ref name="lancet-glob-mal-mort"/> up from 1.0 million deaths in 1990.<ref name="Loz 2012"/> The majority of cases (65%) occur in children under 15 years old.<ref name="lancet-glob-mal-mort"/> About 125 million pregnant women are at risk of infection each year; in [[Sub-Saharan Africa]], maternal malaria is associated with up to 200,000 estimated infant deaths yearly.<ref name="Hartman 2010"/> There are about 10,000 malaria cases per year in Western Europe, and 1300–1500 in the United States.<ref name="Taylor 2012"/> About 900 people died from the disease in Europe between 1993 and 2003.<ref name="Kajfasz 2009"/> Both the global incidence of disease and resulting mortality have declined in recent years. According to the WHO, deaths attributable to malaria in 2010 were reduced by over a third from a 2000 estimate of 985,000, largely due to the widespread use of insecticide-treated nets and artemisinin-based combination therapies.<ref name="Howitt 2012"/> In 2012, there were 207 million cases of malaria.<!-- <ref name=WHO2014/> --> That year, the disease is estimated to have killed between 473,000 and 789,000 people, many of whom were children in Africa.<ref name=WHO2014>{{cite web|title=Malaria Fact sheet N°94|url=http://www.who.int/mediacentre/factsheets/fs094/en/|website=WHO|accessdate=28 August 2014|date=March 2014}}</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; in Sub-Saharan Africa, 85–90% of malaria fatalities occur.<ref name="Layne 2006"/> An estimate for 2009 reported that countries with the highest death rate per 100,000 of population were [[Ivory Coast]] (86.15), [[Angola]] (56.93) and [[Burkina Faso]] (50.66).<ref name="Provost 2011"/> A 2010 estimate indicated the deadliest countries per population were Burkina Faso, [[Mozambique]] and [[Mali]].<ref name="lancet-glob-mal-mort"/> The [[Malaria Atlas Project]] aims to map global [[Endemic (epidemiology)|endemic]] levels of malaria, providing a means with which to determine the global spatial limits of the disease and to assess [[disease burden]].<ref name="Guerra 2007"/><ref name="Hay 2010"/> This effort led to the publication of a map of ''P.&nbsp;falciparum'' endemicity in 2010.<ref name="Gething 2011"/> As of 2010, about 100 countries have endemic malaria.<ref name="World Malaria Report 2012"/><ref name="Feachem 2010"/> Every year, 125 million international travellers visit these countries, and more than 30,000 contract the disease.<ref name="Kajfasz 2009"/>

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="Greenwood 2002"/> Malaria is prevalent in tropical and subtropical regions because of rainfall, consistent high temperatures and high humidity, along with stagnant waters in which mosquito larvae readily mature, providing them with the environment they need for continuous breeding.<ref name="Jamieson 2006"/> In drier areas, outbreaks of malaria have been predicted with reasonable accuracy by mapping rainfall.<ref name="Abeku 2007"/> Malaria is more common in rural areas than in cities. For example, several cities in the [[Greater Mekong Subregion]] of Southeast Asia are essentially malaria-free, but the disease is prevalent in many rural regions, including along international borders and forest fringes.<ref name="Cui 2012"/> In contrast, malaria in Africa is present in both rural and urban areas, though the risk is lower in the larger cities.<ref name="Machault 2011"/>

==History==
{{Main|History of malaria|Mosquito-malaria theory}}

Although the parasite responsible for ''P.&nbsp;falciparum'' malaria has been in existence for 50,000–100,000 years, the population size of the parasite did not increase until about 10,000 years ago, concurrently with advances in agriculture<ref name="Harper 2011"/> and the development of human settlements. Close relatives of the human malaria parasites remain common in chimpanzees. Some evidence suggests that the ''P.&nbsp;falciparum'' malaria may have originated in gorillas.<ref name="Prugnolle 2012"/>

References to the unique periodic fevers of malaria are found throughout recorded history, beginning in 2700 BC in China.<ref name="Cox 2002"/> Hippocrates described periodic fevers, labelling them tertian, quartan, subtertian and quotidian.<ref>{{cite book|last1=Strong|first1=Richard P|title=Stitt's Diagnosis, Prevention and Treatment of Tropical Diseases|date=1944|publisher=The Blakiston company|location=York, PA|page=3|edition=Seventh|accessdate=8 March 2015}}</ref> The Roman [[Columella ]] associated the disease with insects from swamps.<ref>{{cite book|last1=Strong|first1=Richard P|title=Stitt's Diagnosis, Prevention and Treatment of Tropical Diseases|date=1944|publisher=The Blakiston company|location=York, PA|page=3|edition=Seventh|accessdate=8 March 2015}}</ref> Malaria may have contributed to the decline of the [[Roman Empire]],<ref name="Sallares 2001"/> and was so pervasive in Rome that it was known as the "[[Roman Fever (disease)|Roman fever]]".<ref name="Sallares 2003"/> Several regions in ancient Rome were considered at-risk for the disease because of the favourable conditions present for malaria vectors. This included areas such as southern Italy, the island of [[Sardinia]], the [[Pontine Marshes]], the lower regions of coastal [[Etruria]] and the city of [[Rome]] along the [[Tiber River]]. The presence of stagnant water in these places was preferred by mosquitoes for breeding grounds. Irrigated gardens, swamp-like grounds, runoff from agriculture, and drainage problems from road construction led to the increase of standing water.<ref name="Hays 2005"/>
[[File:Ronald Ross.jpg|thumb|left|British doctor [[Ronald Ross]] received the [[Nobel Prize for Physiology or Medicine]] in 1902 for his work on malaria.]]

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>{{cite journal|last1=Reiter|first1=P|title=From Shakespeare to Defoe: malaria in England in the Little Ice Age.|journal=Emerging Infectious Diseases|date=1999|volume=6|issue=1|pages=1–11|pmid=10653562|url=http://www.ncbi.nlm.nih.gov/pubmed/10653562|doi=10.3201/eid0601.000101|pmc=2627969}}</ref> The term first appeared in the English literature about 1829.<ref>{{cite book|last1=Strong|first1=Richard P|title=Stitt's Diagnosis, Prevention and Treatment of Tropical Diseases|date=1944|publisher=The Blakiston company|location=York, PA|page=3|edition=Seventh|accessdate=8 March 2015}}</ref> Malaria was once common in most of Europe and North America,<ref name="Lindemann 1999"/> where it is no longer endemic,<ref name="Gratz 2006"/> though imported cases do occur.<ref name="Webb 2009"/>

Scientific studies on malaria made their first significant advance in 1880, when [[Charles Louis Alphonse Laveran]]—a French army doctor working in the military hospital of [[Constantine, Algeria|Constantine]] in [[Algeria]]—observed parasites inside the red blood cells of infected people for the first time. He therefore proposed that malaria is caused by this organism, the first time a [[protist]] was identified as causing disease.<ref name="Laveran bio"/> For this and later discoveries, he was awarded the 1907 [[Nobel Prize for Physiology or Medicine]]. A year later, [[Carlos Finlay]], a Cuban doctor treating people with [[yellow fever]] in [[Havana]], provided strong evidence that mosquitoes were transmitting disease to and from humans.<ref name="Tan 2008"/> This work followed earlier suggestions by [[Josiah C. Nott]],<ref name="Chernin 1983"/> and work by [[Sir Patrick Manson]], the "father of tropical medicine", on the transmission of [[filariasis]].<ref name="Chernin 1977"/>

In April 1894, a Scottish physician [[Ronald Ross|Sir Ronald Ross]] visited Sir Patrick Manson at his house on Queen Anne Street, London. This visit was the start of four years of collaboration and fervent research that culminated in 1898 when Ross, who was working in the [[Presidency General Hospital]] in [[Kolkata|Calcutta]], proved the complete life-cycle of the malaria parasite in mosquitoes. He thus proved that the mosquito was the vector for malaria in humans 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 name="Ross bio"/> 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 name="CDC Ross"/> 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.<ref name="Simmons 1979"/>

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 fever. Its effectiveness against malaria was found and the [[Jesuit]]s introduced the treatment to Europe around 1640; by 1677, it was included in the [[London Pharmacopoeia]] as an antimalarial treatment.<ref name="Kaufman 2005"/> 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 name="Pelletier 1820"/><ref name="Kyle 1974"/>
[[File:Artemisia annua West Virginia.jpg|thumb|right|''Artemisia annua'', source of the antimalarial drug artemisin]]
Quinine become the predominant malarial medication until the 1920s, when other medications began to be developed. In the 1940s, chloroquine replaced quinine as the treatment of both uncomplicated and severe malaria until resistance supervened, first in Southeast Asia and South America in the 1950s and then globally in the 1980s.<ref name="Achan 2011"/> Artemisinins, discovered by Chinese scientist [[Tu Youyou]] and colleagues in the 1970s from the plant ''[[Artemisia annua]]'', became the recommended treatment for ''P.&nbsp;falciparum'' malaria, administered in combination with other antimalarials as well as in severe disease.<ref name="Hsu 2006"/>

''Plasmodium vivax'' was used between 1917 and the 1940s for [[malariotherapy]]—deliberate injection of malaria parasites to induce fever to combat certain diseases such as tertiary [[syphilis]]. In 1917, the inventor of this technique, [[Julius Wagner-Jauregg]], received the Nobel Prize in Physiology or Medicine for his discoveries. The technique was dangerous, killing about 15% of patients, so it is no longer in use.<ref name="Vogel 2013"/>

The first pesticide used for indoor residual spraying was [[DDT]].<ref name="CDC history"/> 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 [[pesticide resistance|resistant]] mosquitoes in many regions. The DDT resistance shown by ''Anopheles'' mosquitoes can be compared to [[antibiotic resistance]] shown by bacteria. 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.<ref name="van den Berg 2009"/> Before DDT, malaria was successfully eliminated or controlled in tropical areas like Brazil and Egypt by removing or poisoning the breeding grounds of the mosquitoes or the aquatic habitats of the larva stages, for example by applying the highly toxic arsenic compound [[Paris Green]] to places with standing water.<ref name="Killeen 2002"/>

[[Malaria vaccine]]s have been an elusive goal of research. The first promising studies demonstrating the potential for a malaria vaccine were performed in 1967 by immunizing mice with live, radiation-[[Attenuator (genetics)|attenuated]] sporozoites, which provided significant protection to the mice upon subsequent injection with normal, viable sporozoites. Since the 1970s, there has been a considerable effort to develop similar vaccination strategies within humans.<ref name="Vanderberg 2009"/>

==Society and culture==
{{see also|World Malaria Day}}

=== Economic impact ===
[[File:Saving Lives with SMS for Life.jpg|thumb|right|Malaria clinic in Tanzania]]

Malaria is not just a disease commonly associated with poverty: some evidence suggests that it is also a cause of poverty and a major hindrance to [[economic development]].<ref name="IftSoL"/><ref name="Worrall 2005"/> Although tropical regions are most affected, malaria's furthest influence reaches into some temperate zones that have 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 2001"/>

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 the period 1965 to 1990, countries where malaria was common had an average per capita GDP that increased only 0.4% per year, compared to 2.4% per year in other countries.<ref name="Sachs 2002"/>

Poverty can increase the risk of malaria, since those in poverty do not have the financial capacities to prevent or treat the disease. In its entirety, the economic impact of malaria has been estimated to cost Africa US$12 billion every year. The economic impact includes costs of health care, working days lost due to sickness, days lost in education, decreased productivity due to brain damage from cerebral malaria, and loss of investment and tourism.<ref name="Greenwood 2005"/> The disease has a heavy burden in some countries, where it may be responsible for 30–50% of hospital admissions, up to 50% of [[outpatient]] visits, and up to 40% of public health spending.<ref name="Roll Back Malaria WHO"/>

Cerebral malaria is one of the leading causes of neurological disabilities in African children.<ref name="Idro 2010"/> Studies comparing cognitive functions before and after treatment for severe malarial illness continued to show significantly impaired school performance and cognitive abilities even after recovery.<ref name="Fernando 2010"/> Consequently, severe and cerebral malaria have far-reaching [[socioeconomic]] consequences that extend beyond the immediate effects of the disease.<ref name="Ricci 2012"/>

===Counterfeit and substandard drugs===
Sophisticated [[counterfeit drugs|counterfeits]] have been found in several Asian countries such as [[Cambodia]],<ref name="Lon 2006"/> [[People's Republic of China|China]],<ref name="Newton 2008"/> [[Indonesia]], [[Laos]], [[Thailand]], and [[Vietnam]], and are an important cause of avoidable death in those countries.<ref name="Newton 2006"/> The 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 name="Parry 2005"/> 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.<ref name="Gautam 2009"/>

Another clinical and public health concern is the proliferation of substandard antimalarial medicines resulting from inappropriate concentration of ingredients, contamination with other drugs or toxic impurities, poor quality ingredients, poor stability and inadequate packaging.<ref name="Caudron 2008"/> A 2012 study demonstrated that roughly one-third of antimalarial medications in Southeast Asia and Sub-Saharan Africa failed chemical analysis, packaging analysis, or were falsified.<ref name="Nayyar 2012"/>

===War===
[[File:"Don't go to Bed with Malaria Mosquito" - NARA - 514146.tif|thumb|right|World War II poster]]
Throughout history, the contraction of malaria has played a prominent role in the fates of government rulers, nation-states, military personnel, and military actions.<ref name="Russell 2009"/> In 1910, [[Nobel Prize in Medicine]]-winner Ronald Ross (himself a malaria survivor), published a book titled ''The Prevention of Malaria'' that included a chapter titled "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: "The history of malaria in war might almost be taken to be the history of war itself, certainly the history of war in the Christian era. ... It is probably the case that many of the so-called camp fevers, and probably also a considerable proportion of the camp dysentery, of the wars of the sixteenth, seventeenth and eighteenth centuries were malarial in origin."<ref name="Ross 1910"/>

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 name="Bray 2004"/> According to Joseph Patrick Byrne, "Sixty thousand American soldiers died of malaria during the African and South Pacific campaigns."<ref name="Byrne 2008"/>

Significant financial investments have been made to procure existing and create new anti-malarial agents. During [[World War I]] and World War II, inconsistent supplies of the natural anti-malaria drugs [[cinchona bark]] and quinine prompted substantial funding 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 and Prevention]], or CDC) 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".<ref name="autogenerated1"/>

===Eradication efforts===
Several notable attempts are being made to eliminate the parasite from sections of the world, or to eradicate it worldwide. In 2006, the organization [[Malaria No More]] set a public goal of eliminating malaria from Africa by 2015, and the organization plans to dissolve if that goal is accomplished.<ref name="Strom 2011"/> Several malaria vaccines are in clinical trials, which are intended to provide protection for children in endemic areas and reduce the speed of transmission of the disease. {{As of|2012}}, [[The Global Fund to Fight AIDS, Tuberculosis and Malaria]] has distributed 230 million insecticide-treated nets intended to stop mosquito-borne transmission of malaria.<ref name="Global Fund"/> The U.S.-based [[Clinton Foundation]] has worked to manage demand and stabilize prices in the artemisinin market.<ref name="WSJ 2008"/> Other efforts, such as the Malaria Atlas Project, focus on analysing climate and weather information required to accurately predict the spread of malaria based on the availability of habitat of malaria-carrying parasites.<ref name="Guerra 2007"/> The [[Malaria Policy Advisory Committee]] (MPAC) of the [[World Health Organization]] (WHO) was formed in 2012, "to provide strategic advice and technical input to WHO on all aspects of malaria control and elimination".<ref>{{cite web|title=Executive summary and key points|url=http://www.who.int/entity/malaria/publications/world_malaria_report_2013/wmr13_summary_key_points.pdf?ua=1|work=World Malaria Report 2013|publisher=World Health Organization|accessdate=13 February 2014}}</ref> In November 2013, WHO and the malaria vaccine funders group set a goal to develop vaccines designed to interrupt malaria transmission with the long-term goal of malaria eradication.<ref>{{cite web|title=World Malaria Report 2013|url=http://www.who.int/entity/malaria/publications/world_malaria_report_2013/wmr2013_no_profiles.pdf?ua=1|publisher=World Health Organization|accessdate=13 February 2014}}</ref>

Malaria has been successfully eliminated or greatly reduced in certain 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. Several factors contributed, such as the draining of wetland breeding grounds for agriculture and other changes in [[water management]] practices, and advances in sanitation, including greater use of glass windows and screens in dwellings.<ref name="Meade 2010"/> 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 in the 1950s.<ref name="Williams 1963"/> (see [[National Malaria Eradication Program]]) In [[Suriname]], the disease has been cleared from its capital city and coastal areas through a three-pronged approach initiated by the [[Global Malaria Eradication program]] in 1955, involving: vector control through the use of DDT and IRS; regular collection of blood smears from the population to identify existing malaria cases; and providing chemotherapy to all affected individuals.<ref name="Breeveld 2012"/> [[Bhutan]] is pursuing an aggressive malaria elimination strategy, and has achieved a 98.7% decline in microscopy-confirmed cases from 1994 to 2010. In addition to vector control techniques such as IRS in high-risk areas and thorough distribution of long-lasting ITNs, factors such as economic development and increasing access to health services have contributed to Bhutan's successes in reducing malaria incidence.<ref name="Yangzom 2012"/>

==Research==
===Vaccine===
{{See also|Malaria vaccine}}
Immunity (or, more accurately, [[immune tolerance|tolerance]]) to ''P.&nbsp;falciparum'' malaria does occur naturally, but only in response to years of repeated infection.<ref name="Tran 2012"/> An individual can be protected from a ''P.&nbsp;falciparum'' infection if they receive about a thousand bites from mosquitoes that carry a version of the parasite rendered non-infective by a dose of [[X-ray]] [[irradiation]].<ref name="Hill 2011"/> An effective [[Vaccination|vaccine]] is not yet available for malaria, although several are under development.<ref name="Geels 2011"/> The highly [[polymorphism (biology)|polymorphic]] nature of many ''P.&nbsp;falciparum'' proteins results in significant challenges to vaccine design. Vaccine candidates that target antigens on gametes, zygotes, or ookinetes in the mosquito midgut aim to block the transmission of malaria. These transmission-blocking vaccines induce antibodies in the human blood; when a mosquito takes a blood meal from a protected individual, these antibodies prevent the parasite from completing its development in the mosquito.<ref name="Cromptom 2010"/> Other vaccine candidates, targeting the blood-stage of the parasite's life cycle, have been inadequate on their own.<ref name="Graves 2006b"/> For example, [[SPf66]] was tested extensively in areas where the disease is common in the 1990s, but trials showed it to be insufficiently effective.<ref name="Graves 2006"/> Several potential vaccines targeting the pre-erythrocytic stage of the parasite's life cycle are being developed, with [[RTS,S]] as a leading candidate;<ref name="Hill 2011"/> it is expected to be licensed in 2015.<ref name="Riley 2013"/> A US biotech company, [[Sanaria]], is developing a pre-erythrocytic [[attenuated vaccine]] called PfSPZ that uses whole sporozoites to induce an immune response.<ref name="Hoffman 2010"/> In 2006, the [[Malaria Vaccine Advisory Committee]] to the WHO outlined a "Malaria Vaccine Technology Roadmap" that has as one of its landmark objectives to "develop and license a first-generation malaria vaccine that has a protective efficacy of more than 50% against severe disease and death and lasts longer than one year" by 2015.<ref name="Roadmap 2006"/>

===Medications===
Malaria parasites contain [[apicoplast]]s, organelles usually found in plants, complete with their own [[genome]]s. These apicoplasts are thought to have originated through the [[Endosymbiont|endosymbiosis]] of algae and play a crucial role in various aspects of parasite metabolism, such as [[fatty acid biosynthesis]]. Over 400 proteins have been found to be produced by apicoplasts and these are now being investigated as possible targets for novel anti-malarial drugs.<ref name="Kalanon 2010"/>

With the onset of drug-resistant ''Plasmodium'' parasites, new strategies are being developed to combat the widespread disease. One such approach lies in the introduction of synthetic [[pyridoxal]]-amino acid [[adduct]]s, which are taken up by the parasite and ultimately interfere with its ability to create several essential [[B vitamin]]s.<ref name="Müller 2010"/><ref name="Du 2011"/> Antimalarial drugs using [[Organometallic chemistry|synthetic metal-based]] [[coordination complex|complexes]] are attracting research interest.<ref name="Biot 2012"/><ref name="Roux 2012"/>

*(+)-SJ733: Part of a wider class of experimental drugs called [[spiroindolone]]. It inhibits the ATP4 protein of infected red blood cells that cause the cells to shrink and become rigid like the aging cells. This triggers the immune system to eliminate the infected cells from the system as demonstrated in a mouse model. As of 2014, a [[Phases of clinical research#Phase 1|Phase 1 clinical trial]] to assess the safety profile in human is planned by the [[Howard Hughes Medical Institute]].<ref name=atp4>{{cite web|url= http://www.fiercebiotechresearch.com/story/new-malaria-drug-unleashes-immune-system-assault-infected-cells/2014-12-08|title=New malaria drug unleashes an immune system assault on infected cells|author=Carroll, John|publisher=fiercebiotechresearch.com|date=8 December 2014|accessdate=16 December 2014}}</ref>
*NITD246 and [[NITD609]]: Also belonged to the class of spiroindolone and target the ATP4 protein. <ref name=atp4/>

===其他===
A non-chemical vector control strategy involves genetic manipulation of malaria mosquitoes. Advances in [[genetic engineering]] technologies make it possible to introduce foreign DNA into the mosquito genome and either decrease the lifespan of the mosquito, or make it more resistant to the malaria parasite. [[Sterile insect technique]] is a genetic control method whereby large numbers of sterile males mosquitoes are reared and released. Mating with wild females reduces the wild population in the subsequent generation; repeated releases eventually eliminate the target population.<ref name="Raghavendra 2011"/>

[[Genomics]] is central to malaria research. With the [[whole genome sequencing|sequencing]] of ''P.&nbsp;falciparum'', one of its vectors ''Anopheles gambiae'', and the [[human genome]], the genetics of all three organisms in the malaria lifecycle can be studied.<ref name="Aultman 2002"/> Another new application of genetic technology is the ability to produce [[Genetically modified organism|genetically modified]] mosquitoes that do not transmit malaria, potentially allowing [[biological control]] of malaria transmission.<ref name="Ito 2002"/>

==Other animals==
Nearly 200 parasitic ''Plasmodium'' species have been identified that infect [[Plasmodium species infecting birds|birds]], [[Plasmodium species infecting reptiles|reptiles]], and [[Plasmodium species infecting mammals other than primates|other mammals]],<ref name="Rich 2006"/> and about 30 species naturally infect non-human primates.<ref name="Baird 2009"/> Some malaria parasites that affect non-human primates (NHP) serve as [[model organism]]s for human malarial parasites, such as ''[[Plasmodium coatneyi|P.&nbsp;coatneyi]]'' (a model for ''P.&nbsp;falciparum'') and ''[[Plasmodium cynomolgi|P.&nbsp;cynomolgi]]'' (''P.&nbsp;vivax''). Diagnostic techniques used to detect parasites in NHP are similar to those employed for humans.<ref name="Ameri 2010"/> Malaria parasites that infect rodents are widely used as models in research, such as ''[[Plasmodium berghei|P.&nbsp;berghei]]''.<ref name="Mlambo 2008"/> [[Avian malaria]] primarily affects species of the order [[Passeriformes]], and poses a substantial threat to birds of [[Hawaii]], the [[Galapagos]], and other [[archipelago]]es. The parasite ''[[Plasmodium relictum|P.&nbsp;relictum]]'' is known to play a role in limiting the distribution and abundance of [[endemic birds of Hawaii|endemic Hawaiian birds]]. [[Global warming]] is expected to increase the prevalence and global distribution of avian malaria, as elevated temperatures provide optimal conditions for parasite reproduction.<ref name="LaPointe 2012"/>

{{TransH}}


==病理分段==
==病理分段==

2015年5月20日 (三) 15:35的版本

疟疾
Malaria.jpg
人体血液中的恶性疟原虫环状体和配子母细胞
症状intermittent fever[*], periodic fever[*], 肝腫大, 贫血, 脾腫大[*], 黄疸, 昏迷, 發冷
肇因恶性疟原虫, 间日疟原虫, 三日瘧, 卵形瘧, 猴瘧蟲
診斷方法血膜[*], 光学显微镜, 聚合酶链式反应
治療抗疟药, 解熱劑, intravenous fluid replacement[*], 对症治疗
盛行率729、​22、​2、​1,974、​881,730、​343,527、​31,479、​21,309、​177,767、​3,769,051、​500,000,000、​4,114
死亡數445,000、​627,000
醫學專科感染科、​熱帶醫學、​寄生虫学


瘧疾(英語:Malaria)是一種蚊媒病,由寄生性的原生生物界(一種單細胞 微生物瘧原蟲[1]引起,人類及其他動物的全球性急性寄生蟲傳染病。瘧疾引起的典型症狀有發燒倦怠不適英语Malaise嘔吐以及 頭痛。在嚴重的病例中會引起黃疸癲癇發作昏迷死亡[2]。這些症狀通常在被蚊子叮咬後十到十五天內開始出現,沒有受到適當治療的病人(但症狀緩解)可能於數個月後會再次出現這些症狀[1]。而在瘧疾倖存者中,再次感染通常引起的症狀通常較輕微。如果沒有持續暴露在瘧疾環境中,這種少量的抵抗力會在數月至數年間消失[3]

一般來說,瘧疾是透過受感染的雌性瘧蚊叮咬來傳播的。寄生蟲瘧原蟲會透過瘧蚊叮咬從蚊子的唾液中傳入至人類的血液[1],接著瘧原蟲會隨血液移動至肝臟,在肝臟細胞中發育成熟及繁殖。瘧原蟲屬中有五種是可藉由感染人類進行散播[2],多數死亡案例由惡性瘧P. falciparum)、間日瘧P. vivax)及卵形瘧P. ovale)所造成,而三日瘧P. malariae)則產生較輕微的瘧疾症狀[1][2]。另外,猴瘧蟲英语Plasmodium_knowlesiP. knowlesi,又稱諾氏瘧蟲)較少在人類身上造成疾病[1]。診斷瘧疾主要透過顯微鏡檢驗血液抹片英语Blood_film或是加上快速瘧疾抗原診斷測試英语Malaria_antigen_detection_tests[2]。近年發展聚合酶鏈式反應來偵測瘧原蟲的DNA,但目前因為成本及複雜性,而沒有廣泛地應用在瘧疾盛行地區[4]

避免瘧蚊叮咬能夠降低感染瘧疾的風險,透過使用蚊帳以及驅蟲劑 或其他控制蚊蟲生長英语Mosquito contro的方法,像是噴灑殺蟲劑以及清除積水[2]。前往瘧疾盛行區的旅客可以使用幾種藥物來預防瘧疾英语Malaria_prophylaxis,而瘧疾好發地區的嬰兒及過了懷孕初期第一妊娠期孕婦也建議適量使用周效磺胺/比利美胺英语Sulfadoxine/pyrimethamine。20世紀中期以後也出現了一些新的藥物,中國科學家研製的 青蒿素 有很好的抗瘧疾效果。儘管有所需求,但瘧疾尚無疫苗,目前相關研究正在進行中[1]。瘧疾的建議治療是併用青蒿素及另一種抗瘧疾藥物[1][2],包括甲氟喹苯芴醇周效磺胺/比利美胺英语Sulfadoxine/pyrimethamine[5]。如果青蒿素無法取得,則可使用奎寧加上去氧羥四環素[5]。由於擔心抗藥性的增加,建議在瘧疾盛行地區儘可能確診為瘧疾後再開始治療。目前瘧疾逐漸對於幾種藥物發展出抗藥性,例如:具有氯化奎寧(氯喹)抗藥性的惡性瘧已經散布到多數的瘧疾地區,另外青蒿素抗藥性問題在部分東南亞地區日益嚴重[1]

瘧疾普遍存在於熱帶亞熱帶地區,位於赤道周圍的寬大帶狀區域[2]。主要流行地區是 非洲中部南亞東南亞南美北部的熱帶地區,這其中又以 非洲 的疫情最甚。就中國而言,瘧疾主要的流行地帶為華中華南的叢林多山地區,但疫情遠較非洲為輕。世界衛生組織預估2012年,將會有二億七百萬例瘧疾案例,同時也預估該年因患瘧疾死亡人數介於四十七萬三千人至七十八萬九千人之間,多數為非洲的孩童[1]。瘧疾與貧困息息相關,造成經濟發展相當大的負面影響[6][7]。非洲預估每年損失一百二十億美元,因為健康照護的花費增加,勞動力減少,以及瘧疾對觀光旅遊業造成的影響[8]。根據世界衛生組織的統計,2013年全世界的瘧疾病例共有1.98億例。[9][10]造成584,000至855,000人死亡,當中有90%是在非洲發生[11][9]

主要病徵

瘧疾主要症狀[12]

感染疟原虫后8-25天会发病[12],但如果有先服用預防性藥物的人可能會在之後才發生[4]。病人可能会有如下流感樣症狀[13]:忽冷忽热、头痛发热顫栗关节痛呕吐溶血反应、疟原性贫血、黄疸血尿视网膜损害、抽搐[14]。最典型的症状为忽冷忽热循环——先发冷、打冷颤,然后发热、出汗。这是因为疟原虫生活周期具有明显的生理节奏(circadian rhythm),如間日疟原虫(Plasmodium vivax)导致的疟疾发热周期为48小时,因而病患的发烧症状也呈现周期性。如果疟原虫侵入脑部血管,则会导致最为严重的脑部疟疾,这通常会造成病者昏迷。由于早期迹象与流行性感冒有相似之处,许多对该疾病不熟悉的外来旅游者容易将疟疾误认为感冒,从而因为没有得到及时的药物治疗而使得病情恶化。

按照疟疾病征的严重程度不同,疟疾可以分为非重症疟疾(uncomplicated malaria)和重症疟疾(complicated / severe malaria),能有效治疗这两类疟疾的药物不太相同。重症瘧疾通常是由惡性瘧原蟲所導致,因此又稱為惡性瘧疾,通常在感染後9至30天發病[13],得到腦瘧疾的患者常產生神經系統疾病,包括姿態異常英语abnormal posturing眼球震顫英语nystagmus共軛凝視麻痺英语conjugate gaze palsy(眼球無法朝同一方向轉動)、角弓反張抽搐,或昏迷[13]


併發症

瘧疾常常導致一些嚴重的併發症。其中一個症狀是呼吸困難,在惡性瘧疾的患者當中,多達25%的成人和40%的幼童會有此症狀。可能病因為代謝性酸中毒造成的呼吸代償、非心源性肺水腫、併發肺炎,和貧血

如果瘧疾患者同時感染上HIV,死亡風險則會提高。[15]腎臟損傷會導致黑水熱英语blackwater fever,原因是瘧原蟲會造成溶血,使血紅素進入尿液當中,造成尿液呈暗紅色至黑色[13]

惡性瘧疾會導致腦瘧疾,會導致視網膜白化,此為臨床上重要判斷依據。[16]其他症狀包括脾腫大、嚴重頭痛、肝腫大低血糖,以及腎衰竭[13]。腎衰竭則可能導致血紅蛋白尿、自發性出血和凝血功能障礙。[17] 得到瘧疾的孕婦英语Pregnancy-associated malaria可能會造成死胎流產,胎兒體重過輕[18]。特別是在惡性瘧疾,和部分間日瘧原蟲瘧疾上[19]

病原

瘧疾疫區,2006年。[20]
    氯喹及多重耐药性疟疾高发区     氯喹抗药性疟疾发生区     无抗药性疟疾发生区     无疟疾

瘧疾的致病源是瘧原蟲(疟原虫属,Plasmodium spp.),这是一类单细胞真核生物,属于细胞内寄生蟲,它们以瘧蚊蚊子的其中一個屬,瘧蚊屬的部分種類)作為传病媒介,通过雌蚊叮咬吸血来傳播病原体。

疟原虫属生物是顶复合器门(Apicomplexa)的原生生物,这一门的生物几乎都是寄生虫。大部分脊椎动物都可以作为疟原虫的主要宿主,比如啮齿动物,蝙蝠,蜥蜴,鸟等等。这也使得生物学家可以通过建立生物模型(比方说,用老鼠做疟疾病理研究)的方式来研究人类疟疾。

只有四种疟原虫能够感染人类[21][22],包括:

  • 恶性疟原虫Plasmodium falciparum):世界最主要的感染性瘧原蟲(75%),亦是造成患者死亡率最高的疟原虫。[4]


非洲最主要的患者為惡性瘧原蟲,但非洲之外的國家間日瘧原蟲的比例則較高。[23]。雖然曾經有文獻指出人類可能會被一些人猿類傳染瘧疾,但除了諾氏瘧原蟲[22]之外,其餘都沒有什麼公共衛生重要性。[24]


中国以间日疟与恶性疟最为常见,三日疟少见,卵形疟极少发生。恶性疟主要发生在西南与海南。间日疟发生在东北、华北、西北。

全球暖化增加了瘧蚊的活動範圍,但對於瘧疾的傳播影響,至今仍不明確[25][26]

生活史

瘧原蟲的生活史。首先,蚊子藉由叮咬造成瘧原蟲的子孢子(sporozoites)進入體內,随血液运移到肝脏,侵入肝细胞。子孢子在肝细胞内部吸收营养,长大成熟后分裂生殖形成很多小的裂殖子(merozoites)。裂殖子成熟后,破坏肝细胞进入体液、血液中,一部分再侵入肝细胞重复上述循环,一部分侵入红细胞,成为像个戒指的环状体(ring forms)。环状体进一步长大,向四周伸出伪足,称为阿米巴样体或大滋养体(trophozoites)。大滋养体进一步发育形成裂殖体(schizonts),裂殖体成熟后放出很多裂殖子,破坏红细胞后进入血液,继续感染其他红细胞。同時瘧原蟲也會進行有性生殖,此時患者可能又被瘧蚊叮咬,攜入其他健康者身上,延續下一個生活史。

疟原虫的生命周期很复杂。在瘧原蟲的生活始中,雌性瘧蚊(最終宿主)扮演的是一個媒介的角色。雌按蚊叮咬人时,唾液中的疟原虫的长梭形的子孢子(sporozoite)进入人体内,随血液运移到肝脏,侵入肝细胞。子孢子在肝细胞内部吸收营养,长大成熟后分裂生殖形成很多小的裂殖子(merozoites)。裂殖子成熟后,破坏肝细胞进入体液、血液中,一部分再侵入肝细胞重复上述循环,一部分侵入红细胞

在红细胞内,裂殖子逐渐吸收血红蛋白作为营养长大,成为像个戒指的环状体。环状体进一步长大,向四周伸出伪足,称为阿米巴样体或大滋养体(trophozoites)。大滋养体进一步发育形成裂殖体(schizonts),裂殖体成熟后放出很多裂殖子,破坏红细胞后进入血液,继续感染其他红细胞。由于人体内的疟原虫的裂殖子同时破坏大量红细胞进入血液,人体会产生疟疾的典型症状,如发冷发热。如果宿主环境不利,一些裂殖子进入红细胞后可形成大、小配子母细胞。这些配子母细胞在人体中不再进一步发育,如果不能被蚊子吸血时吸走,配子母细胞在人体内可存活60天。

当蚊子吸取受感染人体的血液后,雄、雌配子母细胞(gametocytes)进入蚊子中腸内,进入有性繁殖世代。雌雄配子母細胞會在蚊子的中腸成熟並結合為卵動子,並在腸壁下形成卵囊(oocyte)。卵囊中疟原虫进行无性繁殖,最终形成子孢子。成熟后,卵囊破裂,子孢子进入蚊子体腔,穿透各种组织,进入蚊子唾液腺。蚊子唾液腺中的子孢子可达20万,子孢子在蚊子体内存活70天,准备感染新的脊椎动物宿主[27][28]

除了蚊蟲感染之外,瘧原蟲也有可能藉由輸血感染,但此情況相當罕見。[29]2006年,台北榮民總醫院發生了一起嚴重的院內感染案例,造成4名病患感染惡性瘧疾死亡,即因輸血方式不當。[30]