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Malaria
FromWikipedia,thefreeencyclopedia

Malariaisamosquitoborneinfectiousdiseaseaffectinghumansandotheranimalscausedbyparasitic
protozoans(agroupofsinglecelledmicroorganisms)belongingtothePlasmodiumtype.[1]Malariacauses
symptomsthattypicallyincludefever,fatigue,vomiting,andheadaches.Inseverecasesitcancauseyellow
skin,seizures,coma,ordeath.[2]Symptomsusuallybegintentofifteendaysafterbeingbitten.Ifnotproperly
treated,peoplemayhaverecurrencesofthediseasemonthslater.[1]Inthosewhohaverecentlysurvivedan
infection,reinfectionusuallycausesmildersymptoms.Thispartialresistancedisappearsovermonthstoyearsif
thepersonhasnocontinuingexposuretomalaria.[2]

Malaria

ThediseaseismostcommonlytransmittedbyaninfectedfemaleAnophelesmosquito.Themosquitobite
introducestheparasitesfromthemosquito'ssalivaintoaperson'sblood.[1]Theparasitestraveltotheliver
wheretheymatureandreproduce.FivespeciesofPlasmodiumcaninfectandbespreadbyhumans.[2]Most
deathsarecausedbyP.falciparumbecauseP.vivax,P.ovale,andP.malariaegenerallycauseamilderformof
malaria.[1][2]ThespeciesP.knowlesirarelycausesdiseaseinhumans.[1]Malariaistypicallydiagnosedbythe
microscopicexaminationofbloodusingbloodfilms,orwithantigenbasedrapiddiagnostictests.[2]Methods
thatusethepolymerasechainreactiontodetecttheparasite'sDNAhavebeendeveloped,butarenotwidely
usedinareaswheremalariaiscommonduetotheircostandcomplexity.[3]
Theriskofdiseasecanbereducedbypreventingmosquitobitesthroughtheuseofmosquitonetsandinsect
repellents,orwithmosquitocontrolmeasuressuchassprayinginsecticidesanddrainingstandingwater.[2]
Severalmedicationsareavailabletopreventmalariaintravellerstoareaswherethediseaseiscommon.
Occasionaldosesofthecombinationmedicationsulfadoxine/pyrimethaminearerecommendedininfantsand
afterthefirsttrimesterofpregnancyinareaswithhighratesofmalaria.Despiteaneed,noeffectivevaccine
exists,althougheffortstodeveloponeareongoing.[1]Therecommendedtreatmentformalariaisacombination
ofantimalarialmedicationsthatincludesanartemisinin.[1][2]Thesecondmedicationmaybeeithermefloquine,
lumefantrine,orsulfadoxine/pyrimethamine.[4]Quininealongwithdoxycyclinemaybeusedifanartemisinin
isnotavailable.[4]Itisrecommendedthatinareaswherethediseaseiscommon,malariaisconfirmedif
possiblebeforetreatmentisstartedduetoconcernsofincreasingdrugresistance.Resistanceamongthe

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APlasmodiumfromthesalivaofafemalemosquito
movingacrossamosquitocell
Classificationandexternalresources
Specialty

Infectiousdisease

ICD10

B50(http://apps.who.int/classification
s/icd10/browse/2016/en#/B50)B54(ht
tp://apps.who.int/classifications/icd10/
browse/2016/en#/B54)

ICD9CM

084(http://www.icd9data.com/getICD
9Code.ashx?icd9=084)
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parasiteshasdevelopedtoseveralantimalarialmedicationsforexample,chloroquineresistantP.falciparum
hasspreadtomostmalarialareas,andresistancetoartemisininhasbecomeaprobleminsomepartsof
SoutheastAsia.[1]
Thediseaseiswidespreadinthetropicalandsubtropicalregionsthatexistinabroadbandaroundthe
equator.[2]ThisincludesmuchofSubSaharanAfrica,Asia,andLatinAmerica.In2015,therewere214
millioncasesofmalariaworldwideresultinginanestimated438,000deaths,90%ofwhichoccurredin
Africa.[5]Ratesofdiseasehavedecreasedfrom2000to2015by37%,[5]butincreasedfrom2014duringwhich
therewere198millioncases.[6]Malariaiscommonlyassociatedwithpovertyandhasamajornegativeeffect
oneconomicdevelopment.[7][8]InAfrica,itisestimatedtoresultinlossesofUS$12billionayeardueto
increasedhealthcarecosts,lostabilitytowork,andnegativeeffectsontourism.[9]

Contents
1 Signsandsymptoms
1.1 Complications
2 Cause
2.1 Lifecycle
2.2 Recurrentmalaria
3 Pathophysiology
3.1 Geneticresistance
3.2 Liverdysfunction
4 Diagnosis
4.1 Classification
5 Prevention
5.1 Mosquitocontrol
5.2 Othermethods
5.3 Medications
6 Treatment
6.1 Resistance
7 Prognosis
8 Epidemiology
9 History
10 Societyandculture
10.1 Economicimpact
10.2 Counterfeitandsubstandarddrugs
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OMIM

248310(http://omim.org/entry/24831
0)

DiseasesDB 7728(http://www.diseasesdatabase.co
m/ddb7728.htm)
MedlinePlus 000621(http://www.nlm.nih.gov/medl
ineplus/ency/article/000621.htm)
eMedicine

med/1385(http://www.emedicine.co
m/med/topic1385.htm)emerg/305(htt
p://www.emedicine.com/emerg/topic3
05.htm#)ped/1357(http://www.emedi
cine.com/ped/topic1357.htm#)

PatientUK Malaria(http://patient.info/doctor/mal
ariapro)
MeSH

C03.752.250.552(https://www.nlm.ni
h.gov/cgi/mesh/2016/MB_cgi?mode=
&term=Malaria&field=entry#TreeC0
3.752.250.552)

Orphanet

673(http://www.orpha.net/consor/cgi
bin/OC_Exp.php?lng=en&Expert=67
3)

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11

12
13
14
15

10.2 Counterfeitandsubstandarddrugs
10.3 War
10.4 Eradicationefforts
Research
11.1 Vaccine
11.2 Medications
11.3 Other
Otheranimals
References
Furtherreading
Externallinks

Signsandsymptoms
Thesignsandsymptomsofmalariatypicallybegin825daysfollowinginfection[10]however,symptomsmayoccur
laterinthosewhohavetakenantimalarialmedicationsasprevention.[3]Initialmanifestationsofthediseasecommon
toallmalariaspeciesaresimilartoflulikesymptoms,[11]andcanresembleotherconditionssuchassepsis,
gastroenteritis,andviraldiseases.[3]Thepresentationmayincludeheadache,fever,shivering,jointpain,vomiting,
hemolyticanemia,jaundice,hemoglobinintheurine,retinaldamage,andconvulsions.[12]
Theclassicsymptomofmalariaisparoxysmacyclicaloccurrenceofsuddencoldnessfollowedbyshiveringand
thenfeverandsweating,occurringeverytwodays(tertianfever)inP.vivaxandP.ovaleinfections,andeverythree
days(quartanfever)forP.malariae.P.falciparuminfectioncancauserecurrentfeverevery3648hours,oraless
pronouncedandalmostcontinuousfever.[13]
SeveremalariaisusuallycausedbyP.falciparum(oftenreferredtoasfalciparummalaria).Symptomsoffalciparum
malariaarise930daysafterinfection.[11]Individualswithcerebralmalariafrequentlyexhibitneurologicalsymptoms,
includingabnormalposturing,nystagmus,conjugategazepalsy(failureoftheeyestoturntogetherinthesame
direction),opisthotonus,seizures,orcoma.[11]

Mainsymptomsofmalaria[10]

Complications
Malariahasseveralseriouscomplications.Amongtheseisthedevelopmentofrespiratorydistress,whichoccursinupto25%ofadultsand40%ofchildrenwith
severeP.falciparummalaria.Possiblecausesincluderespiratorycompensationofmetabolicacidosis,noncardiogenicpulmonaryoedema,concomitant
pneumonia,andsevereanaemia.Althoughrareinyoungchildrenwithseveremalaria,acuterespiratorydistresssyndromeoccursin525%ofadultsandupto
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29%ofpregnantwomen.[14]CoinfectionofHIVwithmalariaincreasesmortality.[15]Renalfailureisafeatureofblackwaterfever,wherehemoglobinfromlysed
redbloodcellsleaksintotheurine.[11]
InfectionwithP.falciparummayresultincerebralmalaria,aformofseveremalariathatinvolvesencephalopathy.Itisassociatedwithretinalwhitening,which
maybeausefulclinicalsignindistinguishingmalariafromothercausesoffever.[16]Enlargedspleen,enlargedliverorbothofthese,severeheadache,lowblood
sugar,andhemoglobinintheurinewithrenalfailuremayoccur.[11]Complicationsmayincludespontaneousbleeding,coagulopathy,andshock.[17]
Malariainpregnantwomenisanimportantcauseofstillbirths,infantmortality,abortionandlowbirthweight,[18]particularlyinP.falciparuminfection,butalso
withP.vivax.[19]

Cause
MalariaparasitesbelongtothegenusPlasmodium(phylumApicomplexa).Inhumans,malariaiscausedbyP.falciparum,P.malariae,P.ovale,P.vivaxand
P.knowlesi.[20][21]Amongthoseinfected,P.falciparumisthemostcommonspeciesidentified(~75%)followedbyP.vivax(~20%).[3]AlthoughP.falciparum
traditionallyaccountsforthemajorityofdeaths,[22]recentevidencesuggeststhatP.vivaxmalariaisassociatedwithpotentiallylifethreateningconditionsaboutas
oftenaswithadiagnosisofP.falciparuminfection.[23]P.vivaxproportionallyismorecommonoutsideAfrica.[24]Therehavebeendocumentedhumaninfections
withseveralspeciesofPlasmodiumfromhigherapeshowever,exceptforP.knowlesiazoonoticspeciesthatcausesmalariainmacaques[21]thesearemostly
oflimitedpublichealthimportance.[25]
Globalwarmingislikelytoaffectmalariatransmission,buttheseverityandgeographicdistributionofsucheffectsisuncertain.[26][27]

Lifecycle
InthelifecycleofPlasmodium,afemaleAnophelesmosquito(thedefinitivehost)transmitsamotileinfectiveform(calledthesporozoite)toavertebratehost
suchasahuman(thesecondaryhost),thusactingasatransmissionvector.Asporozoitetravelsthroughthebloodvesselstolivercells(hepatocytes),whereit
reproducesasexually(tissueschizogony),producingthousandsofmerozoites.Theseinfectnewredbloodcellsandinitiateaseriesofasexualmultiplicationcycles
(bloodschizogony)thatproduce8to24newinfectivemerozoites,atwhichpointthecellsburstandtheinfectivecyclebeginsanew.[28]
Othermerozoitesdevelopintoimmaturegametocytes,whicharetheprecursorsofmaleandfemalegametes.Whenafertilisedmosquitobitesaninfectedperson,
gametocytesaretakenupwiththebloodandmatureinthemosquitogut.Themaleandfemalegametocytesfuseandformanookineteafertilized,motilezygote.
Ookinetesdevelopintonewsporozoitesthatmigratetotheinsect'ssalivaryglands,readytoinfectanewvertebratehost.Thesporozoitesareinjectedintotheskin,
inthesaliva,whenthemosquitotakesasubsequentbloodmeal.[29]

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Onlyfemalemosquitoesfeedonbloodmalemosquitoesfeedonplantnectar,anddonottransmitthe
disease.ThefemalesoftheAnophelesgenusofmosquitoprefertofeedatnight.Theyusuallystart
searchingforamealatdusk,andwillcontinuethroughoutthenightuntiltakingameal.[30]Malaria
parasitescanalsobetransmittedbybloodtransfusions,althoughthisisrare.[31]

Recurrentmalaria
Symptomsofmalariacanrecuraftervaryingsymptomfreeperiods.Dependinguponthecause,
recurrencecanbeclassifiedaseitherrecrudescence,relapse,orreinfection.Recrudescenceiswhen
symptomsreturnafterasymptomfreeperiod.Itiscausedbyparasitessurvivinginthebloodasa
resultofinadequateorineffectivetreatment.[32]Relapseiswhensymptomsreappearaftertheparasites
havebeeneliminatedfrombloodbutpersistasdormanthypnozoitesinlivercells.Relapsecommonly
occursbetween824weeksandiscommonlyseenwithP.vivaxandP.ovaleinfections.[3]P.vivax
malariacasesintemperateareasofteninvolveoverwinteringbyhypnozoites,withrelapsesbeginning
theyearafterthemosquitobite.[33]Reinfectionmeanstheparasitethatcausedthepastinfectionwas
eliminatedfromthebodybutanewparasitewasintroduced.Reinfectioncannotreadilybe
distinguishedfromrecrudescence,althoughrecurrenceofinfectionwithintwoweeksoftreatmentfor
theinitialinfectionistypicallyattributedtotreatmentfailure.[34]Peoplemaydevelopsomeimmunity
whenexposedtofrequentinfections.[35]

Pathophysiology
Malariainfectiondevelopsviatwophases:onethatinvolvestheliver(exoerythrocyticphase),andone
thatinvolvesredbloodcells,orerythrocytes(erythrocyticphase).Whenaninfectedmosquitopiercesa
person'sskintotakeabloodmeal,sporozoitesinthemosquito'ssalivaenterthebloodstreamand
migratetotheliverwheretheyinfecthepatocytes,multiplyingasexuallyandasymptomaticallyfora
periodof830days.[36]

Thelifecycleofmalariaparasites.Amosquitocausesan
infectionbyabite.First,sporozoitesenterthebloodstream,
andmigratetotheliver.Theyinfectlivercells,wherethey
multiplyintomerozoites,rupturethelivercells,andreturn
tothebloodstream.Themerozoitesinfectredbloodcells,
wheretheydevelopintoringforms,trophozoitesand
schizontsthatinturnproducefurthermerozoites.Sexual
formsarealsoproduced,which,iftakenupbyamosquito,
willinfecttheinsectandcontinuethelifecycle.

Afterapotentialdormantperiodintheliver,theseorganismsdifferentiatetoyieldthousandsofmerozoites,which,followingruptureoftheirhostcells,escapeinto
thebloodandinfectredbloodcellstobegintheerythrocyticstageofthelifecycle.[36]Theparasiteescapesfromtheliverundetectedbywrappingitselfinthecell
membraneoftheinfectedhostlivercell.[37]
Withintheredbloodcells,theparasitesmultiplyfurther,againasexually,periodicallybreakingoutoftheirhostcellstoinvadefreshredbloodcells.Severalsuch
amplificationcyclesoccur.Thus,classicaldescriptionsofwavesoffeverarisefromsimultaneouswavesofmerozoitesescapingandinfectingredbloodcells.[36]
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SomeP.vivaxsporozoitesdonotimmediatelydevelopintoexoerythrocyticphasemerozoites,butinsteadproduce
hypnozoitesthatremaindormantforperiodsrangingfromseveralmonths(710monthsistypical)toseveralyears.Aftera
periodofdormancy,theyreactivateandproducemerozoites.Hypnozoitesareresponsibleforlongincubationandlate
relapsesinP.vivaxinfections,[33]althoughtheirexistenceinP.ovaleisuncertain.[38]
Theparasiteisrelativelyprotectedfromattackbythebody'simmunesystembecauseformostofitshumanlifecycleit
resideswithintheliverandbloodcellsandisrelativelyinvisibletoimmunesurveillance.However,circulatinginfected
bloodcellsaredestroyedinthespleen.Toavoidthisfate,theP.falciparumparasitedisplaysadhesiveproteinsonthe
surfaceoftheinfectedbloodcells,causingthebloodcellstosticktothewallsofsmallbloodvessels,therebysequestering
theparasitefrompassagethroughthegeneralcirculationandthespleen.[39]Theblockageofthemicrovasculaturecauses
symptomssuchasinplacentalmalaria.[40]Sequesteredredbloodcellscanbreachthebloodbrainbarrierandcause
cerebralmalaria.[41]

Geneticresistance
Accordingtoa2005review,duetothehighlevelsofmortalityandmorbiditycausedbymalariaespeciallythe
P.falciparumspeciesithasplacedthegreatestselectivepressureonthehumangenomeinrecenthistory.Severalgenetic
factorsprovidesomeresistancetoitincludingsicklecelltrait,thalassaemiatraits,glucose6phosphatedehydrogenase
deficiency,andtheabsenceofDuffyantigensonredbloodcells.[42][43]
Theimpactofsicklecelltraitonmalariaimmunityillustratessomeevolutionarytradeoffsthathaveoccurredbecauseof
endemicmalaria.Sicklecelltraitcausesachangeinthehemoglobinmoleculeintheblood.Normally,redbloodcellshave
averyflexible,biconcaveshapethatallowsthemtomovethroughnarrowcapillarieshowever,whenthemodified
hemoglobinSmoleculesareexposedtolowamountsofoxygen,orcrowdtogetherduetodehydration,theycanstick
togetherformingstrandsthatcausethecelltosickleordistortintoacurvedshape.Inthesestrandsthemoleculeisnotas
effectiveintakingorreleasingoxygen,andthecellisnotflexibleenoughtocirculatefreely.Intheearlystagesofmalaria,
theparasitecancauseinfectedredcellstosickle,andsotheyareremovedfromcirculationsooner.Thisreducesthe
frequencywithwhichmalariaparasitescompletetheirlifecycleinthecell.Individualswhoarehomozygous(withtwo
copiesoftheabnormalhemoglobinbetaallele)havesicklecellanaemia,whilethosewhoareheterozygous(withone
abnormalalleleandonenormalallele)experienceresistancetomalariawithoutsevereanemia.Althoughtheshorterlife
expectancyforthosewiththehomozygousconditionwouldtendtodisfavorthetrait'ssurvival,thetraitispreservedin
malariaproneregionsbecauseofthebenefitsprovidedbytheheterozygousform.[43][44]

Micrographofaplacentafroma
stillbirthduetomaternalmalaria.
H&Estain.Redbloodcellsare
anuclearblue/blackstaininginbright
redstructures(redbloodcells)
indicateforeignnucleifromthe
parasites.

Electronmicrographofa
Plasmodiumfalciparuminfectedred
bloodcell(center),illustrating
adhesionprotein"knobs"

Liverdysfunction

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Liverdysfunctionasaresultofmalariaisuncommonandusuallyonlyoccursinthosewithanotherliverconditionsuchasviralhepatitisorchronicliverdisease.
Thesyndromeissometimescalledmalarialhepatitis.[45]Whileithasbeenconsideredarareoccurrence,malarialhepatopathyhasseenanincrease,particularlyin
SoutheastAsiaandIndia.Livercompromiseinpeoplewithmalariacorrelateswithagreaterlikelihoodofcomplicationsanddeath.[45]

Diagnosis
Owingtothenonspecificnatureofthepresentationofsymptoms,diagnosisofmalariainnonendemicareasrequiresa
highdegreeofsuspicion,whichmightbeelicitedbyanyofthefollowing:recenttravelhistory,enlargedspleen,fever,low
numberofplateletsintheblood,andhigherthannormallevelsofbilirubininthebloodcombinedwithanormallevelof
whitebloodcells.[3]
Malariaisusuallyconfirmedbythemicroscopicexaminationofbloodfilmsorbyantigenbasedrapiddiagnostictests
(RDT).[46][47]Insomeareas,RDTsneedtobeabletodistinguishwhetherthemalariasymptomsarecausedbyPlasmodium
falciparumorbyotherspeciesofparasitessincetreatmentstrategiescoulddifferfornonfalciparuminfections.[48]
Microscopyisthemostcommonlyusedmethodtodetectthemalarialparasiteabout165millionbloodfilmswere
examinedformalariain2010.[49]Despiteitswidespreadusage,diagnosisbymicroscopysuffersfromtwomaindrawbacks:
manysettings(especiallyrural)arenotequippedtoperformthetest,andtheaccuracyoftheresultsdependsonboththe
skillofthepersonexaminingthebloodfilmandthelevelsoftheparasiteintheblood.Thesensitivityofbloodfilmsranges
from7590%inoptimumconditions,toaslowas50%.CommerciallyavailableRDTsareoftenmoreaccuratethanblood
filmsatpredictingthepresenceofmalariaparasites,buttheyarewidelyvariableindiagnosticsensitivityandspecificity
dependingonmanufacturer,andareunabletotellhowmanyparasitesarepresent.[49]
Inregionswherelaboratorytestsarereadilyavailable,malariashouldbesuspected,andtestedfor,inanyunwellperson
whohasbeeninanareawheremalariaisendemic.Inareasthatcannotaffordlaboratorydiagnostictests,ithasbecome
commontouseonlyahistoryoffeverastheindicationtotreatformalariathusthecommonteaching"feverequals
malariaunlessprovenotherwise".Adrawbackofthispracticeisoverdiagnosisofmalariaandmismanagementofnon
malarialfever,whichwasteslimitedresources,erodesconfidenceinthehealthcaresystem,andcontributestodrug
resistance.[50]Althoughpolymerasechainreactionbasedtestshavebeendeveloped,theyarenotwidelyusedinareas
wheremalariaiscommonasof2012,duetotheircomplexity.[3]

Classification

Thebloodfilmisthegoldstandard
formalariadiagnosis.

Ringformsandgametocytesof
Plasmodiumfalciparuminhuman
blood

Malariaisclassifiedintoeither"severe"or"uncomplicated"bytheWorldHealthOrganization(WHO).[3]Itisdeemed
severewhenanyofthefollowingcriteriaarepresent,otherwiseitisconsidereduncomplicated.[51]
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Decreasedconsciousness
Significantweaknesssuchthatthepersonisunabletowalk
Inabilitytofeed
Twoormoreconvulsions
Lowbloodpressure(lessthan70mmHginadultsand50mmHginchildren)
Breathingproblems
Circulatoryshock
Kidneyfailureorhemoglobinintheurine
Bleedingproblems,orhemoglobinlessthan50g/L(5g/dL)
Pulmonaryoedema
Bloodglucoselessthan2.2mmol/L(40mg/dL)
Acidosisorlactatelevelsofgreaterthan5mmol/L
Aparasitelevelinthebloodofgreaterthan100,000permicrolitre(L)inlowintensitytransmissionareas,or250,000perLinhighintensitytransmission
areas
CerebralmalariaisdefinedasasevereP.falciparummalariapresentingwithneurologicalsymptoms,includingcoma(withaGlasgowcomascalelessthan11,or
aBlantyrecomascalegreaterthan3),orwithacomathatlastslongerthan30minutesafteraseizure.[52]
Varioustypesofmalariahavebeencalledbythenamesbelow:[53]

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Name

Pathogen

Notes

algidmalaria

Plasmodiumfalciparum

severemalariaaffectingthecardiovascularsystemandcausing
chillsandcirculatoryshock

biliousmalaria

Plasmodiumfalciparum

severemalariaaffectingtheliverandcausingvomitingand
jaundice

cerebralmalaria

Plasmodiumfalciparum

severemalariaaffectingthecerebrum

congenitalmalaria

variousplasmodia

plasmodiumintroducedfromthemotherviathefetalcirculation

falciparummalaria,Plasmodiumfalciparum
malaria,perniciousmalaria

Plasmodiumfalciparum

ovalemalaria,Plasmodiumovalemalaria

Plasmodiumovale

quartanmalaria,malariaemalaria,Plasmodium
malariaemalaria

Plasmodiummalariae

quotidianmalaria

Plasmodiumfalciparum,Plasmodiumvivax paroxysmsdaily(quotidian)

tertianmalaria

Plasmodiumfalciparum,Plasmodiumovale, paroxysmseverythirdday(tertian),countingthedayof
Plasmodiumvivax
occurrenceasthefirst

transfusionmalaria

variousplasmodia

vivaxmalaria,Plasmodiumvivaxmalaria

Plasmodiumvivax

paroxysmseveryfourthday(quartan),countingthedayof
occurrenceasthefirstday

plasmodiumintroducedbybloodtransfusion,needlesharing,or
needlestickinjury

Prevention
Methodsusedtopreventmalariaincludemedications,mosquitoeliminationandthepreventionofbites.Thereisnovaccineformalaria.Thepresenceofmalaria
inanarearequiresacombinationofhighhumanpopulationdensity,highanophelesmosquitopopulationdensityandhighratesoftransmissionfromhumansto
mosquitoesandfrommosquitoestohumans.Ifanyoftheseisloweredsufficiently,theparasitewilleventuallydisappearfromthatarea,ashappenedinNorth
America,EuropeandpartsoftheMiddleEast.However,unlesstheparasiteiseliminatedfromthewholeworld,itcouldbecomereestablishedifconditionsrevert
toacombinationthatfavourstheparasite'sreproduction.Furthermore,thecostperpersonofeliminatinganophelesmosquitoesriseswithdecreasingpopulation
density,makingiteconomicallyunfeasibleinsomeareas.[54]
Preventionofmalariamaybemorecosteffectivethantreatmentofthediseaseinthelongrun,buttheinitialcostsrequiredareoutofreachofmanyoftheworld's
poorestpeople.Thereisawidedifferenceinthecostsofcontrol(i.e.maintenanceoflowendemicity)andeliminationprogramsbetweencountries.Forexample,
inChinawhosegovernmentin2010announcedastrategytopursuemalariaeliminationintheChineseprovincestherequiredinvestmentisasmallproportion
ofpublicexpenditureonhealth.Incontrast,asimilarprograminTanzaniawouldcostanestimatedonefifthofthepublichealthbudget.[55]
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Inareaswheremalariaiscommon,childrenunderfiveyearsoldoftenhaveanemiawhichissometimesduetomalaria.
Givingchildrenwithanemiaintheseareaspreventiveantimalarialmedicationimprovesredbloodcelllevelsslightlybut
didnotaffecttheriskofdeathorneedforhospitalization.[56]

Mosquitocontrol
Vectorcontrolreferstomethodsusedtodecreasemalariabyreducingthelevelsof
transmissionbymosquitoes.Forindividualprotection,themosteffectiveinsect
repellentsarebasedonDEETorpicaridin.[57]Insecticidetreatedmosquitonets
(ITNs)andindoorresidualspraying(IRS)havebeenshowntobehighlyeffectivein
preventingmalariaamongchildreninareaswheremalariaiscommon.[58][59]
Prompttreatmentofconfirmedcaseswithartemisininbasedcombinationtherapies
(ACTs)mayalsoreducetransmission.[60]
Mosquitonetshelpkeepmosquitoesawayfrompeopleandreduceinfectionrates
andtransmissionofmalaria.Netsarenotaperfectbarrierandareoftentreatedwith
aninsecticidedesignedtokillthemosquitobeforeithastimetofindawaypastthe
net.Insecticidetreatednetsareestimatedtobetwiceaseffectiveasuntreatednets
andoffergreaterthan70%protectioncomparedwithnonet.[61]Between2000and
2008,theuseofITNssavedthelivesofanestimated250,000infantsinSub
SaharanAfrica.[62]About13%ofhouseholdsinSubSaharancountriesownedITNs
Mansprayingkeroseneoilinstanding
in2007[63]and31%ofAfricanhouseholdswereestimatedtoownatleastoneITN
water,PanamaCanalZone1912
in2008.In2000,1.7million(1.8%)Africanchildrenlivinginareasoftheworld
wheremalariaiscommonwereprotectedbyanITN.Thatnumberincreasedto20.3
million(18.5%)AfricanchildrenusingITNsin2007,leaving89.6millionchildrenunprotected[64]andto68%African
childrenusingmosquitonetsin2015.[65]Mostnetsareimpregnatedwithpyrethroids,aclassofinsecticideswithlow
toxicity.Theyaremosteffectivewhenusedfromdusktodawn.[66]Itisrecommendedtohangalarge"bednet"abovethe
centerofabedandeithertucktheedgesunderthemattressormakesureitislargeenoughsuchthatittouchesthe
ground.[67]

AnAnophelesstephensimosquito
shortlyafterobtainingbloodfroma
human(thedropletofbloodis
expelledasasurplus).Thismosquito
isavectorofmalaria,andmosquito
controlisaneffectivewayof
reducingitsincidence.

Wallswhereindoorresidualspraying
ofDDThasbeenapplied.The
mosquitoesremainonthewalluntil
theyfalldowndeadonthefloor.

Indoorresidualsprayingisthesprayingofinsecticidesonthewallsinsideahome.Afterfeeding,manymosquitoesrestonanearbysurfacewhiledigestingthe
bloodmeal,soifthewallsofhouseshavebeencoatedwithinsecticides,therestingmosquitoescanbekilledbeforetheycanbiteanotherpersonandtransferthe
malariaparasite.[68]Asof2006,theWorldHealthOrganizationrecommends12insecticidesinIRSoperations,includingDDTandthepyrethroidscyfluthrinand

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deltamethrin.[69]ThispublichealthuseofsmallamountsofDDTispermittedundertheStockholmConvention,which
prohibitsitsagriculturaluse.[70]OneproblemwithallformsofIRSisinsecticideresistance.MosquitoesaffectedbyIRS
tendtorestandliveindoors,andduetotheirritationcausedbyspraying,theirdescendantstendtorestandliveoutdoors,
meaningthattheyarelessaffectedbytheIRS.[71]
Thereareanumberofothermethodstoreducemosquitobitesandslowthespreadofmalaria.Effortstodecreasemosquito
larvabydecreasingtheavailabilityofopenwaterinwhichtheydeveloporbyaddingsubstancestodecreasetheir
developmentiseffectiveinsomelocations.[72]Electronicmosquitorepellentdeviceswhichmakeveryhighfrequency
soundsthataresupposedtokeepfemalemosquitoesaway,donothavesupportingevidence.[73]

Othermethods
Communityparticipationandhealtheducationstrategiespromotingawarenessofmalariaandtheimportanceofcontrol
measureshavebeensuccessfullyusedtoreducetheincidenceofmalariainsomeareasofthedevelopingworld.[74]
Amosquitonetinuse.
Recognizingthediseaseintheearlystagescanstopthediseasefrombecomingfatal.Educationcanalsoinformpeopleto
coveroverareasofstagnant,stillwater,suchaswatertanksthatareidealbreedinggroundsfortheparasiteandmosquito,
thuscuttingdowntheriskofthetransmissionbetweenpeople.Thisisgenerallyusedinurbanareaswheretherearelargecentersofpopulationinaconfinedspace
andtransmissionwouldbemostlikelyintheseareas.[75]Intermittentpreventivetherapyisanotherinterventionthathasbeenusedsuccessfullytocontrolmalaria
inpregnantwomenandinfants,[76]andinpreschoolchildrenwheretransmissionisseasonal.[77]

Medications
Thereareanumberofdrugsthatcanhelppreventorinterruptmalariaintravelerstoplaceswhereinfectioniscommon.Manyofthesedrugsarealsousedin
treatment.Chloroquinemaybeusedwherechloroquineresistantparasitesarenotcommon.[78]InplaceswherePlasmodiumisresistanttooneormore
medications,threemedicationsmefloquine(Lariam),doxycycline(availablegenerically),orthecombinationofatovaquoneandproguanilhydrochloride
(Malarone)arefrequentlyusedwhenprophylaxisisneeded.[78]Doxycyclineandtheatovaquoneplusproguanilcombinationarethebesttoleratedmefloquineis
associatedwithdeath,suicide,andneurologicalandpsychiatricsymptoms.[78]
Theprotectiveeffectdoesnotbeginimmediately,andpeoplevisitingareaswheremalariaexistsusuallystarttakingthedrugsonetotwoweeksbeforearriving
andcontinuetakingthemforfourweeksafterleaving(exceptforatovaquone/proguanil,whichonlyneedstobestartedtwodaysbeforeandcontinuedforseven
daysafterward).[79]Theuseofpreventativedrugsisoftennotpracticalforthosewholiveinareaswheremalariaexists,andtheiruseisusuallyonlyinpregnant
womenandshorttermvisitors.Thisisduetothecostofthedrugs,sideeffectsfromlongtermuse,andthedifficultyinobtainingantimalarialdrugsoutsideof
wealthynations.[80]Duringpregnancy,medicationtopreventmalariahasbeenfoundtoimprovetheweightofthebabyatbirthanddecreasetheriskofanemiain
themother.[81]Theuseofpreventativedrugswheremalariabearingmosquitoesarepresentmayencouragethedevelopmentofpartialresistance.[82]
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Treatment
Malariaistreatedwithantimalarialmedicationstheonesuseddependsonthetypeandseverityofthedisease.While
medicationsagainstfeverarecommonlyused,theireffectsonoutcomesarenotclear.[83]
Simpleoruncomplicatedmalariamaybetreatedwithoralmedications.ThemosteffectivetreatmentforP.falciparum
infectionistheuseofartemisininsincombinationwithotherantimalarials(knownasartemisinincombinationtherapy,or
ACT),whichdecreasesresistancetoanysingledrugcomponent.[84]Theseadditionalantimalarialsinclude:amodiaquine,
lumefantrine,mefloquineorsulfadoxine/pyrimethamine.[85]Anotherrecommendedcombinationisdihydroartemisininand
piperaquine.[86][87]ACTisabout90%effectivewhenusedtotreatuncomplicatedmalaria.[62]Totreatmalariaduring
pregnancy,theWHOrecommendstheuseofquinineplusclindamycinearlyinthepregnancy(1sttrimester),andACTin
laterstages(2ndand3rdtrimesters).[88]Inthe2000s(decade),malariawithpartialresistancetoartemisinsemergedin
SoutheastAsia.[89][90]InfectionwithP.vivax,P.ovaleorP.malariaeusuallydonotrequirehospitalization.Treatmentof
P.vivaxrequiresbothtreatmentofbloodstages(withchloroquineorACT)andclearanceofliverformswith
primaquine.[91]TreatmentwithtafenoquinepreventsrelapsesafterconfirmedP.vivaxmalaria.[92]
SevereandcomplicatedmalariaarealmostalwayscausedbyinfectionwithP.falciparum.Theotherspeciesusuallycause
onlyfebriledisease.[93]Severeandcomplicatedmalariaaremedicalemergenciessincemortalityratesarehigh(10%to
Anadvertisementforquinineasa
50%).[94]Cerebralmalariaistheformofsevereandcomplicatedmalariawiththeworstneurologicalsymptoms.[95]
malariatreatmentfrom1927.
Recommendedtreatmentforseveremalariaistheintravenoususeofantimalarialdrugs.Forseveremalaria,parenteral
artesunatewassuperiortoquinineinbothchildrenandadults.[96]Inanothersystematicreview,artemisininderivatives
(artemetherandarteether)wereasefficaciousasquinineinthetreatmentofcerebralmalariainchildren.[97]Treatmentofseveremalariainvolvessupportive
measuresthatarebestdoneinacriticalcareunit.Thisincludesthemanagementofhighfeversandtheseizuresthatmayresultfromit.Italsoincludesmonitoring
forpoorbreathingeffort,lowbloodsugar,andlowbloodpotassium.[22]

Resistance
Drugresistanceposesagrowingproblemin21stcenturymalariatreatment.[98]Resistanceisnowcommonagainstallclassesofantimalarialdrugsapartfrom
artemisinins.Treatmentofresistantstrainsbecameincreasinglydependentonthisclassofdrugs.Thecostofartemisininslimitstheiruseinthedeveloping
world.[99]MalariastrainsfoundontheCambodiaThailandborderareresistanttocombinationtherapiesthatincludeartemisinins,andmaythereforebe
untreatable.[100]Exposureoftheparasitepopulationtoartemisininmonotherapiesinsubtherapeuticdosesforover30yearsandtheavailabilityofsubstandard
artemisininslikelydrovetheselectionoftheresistantphenotype.[101]ResistancetoartemisininhasbeendetectedinCambodia,Myanmar,Thailand,and
Vietnam,[102]andtherehasbeenemergingresistanceinLaos.[103][104]
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Prognosis
Whenproperlytreated,peoplewithmalariacanusuallyexpectacompleterecovery.[105]However,severe
malariacanprogressextremelyrapidlyandcausedeathwithinhoursordays.[106]Inthemostseverecasesofthe
disease,fatalityratescanreach20%,evenwithintensivecareandtreatment.[3]Overthelongerterm,
developmentalimpairmentshavebeendocumentedinchildrenwhohavesufferedepisodesofsevere
malaria.[107]Chronicinfectionwithoutseverediseasecanoccurinanimmunedeficiencysyndromeassociated
withadecreasedresponsivenesstoSalmonellabacteriaandtheEpsteinBarrvirus.[108]
Duringchildhood,malariacausesanemiaduringaperiodofrapidbraindevelopment,andalsodirectbrain
damageresultingfromcerebralmalaria.[107]Somesurvivorsofcerebralmalariahaveanincreasedriskof
neurologicalandcognitivedeficits,behaviouraldisorders,andepilepsy.[109]Malariaprophylaxiswasshownto
improvecognitivefunctionandschoolperformanceinclinicaltrialswhencomparedtoplacebogroups.[107]

Epidemiology

Distributionofmalariaintheworld:[110]
Elevatedoccurrenceofchloroquineormulti
resistantmalaria
Occurrenceofchloroquineresistantmalaria
NoPlasmodiumfalciparumorchloroquine
resistance
Nomalaria

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Disabilityadjustedlifeyearformalariaper
100,000inhabitantsin2004
nodata

20002500

<10

25002750

0100

27503000

100500

30003250

5001000

32503500

TheWHOestimatesthatin2015therewere214millionnew
10001500
3500
casesofmalariaresultingin438,000deaths.[111]Othershave
15002000
estimatedthenumberofcasesatbetween350and550million
forfalciparummalaria[112]Themajorityofcases(65%)occur
inchildrenunder15yearsold.[113]About125millionpregnantwomenareatriskofinfectioneachyearinSub
SaharanAfrica,maternalmalariaisassociatedwithupto200,000estimatedinfantdeathsyearly.[18]Thereare
about10,000malariacasesperyearinWesternEurope,and13001500intheUnitedStates.[14]About900
peoplediedfromthediseaseinEuropebetween1993and2003.[57]Boththeglobalincidenceofdiseaseand
resultingmortalityhavedeclinedinrecentyears.AccordingtotheWHOandUNICEF,deathsattributableto
malariain2015werereducedby60%[65]froma2000estimateof985,000,largelyduetothewidespreaduseof
insecticidetreatednetsandartemisininbasedcombinationtherapies.[62]In2012,therewere207millioncasesof
malaria.Thatyear,thediseaseisestimatedtohavekilledbetween473,000and789,000people,manyofwhom
werechildreninAfrica.[1]EffortsatdecreasingthediseaseinAfricasincetheturnofmillenniumhavebeen
partiallyeffective,withratesofthediseasedroppingbyanestimatedfortypercentonthecontinent.[114]

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Deathsduetomalariapermillionpersonsin2012
00

55325

12

326679

9501,358

Malariaispresentlyendemicinabroadbandaroundtheequator,inareasoftheAmericas,manypartsofAsia,
andmuchofAfricainSubSaharanAfrica,8590%ofmalariafatalitiesoccur.[115]Anestimatefor2009
reportedthatcountrieswiththehighestdeathrateper100,000ofpopulationwereIvoryCoast(86.15),Angola
(56.93)andBurkinaFaso(50.66).[116]A2010estimateindicatedthedeadliestcountriesperpopulationwere
BurkinaFaso,MozambiqueandMali.[113]TheMalariaAtlasProjectaimstomapglobalendemiclevelsof
malaria,providingameanswithwhichtodeterminetheglobalspatiallimitsofthediseaseandtoassessdisease
burden.[117][118]ThiseffortledtothepublicationofamapofP.falciparumendemicityin2010.[119]Asof2010,
about100countrieshaveendemicmalaria.[120][121]Everyyear,125millioninternationaltravellersvisitthese
countries,andmorethan30,000contractthedisease.[57]

Thegeographicdistributionofmalariawithinlargeregionsiscomplex,andmalariaafflictedandmalariafree
areasareoftenfoundclosetoeachother.[122]Malariaisprevalentintropicalandsubtropicalregionsbecauseof
rainfall,consistenthightemperaturesandhighhumidity,alongwithstagnantwatersinwhichmosquitolarvae
readilymature,providingthemwiththeenvironmenttheyneedforcontinuousbreeding.[123]Indrierareas,outbreaksofmalariahavebeenpredictedwith
reasonableaccuracybymappingrainfall.[124]Malariaismorecommoninruralareasthanincities.Forexample,severalcitiesintheGreaterMekongSubregionof
SoutheastAsiaareessentiallymalariafree,butthediseaseisprevalentinmanyruralregions,includingalonginternationalbordersandforestfringes.[125]In
contrast,malariainAfricaispresentinbothruralandurbanareas,thoughtheriskislowerinthelargercities.[126]
354

680949

History
AlthoughtheparasiteresponsibleforP.falciparummalariahasbeeninexistencefor50,000100,000years,thepopulationsizeoftheparasitedidnotincrease
untilabout10,000yearsago,concurrentlywithadvancesinagriculture[127]andthedevelopmentofhumansettlements.Closerelativesofthehumanmalaria
parasitesremaincommoninchimpanzees.SomeevidencesuggeststhattheP.falciparummalariamayhaveoriginatedingorillas.[128]
Referencestotheuniqueperiodicfeversofmalariaarefoundthroughoutrecordedhistory.[129]Hippocratesdescribedperiodicfevers,labellingthemtertian,
quartan,subtertianandquotidian.[130]TheRomanColumellaassociatedthediseasewithinsectsfromswamps.[130]Malariamayhavecontributedtothedeclineof
theRomanEmpire,[131]andwassopervasiveinRomethatitwasknownasthe"Romanfever".[132]SeveralregionsinancientRomewereconsideredatriskfor
thediseasebecauseofthefavourableconditionspresentformalariavectors.ThisincludedareassuchassouthernItaly,theislandofSardinia,thePontineMarshes,
thelowerregionsofcoastalEtruriaandthecityofRomealongtheTiberRiver.Thepresenceofstagnantwaterintheseplaceswaspreferredbymosquitoesfor
breedinggrounds.Irrigatedgardens,swamplikegrounds,runofffromagriculture,anddrainageproblemsfromroadconstructionledtotheincreaseofstanding
water.[133]

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ThetermmalariaoriginatesfromMedievalItalian:malaaria"badair"thediseasewas
formerlycalledagueormarshfeverduetoitsassociationwithswampsandmarshland.[134]
ThetermfirstappearedintheEnglishliteratureabout1829.[130]Malariawasoncecommon
inmostofEuropeandNorthAmerica,[135]whereitisnolongerendemic,[136]though
importedcasesdooccur.[137]

BritishdoctorRonaldRossreceived
theNobelPrizeforPhysiologyor
Medicinein1902forhisworkon
malaria.

Scientificstudiesonmalariamadetheirfirstsignificantadvancein1880,whenCharles
LouisAlphonseLaveranaFrencharmydoctorworkinginthemilitaryhospitalof
ConstantineinAlgeriaobservedparasitesinsidetheredbloodcellsofinfectedpeoplefor
thefirsttime.Hethereforeproposedthatmalariaiscausedbythisorganism,thefirsttimea
protistwasidentifiedascausingdisease.[138]Forthisandlaterdiscoveries,hewasawarded
the1907NobelPrizeforPhysiologyorMedicine.Ayearlater,CarlosFinlay,aCuban
doctortreatingpeoplewithyellowfeverinHavana,providedstrongevidencethat
mosquitoesweretransmittingdiseasetoandfromhumans.[139]Thisworkfollowedearlier
suggestionsbyJosiahC.Nott,[140]andworkbySirPatrickManson,the"fatheroftropical
medicine",onthetransmissionoffilariasis.[141]

Ancientmalariaoocysts
preservedinDominican
amber

InApril1894,aScottishphysicianSirRonaldRossvisitedSirPatrickMansonathishouseonQueenAnneStreet,London.
Thisvisitwasthestartoffouryearsofcollaborationandferventresearchthatculminatedin1898whenRoss,whowas
workinginthePresidencyGeneralHospitalinCalcutta,provedthecompletelifecycleofthemalariaparasitein
mosquitoes.Hethusprovedthatthemosquitowasthevectorformalariainhumansbyshowingthatcertainmosquito
speciestransmitmalariatobirds.Heisolatedmalariaparasitesfromthesalivaryglandsofmosquitoesthathadfedon
[142]
infectedbirds.
Forthiswork,Rossreceivedthe1902NobelPrizeinMedicine.AfterresigningfromtheIndianMedicalService,Rossworkedatthenewly
establishedLiverpoolSchoolofTropicalMedicineanddirectedmalariacontroleffortsinEgypt,Panama,GreeceandMauritius.[143]ThefindingsofFinlayand
RosswerelaterconfirmedbyamedicalboardheadedbyWalterReedin1900.ItsrecommendationswereimplementedbyWilliamC.Gorgasinthehealth
measuresundertakenduringconstructionofthePanamaCanal.Thispublichealthworksavedthelivesofthousandsofworkersandhelpeddevelopthemethods
usedinfuturepublichealthcampaignsagainstthedisease.[144]
Thefirsteffectivetreatmentformalariacamefromthebarkofcinchonatree,whichcontainsquinine.ThistreegrowsontheslopesoftheAndes,mainlyinPeru.
TheindigenouspeoplesofPerumadeatinctureofcinchonatocontrolfever.ItseffectivenessagainstmalariawasfoundandtheJesuitsintroducedthetreatmentto
Europearound1640by1677,itwasincludedintheLondonPharmacopoeiaasanantimalarialtreatment.[145]Itwasnotuntil1820thattheactiveingredient,
quinine,wasextractedfromthebark,isolatedandnamedbytheFrenchchemistsPierreJosephPelletierandJosephBienaimCaventou.[146][147]

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Quininebecamethepredominantmalarialmedicationuntilthe1920s,whenother
medicationsbegantobedeveloped.Inthe1940s,chloroquinereplacedquinineas
thetreatmentofbothuncomplicatedandseveremalariauntilresistancesupervened,
firstinSoutheastAsiaandSouthAmericainthe1950sandthengloballyinthe
1980s.[148]

ChinesetraditionalChinesemedicine
researcherTuYouyoureceivedthe
NobelPrizeforPhysiologyor
Medicinein2015forherworkon
antimalarialdrugartemisin.

ThemedicinalvalueofArtemisiaannuahasbeenusedbyChineseherbalistsin
traditionalChinesemedicinesfor2,000years.In1596,LiShizhenrecommended
Artemisiaannua,sourceofthe
teamadefromqinghaospecificallytotreatmalariasymptomsinhis"Compendium
antimalarialdrugartemisin
ofMateriaMedica".Artemisinins,discoveredbyChinesescientistTuYouyouand
colleaguesinthe1970sfromtheplantArtemisiaannua,becametherecommended
treatmentforP.falciparummalaria,administeredincombinationwithotherantimalarialsaswellasinseveredisease.[149]
TusaysshewasinfluencedbyatraditionalChineseherbalmedicinesource,TheHandbookofPrescriptionsforEmergency
Treatments,writtenin340byGeHong[150]Forherworkonmalaria,TuYouyoureceivedthe2015NobelPrizein
PhysiologyorMedicine[151]

Plasmodiumvivaxwasusedbetween1917andthe1940sformalariotherapydeliberateinjectionofmalariaparasitesto
inducefevertocombatcertaindiseasessuchastertiarysyphilis.In1927,theinventorofthistechnique,JuliusWagner
Jauregg,receivedtheNobelPrizeinPhysiologyorMedicineforhisdiscoveries.Thetechniquewasdangerous,killingabout15%ofpatients,soitisnolongerin
use.[152]
ThefirstpesticideusedforindoorresidualsprayingwasDDT.[153]Althoughitwasinitiallyusedexclusivelytocombat
malaria,itsusequicklyspreadtoagriculture.Intime,pestcontrol,ratherthandiseasecontrol,cametodominateDDTuse,
andthislargescaleagriculturaluseledtotheevolutionofresistantmosquitoesinmanyregions.TheDDTresistance
shownbyAnophelesmosquitoescanbecomparedtoantibioticresistanceshownbybacteria.Duringthe1960s,awareness
ofthenegativeconsequencesofitsindiscriminateuseincreased,ultimatelyleadingtobansonagriculturalapplicationsof
DDTinmanycountriesinthe1970s.[70]BeforeDDT,malariawassuccessfullyeliminatedorcontrolledintropicalareas
likeBrazilandEgyptbyremovingorpoisoningthebreedinggroundsofthemosquitoesortheaquatichabitatsofthelarva
stages,forexamplebyapplyingthehighlytoxicarseniccompoundParisGreentoplaceswithstandingwater.[154]
Malariavaccineshavebeenanelusivegoalofresearch.Thefirstpromisingstudiesdemonstratingthepotentialfora
malariavaccinewereperformedin1967byimmunizingmicewithlive,radiationattenuatedsporozoites,whichprovided
significantprotectiontothemiceuponsubsequentinjectionwithnormal,viablesporozoites.Sincethe1970s,therehas
beenaconsiderableefforttodevelopsimilarvaccinationstrategiesforhumans.[155]

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U.S.Marineswithmalariainarough
fieldhospitalonGuadalcanal,
October1942

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Societyandculture
Economicimpact
Malariaisnotjustadiseasecommonlyassociatedwithpoverty:someevidencesuggeststhatitisalsoacauseofpoverty
andamajorhindrancetoeconomicdevelopment.[7][8]Althoughtropicalregionsaremostaffected,malaria'sfurthest
influencereachesintosometemperatezonesthathaveextremeseasonalchanges.Thediseasehasbeenassociatedwith
majornegativeeconomiceffectsonregionswhereitiswidespread.Duringthelate19thandearly20thcenturies,itwasa
majorfactorinthesloweconomicdevelopmentoftheAmericansouthernstates.[156]
AcomparisonofaveragepercapitaGDPin1995,adjustedforparityofpurchasingpower,betweencountrieswithmalaria
andcountrieswithoutmalariagivesafivefolddifference($1,526USDversus$8,268USD).Intheperiod1965to1990,
countrieswheremalariawascommonhadanaveragepercapitaGDPthatincreasedonly0.4%peryear,comparedto2.4%
peryearinothercountries.[157]

MalariaclinicinTanzania

Povertycanincreasetheriskofmalaria,sincethoseinpovertydonothavethefinancialcapacitiestopreventortreatthe
disease.Initsentirety,theeconomicimpactofmalariahasbeenestimatedtocostAfricaUS$12billioneveryyear.Theeconomicimpactincludescostsofhealth
care,workingdayslostduetosickness,dayslostineducation,decreasedproductivityduetobraindamagefromcerebralmalaria,andlossofinvestmentand
tourism.[9]Thediseasehasaheavyburdeninsomecountries,whereitmayberesponsiblefor3050%ofhospitaladmissions,upto50%ofoutpatientvisits,and
upto40%ofpublichealthspending.[158]
CerebralmalariaisoneoftheleadingcausesofneurologicaldisabilitiesinAfricanchildren.[109]Studiescomparing
cognitivefunctionsbeforeandaftertreatmentforseveremalarialillnesscontinuedtoshowsignificantlyimpairedschool
performanceandcognitiveabilitiesevenafterrecovery.[107]Consequently,severeandcerebralmalariahavefarreaching
socioeconomicconsequencesthatextendbeyondtheimmediateeffectsofthedisease.[159]

Counterfeitandsubstandarddrugs
SophisticatedcounterfeitshavebeenfoundinseveralAsiancountriessuchasCambodia,[160]China,[161]Indonesia,Laos,
ChildwithmalariainEthiopia
Thailand,andVietnam,andareanimportantcauseofavoidabledeathinthosecountries.[162]TheWHOsaidthatstudies
indicatethatupto40%ofartesunatebasedmalariamedicationsarecounterfeit,especiallyintheGreaterMekongregion
andhaveestablishedarapidalertsystemtoenableinformationaboutcounterfeitdrugstoberapidlyreportedtotherelevantauthoritiesinparticipating
countries.[163]Thereisnoreliablewayfordoctorsorlaypeopletodetectcounterfeitdrugswithouthelpfromalaboratory.Companiesareattemptingtocombat
thepersistenceofcounterfeitdrugsbyusingnewtechnologytoprovidesecurityfromsourcetodistribution.[164]
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Anotherclinicalandpublichealthconcernistheproliferationofsubstandardantimalarialmedicinesresultingfrominappropriateconcentrationofingredients,
contaminationwithotherdrugsortoxicimpurities,poorqualityingredients,poorstabilityandinadequatepackaging.[165]A2012studydemonstratedthatroughly
onethirdofantimalarialmedicationsinSoutheastAsiaandSubSaharanAfricafailedchemicalanalysis,packaginganalysis,orwerefalsified.[166]

War
Throughouthistory,thecontractionofmalariahasplayedaprominentroleinthefatesofgovernmentrulers,nationstates,
militarypersonnel,andmilitaryactions.[167]In1910,NobelPrizeinMedicinewinnerRonaldRoss(himselfamalaria
survivor),publishedabooktitledThePreventionofMalariathatincludedachaptertitled"ThePreventionofMalariain
War."Thechapter'sauthor,ColonelC.H.Melville,ProfessorofHygieneatRoyalArmyMedicalCollegeinLondon,
addressedtheprominentrolethatmalariahashistoricallyplayedduringwars:"Thehistoryofmalariainwarmightalmost
betakentobethehistoryofwaritself,certainlythehistoryofwarintheChristianera....Itisprobablythecasethatmany
ofthesocalledcampfevers,andprobablyalsoaconsiderableproportionofthecampdysentery,ofthewarsofthe
sixteenth,seventeenthandeighteenthcenturiesweremalarialinorigin."[168]
MalariawasthemostimportanthealthhazardencounteredbyU.S.troopsintheSouthPacificduringWorldWarII,where
about500,000menwereinfected.[169]AccordingtoJosephPatrickByrne,"SixtythousandAmericansoldiersdiedof
malariaduringtheAfricanandSouthPacificcampaigns."[170]
Significantfinancialinvestmentshavebeenmadetoprocureexistingandcreatenewantimalarialagents.DuringWorld
WarIandWorldWarII,inconsistentsuppliesofthenaturalantimalariadrugscinchonabarkandquinineprompted
substantialfundingintoresearchanddevelopmentofotherdrugsandvaccines.Americanmilitaryorganizationsconducting
suchresearchinitiativesincludetheNavyMedicalResearchCenter,WalterReedArmyInstituteofResearch,andtheU.S.
ArmyMedicalResearchInstituteofInfectiousDiseasesoftheUSArmedForces.[171]

WorldWarIIposter

Additionally,initiativeshavebeenfoundedsuchasMalariaControlinWarAreas(MCWA),establishedin1942,anditssuccessor,theCommunicableDisease
Center(nowknownastheCentersforDiseaseControlandPrevention,orCDC)establishedin1946.AccordingtotheCDC,MCWA"wasestablishedtocontrol
malariaaroundmilitarytrainingbasesinthesouthernUnitedStatesanditsterritories,wheremalariawasstillproblematic".[172]

Eradicationefforts
Severalnotableattemptsarebeingmadetoeliminatetheparasitefromsectionsoftheworld,ortoeradicateitworldwide.In2006,theorganizationMalariaNo
MoresetapublicgoalofeliminatingmalariafromAfricaby2015,andtheorganizationplanstodissolveifthatgoalisaccomplished.[173]Severalmalaria
vaccinesareinclinicaltrials,whichareintendedtoprovideprotectionforchildreninendemicareasandreducethespeedoftransmissionofthedisease.Asof
2012,TheGlobalFundtoFightAIDS,TuberculosisandMalariahasdistributed230millioninsecticidetreatednetsintendedtostopmosquitobornetransmission
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ofmalaria.[174]TheU.S.basedClintonFoundationhasworkedtomanagedemandandstabilizepricesintheartemisinin
market.[175]Otherefforts,suchastheMalariaAtlasProject,focusonanalysingclimateandweatherinformationrequiredto
accuratelypredictthespreadofmalariabasedontheavailabilityofhabitatofmalariacarryingparasites.[117]TheMalaria
PolicyAdvisoryCommittee(MPAC)oftheWorldHealthOrganization(WHO)wasformedin2012,"toprovidestrategic
adviceandtechnicalinputtoWHOonallaspectsofmalariacontrolandelimination".[176]InNovember2013,WHOand
themalariavaccinefundersgroupsetagoaltodevelopvaccinesdesignedtointerruptmalariatransmissionwiththelong
termgoalofmalariaeradication.[177]
Malariahasbeensuccessfullyeliminatedorgreatlyreducedincertainareas.MalariawasoncecommonintheUnited
MembersoftheMalariaCommission
StatesandsouthernEurope,butvectorcontrolprograms,inconjunctionwiththemonitoringandtreatmentofinfected
oftheLeagueofNationscollecting
humans,eliminateditfromthoseregions.Severalfactorscontributed,suchasthedrainingofwetlandbreedinggroundsfor
larvaeontheDanubedelta,1929
agricultureandotherchangesinwatermanagementpractices,andadvancesinsanitation,includinggreateruseofglass
windowsandscreensindwellings.[178]MalariawaseliminatedfrommostpartsoftheUSAintheearly20thcenturyby
suchmethods,andtheuseofthepesticideDDTandothermeanseliminateditfromtheremainingpocketsintheSouthinthe1950s.[179](seeNationalMalaria
EradicationProgram)InSuriname,thediseasehasbeenclearedfromitscapitalcityandcoastalareasthroughathreeprongedapproachinitiatedbytheGlobal
MalariaEradicationprogramin1955,involving:vectorcontrolthroughtheuseofDDTandIRSregularcollectionofbloodsmearsfromthepopulationto
identifyexistingmalariacasesandprovidingchemotherapytoallaffectedindividuals.[180]Bhutanispursuinganaggressivemalariaeliminationstrategy,andhas
achieveda98.7%declineinmicroscopyconfirmedcasesfrom1994to2010.InadditiontovectorcontroltechniquessuchasIRSinhighriskareasandthorough
distributionoflonglastingITNs,factorssuchaseconomicdevelopmentandincreasingaccesstohealthserviceshavecontributedtoBhutan'ssuccessesin
reducingmalariaincidence.[181]TheUK'sDepartmentforInternationalDevelopmentandtheBillandMelindaGatesFoundationwillspend$4.5bnoverfiveyears
from2016inanefforttoenddeathscausedbythedisease.[182]

Research
TheMalariaEradicationResearchAgenda(malERA)initiativewasaconsultativeprocesstoidentifywhichareasofresearchanddevelopment(R&D)neededto
beaddressedfortheworldwideeradicationofmalaria.[183][184]

Vaccine
Immunity(or,moreaccurately,tolerance)toP.falciparummalariadoesoccurnaturally,butonlyinresponsetoyearsofrepeatedinfection.[35]Anindividualcan
beprotectedfromaP.falciparuminfectioniftheyreceiveaboutathousandbitesfrommosquitoesthatcarryaversionoftheparasiterenderednoninfectivebya
doseofXrayirradiation.[185]Aneffectivevaccineisnotyetavailableformalaria,althoughseveralareunderdevelopment.[186]Thehighlypolymorphicnatureof
manyP.falciparumproteinsresultsinsignificantchallengestovaccinedesign.Vaccinecandidatesthattargetantigensongametes,zygotes,orookinetesinthe
mosquitomidgutaimtoblockthetransmissionofmalaria.Thesetransmissionblockingvaccinesinduceantibodiesinthehumanbloodwhenamosquitotakesa
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bloodmealfromaprotectedindividual,theseantibodiespreventtheparasitefromcompletingitsdevelopmentinthemosquito.[187]Othervaccinecandidates,
targetingthebloodstageoftheparasite'slifecycle,havebeeninadequateontheirown.[188]Forexample,SPf66wastestedextensivelyinareaswherethedisease
iscommoninthe1990s,buttrialsshowedittobeinsufficientlyeffective.[189]Severalpotentialvaccinestargetingthepreerythrocyticstageoftheparasite'slife
cyclearebeingdeveloped,withRTS,Sasaleadingcandidate[185]itisexpectedtobelicensedin2015.[108]AUSbiotechcompany,Sanaria,isdevelopingapre
erythrocyticattenuatedvaccinecalledPfSPZthatuseswholesporozoitestoinduceanimmuneresponse.[190]In2006,theMalariaVaccineAdvisoryCommitteeto
theWHOoutlineda"MalariaVaccineTechnologyRoadmap"thathasasoneofitslandmarkobjectivesto"developandlicenseafirstgenerationmalariavaccine
thathasaprotectiveefficacyofmorethan50%againstseverediseaseanddeathandlastslongerthanoneyear"by2015.[191]

Medications
Malariaparasitescontainapicoplasts,organellesusuallyfoundinplants,completewiththeirowngenomes.Theseapicoplastsarethoughttohaveoriginated
throughtheendosymbiosisofalgaeandplayacrucialroleinvariousaspectsofparasitemetabolism,suchasfattyacidbiosynthesis.Over400proteinshavebeen
foundtobeproducedbyapicoplastsandthesearenowbeinginvestigatedaspossibletargetsfornovelantimalarialdrugs.[192]
WiththeonsetofdrugresistantPlasmodiumparasites,newstrategiesarebeingdevelopedtocombatthewidespreaddisease.Onesuchapproachliesinthe
introductionofsyntheticpyridoxalaminoacidadducts,whicharetakenupbytheparasiteandultimatelyinterferewithitsabilitytocreateseveralessentialB
vitamins.[193][194]Antimalarialdrugsusingsyntheticmetalbasedcomplexesareattractingresearchinterest.[195][196]
(+)SJ733:Partofawiderclassofexperimentaldrugscalledspiroindolone.ItinhibitstheATP4proteinofinfectedredbloodcellsthatcausethecellsto
shrinkandbecomerigidliketheagingcells.Thistriggerstheimmunesystemtoeliminatetheinfectedcellsfromthesystemasdemonstratedinamouse
model.Asof2014,aPhase1clinicaltrialtoassessthesafetyprofileinhumanisplannedbytheHowardHughesMedicalInstitute.[197]
NITD246andNITD609:AlsobelongedtotheclassofspiroindoloneandtargettheATP4protein.[197]

Other
Anonchemicalvectorcontrolstrategyinvolvesgeneticmanipulationofmalariamosquitoes.Advancesingeneticengineeringtechnologiesmakeitpossibleto
introduceforeignDNAintothemosquitogenomeandeitherdecreasethelifespanofthemosquito,ormakeitmoreresistanttothemalariaparasite.Sterileinsect
techniqueisageneticcontrolmethodwherebylargenumbersofsterilemalemosquitoesarerearedandreleased.Matingwithwildfemalesreducesthewild
populationinthesubsequentgenerationrepeatedreleaseseventuallyeliminatethetargetpopulation.[61]
Genomicsiscentraltomalariaresearch.WiththesequencingofP.falciparum,oneofitsvectorsAnophelesgambiae,andthehumangenome,thegeneticsofall
threeorganismsinthemalarialifecyclecanbestudied.[198]Anothernewapplicationofgenetictechnologyistheabilitytoproducegeneticallymodified
mosquitoesthatdonottransmitmalaria,potentiallyallowingbiologicalcontrolofmalariatransmission.[199]

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Inonestudy,ageneticallymodifiedstrainofAnophelesstephensiwascreatedthatnolongersupportedmalariatransmission,andthisresistancewaspasseddown
tomosquitooffspring.[200]
Genedriveisatechniqueforchangingwildpopulations,forinstancetocombatinsectssotheycannottransmitdiseases(inparticularmosquitoesinthecasesof
malariaandzika).[201]

Otheranimals
Nearly200parasiticPlasmodiumspecieshavebeenidentifiedthatinfectbirds,reptiles,andothermammals,[202]andabout30speciesnaturallyinfectnonhuman
primates.[203]Somemalariaparasitesthataffectnonhumanprimates(NHP)serveasmodelorganismsforhumanmalarialparasites,suchasP.coatneyi(amodel
forP.falciparum)andP.cynomolgi(P.vivax).DiagnostictechniquesusedtodetectparasitesinNHParesimilartothoseemployedforhumans.[204]Malaria
parasitesthatinfectrodentsarewidelyusedasmodelsinresearch,suchasP.berghei.[205]AvianmalariaprimarilyaffectsspeciesoftheorderPasseriformes,and
posesasubstantialthreattobirdsofHawaii,theGalapagos,andotherarchipelagoes.TheparasiteP.relictumisknowntoplayaroleinlimitingthedistribution
andabundanceofendemicHawaiianbirds.Globalwarmingisexpectedtoincreasetheprevalenceandglobaldistributionofavianmalaria,aselevated
temperaturesprovideoptimalconditionsforparasitereproduction.[206]

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MalariaWikipedia

Citedliterature
WHO(2010).GuidelinesfortheTreatmentofMalaria(PDF)(Report)(2nded.).WorldHealthOrganization.ISBN9789241547925.
SchlagenhaufLawlorP(2008).Travelers'Malaria.PMPHUSA.ISBN9781550093360.

Furtherreading
BynumWF,OveryC(1998).TheBeastintheMosquito:TheCorrespondenceofRonaldRossandPatrickManson.WellcomeInstituteSeriesinThe
HistoryofMedicine.Rodopi.ISBN9789042007215.
Guidelinesforthetreatmentofmalaria(3rded.).WorldHealthOrganization.2015.ISBN9789241549127.

Externallinks
Malaria(https://www.dmoz.org/Health/Conditions_and_Diseases/Infectious_Diseases/Parasitic/Malaria)atDMOZ
WHOsiteonmalaria(http://www.emro.who.int/entity/malariacontrolandelimination/)
UNHCOsiteonmalaria(http://www.unhco.org/malaria/)
GlobalMalariaActionPlan(http://www.rollbackmalaria.org/gmap/)(2008)
DoctorsWithoutBorders/MdecinsSansFrontiresMalaria(http://doctorswithoutborders.org/news/issue.cfm?id=2395)informationpages
WHO/TDRMalariaDatabase(https://web.archive.org/web/20130520072620/http://www.wehi.edu.au/other_domains/MalDB/who.html)viatheWayback
Machine
Antimalariaandsustainabledevelopment(http://www.antimalariaomd.org/en/index.php)
WorldwideAntimalarialResistanceNetwork(WWARN)(http://www.wwarn.org)
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