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Malaria

AsaPhichaphop

15/11/2010

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Outline Pathogenesis Epidermiology Clinicalmanifesta?on Inves?ga?on Diagnosis

treatment

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Malaria

Malariaisamajorpublichealthprobleminwarmclimatesespeciallyin

developingcountries.

Itisaleadingcauseofdiseaseanddeathamongchildren

underfiveyears,pregnantwomenandnon-immunetravellers/immigrants. Childrenunder5arethemajoratriskgroupin

malariousregions.Inset:AnAnophelesmosquito

takingabloodmeal

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Theburdenofmalaria

Thedirectburdenofmalaria

morbidityandmortality

Every year, there are about500 million clinical aNacks ofmalaria. Of these, 2-3 million

aresevereandabout1millionpeo ple d ie (ab out 3000deathseveryday).

M a l a r i a i n p r e g n a n c yaccounts for about 25% ofcases of severe maternalanaemia and 10-20% of low

birthweight. Low birthweightdue to malaria accounts forabout 5-10% of neonatal andinfantsdeaths.

Theindirectburdenofmalaria

Humandevelopment:Impairedintellectualdevelopment,developmentalabnormali?es

(especiallyfollowingcerebralmalaria),lostschoolaNendanceandproduc?vityatwork

Economics:Malariaretardseconomicdevelopmentinthedevelopingworld.Thecostofa

singleboutofmalariaisequivalenttoover10workingdaysinAfrica.Thecostoftreatmentisbetween$US0.08and$US5.30,dependingonthetypeofdrugsprescribedasrequiredbythelocalpaNernofdrugresistance.

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Pathogenesis femaleanophelinemosquitoinoculatesplasmodial

sporozoitesfromitssalivaryglandduringabloodmeal

mo?leformsofthemalarialparasitearecarriedrapidlyviathebloodstreamtotheliver,wheretheyinvadehepa?c

parenchymalcells beginaperiodofasexualreproduc?on amplifica?onprocess Theswolleninfectedlivercelleventuallybursts,discharging

mo?lemerozoitesintothebloodstream P.vivaxandP.ovaleinfec?ons,apropor?onofthe

intrahepa?cformsdonotdivideimmediatelybutremaindormantforaperiodrangingfrom3weekstoayearorlonger

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AYerentryintothebloodstream,merozoitesrapidlyinvadeerythrocytesandbecometrophozoites

ANachmentismediatedviaaspecificerythrocytesurfacereceptor

Bytheendofthe48-hintraerythrocy?clifecycleRBCthenrupturestorelease630daughtermerozoites,eachpoten?allycapableofinvadinganewRBCandrepea?ngthecycle

Pathogenesis

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AYerbeingingestedinthebloodmealofabi?ngfemaleanophelinemosquito,themale

andfemalegametocytesformazygoteinthe

insect'smidgut.

Oocystmigrateinthehemolymphtothesalivaryglandofthemosquitotoawait

inocula?onintoanotherhuman

Pathogenesis

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ErythrocyteChangesinMalaria AYerinvadinganerythrocyte,thegrowing

malarialparasiteprogressivelyconsumesanddegradesintracellularproteins,principally

hemoglobin TheparasitealsoalterstheRBCmembraneby

changingitstransportproper?es,exposingcryp?csurfacean?gens,andinser?ngnew

parasite-derivedproteins RBCbecomesmoreirregularinshape,more

an?genic,andlessdeformable

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intercellularadhesionmolecule1(ICAM-1)isprobablythemostimportantinthebrain

chondroi?nsulfateBintheplacenta,andCD36inmostotherorgans

AYer12-15hrodcellinvasionknobappearcall

PfEMP1(erythrocytemembraneadhesiveprotein)

aNachtoseveralvascularreceptorCytoadherence

P.falciparuminfectedRBCsmayalso

adheretouninfectedRBCs(toformroseNes)andtootherparasi?zederythrocytes(agglu?na?on)

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TheprocessofcytoadherencerosseNeandagglu?na?onresultinSequestra?onofRBC

invitalorgancausemicrovascularocclusion

Infalciparummalariaonlytheyoungerringformsof

theasexualparasitesareseencircula?nginthe

peripheralblood,andthelevelofperipheral

parasitemiaunderes?matesthetruenumberof

parasiteswithinthebody

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ParasitemiaOtherthree("benign")malarias,sequestra?ondoesnotoccur,andallstagesoftheparasite's

developmentareevidentonperipheralbloodsmears

producealevelofparasitemiathatisseldom>2% P.falciparumcaninvadeerythrocytesofall

agesandmaybeassociatedwithveryhigh

levelsofparasitemia.

youngRBCs(P.vivax,P.ovale)oroldcells(P.malariae)

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Hostresponse onspecifichostdefensemechanismsstopthe

infec?on'sexpansion,andthesubsequentspecificimmuneresponsecontrolstheinfec?on

ac?va?onofmacrophagesandthereleaseofproinflammatorymononuclearcellderivedcytokines

Temperaturesof40Cdamagematureparasites inuntreatedinfec?ons,theeffectofsuch

temperaturesistofurthersynchronizetheparasi?ccycle

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ImmuneindividualshaveapolyclonalincreaseinserumlevelsofIgM,IgG,andIgA,although

muchofthisan?bodyisunrelatedto

protec?on.An?bodiestoavarietyofparasi?can?genspresumablyactinconcerttolimitin

vivoreplica?onoftheparasite.Inthecaseof

falciparummalaria,themostimportantofthesean?gensisthesurfaceadhesinthe

variantproteinPfEMP1

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MalariaImmunity(cont.)

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Epidermiology

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..2553:32553152553

. . . . . . .. . . . . .2551 1,861 1,892 1,441 1,660 1,534 1,417 1,779 3,129 4,188 3,005 2,327 1,831

2552 1,508 2,237 1,535 1,172 901 1,028 1,623 2,925 3518 2463 2166 1769

2553* 1,564 2,176 2024 1379 1410 877 688

0

1,000

2,000

3,000

4,0005,000

6,000

7,000

8,000

9,00010,000 2551 2552 2553*

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10 2552 ( ) ABER SPR API..

P.F P.V P.M Mix % % %25

52

525,66

9 279455 8261 2785 5368 3 10553.16 2.96 15.7225

52

465,58

8 94954 2077 1124 951 0 2

20.

39 2.19 4.46

25

52

207,64

2 182186 1567 759 771 6 3187.74 0.86 7.5525

52

966,12

8 83197 1099 443 649 3 4

8.

61 1.32 1.14

25

52

706,52

8 36214 1019 600 416 0 35.13 2.81 1.4425

52

524,67

3 61297 896 402 491 0 311.68 1.46 1.71

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Chart:MalariaCasesper100,000people.

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Epidermiology CommoninTropicalzone,subtropicalzone,

temporatezone CommoninTropicalzone,subtropicalzone,temporatezone

P.falciparumpredominatesinAfrica,ewGuinea,andHai?;P.

vivaxismorecommoninCentralAmerica

TheprevalenceofthesetwospeciesisapproximatelyequalinSouthAmerica,theIndiansubcon?nent,easternAsia,andOceania

P.malariaeisfoundinmostendemicareas,especiallythroughoutsub-SaharanAfrica,butismuchless

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Clinicalmanifesta?on

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This is usually seen in older children andadults who have acquired natural immunity

toclinicaldiseaseasaconsequenceofliving

inareaswithhighmalaria .There

aremalariaparasitesintheperipheralbloodbutnosymptoms.Theseindividualsmaybe

i m p o r t a n t r e s e r v o i r s f o r d i s e a s e

transmission.

Some individuals may even develop an?-

parasite immunity so that they do not

parasitaemiafollowinginfec?on.parasitaemiafollowinginfec?on.

A.Asymptoma?cparasitaemia

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B.Simple,uncomplicatedmalaria

Childrenwithmalariawai?ngtobeseenatamalariaclinicinthesouthwesternpartof

igeria.Iden?fyingchildrenwithsevere

malaria,andgivingthemprompttreatment,

isamajorchallengewhenlargenumbers

aNendclinics.

Thiscanoccuratanyagebutitismorelikelytobeseeninindividuals

withsomedegreeofimmunityto

malaria.Theaffectedperson,

thoughill,doesnotmanifestlife-threateningdisease.

Feveristhemostconstantsymptom

ofmalaria.Itmayoccurin

paroxysmswhenlysisofredcellsreleasesmerozoitesresul?ngin

fever,chillsandrigors

(uncontrollableshivering).

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Theperiodicityofmalariafever

Erythrocy?cschizogonyis

the?metakenfor

trophozoitestomature

intomerozoitesbefore

releasewhenthecellruptures.

Itisshortestin

P.falciparum(36hours),intermediateinP.vivax

andP.ovale(48hours)and

longestinP.malariae(76

hours .

otehowthefrequencyofspikesoffever

differaccordingtothePlasmodiumspecies.Inprac?ce,spikesoffeverinP.

falciparum,occurirregularly-probably

becauseofthepresenceofparasitesat

variousstagesofdevelopment.

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Otherfeaturesofsimple,

uncomplicatedmalariainclude:o Vomitingo Diarrhoea more commonly seen in young children and, when vomiting also occurs,

may be misdiagnosed as viral gastroenteritis

o Convulsions commonly seen in young children. Malaria is the leading cause ofconvulsions with fever in African children.

o Pallor resulting mainly from the lysis of red blood cells. Malaria also reduces thesynthesis of red blood cells in the bone marrow.

o Jaundice mainly due to haemolysis.Malaria is a multisystem disease. Other common clinical features are:

o Anorexiao Cougho

Headache

o Malaiseo Muscle acheso Splenomegalyo Tender hepatomegalyThese clinical features occur in mild malaria. However, the infection requires

urgent diagnosis and management to prevent progression to severe disease.

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C.Severeandcomplicatedmalaria

1. Cerebralmalaria2. Severemalariaanaemia3. Hypoglycaemia4. Metabolicacidosis

5. Acuterenalfailure6. Pulmonaryoedema7. Circulatorycollapse,shock

oralgidmalaria8. Blackwaterfever

earlyallseverediseaseandthees?mated>1milliondeaths

frommalariaareduetoP.falciparum.Althoughsevere

malariaisbothpreventableandtreatable,itisfrequentlya

fataldisease.

Thefollowingare8importantseveremanifesta?onsof

malaria:Clickoneachseveremanifesta?onfordetails

ote:Itiscommonforanindividualpa?enttohave

morethanoneseveremanifesta?onofmalaria!

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1.Cerebralmalaria-clinical

A4yearoldboywhowasdeeply

comatoseandhadpersistent

devia?onoftheeyes

Themostwell-knownseveremanifesta?onofmalaria

Definedas: unarousablecomapersis?ngfor

morethanonehour

withasexualformsofP.falciparumintheperipheralblood

othercommoncausesofencephalopathyexcluded*

Occursmostcommonlyinyoungchildrenalthoughnon-immuneadultsarealsoatrisk

Cerebralmalariacanrapidlyprogresstodeath,evenwithappropriatetreatment.Casefatalityisbetween20-30%.Insurvivors,resolu?onofcomausuallyoccurswithin1-2daysinchildrenandwithin2-4daysinadultsbutmaybecomplicatedby

neurologicalsequelaein~5%adultsand>10%ofchildren.

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Theillnessmaystartwithdrowsinessandconfusionandthenprogresstocoma.ThelossofconsciousnessisoYenpreceded

byrepeatedconvulsions.Re?nalhaemorrhagesmaybeseen

onfundoscopy.

*oneoftheclinicalfeaturesarepathognomonic,malariaparasitaemiaiscommoninpeoplelivinginendemicareasand

comamaycomplicatemanyillnesses.Therefore,aclinical

diagnosisofcerebralmalariaismadeonlyaYerothercommoncausesofcoma(e.g.meningi?s)havebeen

excluded.

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Ayounggirlwithcerebralmalaria.otetheabnormal,decerebrateposturing

Cerebralmalaria-pathophysiology

A3yearoldboywithimpairedconsciousness,grimacingandmarkedextensorposturingofthearms

Theexactpathogenesisofcerebral

malariaisnotwellunderstood.

Itisbelievedtoresultfrom

sequestra?onofparasi?sedredcells

inthesmallbloodvesselsinthebrain.

Theconsequencesofthisinclude:

reducedcerebralbloodflowcerebralhypoxiareleaseofcytokineswhichinturninducethereleaseofnitrousoxide,a

knowndepressorofconsciousness

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2.Severemalariaanaemia

Definedasahaematocritof

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Bloodsugar

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Lac?cacidosisisamajorcontributorandprobablyresultsfrom?ssueanoxiaandanaerobicglycolysis

Presentswithdeep,rapidrespira?ons(asindiabe?cketoacidosis)

Back

4.Metabolicacidosis

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occursalmostexclusivelyinadultsandolderchildreninareasofunstablemalaria

affectedpa?entsareusuallyoliguric(urinaryoutput

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Acutepulmonaryoedema,developingshortlyaYerdeliveryinawomanwithsevereP.

falciparummalaria

6.Acutepulmonaryoedema

Back

Thisisagraveandusuallyfatalmanifesta?onofsevere

falciparummalariaandoccurs

mainlyinadults.Hyperparasitaemia,renalfailure

andpregnancyarerecognised

predisposingfactorsandthecondi?oniscommonlyassociated

withhypoglycaemiaand

metabolicacidosis.

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Featuresofcirculatorycollapse(cold/clammyskin,

hypotension,peripheralcyanosis,weak/threadypulses)

maybeseeninpa?entswithsevereP.falciparum

malaria.

Algidmalariaischaracterisedbyhypotension,vomi?ng,

diarrhoea,rapidrespira?onandoliguria.Thiscondi?onis

associatedwithapoorprognosis.

7.Circulatorycollapse,shock,algid

malaria

Back

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Adropofbloodisspreadovera

smallarea.Whendry,theslide

isstainedwithFieldsor

Giemsastains.Theredcellslyseleavingbehindthe

parasites.

Usedtodetectparasites,evenifparasitaemiais

low

Lessusefulforspecia?on

Thickbloodfilm

Back

Inves?ga?on

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Asmalldropofbloodis

spreadacrossamicroscope

slide,fixedinmethanoland

stainedwithGiemsastain.

Themicroscopistfindstheareaofthefilmwherered

cellsarelyingnexttoeach

other.Thefinedetailsof

theparasitescanbe

examinedtodeterminethe

species.

Usedforspecia?on Doesnotdetectlow

parasitaemia

Thinbloodfilm

Back

Inves?ga?on

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Evalua?onofbloodsmear 1.malariabloodsmear 2.speciesstage

3.malaria

100oilfield

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picture

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P.falciparum

oungtrophoziotes Oldtrophozoites

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MatureSchizontes

Malegametocyte

Femalegametocytes

P.falciparum

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P.Vivax

oungtrophoziotes

Matureschizontes

Femalegametocytes

Male ametoc tes

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Typicalmorphology

Ameboidform

P.vivax FimbriatedRBCP.Ovale

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P.malariae

RingformBandform

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PlasmodiumKnowlesi Plasmodiumknowlesi:aspeciesofprotozoan

fromSoutheastAsiathatcausesmonkey

malariawithaquo?dian(1) fevercycle;highlyfatalinrhesusmonkeys;

naturallyacquiredbyahumaninMalaysia,

andalsotransmiNedtohumans

bandform ConfirmDiagnosisby:PCR

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ElectronMicroscope Wrightstain

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Othermethodsofdiagnosisofmalaria

Thesearenotrou?nelyusedinclinicalprac?ce.Theyinclude:

a) An?gencapturekits.Usesadips?ckandafingerprickbloodsample.Rapidtest-resultsareavailablein10-15minutes.Expensiveandsensi?vitydropswithdecreasing

parasitaemia.b) PCRbasedtechniques.DetectsDAormRAsequences

specifictoPlasmodium.Sensi?vityandspecificityhighbuttestisexpensive,takesseveralhoursandrequirestechnicalexper?se.

c) Fluorescenttechniques.Rela?velylowspecificityandsensi?vity.Cannotiden?fytheparasitespecies.Expensive

d) Serologictests.Basedonimmunofluorescencedetec?onofan?bodiesagainstPlasmodiumspecies.Usefulfor

epidemiologicandnotdiagnos?cpurposes.

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treatmentotinThailand

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treatment

All:exceptpapuanewguinea&Indonesia

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TreatmentinThailand P.falciparumnotsevere Day1

artesunate(50mg)6tab,mefloquine(250mg)3tabmefloquine(250)2tab:

mefloquine

Day2

artesunate(50mg)6tab,primaquine(15mg)2tab

mefloquine

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Treatment() Primaquine:aNackhypnoziotedose30mgdose

relapse28 Artesunate2.4MKDthen1.2

MKDOD2nddose=1.2MKDat12,24hr

RelapseP.vivax,P.ovaleChloroquinedose+Primaquinedose

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Thankyou