Download Viral Haemorrhagic Fevers

Viral Haemorrhagic Fevers
OxfordMedicine
OSHManualofChildhoodInfections:TheBlueBook(3ed.)
EditedbyMikeSharland,AndrewCant,E.GrahamDavies,DavidA.C.Elliman,
SusannaEsposito,AdamFinn,JimGray,PaulT.Heath,HermioneLyall,AndrewJ.
Pollard,MaryE.Ramsay,AndrewRiordan,andDelaneShingadia
Publisher: OxfordUniversityPress
PrintISBN-13: 9780199573585
DOI: 10.1093/med/9780199573585.001.0001
PrintPublicationDate: Apr2011
Publishedonline: Oct2011
ViralHaemorrhagicFevers
Chapter: ViralHaemorrhagicFevers
DOI: 10.1093/med/9780199573585.003.0409
NameandNatureofOrganisms[link]
Epidemiology[link]
TransmissionandIncubationPeriod[link]
ClinicalFeaturesandSequelae[link]
Diagnosis[link]
ManagementandTreatment[link]
Prevention[link]
FurtherReading[link]
seealsoChapters13,14,34,42
NameandNatureofOrganisms
•Viralhaemorrhagicfevers(VHFs)compriseadiversegroupofinfectionscharacterized
byfebrileillnessesandinsome,highcasefatalityrates.Manyaretransmittedfromperson
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Viral Haemorrhagic Fevers
toperson.
•Thediseasesinclude:Lassafever,Ebolahaemorrhagicfever,Marburghaemorrhagic
fever,Crimean-Congohaemorrhagicfever(CCHF),theSouthAmericanhaemorrhagic
fevers(Argentinian,Bolivian,VenezuelanandBrazilian),KyasanurforestdiseaseandOmsk
haemorrhagicfever,andhaemorrhagicfeverwithrenalsyndrome(HFRS).Someformsof
denguevirusinfectioncanleadtoserioushaemorrhagicdisease,knownasdengue
haemorrhagicfever(DHF).
•TheVHFsarecausedbydistinctRNAvirusesthataremembersoffourviralfamilies:
Arenaviridae,Bunyaviridae,Filoviridae,andFlaviviridae.
•Arenaviruses:sixvirusesarecurrentlyknowntocausehaemorrhagicdiseaseinhumans.
ThefamilyisdividedinOldWorld(LassaandLujoviruses),andNewWorld(Junin,
Machupo,Chapare,GuanaritoandSabiáviruses).Allarenavirusesareenveloped,
pleomorphic,bisegmented,single-stranded,60to>200nm.
•Bunyaviridae:ThefamilyincludesCCHFvirus(genusNairovirus),andhantaviruses
includingSeoul,Puumala,Dobrava.Thevirusesareenveloped,segmented,andsinglestranded,90–120nm.
•Filoviridae:ThisfamilycontainsonlyMarburgandEbolaviruses.Therearefivesubtypes
ofEbola,fourofwhichcausediseaseinhumans;Sudan,Zaire,Coted'Ivoire,and
Bundibugyo.Thefifthebolavirustype,Reston,hasbeenfoundinprimatesandpigs,and
whileinducinganantibodyresponseinhumans,hasnotthusfarcausedsymptomatic
infection.Thevirusesareenveloped,filamentousandnon-segmented,80×800–1000nm.
•Flaviviridae:Thislargefamilyofvirusesincludesdengueandyellowfevervirusesaswell
astheagentsresponsibleforKyasanurforestdiseaseandOmskhaemorrhagicfever.
Therearefourdistinctserotypesofdenguevirus(DEN1,DEN2,DEN3,andDEN4).They
areenveloped,non-segmented,single-stranded,50nm.
•Thearenaviruses,filoviruses,andCCHFvirusareclassifiedashazardgroup4asthey
presentaserioushazardtolaboratoryworkers.
Epidemiology
•Lassafever:Reservoiristhemultimammaterat(Mastomysspecies).Diseaseis
endemicinWestAfrica,particularlyGuinea,Liberia,SierraLeone,andNigeria.Many
thousandcasesarethoughttooccureachyearintheseendemiccountries.Imported
casesarerare,buthaveoccurredinEurope,NorthAmericaandelsewhere,almost
exclusivelyinpersonswithhigh-riskoccupationssuchasmedicalorotheraidworkers.
•Lujovirus:ThishasbeenrecentlydescribedfollowingasmalloutbreakinSouthAfricain
2008.TheindexcaseacquiredinfectioninZambia,andthreesecondaryandonetertiary
transmissionsfollowedafterthepatientwasrepatriatedtoahospitalinSouthAfrica.Four
infectionswerefatal.Littleisyetknownoftheepidemiologyofthisvirus,butarodent
reservoirislikely.
•SouthAmericanArenaviruses:Allarerodentborne(fieldvoles,canerats,cotton
rats),andeachvirusoccursinadifferentcountry;JuninvirusinArgentina,Machupoand
ChaparevirusesinBolivia,GuanaritovirusinVenezuela,andSabiávirusinBrazil.
ArgentineHF(Juninvirus)isthecommonestofthese,althoughitsincidencehasdeclined
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Viral Haemorrhagic Fevers
sinceuseofaneffectivevaccine.AresurgenceofBolivianHFwasnotedin2007–8.
ImportedcasesareveryrareoutsidetheAmericas.Laboratory-acquiredinfectionshave
occurred.
•Ebola:Thereservoirisprobablyinbats;non-humanprimatesandothermammalsalso
susceptible.ThefourpathogenicsubtypesarefoundinCentralandWestAfrica:Republic
ofCongo,DemocraticRepublicofCongo,Gabon,Sudan,andUganda.EbolaRestonhas
onlybeenfoundintheWesternPacificandhasnottodatecausedillnessinhumans.
Sporadicoutbreaksoccurwhichmaybeextensivewithhundredsofcases.Importedcases
areveryrare.Laboratory-acquiredinfectionshaveoccurred.
•Marburg:Thereservoirisalmostcertainlyfruitbats,andcertainmonkeyspeciesare
susceptibletoinfection.FoundinCentralandWestAfrica:Kenya,Uganda,Democratic
RepublicofCongo,Angola.Sporadiccasesandoutbreaksoccur,thelargestofwhichwas
inAngolain2004–5.Importedcasesareveryrare.Twocasesoccurredin2008,onein
HollandandoneintheUSA,andbothfollowedavisittoabatinfestedcaveinthe
MaramagamboForest,Uganda.
•CCHF:Reservoirinlivestock,smallmammalsandbirds;tick-borne.CCHFvirusisthe
mostwidelydistributedagentofseverehaemorrhagicfeverknownandisenzooticfrom
westernChinaacrosstoeasternEurope,theMiddleEast,anddowntosouthernAfrica.This
rangereflectsthedistributionoftheHyalommatickswhicharethemainvector.Several
hundredcasesoccurperyearinTurkey,theBalkans,andsouthernpartsoftheRussian
Federation.Epidemicyearscanoccur.Importedcasesappeartoberare.
•Hantaviruses:Rodentborne(variousspeciesincludingvoles,mice,rats)andeach
virushasaspecificrodenthost.ThereisvariabledistributioninEurope,Asia,andthe
Americasdependingonbothviralandrodentspecies.Seoulvirusisfoundworldwide,
particularlyinAsia,whilePuumalaandDobravavirusoccurinEurope.Puumalavirusis
responsibleforamildformofHFRSknownasnephropathiaendemica.About150000cases
ofHFRSarethoughttooccurworldwideeachyear,andmanythousandofthosearein
Europe.
•Dengue:Amosquito-borneinfectiontransmittedbyAedesspecies,principallyAedes
aegyptiandAedesalbopictus.Dengueisendemicinover100countriesintropicaland
subtropicalregionsoftheworld.WHOestimatesthereare750millioncasesofdengue
feverperyear,ofwhichupto500000areDHF.Importedcasesofdenguefeverare
relativelycommoninEurope,andcasesofDHFarealsoseen.
•Omskhaemorrhagicfever/Kyasanurforestdisease.Thesetick-borneinfections
aregeographicallylimitedtothewesternSiberiaregionsofOmsk,Novosibirsk,Kurgan,and
Tyumen,andtheKyasanurForestinsouthernIndia,respectively,andsoarenot
consideredfurther.
TransmissionandIncubationPeriod
•Lassafever:Virusisshedintheurineanddroppingsofinfectedmultimammaterats,and
mosthumaninfectionsarisethroughcontactwithmaterialscontaminatedbythese.Personto-persontransmissionalsooccursviadirectcontactwithbodyfluids(blood,semen,
respiratorysecretions,urine)ofaninfectedperson.Symptomaticpatientsareconsidered
infectious,andurinemaybeintermittentlypositiveforupto2months.Sexualtransmission
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Viral Haemorrhagic Fevers
ispossibleasvirusremainsdetectableinsemenforupto3monthspost-symptomonset.
Theincubationperiodis7–10days,witharangeof3–21days.
•SouthAmericanarenaviruses:Transmissiontohumansoccursviadirectcontactwith
infectedrodents,orthroughinhalationofinfectiousrodentfluidsandexcreta.Argentine
haemorrhagicfeverisparticularlyseeninagriculturalworkersharvestingmaizefields
whererodentsareplentiful.Person-to-persontransmissionhasbeendocumentedwithJunin
andMachupoviruses.Theincubationperiodisfrom7to14days,witharangeof5–21
days.
•EbolaandMarburg:Theindexcaseinanoutbreakusuallyfollowscontactwithan
infectedanimal(anon-humanprimateorothermammal,orabat).Virusisthentransmitted
toothersthroughdirectcontactwiththeblood,secretions,organsorotherbodyfluidsof
infectedpersons,orwithfomitescontaminatedbybodyfluids.Symptomaticpatientsare
consideredinfectious,andaremostinfectiousasdiseasebecomessevere.Infectionin
healthcareworkersandcaregivershasbeenanotablefeatureinoutbreaks.Sexual
transmissionhasbeenreported3monthspostonsetofsymptoms.Theincubationperiod
forEbolais2–21days,andforMarburgis3–10days.
•CCHF:Infectionisacquiredthroughthebiteorcrushingofaninfectedtick,orthrough
contactwithbloodofaninfectedanimal.Person-to-persontransmissionoccursviadirect
contactwiththeblood,secretions,organsorotherbodyfluidsofinfectedpersons;
symptomaticpatientsareconsideredinfectious.Nosocomialtransmissionremainsa
probleminendemicareas.Theincubationperiodappearstovarywithrouteof
transmission.Followingatickbite,itisusually1–3days,andupto9days;butfollowing
contactwithinfectedbloodortissuesitisusually5–6days,upto13days.
•Hantaviruses:Virusisshedinurine,faeces,andsalivaoftherodenthost,andmost
humaninfectionsarethoughttoariseviainhalationofinfectedaerosolsfromtheseexcreta.
Person-to-persontransmissionisrare.Theincubationperiodis2–4weeksfortheviruses
causingHFRS.
•Dengue.InfectionfollowsthebiteofaninfectiveAedesmosquito.Person-to-person
transmissiondoesnotoccur,althoughduringtheviraemicphasebloodisinfectiveforbiting
mosquitoes.Theincubationperiodis4–7days,witharangeof3–14days.
ClinicalFeaturesandSequelae
•Lassafever:Clinicallyinfectionrangesfrommildtoasymptomatic(80%ofcases)toa
severefulminatinginfection.Onsetisgradualwithfever,chills,malaise,headache,myalgia,
andsorethroat.Nausea,vomiting,diarrhoeaorcoughmaybepresent,andexudative
pharyngealinflammationiscommon.Inseverecases,shock,encephalopathy,renaland
circulatoryfailuremaydevelopprogressingtoseverehaemorrhage.Overallthemortality
rateis1–3%,butisaround15%inhospitalizedcases.Mortalityratesarehigh(730%)in
thethirdtrimesterofpregnancy,andfetaldeathapproaches100%.Themostnotable
complicationisacutehearinglossandsensorineuralhearingdeficitoccursin25–30%of
patientsandmaypersistforlife.Itdoesnotappeartobeassociatedwithdiseaseseverity.
•SouthAmericanhaemorrhagicfevers:Theclinicalpictureisconsistentforallthese
viruses:onsetisgradualwithfever,malaise,myalgia,backpain,andheadache.Petechiae
andhaemorrhagedevelopafterafewdays,andneurologicalmanifestationsmayfollow
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Viral Haemorrhagic Fevers
withtremorofhandsandtongue,seizures,andcoma.Bloodlossisusuallyminor,butthe
haematocritrisesascapillaryleaksyndromebecomesmoresevere.Renalimpairmentis
verycommoninArgentinehaemorrhagicfever.Overallmortalityratesvaryfrom5%to
30%,andarehighestinthethirdtrimesterofpregnancy.Fetalmortalityishigh.
•EbolaandMarburg:Onsetissuddenwithheadache,highfever,andbackpain.
Prostrationfollowsrapidlywithpharyngitis,vomiting,severewaterydiarrhoea,
conjunctivitis,andameasles-likerash.Neurologicalmanifestationsincludeseverelethargy,
irritability,andconfusion.Haemorrhagicmanifestationsdevelopafter75days,andmay
progresstoseverebloodlossanddeath.Overallthemortalityratesareveryhigh;between
50%and90%.Fetallossiscommonwheninfectionoccursduringpregnancy.
Convalescenceisslowanddebilitating,andsurvivorsmayhaveprolongedamnesia.
•CCHF:Onsetissuddenwithfever,myalgia,dizziness,neckpainandstiffness,backache,
headache,soreeyes,andphotophobia.Nausea,vomiting,diarrhoea,andsorethroatmay
alsooccur.Haemorrhagicmanifestationsdevelopafter75daysandmaybeextensivewith
petechialrash,bruising,ecchymosesandgeneralizedbleedingofthegumsandorifices.In
severecasesmultiorganfailuredevelops.Upto50%ofcasesarefatal,butmortalityrates
varyconsiderably.
•HFRS:Theseareagroupofclinicallysimilarillnessescharacterizedbyfever,headache,
malaise,gastrointestinalsymptoms,andrenalimpairment.Onsetissudden.Petechialand
conjunctivalhaemorrhagemayprecedeperiodsofhypotensionfollowedbyhypovolaemic
shock.Mostinfectionsdonotexhibitovertsignsofbleedingorinternalhaemorrhage.The
mortalityrateisupto15%,butinEurope,Puumalavirusinfectionisgenerallyamild
disease(nephropathiaendemica)thatisrarelyhaemorrhagicandhasacasefatalityrate
<1%.
•Denguefever/DHF.Mostdengueinfectionsareeitherasymptomatic,orafebrile
influenza-likeillness.However,DHFisapotentiallyfatalcomplicationofclassicaldengue
fever,thepathogenesisofwhichisstillunclear.Strainvariabilitymayhavearole,butthe
mainhypothesissurroundstheimmuneresponsetosequentialinfectionswithdifferentviral
serotypes.Denguefeverstartswithfever,nausea,severeheadache,andbackpain.Acute
illnessisrelativelyshort-livedalthoughincapacitating.DHFistypicallyseeninchildren<15
yearsoldandischaracterizedbyrapiddeteriorationandprostration,withhaemorrhage
andshocksecondarytocirculatorycollapse.Petechiaeandecchymosesappear.Mortality
ratesofDHFcanexceed20%intheabsenceofcirculatorysupport,butare<2%with
appropriatemanagement.
Diagnosis
•Forallthehazardgroup4haemorrhagicfeverviruses,diagnostictestingmustbecarried
outinadesignatedlaboratorywithcontainmentlevel4facilities.
•ThediagnosisofaVHFshouldbeconsideredinallpatientsreturningfromanendemic
areaandpresentingwithcompatiblesymptoms.
•Inthefirstfewdaysofillness,diagnosisisachievedbyvirusdetectioninbloodortissue
samples—virusisolation;detectionofviralantigensintissuebyimmunofluorescenceor
EIA;detectionofviralnucleicacidbyPCR.
•SerologicaltestingbydetectionofIgMandIgGantibodiesinserumbyELISAor
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Viral Haemorrhagic Fevers
fluorescentantibodytest(FAT).IgMmaybedetectableverysoonaftersymptomonset.For
denguediagnosis,serologicalcross-reactionswithotherflavivirusesmustberigorously
excluded.
•Theremaybeanumberofpossibledifferentialdiagnosesdependingonthecountryof
exposure,includingmalaria,typhoid,leptospirosis,rickettsialinfections.
•Dualpathologyispossible.
ManagementandTreatment
•Seekadviceassoonaspossible,andtransferpatienttoaspecialistunitifappropriate
•ForLassa,CCHF,Ebola,Marburg,andSouthAmericanarenaviruses,patientsmustbe
managedinstrictisolation(inanegativepressureroomifavailable),withfullinfection
controlprecautions.Contactsshouldberestrictedtoessentialpersonnelonly,andinvasive
proceduresincludingvenepunctureshouldbeminimized.
•Symptomaticandsupportivetreatmentisessential,particularlyfluidandelectrolyte
balance,replacementofplasmalossduringperiodofcapillaryleakage,volume
replacement,andreplacementofcoagulationfactorsandplatelets.
•ThesupportivecareofpatientscriticallyillwithaVHFshouldbethesameasthe
conventionalcareprovidedtopatientswithothercausesofmultisystemfailure.
•RenalfailurewitholiguriaisaprominentfeatureofHFRSandmaybeseeninotherVHFs
asintravascularvolumedepletionbecomesmorepronounced.InHFRS,themanagementof
oliguriamayrequirehaemodialysisorperitonealdialysis.
•Monitorplateletsandhaematocrit,andvirologicalindices(i.e.PCRpositivityandviral
load)inbloodandurine.
•Inseverecases,therapywillberequiredforshockandbloodloss.
•AntiviraltherapywithribavirinisrecommendedforLassafever,ArgentineHF(andis
probablyeffectiveforotherarenaviruses),andCCHF.
•IVribavirinshouldbegivenearlyinthecourseofdisease.Thereissomeevidencethat
ribavirintreatmentreducesrenalcomplicationsinHFRS.
•ConvalescentimmuneplasmahasbeenusedwithbeneficialeffectagainstArgentine
haemorrhagicfever,butisonlyavailableinArgentina.
•Noantiviraltherapeuticoptionscurrentlyexistforotherhaemorrhagicfevers.
Prevention
LassaandOtherArenaviruses,CCHF,Ebola,Marburg
•Strictbarrierprecautionswhenmanagingpatientsareessentialtominimizeexposureof
healthcareworkers,otherhospitalstaff,andfamilymembers,andthuspreventnosocomial
transmission.Non-essentialstaffandvisitorsshouldberestricted.
•Allpersonsenteringtheroommustbeglovedandgowned,withfaceshieldsandeye
protectionforthosecomingwithin1m(3ft).
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Viral Haemorrhagic Fevers
•Preventionofpercutaneousinjuriesassociatedwiththeuseanddisposalofsharpsis
vital.
•Keeplaboratoryteststotheminimumnecessaryforclinicalmanagementinorderto
reducepotentialexposurestolaboratorystaff.Samplesmustbeappropriatelylabelledand
thelaboratoryalertedastotheirhigh-riskstatus.
•Standardprotocolsforlaundry,cleaning,anddisinfectionmaybefollowedwherethereis
nocontaminationbyblood/bodyfluids.
•Safeandeffectivedisinfectionanddecontaminationproceduresarerequiredformaterials
contaminatedwithblood/bodyfluids(includingpersonalprotectiveequipment,linens,
fomites,equipment,andpatientsamplessentfordiagnosticinvestigations).Persons
carryingoutdecontaminationmustbeappropriatelyprotected.Contaminated
environmentalsurfacesshouldbecleanedwithhypochloritesolution(5000ppmavailable
chlorine),unlessthecontaminationisheavy,inwhichcasehypochloritesolutions
containing10000ppmavailablechlorineshouldbeused.Wherepossible,contaminated
materialsandsamplesshouldbedouble-baggedthenautoclavedorincinerated.
•Contacttracing:Allpersonshavingcontactwiththecasesincetheybecame
symptomaticmustbeidentifiedandriskassessed.Thosewithclosecontactmustbe
monitoredbydailytemperaturechecksfor21daysfollowingtheirlastcontact.
•Thereisnoevidencetosuggestthatpostexposureprophylaxiswithribaviriniseffective.
•Novaccinesarecurrentlyavailable,exceptforArgentinehaemorrhagicfever.This
vaccineisonlyavailableinArgentina,whereithasbeenusedsincethe1990s,andbeen
responsibleadecreaseinincidenceofthisdisease.
•Preventionofnaturallyacquiredcasesinendemicareas—controlofrodentandinsect
vectors,rodent-proofstoragecontainers,andavoidanceofinsectbitesorexposureto
bodyfluidsofinfectedanimals.
DengueandHantavirus
•Normalcontrolofinfectionproceduresapplywhenmanagingpatients.
•Contacttracingnotrequired.
•Novaccinescurrentlyavailable.
•Preventionofnaturallyacquiredcasesinendemicareas—controlofrodentandinsect
vectors,rodent-proofstoragecontainers,andavoidanceofinsectbites.
FurtherReading
HowardCR.ViralHaemorrhagicFevers,PerspectivesinMedicalVirology,Volume11.2003,
Elsevier.
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