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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 Page 1 of 8 PRINTED FROM OXFORD MEDICINE ONLINE (www.oxfordmedicine.com). (c) Oxford University Press, 2014. All Rights Reserved. Under the terms of the licence agreement, an individual user may print out a PDF of a single chapter of a title in Oxford Medicine Online for personal use (for details see Privacy Policy).date: 14 October 2014 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 Page 2 of 8 PRINTED FROM OXFORD MEDICINE ONLINE (www.oxfordmedicine.com). (c) Oxford University Press, 2014. All Rights Reserved. Under the terms of the licence agreement, an individual user may print out a PDF of a single chapter of a title in Oxford Medicine Online for personal use (for details see Privacy Policy).date: 14 October 2014 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 Page 3 of 8 PRINTED FROM OXFORD MEDICINE ONLINE (www.oxfordmedicine.com). (c) Oxford University Press, 2014. All Rights Reserved. Under the terms of the licence agreement, an individual user may print out a PDF of a single chapter of a title in Oxford Medicine Online for personal use (for details see Privacy Policy).date: 14 October 2014 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 Page 4 of 8 PRINTED FROM OXFORD MEDICINE ONLINE (www.oxfordmedicine.com). (c) Oxford University Press, 2014. All Rights Reserved. Under the terms of the licence agreement, an individual user may print out a PDF of a single chapter of a title in Oxford Medicine Online for personal use (for details see Privacy Policy).date: 14 October 2014 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 Page 5 of 8 PRINTED FROM OXFORD MEDICINE ONLINE (www.oxfordmedicine.com). (c) Oxford University Press, 2014. All Rights Reserved. Under the terms of the licence agreement, an individual user may print out a PDF of a single chapter of a title in Oxford Medicine Online for personal use (for details see Privacy Policy).date: 14 October 2014 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). Page 6 of 8 PRINTED FROM OXFORD MEDICINE ONLINE (www.oxfordmedicine.com). (c) Oxford University Press, 2014. All Rights Reserved. Under the terms of the licence agreement, an individual user may print out a PDF of a single chapter of a title in Oxford Medicine Online for personal use (for details see Privacy Policy).date: 14 October 2014 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. Page 7 of 8 PRINTED FROM OXFORD MEDICINE ONLINE (www.oxfordmedicine.com). (c) Oxford University Press, 2014. All Rights Reserved. Under the terms of the licence agreement, an individual user may print out a PDF of a single chapter of a title in Oxford Medicine Online for personal use (for details see Privacy Policy).date: 14 October 2014 Viral Haemorrhagic Fevers Page 8 of 8 PRINTED FROM OXFORD MEDICINE ONLINE (www.oxfordmedicine.com). (c) Oxford University Press, 2014. All Rights Reserved. Under the terms of the licence agreement, an individual user may print out a PDF of a single chapter of a title in Oxford Medicine Online for personal use (for details see Privacy Policy).date: 14 October 2014