9 HFRS合并腎病綜合征的出血熱

HemorrhagicFeverwithRenalSyndromeDepartmentofInfectiousDiseasesThirdAffiliatedHospitalofSunYat-senUniversity

LinYang1■Definition

▲Infectiousdiseaseswithnaturalsource

▲Pathogen:Hantanvirus

▲Characterizedbyfever,hemorrhage,proteinuria,shockandacuterenalfailure.FivephasesinthetypicalcasesFebrilephase,Hypotensive(shock)phase,Oliguricphase,Diureticphase,Convalescentphase2EpidemicHemorrhagicFever(EHF)SuggestednamebyWHOin1982:HemorrhagicFeverwithRenalSyndrome(HFRS)3Hantanvirus▲MemberofthefamilyofBunyaviridae▲FeatureofvirusSingle-strandnegativeRNAvirusCircularorovalinshape78~210nmindiameter

Envelopeproteins:glycoprotein1(G1)glycoprotein2(G2)

Viralgenome—RNA:LMSgene■Etiology4

Viralproteins

L---PolymeraseM---EnvelopeproteinG1andG2

themembraneantigenG2:containneutrolizationantigen(vaccineantigen)S---Nucleocapsidprotein:

strongantigenicityandimmunogenicity,andcontainingcomplementbindingantigen.

56HumanHFRS:

causedbyfourtypeofvirus:hantaanvirus(typeI,HTNV)seoulvirus(typeII,SEOV)puumalavirus(typeIII,PUUV)dobrava-belgradevirus(DEOV)

China:HantaanvirusSeoulvirushantaanvirusandDEOVshowstrongerpathogenicitythantypeIIandIIIvirus7

▲Resistanceofvirus

Lowresistance:Inactivatedbyacid(<pH5.0),ethanol,ether,chloroform.heatin56oCfor30minor100oCfor1min.Besensitivetoalcoholultravioletrays8■Epidemiology

1.Sourcesofinfection

?

Inourcountry:Apodemusagrarius(黑線姬鼠)Musnorvegicus(褐家鼠)

Apodemussylvaticus(大林姬鼠)Citellusundulatus(長尾黃鼠)

?LaboratoryRats

?Otheranimals:catsdogsrabbits

Patients:unimportantInfectedfieldrats,houserats9Apodemusagrarius黑線姬鼠Musnorvegicus褐家鼠

102.Modesoftransmission:Five

1>.Air-bornetransmission

viainhaleaerosolcontaminatedwithvirus-containingexcretionorsecretionofrats

2>.Food-bornetransmission

viaoralandesophagealmucosa

(eatfoodcontaminatedwithvirus-containingexcretionorsecretionofrats)11

3>.Infectionviacontact

Bebittenbyrats.woundiscontaminatedwithvirus-containingexcretionsorsecretionsofrats.4>.Verticaltransmission:

mothertobaby,veryrare5>.

Arthropod-borne:

ratsmite,redmite,harvestmitemaycarryHantanvirus.Needtobeconfirmed

12

3.Epidemicfeatures

1>.Districtlocalization:

mainlyinAsia,

EuropeandAfrica,AmericaInChina:higherincidence

exceptforQinghaiandXizhangprovinces

2>.Seasonality

Mayoccuralltheyear,howeverseasonality

?NovembertoJanuaryandMaytoJuly

transmittedbyApodemusagrarius(黑線姬鼠)?MarchtoMaytransmittedbyhouseratsEpidemicpeak:three13

3>.Epidemicform

threekindsofepidemicform:sporadic,endemic,seldomepidemic4>.Occupationandage

?Residentsincountryside

?urbanandruralworker

Mostvictimsareyoungadults.144.Susceptibility

?Susceptibilityisuniversal?Lowrateofcovertinfection(3.5.-4.3%).?Stableimmunityobtainfromillness

IgGagainsttypeIvirus:lastfor1-30yearsIgGagansttypeIIvirus:lastless2years15■Pathogenesis

PathogenesisofHFRSisnotsoclear.

▲Virusistheinitiator

▲Immuneresponses,humoralandcellularimmuneresponse,bothinvolvesinthepathogenesis

161.DirectdamagebyHantanvirus

Virusinfection---replicationininfectedcells,especiallyinendotheliocytesofsmallbloodvessels---damageoncells.2.Immune-mediateddamage

TypeIII,I,II,andIVhypersensitivityreactions;CTLreaction-mediateddamage;Cytokine-mediatedcellsdamage171>TypeIIIhypersensitivityreaction

Hantanvirusinfection—inducespecificantibodies—immunecomplex-activatingcomplements-accumulationofimmunecomplexinsmallbloodvessels,basementofglomerulusandrenaltubule---damage18

2>Otherhypersensitivityreaction

TypeI--IgEmediateddamage.TypeII--linearIgGimmunecomplex–accumulationinplateletandbasementmembranesofrenaltubuleTypeIV—CD8+cellmediatedimmunedamage.19

3>.Cellularimmuneresponse:

Hantanvirusinfection–activationofCD8+

Tcells—CTLresponse–releaselymphokines—damage

4>.Hantanvirus—lymphocyteandmacrophage—cytokins:

suchasinterleukin1(IL-1),IFNr,tumornecrosisfactor(TNF)—damage20

■Pathophysiology

1.Shock

Primaryshockandsecondaryshock

2.Hemorrhage

3.Acuterenalfailure21

1.shock

Virusandimmuneresponse---smallbloodvesseldamage---permeabilityofvessel---plasmaexudation---bloodvolume---bloodconcentrate,viscosityofblood---DIC---bloodflow---bloodvolume---hypotensionshock22

Secondaryshock:

Occurindiureticphase

Reasons:

SeverehemorrhageSecondaryinfectionImbalanceoffluid,electrolytes

23

2.Hemorrhage

Petechia,ecchymosisinskinandmucosas,visceralbleeding

Reasons:Capillarydamage;Plateletdecreaseanddysfunction;DIC;increasedHeparin-likesubstance;anuria243.Acuterenalfailure

Reasons:Six

1>.Exudationofplasma,bloodvolumebloodconcentrate---bloodflowinkidneyglomerularfiltraterate(GFR)2>.Immune-mediatedkidneydamage

smallvesselandrenaltubule3>.Renalinterstitialhemorrhageandedema---crushrenaltubule254>.Renaltissuenecrosis5>.ActivationofreninangiotensinII—renalarterialcontract---renalcortexbloodflow–GFR(glomerularfiltraterate)6>.Renaltubulewasblockedbyproteinsandcasts26■Pathology

1.Organofpathologicaldamage

▲Smallbloodvesselandkidney

▲OtherorgansSuchasheart,liverandbrains,soon.

272.Pathologicalfeature

pathologicalchanges

Endotheliocytesofsmallbloodvesselcongestion,edema,hemorrhage,necrosis.pathognomoniclesionofHFRSinkidneys.

Similarpathologicalchangesinvariousorgans.

withoutsignificantinflammatoryreaction28■ClinicalManifestations

▲

Incubationperiod:1-2weeks

▲

Threemajormanifestations:

1>pyrexia,intoxication2>hyperemiaandhemorrhage

3>hypotensionandrenalmalfunction

▲

Fivetypicalphase.Fiveclinictypes29

A:Fivetypicalphase

1.Febrilephase2.Hypotensive(shock)phase3.Oliguricphase4.Diureticphase5.Convalescentphase301.Febrilephase

PyrexiaIntoxicationsymptomsCapillarydamagesignsKidneydamagesigns■ClinicalManifestations311.Febrilephase

1>.Pyrexia

acuteonset,39oC-40oC,lasts3-7daysFeatureofpyrexia:Sustainedfeverorremittentfever.

Formostcases,goingtomoreseriouswithpyrexiagraduallydisappeared322>.Intoxicationsymptoms

a.Threeache:

headache,lumbago,orbitalpain

headachebecauseofsmallvesselexpansion

lumbago,orbitalpain.becauseofhyperemiaandedemaintissue.

b.Gastrointestinalsymptoms

hiccupvomitingabdominalpainanddiarrhea333>.Capillarydamagesigns

a.hyperemia

Flushoverface,neckandchestskin

(threeredflush)

drunkennessb.HemorrhageFormostcases,petechia,ecchymosis,orstripe-shapedbleedinginchestandbackskin,conjunctivableeding.Forapartialcases,hematuria,DIC

34

c.Exudativeedema

mainlybabularconjunctivaedema.palpebraedemaandfaceedema

4>.Kidneydamagesigns

Proteinuria,sometimeswithcasts,bloodcellsandmembrane-shapedsubstanceconsistingofprotein,bloodcellsandmucosalepithelia.35Summaryinfebrilephase

Pyrexia,threeflush,threeache,hemorrhageandconjunctivaedema,malaise,

proteinuria,sometimeswithcasts,bloodcellsandmembrane-shapedsubstance363738392.Hypotensive(shock)phase

1>Occurduringdefeverscencein4to5daysofdiseasescourse,lasts1to3days.2>.Mainsigns:Hypotensionorshock3>.nausea,vomiting,abdominalpain.Platelet,hematocritvalue

proteinuria,leukocytosis,atypicallymphocytes>10%■ClinicalManifestations403.Oliguricphase

Oliguriaoranuria

UremiaMetabolicacidosisandimbalanceoffluidsandelectrolyte

■ClinicalManifestations41

3.Oliguricphase

Occurduringorsoonafterhypotensivephase,in5to8daysofdiseasescourse,lasts2-5days.

1>.Oliguriaoranuria

Oliguria:urinevolume<500ml/24h

Anuria:urinevolume<50ml/24h42

2>.Uremia

a.gastrointestinalsymptoms

hiccup,vomiting,abdominalpain,diarrhea

b.Aggravatinghemorrhage

hemoptysis(咳血),hematemesis(咯血),hematuria(血尿)ormelena

c.Nervoussystemsymptoms

433>.Metabolicacidosisandimbalanceoffluidsandelectrolyte

▲

Metabolicacidosis

▲fatalhyperkalemia

▲hypervolemicsyndromeedemaandrestlessnesshighbloodpressureengorgedneckveins.444Diureticphase

▲Urine>3000ml/24hOccurin9to14daysofdiseasescourse,lastfor1dayorseveralmonths

▲

Threephase

accordingtourinevolumeandazotemiasigns

?

Transitionphase

?

Earlystageofdiureticphase

?Latestageofdiureticphase■ClinicalManifestations45

1>.Transitionphase

a.Urinefrom500mlto2000ml/24hb.BUNandCrpersistentlyc.Stateofpatientmaychangetomoreserious.moreseriousalthoughurineincreasehighmortality462>.Earlystageofdiureticphaseurinevolume>2000ml/24h

nomarkeddecreaseinazotemia3>.Latestageofdiureticphase

a.urinevolume>3000ml/24hinmostofcases:4000to8000/24h,15000ml/24h

b.azotemiaimproving,BUNfallingdownc.Secondaryshock,dehydrationhypokalemia,hyponatremia47

5.Convalescentphase

urinereturnto1000-2000ml/24hnormalappetitetaking1-3monthsforrecoveringFivephasebenotseenineverycase.hypotensionand/oroliguriaphasemaybeabsentinatypicalcases■ClinicalManifestations48B:Fiveclinictypes

1.Mildtype2.Moderate

3.Severe4.Veryserious5.Atypicaltype491.Mildtype:

T<39oC,mildintoxicationsymptomswithoutoliguriaandshock50

2.Moderate:

T>39oC,severeintoxicatingsymptoms,drunkenness,conjunctivaedema,hemorrhage,hypotension,oliguriaandmarkedproteinuria.51

3.Severe:

T>40°C,moresevereintoxicatingsymptoms,shock,bleeding,

oliguriaforlessthan5daysoranuriaforlessthan2days.

524.Veryserious:Thesymptomsandsignsinseveretypewithoneoffollowingsixsigns:

1>.hard-correctiveshock2>.bleedinginmainorgan3>.acuterenalfailure4>.Cardiacfailurepulmonaryedema5>.ComplicationinCentralnervoussystem6>.Serioussecondaryinfection535.Atypical

T<38°C,atypicalsymptoms54

■

LaboratoryFinding

1.Bloodroutine

leukocytosis,15-50x109/L,neutrophilsdominatedinearlystage,lymphocytesinlatestage.

Atypicallymphocytes10%~15%hematocritvalueandhemoglobinrise,thrombocytopenia55

2.Urineroutine

Proteinuria,sometimeswithcasts,bloodcellsandmembrane-shapedsubstance,consistingofprotein,bloodcellsandmucosalepithelia.

maybefoundinseconddayofdiseasescourse

56

3.Bloodbiochemicalexamination

BUNandCrincreased.

CO2-CPdecreased.hyperkalemiainoliguricphase.hypokalemiaindiureticphase.

57

4.Bloodcoagulatingfunctionexamination

thrombocytopenia,plateletprolongatedPTFibrinogendecreasedsecondaryfibrinlysis

585.Serologicaltests

HantanvirusantigenandspecificantibodytestbyIFAT,ELISA,RIAorWB.Antibodyagainstnuclearproteinisusefulfordiagnosis.

1>IgMantibody:1:20positive:diagnosismarker2>IgGantibody:>4times/weekusefulfordiagnosis.Anti-G2---

estimateprognosis.

6.Molecularbiologicaltests

ViralRNAbyRT-PCR59■Complications1.Visceralbleeding

Intracraniahemorrhagehemoptysis,hematemesis,hematuria,cerebralhemorrhage

602.Complicationincentralnervoussystem

EncephalitisandmeningitisIntracranialhemorrhageandcerebraledema61

3.Pneumonedema

commonlyoccurinhypotensivephaseandoliguricphase.ARDS:Mortality~67%)

(Adultrespiratorydistresssyndrome)

Reasons:

increasingpermeabilityofthepulmonarycapillarries,anddecreasinginalveolarsurfaceactivatingsubstances62

4.Others

Secondaryinfectionwithbacterials

Spontaneousruptureofthekidneys

Hepatitis,myocarditis,pericarditis

63■Diagnosis

▲Epidemiologicdata

▲Clinicalfeature

▲Laboratoryexaminations

641.Epidemiologicdata

place,season,historyofcontactingratsorexcretionandsecretionsofrats

652.Clinicalfeaturesthreemanifestationsinearlystageandthecourseoffivephaseintypicalcase?Pyrexia,“threeaches〞,intoxicatingsymptoms?“Threeflush〞:face,neckandchestskin.conjunctivacongestionandedema.hemorrhage?Oliguria,renalregionpainonpercussion?FivephaseintypicalcaseFivephaseisnotobservedineverycase.hypotensionand/oroliguriaphasemaybeabsentinatypicalcases663.Laboratorydata1>.Blood

Leukocytosis

atypicallymphocytes>10%

thrombocytopenia.2>.Urine:

proteinuria.membrane-shapedsubstanceinurine.3>.Virusantigenandantibody

ViralRNAbyRT-PCR67■

Differentialdiagnosis

1.Infebrilephasewithcommoncold,influenza,Septicemia.2.InHypotensivephasewithotherinfectionshock

3.Pyrexia,intracraniahemorrhageandcerebraledemawithmeningococcalmeningitis

684.Oliguriaandrenalfailurewithacutenephritis

5.PyrexiaandhemorrhagewithLeptospirosis6.Markedhemorrhagewith:

thrombocytopenicpurpura,gastrointestinalbleedingcausedbygastriculcer.69■

Prognosis

Fatalityisrelatedtoclinicaltype,whetherbeingtreatedearlier.mortality1%~5%.majorreasonsfordeath:renalfailure,cerebralherniasecondarysepticemiamassivebleeding.

mortalityhigherininfectionwithtypeIvirus.70■Treatment

▲Principleoftreatment

●Diagnosis,restandtreatmentinearly

●Treatmentinnearhospital

71▲Treatment

Supportivetreatment

Anti-viraltherapy

Symptomatictreatment721.Supportivetreatment

bedresteasydigestivefoodvitaminsintravenousfluidscontainingsuitableglucose,electrolytes732.Treatmentinfebrilephase

Principleoftreatment

a>.Anti-virustherapyb>.Reduceexudationofplasmac>.Reduceintoxicatingsymptomsd>.PreventingfromDIC74

1>.Anti-viraltherapy:important

givinganti-virusdruginearlystage.(Ribavirin(virazole)

1.0givdripwith10%GSqdfor3-5days

2>.Reducepermeabilityofsmallvesselandexudation

LutinandVitaminC

75

3>.Reduceintoxicatingsymptoms

a>ForhyperpyrexiaPhysicalmeasurestodecreasetemperature.Forexample:puttingice-bagonhead,neckorbigvessellocation.

Avoidingusingheavyantipyretics

b>.CorticosteroidsforhyperpyrexiaandheavyintoxicatingsymptomsDexamethasone5-10mgiv.Dripc>c>.Anti-vomiting:20mgofPaspertinim764>.PreventionfromDIC

a>.ReducethebloodviscosityDanshensolution,Dextran40

b>.anti-coagulationtherapyHeparinshouldbegivenoncetheCTislessthan3minorAPTTlessthan34seconds.77

3.TreatmentinHypotensivephase

Principleoftreatment:

?Supplementbloodvolume

?Correctmetabolicacidosis

781>.Supplementbloodvolume

A.Principle:

earlyrapidlyadequateB:kindsoffluids:

CrystalloidfluidsandColloidfluidscontainingsuitableglucose,electrolytesandvitamins:

Ringer’sSolutionNormalsalinesolutionDextran,20%MannitolPlasma,albumin,Artificialplasma.792>Correctmetabolicacidosis

5%sodiumbicarbonatesolution.TheamountcalculatedaccordingtoCO2CPvalue.

3>.Bloodvesselactivatingdrugs

forhypotensionandshock:aramine,dopamine,etal.

804>.Corticosteroids

Reduceseveretoxemia,ReducepermeationofsmallvesselImprovingmicrocirculationoftissue.10~20mgofDexamethasoneisgivenbyintravenousdrip.81

4.Treatmentinoliguricphase

Principleoftreatment:

?Balanceintra-environment

?Diuretictherapy?Catharsistherapyforpreventingfromhypervolemia?Dialysistherapy821>.Balanceintra-environment

a>.Correctimbalanceoffluidelectrolytes,acid-base

Closelyobserveandrecordurinevolume.Examinebloodbiochemicalparameterandrenalfunction

adjustingamountoffluidandelectrolytes

83

b>.Reducingproteindegradationandcontrolofazotemia.

Foodcontaininghighvitaminshighcarbohydrate,lowprotein.Fortheseriouspatient:Supplementglucose200~300geverydaybyintravenousdrip20-25%GSwithinsulin.84

2>.Diureticforoliguria

20%Mannitolsolution,givenintravenouslylasix(furosemide),giveninjectionintravenouslywithgrudualyincreasingdose,andrepeatingevery4to6hoursaccordingtotheurineamounts.3>Catharsistherapyforhypervolemia

inducingdiarrheatotakeoutfluidsbyintestinal.

50%MagnesiumSulfatesolution20%Mannitolsolution

85ReducingbloodvolumetherapyForhypervolemiawithcardiacfailureandpulmonaryedema,takingout300ml~400mlbloodmaybeuseful.usedrarenow864>.Dialysistherapyforseriousazotemia

▲veryimportant,savelife

▲HemodialysisorPeritonealdialysis

87▲

MarkerofgivingDialysistherapy:

Oligurialastsfor4daysoranurialastsfor24hourswithoneoffollowingfivesigns:a>.SeralBUN>28.56mmol/L;b>.BUNincreasingmorethan7.14mmol/Leveryday;C>.Bloodpotassium>6mmol/L;d>.hypervolemiaor/andpulmonaryedema;e>.beingterriblefretfulorcerebraledema.885.TreatmentinDiureticphasea.Keepingbalanceoffluidandelectrolytes.b.Preventingandtreatmentsecondaryinfection:antibiotics89

6.Convalescentphase

a:Supplementnutritionfood.b:Examiningofrenalfunction,bloodpressure,pituitaryfunctionatregularinterval.907.Complicationstreatment

1>.Hemostaticstherapyforheavybleeding

suchasgastrointestinalhemorrhagetreatmentofDIC:accordingtodifferentphaseofDIC,givingEACA,protamine,respectively.912>.TreatmentARDS

a:Controlofamountofintravenousinfusion.b:Givingoxygen,ormechanicalventilation:positiveendexpiratorypressure.c.Corticosteroids:20to30mgofdexamethasoned.Cedilanidforcardiacfailure.923>.Treatmentof