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1、Flavivirus病原微生物 Pathogen BiologyFlaviviridaePestivirusesFlavivirusesHepaciviridaeHepatitis C virusBVD, Hog cholera, Border diseaseYellow feverJapanese encephalitisSt. Louis encephalitisDengueWest Nile virus(arthropods, biological vectors)Togaviruses and FlavivirusesnTogaviruses Human PathogenspAlpha
2、virus ArbovirusespRubivirus Rubella viruspArterivirus NonenFlaviviruses ArbovirusespHepaciviridae HCVpPestivirus Nonepall Flaviviruses share a common antigennEnvelope glycoproteinnHemagglutininp65 different types of flaviviruspone-third human pathogenspseveral antigenic subgroupsnmite bornentick bor
3、neFlaviviruses: ClassificationpReplicationincytoplasmpvirionsassembledingolgiandSmoothERpTransportedbyvesiclestoplasmamembranepVirusRNAactsasmRNAncapped,nopolyAtailnmRNA-proteinnmRNA-antisenseRNAnAntisenseRNA-senseRNAFlavivirusespEncephalitisnSt.louisencelphalitis,Japaneseencephalitis,Powassan,tickb
4、orneencephalitispFebrileillnesswithrashnDengueviruspHemorrhagicfevernKyasanurForestviruspHemorrhagicfeverwithhepatitisnYellowfevervirusFlaviviruses: Clinical manifestationsArthropodVectorsAedes Aegyti （伊蚊）Assorted Ticks （虱、蜱）Culex Mosquito （库蚊）Phlebotmine Sandfly （吸血白蛉）Transmissionphuman-arthropod-h
5、umanpanimal-arthropod-humanpmixHuman-Arthropod-HumanDengue Reservoir may be in either man or arthropod vectorIn the latter transovarial transmission may take placeAnimal-Arthropod-HumanJapanese encephalitisThe reservoir is in an animal, The virus is maintained in nature in a transmission cycle invol
6、ving the arthropod vector and animalMan becomes infected incidentallyJapanese EncephalitisBackgroundp1870s: Japann“Summer encephalitis” epidemicsp1924: Great epidemic in Japann6,125 human cases; 3,797 deathsp1934: Reproduce the disease in monkeyp1935: First isolatednBrain from a fatal human encephal
7、itis casep1938: Isolated from Culex tritaeniorhynchusBackgroundp1940-1978nDisease spread with epidemics in China, Korea, and Indiap1983: Immunization in South KoreanStarted as early as age 3nEndemic areas started earlierp1983-1987: Vaccine available in U.S. on investigational basisPathogen-JEV and F
8、lavivirusespJEV is one of 66 flavivirusespbelongs to the Japanese encephalitis serocomplex, which is composed of several flavivirusesnAlfuy, Koutango, Kokobera, Kunjin, Murray Valley encephalitis, Japanese encephalitis, Stratford, Usutu, West Nile, and St. Louis encephalitis. nUsutu virus, an Africa
9、n mosquito-borne flavivirus, emerged in 2002 and since then has appeared in many European countries, presenting even further surveillance and transmission challenges. Vazquez A, et al. Euro Surveill. 2011;16:Non-segmented, single stranded, positive sense RNA viruses related to hepaciviruses and GB v
10、irusesSpherical, 40-60 nm in diameterLipid envelope covered with surface projections, especially E, pre-M and M proteinsWest NileKunjinJapanese encephalitisMurray Valley encephalitisSt. Louis encephalitisdengue-1dengue-3dengue-2dengue-4yellow feverCentral European encephalitisFar Eastern encephaliti
11、sPowassanDakar batJapaneseencephalitisdenguenonetick-borneencephalitisnoneXIVXIIXVIIIVIIImosquito-bornetick-borneno vectorvirusserocomplexcladeclusterFlavivirus genus. The dendrogram on the left shows the relationships of selected flaviviruses based on a recent phylogenetic analysis. The serologic a
12、nd phylogenetic classifications of these viruses are indicated to the right.Fields Virology, 4th Edition. Philadelphia, Lippincott-Williams & Wilkins. 2001, p 995Flaviviruses (some), mosquito-borneS. Asia, Japan, Korea, China,India, Philippines, etc.VaccineAfrica, Middle East, southern France, Forme
13、r Soviet Union, India, Indonesia, USScreening blood and blood products for the virusAustralia, New GuineaNoneNorth and South AmericaNoneJapanese encephalitisMurray Valley encephalitisWest Nile VirusencephalitisSt. Louis encephalitisJEV Genotypic VariantsType IChina, India, Japan, Nepal, Sri Lanka, T
14、aiwan, and VietnamType IICambodia and N. ThailandType IIIIndonesia, Malaysia, and S. ThailandVaccine targetType IVIndonesian and Malaysian regionsJEVGeographic distribution of medically important flavivirusestransmissionA, Regions with yellow fever viral transmission. B, Regions with Japanese enceph
15、alitis virus transmission. C, Countries with West Nile virus transmission. D, Countries with tick-borne encephalitis transmission Strauss, Viruses and Human Disease. San Diego, Academic Press, 2002All flaviviruses would appear similar to DengueEpidemiologyOnly distributes in AsiaPrimarily a disease
16、of rural AsiaVector mosquitoes proliferate in close association with birds and pigsBirds and pigs are the major amplifying hostsMany other mammals and reptiles infected as well, long term viremia documented in bats, othersCulex tritaeniorhynchus the principal vector but many other mosquitoes are com
17、petent and can transmitC. pipiensC. quinquefasciatusSpecies of Aedes, AnophelesVirus overwinters in mosquitoes as well as vertical transmissionTraditional seasonal spread (spring/summer) heavily impacted by rice paddy floodingA single rice paddy can produce 30,000 mosquitoes per dayIncidence and Pre
18、valencepCommonest cause of encephalitis in AsiapIn hyperendemic areas half of all cases occur in children under 4 years of age, nearly all before age 10pNearly 100% seroprevalence by adulthood in heavily infected areaspEpidemic and endemic formsp20,000 cases and 6,000 deaths annually a gross underes
19、timatepMathematical modeling predicts 175,000 annual cases, 43,750 fatalities, 78,750 with disabilityIncidence and PrevalencepRatio of apparent to inapparent infection ranges from 1:250 in susceptible Asians to 1:63 in adult US marines, 1:18 in Torres strait outbreakpRatio affected by age, virulence
20、 of the strain of virus, cross protective immunity from other flaviviruses (dengue)pRisk to travelers 1 case per 50,000 months of exposureEpidemiologypSymptomatic Japanese encephalitis has a male-to-female ratio of 1.5:1. pSerologic evidence of JEV infection in endemic rural areas is found in nearly
21、 all inhabitants by early adulthood. pMost symptomatic infections in endemic areas occur in young children (aged 2-10 y) and elderly people. pIn nonendemic areas, JEV infection has no age predilection. EpidemiologypOccurrence in the United nIn the United States, Japanese encephalitis develops mostly
22、 among military personnel, expatriates, and, rarely, returning travelers. From 1978-1993, 12 cases occurred in the United States. The risk of symptomatic infection among travelers is estimated to be 1 case per 150,000 person-months in an endemic area. Outbreaks are rare in the US territories of Guam
23、 and SaipanEpidemiologypInternational occurrence nJapanese encephalitis is a seasonal disease, mostly occurring from June to September. nGlobally, more than 45,000 cases are reported each year pIn Chinan8090% case all focus on July, August, SeptembernSouth China: June JulynNorth China: July AugustnN
24、E: August SeptembernShanghai: late July early AugustTransmissionpVector-bornepEnzootic cyclenMosquitoes: Culex speciespCulex tritaeniorhychusnReservoir/amplifying hostspPigs, bats, Ardeid (wading) birdspPossibly reptiles and amphibiansnIncidental hostspHorses, humans, othersCenter for Food Security
25、and Public Health, Iowa State University, 2011Mode of TransmissionPlotkin, Orenstein. Vaccines, 4th ed. P 928Morbidity/MortalitypSwinenMortality high in piglets; rare in adultspEquinenMortality rare (5%) pHumansnMortality: 5 to 40%nSerious neurologic sequelae: 45 to 70%Subcutaneous injectionRegional
26、 lymph nodesExtraneural Tissues Connective tissue Striated muscle Pancreas Adrenal Smooth muscleEfferent lymphaticsThoracic ductPlasma ViremiaReticuloendothelialcell clearanceHumoral antibodyOlfactory epitheliumVascular endotheliumNeural ParenchymaNeurons, Glia(?)CNS antibodylymphocytes, macrophageC
27、ellular dysfunction Cellular lysisInflammation?PathogenesisModified based on Fields Virology, Vol 1, Fourth Edition. Lippincott-Williams & Wilkins , pp 1057, 2001BBBSubclinical formMild formCNS Japanese EncephalitisLight typeMedium typeSevere typeClinical Manifestationsp35,000-50,000 cases annuallyp
28、Less than 1 case/year in U.S.nMilitary, travelerspMost asymptomatic or mild signsp1 per 250 JEV infections results in symptomatic disease pChildren and elderlynHighest risk for severe diseaseClinical ManifestationpHistory of mosquito exposure in an endemic areapIncubation period average: 6-8 days, w
29、ith a range of 5-15 dayspProdromal period: several daysnFever 39-40nHeadachenNauseanDiarrheanVomitingnMyalgiaClinical ManifestationspIncubation 6-16 days. Spectrum from mild febrile headache to severe encephalitispHeadache, fever, nausea, vomiting, drowsiness. Abdominal pain and diarrhea common in c
30、hildrenpProgression over several days to severe diseasenDull, mask-like faciesnMuscular rigiditynCranial nerve palsiesnTremulous eye and extremity muscle movementsnGeneralized and localized paresis, incoordination, pathologic reflexespSeizures frequent in children, 40, coma, persistently twitch, mig
31、ht have failure ofrespiratory, might have sequelaepFulminate type nTmax 40 high fever, deep coma, intractable seizure, centrally respiratory failure during very short period, severe sequelae for survivalsTypeTemperature（）Level of consciousnessseizureMeningealIrritation/Pathological reflexRespiratory
32、 failureNeuropsychiatric sequelaeLight38-39arousenolightnonoMild39-40lethargy/delirium/obtundationoccasionallyobviousnonoSevere 40Studor/comafrequent/persistentobviousmightmightFulminate 40Deep comaintractableobviousrapidoftenClinical ManifestationClinical Manifestation: SeverepAcute encephalitis nH
33、eadache, high fever, stiff neck, stupornMay progress to paralysis, seizures, convulsions, coma, and deathpNeuropsychiatric sequelaen45 to 70% of survivorspIn utero infection possiblenAbortion of fetusPost Mortem LesionspPan-encephalitispInfected neurons throughout CNSpOccasional microscopic necrotic
34、 focipThalamus generally severely affectedSingh, AJNR 2001;22:1131Magnetic Resonance Abnormalities in Severe JEKalita, AJNR 2000;21:1978Substantia nigra involvementBilateral asymmetric thalamic hyperintensity Chinese Medical Journal 1997;60:10514 days after onset. Thalamicand basal ganglia involveme
35、ntBasal GangliaThalamiMidbrain involvement220 days post onset. Hyperintenselesions at globus pallidus bilaterallyMRI in Flaviviral EncephalitisSolomon, NEJM 2004T2-Weighted Images showing Thalamic enhancement and swelling in :(A) Japanese encephalitis (B) West Nile Encephalitis (C) Murray Valley Enc
36、ephalitisJapaneseencephalitisWest NileencephalitisMurray ValleyencephalitisSummary on Clinical ManifestationpSpecial seasonal onset, endemic areapHistory of mosquito exposure in an endemic areapAbsent or partial vaccination pquick onset, headache, high fever, variable CNS symtoms including: nneck st
37、iffness, stupor, disorientation, coma, tremors, occasional convulsions (especially in infants) and spastic (but rarely flaccid) paralysisDiagnosispHistory of mosquito exposure in an endemic area.pClinical diagnosis is unreliablepIgM capture EIA the most widely used methodpCSF or serum positive in 75
38、% of patients within 4 days of symptom onset, nearly 100% within 7 dayspBoth serum and CSF should be tested to maximize sensitivityDiagnosispLaboratory confirmation requiredpSuspected casenAntibody titer: HI, IFA, CF, ELISAnJE-specific IgM in serum or CSFpDefinitive casenVirus isolation: CSF, brainD
39、iagnosisCase Definition - Suspected casenAcute onset of fever ( 7 days)nchange in mental status With/ withoutnNew onset of seizures (excluding febrile seizures)n (Other early clinical findings - may include irritability, somnolence or abnormal behavior greater than that seen with usual febrile illne
40、ss)Case ClassificationLaboratory-Confirmed caseSuspected case with any one of the following markers:n Presence of Ig M antibody in serum and/ or CSFn Four fold difference in Ig G antibody titer in paired seran Virus isolation from brain tissuen Antigen detection by immunofluroscencen Nucleic acid de
41、tection by PCRIn the sentinel surveillance network JE will be diagnosed by Ig M Capture ELISA, and virus isolation can be done in National Reference laboratoryDiagnosisProbable CasesSuspected case in close geographic and temporal relationship to a laboratory-confirmed case of JE in an outbreakAcute
42、Encephalitis Syndrome due to other agentA suspected case in which diagnostic testing is performed and an etiological agent other than JE is identifiedAcute Encephalitis Syndrome due to unknown agentA suspected case in which no diagnostic testing is performed / no etiological agent was identified / t
43、est results were indeterminateLaboratory WorkuppComplete blood counts: nEarly stage: WBC PMN dominantpPeripheral blood smear - Malarial parasite pBlood glucose pCSF and Blood for serology by IgM ELISA/ virus isolation, CSF is preferred since by the time patient presents with CNS manifestations the l
44、evel of viremia in blood has decreased and there is cross reaction with other flavivirusesDifferential DiagnosispNoninfectious conditions:nCNS lupus erythematosusnCNS tumors (nonmetastatic)nCerebrovascular diseasespBacterial infectionsnPyogenic focal brain abscessnTuberculous meningitisnMycoplasma m
45、eningitisnShigellosisnTyphoid fevernTuberculosisnRocky Mountain spotted feverDifferential DiagnosispViral infectionsnArboviral diseases (West Nile virus, Murray Valley encephalitis)nNipah virus infectionnCalifornia encephalitisnEnterovirus infectionnHerpes simplexnDengue feverTreatmentpNo known trea
46、tment other than aggressive symptom managementpManagement of JE is essentially symptomaticnRefer the severe to health facilitynAirway and Breathing, ventilation if necessarynConvulsionnCirculationnTemperature control is critical, 38PrognosispOnly 1 per 250 Japanese encephalitis virus (JEV) infection
47、s results in symptomatic diseasepTwo factors for a good prognosisnhigh concentrations of neutralizing Abs in CSFnhigh levels of JEV IgG in the CSFPrognosispPoor prognostic factorsnAge younger than 10 years nLow Glasgow coma scale nHyponatremianShock nPresence of immune complexes in CSFnPresence of i
48、ncreased amounts of antineurofilament antibodiesnIncreased levels of tumor necrosis factornCoexisting neurocysticercosis nRespiratory dysfunctionnBabinskys signnFrequent or prolonged seizuresnProlonged fevernAlbuminurianHigh viral replication in the brainNeuropsychiatric SequelaepOccur in 45-70% of
49、survivors, particularly severe in childrenpParkinsonismpSeizurespParalysispMental retardationpPsychiatric disordersLucknow, Northern India. Washington PostVaccines for JE viruspTwo vaccines are manufactured and distributed in ChinanInactivated vaccine grown in primary hamster kidney cellsnLive atten
50、uated vaccine (SA14-14-2) grown in hamster kidney cellspThe third is manufactured in Japan and distributed abroad by arrangement with Sanofi-PasteurnLicensed as JE-VAXR and is the only FDA approved vaccine for use in the U.S.nHas been in wide use worldwide since the 1960snThree subcutaneous injectio
51、ns over a month with a booster at 3 yearsn91% efficacy in a large field trial in ThailandSafety of Current JE VaccinepSide effects “Generally inconsequential.” Local tenderness or mild systemic symptoms in 10-30% - Fields virologypNo neurologic events in Japanese surveillancepInfrequent allergic rea
52、ctions in adult travelersnUrticaria, angioedema, bronchospasm, erythema nodosum and e. multiformepIncidence varies in different reports: 2/1000 to 1%p14,000 US Marines, 11 pruritus, 26 urticarianHistory of urticaria after hymenoptera envenomation or other provocations caused a relative risk increase
53、 of 9.1nNone of the reactions were severe or life threateningpCase control study in Australia identified increased reaction risk if excessive alcohol consumption in 48 hours after vaccination (p= 0.005)The Need for a New JE VaccinepGiving 3 doses of vaccine to remote communities is logistically diff
54、icultnIn the Torres strait outbreak it took 2 mobile teams covering 14 communities on 13 islands 4 months to deliver 9,046 vaccinations to 3,440 peoplenVaccine availabilitynNeed for refrigerationpExpense of vaccine manufacture pConcerns about effectivenesspConcerns about side effectsJE-VAX RpManufac
55、tured by The Research Foundation for Microbial Diseases of Osaka University (BIKEN)pThe Nakayama-NIH strain from a 1935 fatal human case of JEpGrown via intracerebral mouse inoculation pHighly purified. 2 ng/ml of myelin basic proteinpStabilized with gelatine, preserved with 0.007% thimerosalPrevent
56、ionKill mosquitoes Inoculation of vaccinelive attenuated vaccines Cell culture-derived inactivated vaccine (primary hamster kidney cell )children 6 months 10 year old in epidemic regionJE is a vaccine preventable disease JE virus!Preventionpclinical manifestationspknown risk of exposurep isolation of viruspincrease in IgMnminimal value if repeat infectionFlaviviruses: DiagnosispreducemosquitovectorpyellowfeverattenuatedvaccinepJapaneseencephalitis-inactivatedvirusptickborneencephalitis-inactivedvirusFlaviviruses: C新浪微博：张婷医生
