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VHF Encephalitis

VHF Encephalitis. Prof. Dr. Mehmet BAKIR. Definition of Viral Hemorrhagic Fever. Fever Myalgia Bleeding including dermal , intradermal , gastrointestinal system , and vaginal or another organ/ system. The etiology of VHF. Filoviridae ( Marburg virus ve Ebola virus )

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VHF Encephalitis

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  1. VHF Encephalitis Prof. Dr. Mehmet BAKIR

  2. Definition of ViralHemorrhagicFever • Fever • Myalgia • Bleedingincludingdermal, intradermal, gastrointestinalsystem,andvaginaloranother organ/system

  3. Theetiology of VHF • Filoviridae (Marburgvirus ve Ebola virus) • Arenaviridae (Lassavirus, Junin, Machupo, Sabia, andGuanaritovirus) • Lassa ,andJuninvirus can causeencephalitis,andmenengitis • Bunyaviridae (Crimean-Congohemorrhagicfevervirus [CCHFV], RiftValleyfevervirus [RVFV] ,Hantavirus) • RVF andToscanavirus can causeencephalitis, andmenengitis • Flaviviridae • YellowfevervirusandDenguevirus, West Nilevirus • DENV and WNF can causeencephalitis, andmenengitis

  4. West NileVirus • FromFlaviviridae family andthe Flavivirusgenus • WNV is a positive sensesingle stranded RNA virus and an importantpathogen for humans,horses, dogs, birds and reptiles • Birdsareconsideredto be the main reservoir hostsof WNV, • Migratorybirds play an important role in its spreading • Thenaturalcycle of WNV typically involves ornithophilicCulex mosquitoes feeding on avian hosts • From humantohuman can be transportedbytransfusionortransplantation of organs Monath andHeinz 1996, Rappole et al. 2000, Appersonet al. 2004, Iwamoto 2003, Pealer LN 2003,

  5. Horses are highly susceptible • Thelatestoutbreaksof WNVincludean increasedproportion of neurological disease inboth humans and horses • Mortality rates among clinically affectedhorses have been estimated around 38%, 28%,44% and 42% during outbreaks in the USA,France (2000), Morrocco and Italy (1998), respectively • West Nile virus has a wide geographicaldistrubution that includes countries of Europe,Asia, Africa, Australia, andAmerica • WNNDwereconfirmedbyEuropean countries such as Greece (197 cases) , Romania (54 cases), Italy (3 cases), Hungary (15 cases),Portugal (1 case) and Spain (1 case) [5] in 2010 Castillo-OlivaresandWood 2004, Petersen and Roehrig2001, TberAbdelhaq 1996, Cantile et al.2001,Murgue et al. 2001, Ostlund et al. 2001, HubalekandHalouzka 1999, Savage et al. 1999, Hayes et al. 2005

  6. West NileVırus • Thefirst acute human WNV infection cases weredocumentedandreportedfrom Manisa province inTurkey. • From July to November in 2010, 47 cases of WNV infectionwere detected(35 were probable, 12 wereconfirmed) • Thecentral nervous systemmanifestationswerefound in 40 patients

  7. WNV • An otherstudywasperformed at Hacettepe UniversityHospital. Paired serum andcerebrospinalfluid (CSF) samplesfrom 87 adultpatientswiththepreliminarydiagnosis of asepticmeningitis/encephalitis of unknownetiologywereevaluatedretrospectivelytoidentify WNV-relatedsyndromes. • WNV IgMandIgGantibodiesweredetected in 9.2% (8/87) and 3.4% (3/87) of the serum samples, respectively. Ergünay K, et al, 2010

  8. Inthisstudy, 371 samplefrom 234 individualswerecollectedfrom Ankara andIzmir • Twocases of WNV CNS infectionsand 14 cases of TOSV infectionswereidentifiedviaserologicaltesting

  9. Surveillance and outbreak reportsEmergence of West Nile virus infections in humans inTurkey, 2010 to 2011H Kalaycioglu (h.kalaycioglu@hotmail.com)1, G Korukluoglu1, A Ozkul2, O Oncul1, S Tosun3, O Karabay4, A Gozalan1, Y Uyar1,D Y Caglayık1, G Atasoylu5, A B Altas1, S Yolbakan1, T N Ozden5, F Bayrakdar1, N Sezak3, T S Pelıtlı6, Z O Kurtcebe6, E Aydın6,M Ertek11. Refik Saydam National Public Health Agency, Ankara, Turkey2. Ankara University, Faculty of Veterinary Medicine, Department of Virology, Ankara, Turkey3. State Hospital, Manisa, Turkey4. Training and Research Hospital, Sakarya, Turkey5. Provincial Health Directorate, Manisa, Turkey6. Ministry of Health, General Directorate of Primary Health Care, Ankara, Turkey Province of residence The overall incidence of WNV infections wasdeteced in 0.19 cases per 100,000 population in humans in a sureveillancestudy in Turkey, 2010 to 2011

  10. United States, 2011 MMWR / July 13, 2012 / Vol. 61 / No. 27

  11. WNV recognized in North America in 1999 and is themostfrequentcause of epidemicmeningoencephalitis in North America. • Between 1999 and 2009, over 12,000 cases of WNND werereported in the United States. Debiasi RL, 2011

  12. In WNV infection • Pathological changes within the central nervoussystemdevelopas a direct result of viral proliferation within neuronal and glial cells, cytotoxic immune response to infected cells, diffuse perivascular inflammation, and microglialnoduleformation Smith RD, Hum Pathol 2004; Agamanolis DP,AnnNeurol 2003 Gyure KA. J Neuropathol Exp Neurol 2009

  13. West NileVırus • Incubation period is 2-15 days. • Asymptomatic infection, West Nile Fever, and West Nileneuroinvasive disease (WNND)followthisincubationperiod. • Of allcases, 80% is asymptomaticand 20% is symptomatic. • Lessthan 1% of symptomaticcaseshave a neuroinvasivedisease. • Most of illnesses is seen as “West Nile fever”and observed as clinical symptoms and findings asfollows:Self-limited dengue-like illness • Fever, headache, retro-orbitalpain, back pain,fatigue, arthralgia, and myalgia, anorexia, nausea, vomiting, diarrhea, maculopapularrash,lymphadenopathy Hayes et al. 2005, PetersenandMarfin 2002, Solomon and Vaughn 2002

  14. West Nileneuroinvasive disease (WNND) • WNND includes severe neurologic illness categories • Clinicalandlaboratoryfindingsseen in the WNV meningitisinclude fever, nuchal rigidity, CSF pleocytosis. • Encephalitisincludes 60% of WNNDcasesandthere is ususally altered mental status in thesecasesconsisting of peoplelessthan 55 yearsoldorimmunocompromisedpatients • Theotherneuroinvassivedisorders of WNV include • meningoencephalitis, • acute flaccid paralysis, • tremor, myoclonusor both tremor and myoclonus, • and parkinsonism

  15. Diagnosis of WNND • Manypatientswith WNND have normal neuroimagingstatus but abnormalitiesmay be present in areasincludingthebasalganglia, thalamus, cerebellum, andbrainstem • CSF protein is elevated • Cerebrospinalfluidinvariablyshows a pleocytosis, with a predominance of neutrophils in uptohalfthepatients. • Withdemonstration of WNV-specificIgMantibodies in cerebrospinalfluidor serum approximatellyhalf of allcaseswill be positive in thefirst 7 dayswhereasIg G Antibodieswill be positive in 7-21 days • RNA in serum and/or CSF can be detectedby PCR method.

  16. Therapyandprevention Therapy Prevention Repellentsand body protectiveclothing can use to avoid the bite of the mosquito It can use insecticides for mosquitoes There are studies for vaccine but not availablefor general use • there is no proven therapy for WNND, • several vaccines and antiviral therapy with antibodies, antisense oligonucleotides, and interferon preparations are currently undergoing human clinical trials. • Supportivetherapy has to be carriedout.

  17. DengueHaemorrhagicFevervirus • Virus is fromFlaviviridaefamilyandFlavivirusgenus • Dengue is an RNA virus that is grouped intofour serotypes (DENV-1 through DENV-4). • Thisvirus is • non-enveloped, • spherical with a diameter of 50nm • and a positive-sense,single-stranded RNA genome.

  18. DENV epidemiology • Thisinfection is the most destructive arboviral disease • The number of countries reportingoutbreaks has increased 10-fold since the last 30years. • Dengueis a worldwide condition spread throughout the tropicaland subtropical zones between 30 N and 40 S. • Thesecountriesare: • Pacific-Asian region, Americas, Middle East, and Africa. • Approximately 50-100million infections occur each year resulting inapproximately 25,000 deaths. • Vectorsare the mosquitoesAedesaegypti and Aedesalbopictus • Dengue representsthe second leading cause of acute fever in travellers

  19. The incidence of neurological symptoms among denguepatients variesfrom 1% to 25% in all dengueadmissions • In Indonesia, 70% of virologicallyconfirmed fatal dengue infections (n=30) presented withone or more neurological signs,and 7% of those admittedfor viral encephalitis turned out to be dengue-infected. • Inanother study , 4.2% of patients with neurologicalsymptomstestedpositivefordengue. Thakare J, . et al1996, KankirawatanaP, et al. 2000, SolomonT, et all,2000, Puccioni-Sohler et al.,2000,. Jackson et al., 2008,Garcia-Rivera EJ, et all, 2002

  20. Inthisstudy, theauthorsreviewedtheetiology of viralmenengitisandencephalitis in a dengueendemicregion, in Brazil. Dengueviralencephalitisbroughtabout 47% of allencephalitiscases. Journal of the Neurological Sciences 303 (2011) 75–79

  21. Inthesamestudymentionedabove, Dengueviralmenengitis is 10% of allmenegitiscases. Journal of the Neurological Sciences 303 (2011) 75–79

  22. ççççççççççççççççççççççççççççççççzvöbcööööööööööööööööööööööööööööööcbzvnbnb.önbnççççççççççççççççççççççççççççççççzvöbcööööööööööööööööööööööööööööööcbzvnbnb.önbn Inthisstudy, theauthorsincluded 265 cases of AFE and 39 patientswereevaluated as dengueencephalopathy

  23. NeurologicalManifestations of Dengue • From the pathogenesis point of view, neurological manifestations of dengue can begroupedintothreecategories: • (1) Related to neurotropic effect of virus (encephalitis); • (2) Related to systemic complication of dengue infection (encephalopathy); • (3) Post infectiouslikeacutedisseminatedencephalomyelitis, myelitis, Guillain-Barresyndrome, opticneuritis. Murthy JMK. Neurologicalcomplication of dengueinfection. NeurolIndia. 2010; 58: 581-84.

  24. Clinicalmanifestations Patients with Symptomatic DengueFever have: Patients with Dengue Hemorrhagic Feverand Shock Syndrome (the most severe form) have: Hepatomegaly Hemorrhage(includingepistaxis, gingival hemorrhage, and gastrointestinal hemorrhage) Disseminatedintravascular coagulation, plasma leak, and shock may befatal during this phase. • malaise, headache, myalgias, retro-orbital pain, bone pain, arthralgias, nausea, vomiting • petechiae, and a diffuse erythematousmaculopapular rash Neurological complicationsareuncommonmanifestations of dengue fever, Neurological dengue is classified as a form of SevereDengue (WHO 1997, 2009).

  25. Neurlogicalcomplications • Encephalitis is the most common clinicalstatus (from 4.2% toas much as 51%) and has followingcharacteristics: • Fever, headaches, altered consciousness or personality,seizures, or focal neurological signs • myalgias, diarrhea, joint or abdominal pain,rash, and bleedingsare reported in only 50%of encephalitis cases • Theotherclinicalstatuesinclude meningitisand myelitis • Acutedisseminatedencephalomyelitis(ADEM) is rarely described in association withdengue infection

  26. Laboratoryfindings • CTand MRI findings: • hemorrhages, diffuse cerebral edema, • focal abnormalities involving the globuspallidus, the hippocampus, the thalamus, andthe internal capsule • Analysis of CSF:lymphomononuclearpleocytosisand normal glucoselevels • However, normal CSF cellularity has beenshown in more than half of patients withdengue encephalitis.

  27. Diagnosis • Cellculturefor DENV • RT-PCR fordetecting of viral RNAin serum, plasma, or CSF • ELISA for identifyingdengue virus specific IgMandor immunoglobulin G in serumobtained during the acute and convalescent phases ofinfection

  28. Management of DengueFever • There is no specific anti viral treatment and • The management is essentially supportive and symptomatic (Bedrest) • The key to success is frequent monitoring and changing strategies depending on clinical and laboratory evaluations • (Fluid, electrolyte, blood and blood products)

  29. Prognosis • Mortality rates vary from 5% to 22% • Causes of deathinclude multi-organ failure, hemorrhagic complications,and circulatory collapse. • Most patients completelyrecover by the time of hospital discharge • Neurologicalsequelaeinclude: • spasticparesis, • staticmyelopathy following transverse myelitis, • residualspasticity, • prolonged drowsiness, • residual paralysisandParkinsoniansyndrome.

  30. Prevention • Tissue culture-based vaccines for dengue virus types are immunogenic but not available for general use • Repellentsand body protectiveclothing can use to avoid the bite of the mosquito • It can use insecticides for mosquitoes

  31. Arenaviridae • At least eight arenavirusesare known to cause human disease • New World viruses, • Junin virus (JUNV), Machupo virus (MACV), Guanarito virus(GTOV), and Sabia virus (SABV) (all members of lineage B)are etiologic agents of hemorrhagic fever syndromes in SouthAmerica, • Whitewater Arroyo virus (WWAV) (lineageA) has been linked to two fatalities in North America . • Old World viruses • Lassavirus (LASV), Lujovirus, andlymphocyticchoriomeningitisvirus (LCMV

  32. Arenaviridae • Arenaviridae is a sphericalorpleomorphicvirion (witha diameter of 50–300 nm) withenvelopeand has single-stranded RNA • Virus is inactivated by: • heating to 56oF, • pH<5.5 or >8.5, and • UV/gamma irradiation • Chemical agents like 0.5% sodiumhypocorite, 0.5% phenol and 10% formalin are sufficientlygoodinactivantsagainstthevirus.

  33. Lassavirus • Lassa virus and Lujo virus can cause hemorrhagic fevers andLassa feveraccounts for 10 to 15% of adult medicaladmissions in West Africa • Rodent-to-human transmission (the “multimammate rat”, Mastomysspecies-complex) • Infectedrodentsremain as carriers throughout their life (no clinicalsymptoms) • Infectedrodentsexcrete the virus through theurine, saliva, respiratory secretion

  34. Lassavirus • Humaninfections can occur : • when individuals are exposed to aerosolforms of the virus • or after direct contact between infectious materialsandabraded skin. • Ingestion of foodormaterialscontaminatedbyinfectedrodentexcreta • Thevirus can be isolated in the blood, faeces, urine, throatswab, vomit, semen and saliva of infected persons ( during 30 daysormore ) • Infected personspresent serious threat to the environment • Healthcare workers are at risk if proper barrier nursing andinfection control are not maintained.

  35. Pathogensis • Theilness is developedby : • endothelial cell damage/capillary leak, • platelet dysfunction, • suppressed cardiac function, • cytokines and other soluble mediators of shock and inflammation

  36. Clinical aspects • Incubation period is approximately5-21 days • Typical symptomsinclude: • gradual onset of fever, headache, malaise, • pharyngitis, myalgias, retro-sternal pain, cough, vomiting arthralgia, weakness, sizziness, abdominalpain, diarrhea • A minoritygroup present with classic symptoms of bleeding, neck/facial swelling and shock.

  37. Lassavirus • Neurological signsinclude confusion, disorientation, locomotor dysfunction, tremors, convulsions and coma. • The clinical picture can vary. • Encephalopathy was the most prominent syndrome. • Severely ill patients may dieand the mortality rate is particularly high among pregnant women. • Convalescence can be prolonged in patients who recover. • Transient or permanent deafness often occurs.

  38. Diagnosis • Virusisolation • ELISA for antigen of virusandIgMorIgGforvirus • Immunohistochemistry (for post-mortem diagnosis) • RT-PCRfordetecting RNA of virus

  39. Treatment • Itincludes supportive measuresandribavirin. • Ribavirin is most effective when started within the first 6 days of illness • Its major toxicity is mild hemolysis and suppression of erythropoesis. Both is reversible. • Presently, itcontraindicates in pregnancy, although it may be warranted if mother’s life is at risk

  40. Poor prognosis • Poorprognosis can be dueto: • highviremia, • high serum AST levels as morethan150 IU/L • bleeding • encephalitis • edema • third trimester of pregnancy

  41. Preventionandcontrol • Programs for rodent control and avoidance • Health education strategies for preventing infections in people living in endemicarea • Hospital training programs to avoid nosocomial spread • Diagnostic technology transfer • Specific antiviral chemotherapy (ribavirin) • There are studies for vaccine but not availablefor general use

  42. Bunyaviridae family, Phlebovirusgenus (10 sercomplex) Sandflyfeverserocomplex • SandflyfeverNaplesgroup • Granada virus • Massilavirus • Puniquevirus • SandflyfeverNaplesvirus • Toscanavirus • SandflyfeverSiciliangroup • Belterravirus • Chagresvirus • Corfuvirus • RiftValleyfevervirus • SandflyfeverCyprusvirus • SandflyfeverSicilianvirus • SandflyfeverTurkeyvirus • Virus has a single-stranded RNA genomewithlipid-enveloped • The genome consists of three segments: the large(L), themedium (M),the small (S)

  43. Phlebovirus (RVFV) • RVFV is a highly pathogenic virus that can cause lethaldisease in both humans and ruminant animals • RVFV is transmittedprimarily by Aedesmcintoshimosquitoes, • The virus has beendetected in 23 species ofmosquitoes • RVF outbreaks in human populations vary in size, intensity andlocation with these parameters dependent upon rainfall andmosquito abundance • Humans is infectedby direct contact or aerosol. • Tissue or body fluids of animals (aborted fetuses, slaughter, necropsy) arecontagious

  44. Chronology of Phlebovirus (RVFV) epidemia • 1987: Senegal • 1997-98: KenyaLargest outbreak reported (89,000 humans cases - 478 deaths) • 2000-01: Saudi Arabia and Yemen (First outbreak outside of Africa) • 2003: Egypt (45 cases; 17 deaths) • 2006-7: Kenya ( Spread to surrounding areas, 1000+ human cases, 300 deaths) • The largest recorded outbreak of RVFwas in Egypt in 1977 with 10,000 to 20,000 human cases [8,9]. • 2010: South Africa (over 250 laboratory confirmed cases with an approximate case fatality rate of 11%)

  45. Phlebovirus(SandflyandTosconavirus) • Virus transmitted to humans by insects ofPhlebotomusgenus (P. perniciosusandPhlebotomusperfiliewi ) • Thevirus has been detected in Italy and Spain • Virusrecentlyspread to many other MediterraneanandEurope countriessuch as: • Turkey, Cyprus, Greece, France, Portugal, Germany • Most cases of the diseasehave been reported in residents in or travellers totheMediterraneanarea. • (Amaroet al., 2011; Brisbarre et al., 2011; Depaquitet al., 2010, DiNicuolo et al,2005 ,Ergünay et all. 2012,F.de Ory et al, 2013, Colomba et al 2011,

  46. Phlebovirus(SandflyandTosconavirus) • Incubation period ranges from a few days to2 weeks, • Clinicalsymptomsare: • headache (100%, ), • fever (76%–97%), • nausea and vomiting(67%–88%) • myalgias (18%). • Physical examination findingsare: • neck rigidity (53%–95%), Kernig signs(87%), • poor levels of consciousness (12%), • Tremors(2.6%), • paresis (1.7%), and nystagmus (5.2%) (L. • Laboratoryfindings of CSFincludecellsmorethan5–10 with normoglycorachia and normoproteinorachia. • Blood samples may show leukocytosis(29%) or leukopenia (6%). Charrel et al, 2005

  47. Phlebovirus(RiftValleyfevervirus) • Incubation period is 2 to 6 daysand it occurs often asymptomaticandwithInfluenza-like illness (Fever, headache, myalgia, vomiting). Thepatients recoverbetween 2 to 7 days. • Asmall percentage (1%) of patients has: • Encephalitis, • Retinalvasculitis, • Hemorrhagic feverwith melena, hematemesis, petechia, jaundice, shock, comaand • case-fatality is about50%

  48. Diagnosis • Diagnosis is based on • virus isolation • antigen detection • RT-PCR • serology • Treatmentincludes: • Symptomatic and supportive therapy • Replacement of coagulation factors • Ribavirin may alsobe helpful

  49. Preventionandcontrolfor RVFV • Thereareattenuatedandinactivatedvaccineforanimal • But there is a limiteduseforhumans • Vectorcontrol • Animalhousingcontrol • Barrierprecautions

  50. Conclusion • Differentviruses in VHF group can be thecause of ilnessessuch as encephalitis, mengitidisandotherneuroinvassivediseaases in contaminatedparts of theworldand in travellers • Ouraim is mainlytodiagnosissuchillnesses ,andtomakeappropriatetreatment in due time andtoprevent • Forthispurposeseverelresearchworkshaveto be carriedout, in ordertodevelopenewtreatmentmethodsandmedicine

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