布氏杆菌病课件_2

1 BRUCELLOSIS 2 Introduction HistoryBrucellosis Diseaseofdomesticandwildanimals zoonosis Transmittabletohumans Ithasdifferentnon specificsymptomsandsigns Nodisease notexceptingtuberculosisandsyphilis ismoreproteaninitsmanifestations Simpson Marston SurgeonservingwithRoyalArtilleryduringCrimeanwar reportedfirstaccuratedescriptionofhumanbrucellosis 1886 BruceisolatedMicrococcus laterBrucella Melitensisfromspleensofmaltafevervictims 3 IntroductionandHistory Cont d Zamit maltesephysician identifiednativegoatsasinfectionreservoir duringhisworkwithMediterraneanfevercommission1904 1907 Healsoidentifiedfreshgoat smilkasvehicleoftransmittingdiseasefromanimalstohumans 1895 Bang DanishVeterinarian identifiedBacillus laterBrucella abortusascauseofcontagiousabortionsincattle Evans Americanbacteriologist recognizedrelationofMaltafeveragentandBang sdisease 4 IntroductionandHistory Cont d Genus Bacillus micrococcus causingMaltafever renamedBrucella tohonorBruce Traum 1914 isolatedBrucellaCanis fromabortedKennel breddogs Carmichael 1966 isolatedBrucellaCanis fromabortedKennel breddogs BrucellaovisfromsheepandBrucellaneotomaefromdesertwoodrats addedtoBrucellaspecies buttodatethesetwonotshowntocausehumaninfections 5 IntroductionandHistory cont d 1994 BritishandAmericanworkers independ ently isolatedpreviuouslyunknownBrucellaorganismfromcarcassesofmarinemammalsandcetaceansonScotlandcoast andfromdolphininCalifornia Theseisolates homogenouswithdistinctivemetabolic sensitivitiestodye phagesensitivity tentativelynamedBrucellaMaris 6 THEPATHOGENBrucellae Small GNcocobacilli non motile non sporeforming Brucellaegrowaerobically Somespp Requiresupplementalcarbondioxideforprimaryisolation Anyhigh qualitypeptone basedmediaenrichedwithbloodorserumserveforinvitrocultivation Isolationformclinicalspecimensrequireprolonged 30days incubation Brucellastrainsalwayscatalse positive butoxidaseandureaseandH2Sproductionvary 7 ThePathogen cont d MajorBrucellaespeciesandtheirbiovarsdifferentiatedbyselectiveinhibitionofgrowthonmediacontainingdyes e g Thioninandbasicfuchsin GenusBrucelladividedintosix possiblyseven nomenspp onbasisofpreferredhostsandcultural metabolicandantigeniccharacteristics DNA DNAhybridizationstudiesshownremarkable 95 homologybetweenstrains suggestingmono specificgemswithsubspeciescorrespondingevolutionarylineageadaptedtospecifichosts 8 ThePathogen cont d WilsonandMiles firstdescribedmajorcellwallantigenandvirulencefactorofbrucellaetobeS LpscontainingAandMantigens Presenceof4 amino 4 6dideoxymannoseinLpsisresponsibleforantigeniccross reactionwithotherG N B e g vibriocholerae01andYersinia09 Numerousproteinantigensmaybeimportantininducingprotectiveimmunity 9 EpidemiologyBrucellosis zoonosis allinfections derivedirectlyorindirectlyfromanimalsexposure Diseaseexistsworld wide esp Mediterranean ArabicPeninsula Indiansubcontinent partsofMexicoandCentralSouthAmerica B abortusfoundmainlyincattle butothersspp likebuffalo camels talescanbeaffected B Melitensisprimaryaffectsgoatsandsheep Camelscanbeimportantsourceinsomecountries B Suisbiovars1 3indomesticandferalswine causeabattoir assoc humandisease 10 Epidemiology Cont d B Canis Leastcommoncauseofhumandisease Animals Brucellosis Ch Infection persistingforlife Brucellaelocalizationinreproductiveorgans accountsformajormanifestations abortionandsterility Brucellaeshedinlargenumbersin Milk urine cyeticproductsofinfectedanimals 11 Epidemiology Cont d Thus Brucellosisconstitutesoccupationalriskfor farmers veterinarians abattoirsandLaboratorypersonnel Routesoftransmissiontohumaninclude Directorcontactwithanimalsortheirsecretions throughcutsandskinabrasions Infectedaerosolsinhaledorinoculatedintoeyeconjunctivalsac Ingestionofunpasteurizeddairyproducts 12 Epidemiology Cont d Meatproducts raresourceofinfectionbecause Meatisrarelyeatenrawandorganismsarepresentinlownumberofmuscletissue Bloodandbonemarrowmaytransmitdiseasewheningestedinsomecultures Human to humantransmission Unusual butrarecasessuspectedtobesexuallytransmitted 13 Epidemiology cont d Onecasereportedrecently presumptivelyduetointra uterinetransmission Aidspatient pronetoinfectionsbyzoonoses butBrucellosisoccurredinveryfewofthesepatients IfCD4notseverelydepressed courseofbrucellosisinAidspts notdifferentfromdiseaseinimmunocompetentpts Brucellosisnotrareinchildrenaspreviouslybelieved Brucellosismanifestssimilarlyin Neonates childrenandadults 14 PathogenesisB melitensisandB suis morevirulentthanB abortusandB canis InfectionwithanyB species includingattenuatedvaccinestrainscancauseserioushumandisease Diseasedeterminedby Hostnutritionalandimmunestatus Sizeofinfectiousinoculum Routeoftransmission Ex LowgastricjuicePH moreeffectiveinpreventingB abortusthanB melitensisinfectionwhenadministeredbyoralroute 15 Pathogenesis cont d Therefore drugsthatdecreasegastricaciditywereimplicatedinfoodbornebrucellosis Oncebrucellaegainentrytobody PMN Leukocytesattractedtoinoculationsitebychemotaxis Normalhumanserumhaslimitedbactericidalactivityagainstbrucellae butiteffectivelyopsonizesbacteriaforphagocytosisbyPMN Leukocytes 16 Pathogenesis cont d Brucellae Facultativeintracellular slowlydividingpathogenswithcapacitytosurviveandmultiplywithinhostphagocyticcells MechanismbywhichbrucellaeevadeintracellularkillingbyPMN Leukocytesincompletelyunder stood itispossiblethatbacteriapropertyenablethemtoescapedetection Factorscontributingtointracellularsurvival Productionofadenineandguaninemonophos phate 17 Pathogenesis cont d Thesesuppressmyeloperoxide H2O2 halidesystemandcu znsuperoxidedismutase whicheliminatesreactiveoxygenintermediates Spinkcomparedbrucellosiswithtyphoidfeverbecausebacteriaenterlymphaticandreplicatewithinregionallymphnodes Hematogenousdisseminationthenfollowedbylocalizationofbacteriawithinorgansrichinreticuloendothelialsystem e g liver spleenandB marrow 18 Pathogenesis Cont d Brucellaeingestedbymononuclearphagocytessurviveandreplicateinitially Intracellularsurvivalwithinmacrophagesfacilitatedbyinhibitionofphagoxome Lysosomefusionbysolubleproductsofbrucellae andproductionofstress inducedproteins Eventualeliminationofvirulentbrucellaedependsonactivationofmacrophagesthroughdevelop mentofTh 1typecell mediatedimmunity Cytokinescontributingtoanti brucellaactivityofactivatedmacrophagesinclude TNF alpha TNF gamma IL 1 IL 12 19 Pathogenesis cont d Majordeterminantofvirulenceandimmuno dominantantigenofBrucellaisS Lps GrowthofB abortusincattleplacentaltissueapparentlyenhancedbyeruthritol thismayexplainlocalizationofbrucellaeingenitaltractsofungulates 20 HOSTIMMUNITYGeneticstudiesinvariousanimalsshowedthatresistancetointracellularpathogensispolygenic butsinglegenesrecognizedtohavemajoreffectonimmune mediatedresistance Selectedbreedingofcattleyieldedevidenceforgeneticdeterminationofresistancetobovinebrucellosis DatasuggestedthatresistancereflectedinimmunoglobulinallotypesandindifferenceinabilityofmacrophagestocontrolB abortusreplicationinvitro 21 HostImmunity Cont d S Lpsismajordeterofvirulenceofbrucellaeanddominatesantibodyresponse Humoralanti bodiestoS Lpsconfershort termprotectionasshownbypassivetransferexperimentsusingmonoclonalandpolyclonalantibodies AntibodiestoS Lpsusedfordiagnosiswhenbacterialisolationisunsuccessful Varietyofserologictestsusedtomeasureanti bodiestobrucellae Earliestwasserumagglutina tiontest SAT devisedbyWrightandSmith1897 SAT Measurestotalquantityofagglutinatinganti bodies butdoesnotdistinguishbetweenimmuno globulinisotypes 22 HOSTIMMUNITY Cont d Intime IgMantibodiestitersdecline andwithtreatmentIgGantibodiestitersfallconsistentwithrecovery FailureofIgGtitertodeclineisprognosticofrelapseorchronicinfection Currently thereisinterestincytoplasmicproteinantigensinbothsmoothandroughstrains whichcouldbeusedfordiagnosticpurposes ReddinandcolleaguesmodifiedSAT byadding2 mercapto ethanol 2ME todifferentiateagglutina tionbyIgG antibodies andshowedthatIGantibodiescorrelatedwellwithactiveinfection HostImmunity cont d CombinationofSATand2MEtestshowntobeusefultomonitorBrucellosiscourseandresponsetotherapy Applicationofenzyme linkedimmunoabsorbentassay ELISA measuresimmuneresponsetotherapy IgMantibodiesappearwithin1stweekofinfectionandfollowedbyswitchtoIgGsynthesisafter2ndweek Intime IgMantibodiestitersdeclineandwithtreat mentIgGantibodies titersfallconsistentwithrecovery 24 HostImmunity cont d FailureofIgGtitertodeclineisprognosticofrelapseorchronicinfection Currently thereisinterestincytoplasmicproteinantigensinbothsmoothandroughstrains whichcouldbeusedfordiagnosticpurposes 25 ClinicalManifestationSymptomsofBrucellosis non specific e g fever sweats malaise anorexia headache backpain Onset acuteorinsidious beginningwithin2to4weeksafterinoculation An Undulant feverpatternobservedifpatientsgountreatedforlongperiods Somepatientsc omalodoroussweatandpeculiarmouthtaste Depressioncommonandoftenoutofproportiontoseverityofsymptoms Incomparisontoplethoraofsomaticcomplaints physicalabnormalitiesarefew Mildlymphadenopathyreportedin10to20 ofcases 26 ClinicalManifestationSplenomegalyorhepatomegalyin20to30 ofcases Brucellosis systemicinfectioninwhichanyorganorsystemofthebodycanbeinvolved Attemptstocategorizethediseaseintoacute subacuteandchronic accordingtosymptoms lengthandseverityarepurelyarbitrary Diseasereferredtofocalorlocalizedwheninvolvementofspecificorganpredominates However thereislittleevidencethatsuchcomplicationrepresentdistinctsubsetofpatients 27 ClinicalManifestation cont d WhenCNSorheartinvolved suchcases difficulttotreatandoutcomecanbeaffected Problemininterpretingliteratureonbrucellosisisdifferentiatingacuteandchronicformsofbrucellosis Becauseofnecessitytotreatpatientsforprolongedperiods relapsenotuncommon especiallyiftherapydiscontinuedprematurely Mostrelapsesoccurwithin3to6monthsofdiscontinuingtherapy Diseaseconsideredchronicifinfectionpersistsmorethan12months arbitrarydefinition 28 ClinicalManifestation cont d ChronicBrucellosisusuallycausedbypersistingdeepfociofinfection e g suppurativelesionsinbone joints liver spleenorkidneys Incontrast somepatientsexperiencedelyaedconvalescenceaftertreatment withpersistingnon specificcomplaintsofillhealth notablyfatigue Suchdiseasedistinguishedfromtruechronicbrucellosisbyabsenceofobjectivesignsofdisease asfever inaddition chronicbrucellosischaracterizedbypersistentlyhighIgGantibodiestitresinserum but 29 ClinicalManifestation cont d Patientswithdelayedconvalescence poorlyunderstood someauthoritiesattributethattopre existingpsychoneurosisexacerbatedbybrucellosis Suchpatientspresentdiagnosticdilemma becausetheircomplaintsresemblebrucellosis butfurtherantimicrobialtherapy ineffective andpatientsoftenbelievetheysufferfromincurablebrucellosis 30 ClinicalManifestation cont d Patientswithdelayedconvalescence poorlyunderstood someauthoritiesattributethattopre existingpsychoneurosisexacerbatedbybrucellosis Suchpatientspresentdiagnosticdilemma becausetheircomplaintsresemblebrucellosis butfurtherantimicrobialtherapy ineffective andpatientsoftenbelievetheysufferfromincurablebrucellosis Relapsenotusuallycausedbyantibioticresistance becausestrainsofbrucellaeisolatedduringrelapsehaveantibiogramidenticaltooriginalinfectingstrains 31 ComplicationsNervousSystemDirectCNSinvasionbybrucellosislessthan5 althoughdepressionandmentalinattentionoccurcommonlyinbrucellosis CNSComplications Meningitis Encephalitis Myelitis radiculoneuritis 32 Complications cont d Brainabscess Epiduralabscess Demyelinatingsyndromes Meningovascularsyndromes Acuteandchronicmeningitis MostfrequentCNScomplication andcanbepresentingfinding oroccurlateindiseasecourse Brucellameningitisdifficulttodistinguishfromothercausesofmeningitis 33 Complications cont d Nuchalrigidityoccursin 50 ofcases BrucellameningitisdifficulttodistinguishfromothercausesCSF Lymphocyticpleocytosis elevatedprotein lowtonormalglucose G stainusuallynegative Culturepositive 25 ofcases DiagnosismadebyfindingspecificantibodiesinCSF 34 Histologicfindings Inflammationofleptomeninges Adhesivearachnoiditis Vasculitis LeukoencephalitisGIT70 ofpatientswithbrucellosis Anorexia abd Pain nausea vomiting diarrheaorconstipation 35 GIT70 ofpatientswithbrucellosis cont d Pathologiclesions Intestinalmucosahyperemiawithpeyer spatchesinflammation AcuteileitisradiologicallyandhistologicallyinpatientswithcolitisB melitensis Hepatobiliarysystem HPS Liver largestreticuloendothelialorgan probablyalwaysinvolvedinbrucellosis LFT usuallyslightlyelevated 36 Hepatobiliarysystem HPS Brucellahepatitispathologicfindingsspectrumisvariable B abortusinfection Granulomasindistinguishablefromsarcoidosis Incontrast B melitensis Lesionsrangefromsmall almostinsignificantmononuclearcellaggregatessurroundingfociofnecrosisscatteredthroughoutparenchyma todiffusenon specificinflammationresemblingviralhepatitis 37 Hepatobiliarysystem HPS cont d Occasionally Collectionsofmononuclearcellsformingloosegranulomamaybefound SuppurativeabscessofliverandspleencommonwithB suisinfection andoccasionallywithB melitensis Hepaticlesionsresolvewithantimicrobialtherapy andinabsenceofothercauses HCVmHBV alcoholabuse Nocirrhosis despiteinflammationseverity 38 Hepatobiliarysystem HPS cont d Brucellararelycausesacutecholecystitis pancreatitisandspontaneousbacterialperitonitis SBP MSS Osteoarticularcomplicationsreportedin20 60 ofpts infectedwithbrucellosis Boneandjointlesionsinclude Arthritis Spondylitis 39 MSS Osteoarticularcomplicationsreportedin20 60 ofpts infectedwithbrucellosis Boneandjointlesionsinclude Arthritis Spondylitis Osteomyelitis Tenosynovitis Bursitis Sacroiliitismostcommonlyreportedcomplication 40 MSS cont d Synovialfluidanalysisfrombrucellaeffusionsreveal Mononuclearcellspredominance andbrucellaerecoveredinabout50 ofcases Reactivepostinfectiousspondyloarthropathydescribedinsomepts Thismaybecausedbycirculatingimmunecomplexes butnoassociationfoundwithspecificHLAphenotype Spondylitis predominantly involvinglumbarspinemorecommonamongelderlypts andrarelyassociatedwithparaspinalabscess 41 MSS cont d Radiographicabnormalitygenerallyoccurlate butbonescansmaydetectinflammationearlyindisease Bonescanusefulindifferentiatingsacroiliitisfromhipjointinvolvement Earliestradiographicfindingsinspondylitis straighteningofspineandnarrowingofdiskspace CTscanusefulfordetecting Jointdestruction Vertebralosteomyelitis Paraspinalabscess 42 C V S Endocarditisoccursinlessthan2 ofcases butaccountsformajorityofbrucellosis relateddeaths Beforeeffectivetherapy includingvalvereplace mentsurgery Brucellaendocarditisisnearlyalwaysfatal Aorticvalveisaffectedmoreoftenthanmitralvalve Bothnativeandprostheticvalveinfectionsreported 43 C V S cont d Mycoticaneurysmsofbrain aortaandothervesselsaresecondarycomplications especiallyinB suisinfections 44 RespiratorySystem Airbornetransmissionofbrucellosiscommoninabbatoirs Respiratorytractinvolvementrangesfromflu likeillnesswithnormalchestradiographresultstobronchitis broncopneumonia lungnodules miliarylesions hilaradenopathyandpleuraleffusions Rarelybrucellaeidentifiedbystainorcultureofexpectoratedsputum 45 G U T Renalinvolvementisrare althoughbrucellahavebeenrecoveredfromurine Interstitialnephritis pyelonephritis exudativeglomerulonephritis andIgAnephropathyhavebeenreported Orchitisoccursinup20 ofmenwithbrucellosis Testesorepididymisinfiltratedwithlympho cytesandplasmacellsandthereisatrophyofseminiferoustubules 46 G U T cont d Inwomen rarecasessalpingitis cervicitisandpelvicabscessreported Principalbrucellosisinanimalsisspontaneousabortionandpresenceoferythritolintissuesofsusceptibleanimals thoughttoplayroleinlocalizationofbrucellaeingenitaltract Brucellosiscanresultinhumanabortions butunclearwhetheritismorefrequentthanwithotherbacteremicinfections 47 HematologicComplications Hematologicmanifestationsofbrucellosisinclude anemia leukopenia thrombo cytopeniaandclottingdisorders GranulomasfoundinB marrowinupto75 ofcases buttheyaresmallandindistinct Severethrombocytopeniawithcutaneouspurpurareportedandmaybeassociatedwithantiplateletsantibodies orhemophagocytichistiocytesinbonemarrow 48 CutaneousComplications Cutaneouslesionsoccurin5 ofpatientswithbrucellosis Manytransient nonspecificlesionsdescribed includingrashes papules ulcers petechiae purpura andvasculitis 49 OcularComplications Manyocularcomplicationsreportedinpatientswithbrucellosis Uveitis latemanifestation consistingofchroniciridocyclitis mummularkeratitis multifocalchoroiditis andopticneuritis Brucellauveitisconsiderednon infectiousimmuneresponsethatresponsetotopicalandsystemiccorticosteroidtherapy Rarecasesofendophthalmitisreported inwhichbrucellaeisolatedfromvitreoushumor 50 Diagnosis Becausesx ofbrucellosisnonspecific itisimportantto Obtaindetailedhistoryincluding Occupation exposuretoanimals traveltoenzooticareas andingestionofhigh riskfoods asunpasteurizeddairyproducts WBC normalorlow andmaynotsuggestinfectiousprocess Anemia leukopenia andthrombocytopenia commonfindings 51 Diagnosis cont d E S R variableandoflittlediagnosticvalue Diagnosisofbrucellosismadewithcertainty whenbrucellaerecoveredfromblood bonemarrow orothertissues Rateofisolationfrombloodrangesfrom15 70 dependingonmethodsusedandincubationperiod Whenbrucellosisissuspected Lab shouldbeinformedtomaintainculturesforminimumof4weeks 52 Diagnosis cont d Bonemarrowcultureshavehigheryieldthanblood MostLabs Nowuserapidisolationtechniques e g BACTEC DupontIsolator etc whicharesatisfactoryforrecoveringbrucellae Fasterisolationtimereportedforlysisconcentrationmethod PreliminarystudiesusingPCR withrandomorselectedprimers arepromising butrequireadditionalevaluation 53 Diagnosis cont d Presumptiveidentificationofbrucellaspp Madeonthebasisofmorphologic cultural andsero logicfeatures butconfirmationrequires Oxidativemetabolism Phage typing orgenotypingprocedures Resultsofrapidbacterialidentificationsystemshouldbeinterpretedwithcaution becausesomebrucellaisolatesmisidentifiedasmoraxellaphenylpyruvica 54 Diagnosis cont d Intheabsenceofbacteriologicconfirmation presumptivediagnosismadeonthebasisofhighorrisingtitersofspecificantibodies Varietyofserologictestsappliedtobrucellosis