Diagnostic criteria and problems in infective endocarditis | Heart

The pathological hallmark of endocarditis is the demonstration of inflammatory changes in valvar tissue and/or vegetations, characteristically at the site of ... Skiptomaincontent YouarehereHome Archive Volume90, Issue6 Diagnosticcriteriaandproblemsininfectiveendocarditis Emailalerts ArticleText Articlemenu ArticleText Articleinfo CitationTools Share RapidResponses Articlemetrics Alerts PDF Mini-symposium DiagnosticcriteriaandproblemsininfectiveendocarditisFree BDPrendergastCorrespondenceto:DrBernardDPrendergastNorth-WestRegionalCardiothoracicCentre,WythenshaweHospital,SouthmoorRoad,ManchesterM239LT,UK;bernard.prendergastsmuht.nwest.nhs.uk http://dx.doi.org/10.1136/hrt.2003.029850 StatisticsfromAltmetric.com infectiveendocarditisDukecriteriaStaphylococcusaureusCoxiellaburnetti Fewdiseasespresentgreaterdifficultiesinthewayofdiagnosisthanmalignantendocarditis,difficultieswhichinmanycasesarepracticallyinsurmountable.Itisnodisparagementtothemanyskilledphysicianswhohaveputtheircasesuponrecordtosaythat,infullyone-halfthediagnosiswasmadepostmortem.—WilliamOsler1885 Osler’sportentouswordsareasrelevantnowaswhenoriginallypublished.Despiteimprovedpreventivestrategies,rationalantibioticprescribing,advancesinimaging,andincreasinguseofearlylifesavingcardiacsurgery,theincidenceofinfectiveendocarditisremainshighat1.7–6.2per100000personyearsintheUSAandEurope,withaoneyearmortalityapproaching40%.1Theclassicalpatientwithinfectiveendocarditisdescribedintextbooksnolongerrepresentsthemajorityofcasesinpractice.Theemergenceofstaphylococcalinfection,oftenassociatedwithindwellingdevices,co-existentmedicalconditionsandresistanttoconventionalantibioticregimes,avarietyofotheratypicalorganisms,andthepersistentsyndromeofculturenegativeendocarditismakediagnosisandtreatmentasgreatachallengeasever. DIAGNOSTICCRITERIAANDTHEIRLIMITATIONS TheoriginalvonReyndiagnosticcriteriaforinfectiveendocarditis,2baseduponclinicalandmicrobiologicalfeatures,havenowbeensurpassedbytheDukecriteria3whichemphasisetheroleofechocardiography,thekeyimagingtoolforbothdiagnosisandassessmentofprognosis.ManystudieshavenowdemonstratedthesuperiorityoftheDukecriteriaandarecentscientificstatementoftheAmericanHeartAssociationconcludedthattheyshouldbeadoptedastheprimarydiagnosticschemaintheclinicalevaluationofpatientsinwhominfectiveendocarditisissuspected.4Nevertheless,cleardeficienciesremain.Thus,inoneseries5of93patientswithpathologicallyconfirmedinfectiveendocarditis(affectinganativevalvein63andaprostheticvalveintheremainder),22weremisclassifiedas“possible”casesusingtheDukecriteria,yieldingasensitivityofonly76%.Echocardiographicmajorcriteriawerepresentin19patientsbutbloodcultureswerenegativein21.Thecauseofnegativebloodcultureswaspriorantibiotictreatmentin11patientsandQfeverendocarditisdetectedbypositiveserologyinthree.TheDukecriteriahavealsobeenshowntobeoflowervalueinotherimportantpatientgroups,includingthosewithinfectionaffectingaprostheticvalveorpacemakerleadandtherightheartindrugabusingpatients. CULTURENEGATIVEINFECTIVEENDOCARDITISANDATYPICALORGANISMS Negativebloodculturesoccurin2.5–31%ofallcasesofinfectiveendocarditis,oftendelayingdiagnosisandtheonsetoftreatmentwithprofoundimpactonclinicaloutcome.Moreover,thesensitivityoftheDukecriteria,whichrelyheavilyonmicrobiologicalindices,isdiminishedinthissetting.Negativeculturesarisemostcommonlyasaconsequenceofpriorantibioticadministration,butanincreasinglycommonscenarioisinfectionbyfastidiousorganismswithlimitedproliferationunderconventionalcultureconditions,orrequiringspecialisedtoolsforidentification.SuchpathogensincludeCoxiella,Legionella,theHACEKgroup(Haemophilusspecies,Actinobacillusactinomycetemcomitans,Cardiobacteriumhominis,Eikenellacorrodens,andKingellakingae),Chlamydia,Bartonella,Tropherymawhippelii,andfungi,includingCandida,Histoplasma,andAspergillusspecies,andTorulopsisglabrata.Theseorganismsmaybeparticularlycommonincasesofinfectiveendocarditisaffectingpatientswithprostheticvalves,indwellingvenouslines,pacemakers,renalfailure,andimmunocompromisedstates. MODIFIEDCRITERIAANDNEWDIAGNOSTICTECHNIQUES In1997,LamasandEykynproposedanumberofclinicalmodificationstotheDukecriteriatoincludenewlydiagnosedsplenomegalyorclubbing,elevatedinflammatorymarkers,haematuria,andthepresenceofcentralandperipheralvenouslines(“theStThomasmodifications”).6Simultaneously,recognitionoftheroleofQfever,aworldwidezoonosiscausedbyCoxiellaburnettiandaparticularlyfrequentcauseofinfectiveendocarditisinFrance,increasingprevalenceofstaphylococcalinfection,andwidespreaduseoftransoesophagealechocardiographyresultedinfurthermodifications;theseinvolvedincorporatingtheacceptanceofpositiveQfeverserologyorbacteraemiacausedbyStaphylococcusaureus(regardlessofitssource)asmajorcriteriaandtheeliminationofminorechocardiographiccriteria(table1).7,8Arecentstudycomparedthesemodificationsinpathologicallyprovenyetculturenegativecases.9Only21%wereclassifiedasdefinitebytheoriginalDukecriteria,while32%weredefinitebythemodifiedDukecriteria,andtheStThomasmodificationsclassified62%correctly.Interestingly,thefouradditionalcasesidentifiedcorrectlybythemodifiedDukecriteriawereupgradedonaccountofpositiveQfeverserology.Furthermore,carefulscrutinyledtoidentificationofthecausativeorganisminalmost50%ofculturenegativecases,achievedbyserology(Cburnetti,Bartonella,Chlamydiapsittaci)in24%,cultureoftheexcisedvalvein14%,microscopyoftheexcisedvalvein5%,andnon-valveculturein6%.Viewthistable:Viewinline Viewpopup Table1 Dukecriteriaforthediagnosisofinfectiveendocarditisandproposedmodifications Histological/immunologicaltechniques HistologicalfindingsareincludedintheDukeandvonReyndiagnosticcriteriaandpathologicalexaminationofresectedvalvartissueorembolicfragmentsremainsthegoldstandardforthediagnosisofinfectiveendocarditis.Pathologicalexaminationmayalsoguideantimicrobialtreatmentifthecausativeagentcanbeidentifiedbymeansofspecialstainsorimmunohistologicaltechniques,andallowdistinctionfromconditionswhoseechocardiographicfeaturesmimicinfectiveendocarditis(forexample,myxomas,fibroelastomas,andrheumatoidnodules).Itshouldbenotedthatspecimensarepotentiallyinfectioustotheexaminer,particularlywhenQfeverissuspected.Thepathologicalhallmarkofendocarditisisthedemonstrationofinflammatorychangesinvalvartissueand/orvegetations,characteristicallyatthesiteofattachmentorbaseofavegetation.Thisfindingisnotspecific,however,andinflammationisalsoafeatureofdegenerativeandothervalvepathology.Electronmicroscopyhashighsensitivityandmayhelptocharacterisenewmicroorganisms.However,itistimeconsumingandexpensiveandthereforereservedforcasesinwhichothertechniquesfailtodetectanorganism.Histologicalcriteriaforthediagnosisofendocarditishavebeenproposed(table2)andavarietyofspecialisedstainsandimmunohistologicaltechniques(immunoperoxidasestaining,enzymelinkedimmunosorbent(ELISA)andimmunofluorescent(ELIFA)assays,anddirectimmunofluorescenceusingfluoresceinconjugatedmonoclonalantibodies)arenowavailabletoallowtheidentificationofelusivebacteriaandfungi(table3).10,11CburnettiandBartonellaspeciesarethemostcommonaetiologicalagentsinculturenegativeendocarditisandmaybeeasilydetectedbyserologicaltestingusingindirectimmunofluorescenceorELISA.ImmunologicalanalysisofurinemayalsoallowdetectionofmicroorganismdegradationproductsandELISAdetectionofLegionellaspecieshasbeendescribedusingthistechnique.However,theincorporationofthesetechniquesintoaccepteddiagnosticcriteriaawaitsprospectivevalidation.Viewthistable:Viewinline Viewpopup Table2 Proposedhistologicalcriteriafordiagnosisofinfectiveendocarditis Viewthistable:Viewinline Viewpopup Table3 Mainhistologicalstainsusedforthediagnosisofinfectiveendocarditis Moleculartechniques Severalmolecularapproacheshavebeenassessedforthedetectionandidentificationofpathogensinawidevarietyofinfectiousdiseases.Thepolymerasechainreaction(PCR)utilisingnucleicacidtargetorsignalamplification,aloneorincombinationwithsequenceanalysis,ismostwidelyusedandallowsrapidandreliabledetectionoffastidiousandnon-culturableagentsinbloodandsurgicalmaterialofpatientswithinfectiveendocarditis.12Itmayalsobeofvaluewhenphenotypiccharacterisationisessentialfollowingisolationoftwoormoreorganismsinseparatecultures(mostcommonlycausedbycontaminationwithskincommensalsduringsamplingorpolymicrobialinfectioninintravenousdrugabusers).Indeed,theincorporationofsuchtechniquesasamajorDukediagnosticcriterionhasbeenproposedwithwidespreadsupport.13SpecificprimersarenowavailableformanybacterialagentsincludingTwhippelii,Cburnetti,andspeciesofBartonella,Chlamydia,Brucella,Legionella,Mycobacteria,andMycoplasma.FutureimprovementsincludethepossibilityofquantitationbyrealtimePCReliminatingtheneedforgelelectrophoresiswithfaster,moreaccurateresults,andthepossibilityofinvestigatingcommonantimicrobialresistancegenesenablingatargetedapproachtoantibiotictreatment.14 Inarecentvalidationstudyofthesemolecularmethods,Grijalvaandcolleagues15reportedtheinvestigationofvalvarspecimensof15patientswithdefinite,thoughculturenegative,infectiveendocarditisundergoingsurgery.Thecausativeorganismwasidentifiedin14(93%)oftheculturenegativecases(streptococci3,staphylococci2,enterobacter1,Twhippelii1,Borreliaburgdorferi1,Candidaalbicans1,Aspergillusspecies2,unspecified3)while13matchedcontrolsyieldednegativeresults.Analysiswascompletewithin8hoursandwithin48hoursifsequencingwasrequired. PROPOSEDAPPROACH Optimalantisepticskinpreparationisimportantandatleast10mlofblood(lessinchildren)shouldbeobtainedforeachculture.Bacteraemiaisusuallycontinuousandthereisnorationalefortimingbloodculturestocoincidewithpeaksofpyrexia.Ifthereisahistoryofpriorantibiotictreatment,maximumdiagnosticyieldmaybeachievedbydilutingtheculturebrothandconsideringtheuseofsodiumpolyanetholsulfonateoradedicatedadsorbentresin,bothofwhichinactivateantimicrobialeffects.Multipleseparatebloodculturesarerequiredandmostguidelinesrecommendatleasttwo,andmostusuallythreesets.Althoughendocarditiscausedbyanaerobesisuncommon,bloodculturesshouldbeincubatedinbothaerobicandanaerobicatmospherestodetectorganismssuchasBacteroidesorClostridiumspecies. Ifallbloodculturesremainnegativeatfivedaysbutinfectiveendocarditisremainslikelyonclinicalgrounds,subcultureontochocolateagarplatesmayallowidentificationofanatypicalorganism,althoughprolongedcultureforupto2–3weeksisassociatedwithrisinglikelihoodofcontamination.Atthisstage,therefore,serumshouldbeanalysedforantibodiestoorganismsthatcannotbeculturedbyroutinemethods,and,ifavailable,antibodiestoGrampositivebacterialcellwalls.Excisedvalves,vegetationsorotherrelevantmaterialshouldundergomicroscopy,culture,histopathology,andrelevantmoleculartechniques(usuallyPCR)whichcanalsobeappliedtonewlyacquiredbloodsamplesortheoriginalgrowthnegativebloodculturesubstrate. CONCLUSIONS Todate,definitivestudiesofinfectiveendocarditishavebeendifficulttoperformbecauseofitsheterogenousnature.Launchedin1999,theInternationalCollaborationonEndocarditiswasconceivedtodevelopalargeglobaldatabaseofpatientswhoseclinical,echocardiographic,andmicrobiologicalfindingshavebeencharacterisedusingstandardmethodology.Theassociatednetworkofinvestigatorsandorganisationalinfrastructurewillprovidetheplatformforlargerandomisedtrialstotesttherapeuticstrategies.16Thisresourceofferstheopportunityformajoradvancesinourunderstandingandtreatmentofinfectiveendocarditisoverthenexttwodecades. ModificationoftheoriginalDukecriteriaisnowproposedtoenhancediagnosticsensitivity,especiallyinculturenegativecases.Increasedemphasisonsymptomsandsigns6coupledwithimprovedlikelihoodofidentificationofacausativepathogenusingserology,7,8additionalculture,11ornewerhistological10,11andmoleculartechniques12,13willimprovethesensitivityofthediagnosisandincreasetherapeuticspecificity.Thesemeasures,combinedwithclosecollaborationandcommunicationbetweenthecardiologist,cardiacsurgeon,andmicrobiologist,areessentialtoensureoptimaldiagnosisandmanagementandafavourableimpactonpatientoutcome. 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