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LeptospirosisWorkup:ApproachConsiderations,Culture,MicroscopicAgglutinationTesting

LeptospirosisWorkup
Author:SandraGGompf,MD,FACP,FIDSAChiefEditor:MichaelStuartBronze,MDmore...
Updated:Apr14,2015

ApproachConsiderations
Leptospiresgrowslowlyinculture,andrecoveryratesarelow.Serologictestsare
availableonlyinspecializedlaboratories,andthesensitivityofacuteserologictests
islow.Consequently,thosetestsshouldnotbethebasisonwhichtreatmentis
initiated.Inapatientwithcompatiblesymptomsandaplausibleexposurehistory,
empirictherapyshouldbestarted.
Laboratorystudiesareusedfortwopurposes:toconfirmthediagnosisandto
determinetheextentoforganinvolvementandseverityofcomplications.Laboratory
confirmationofleptospirosiscanbeaccomplishedthroughisolationofthepathogen
orbyserologictesting.
Isolationoftheleptospiresfromhumantissueorbodyfluidsisthecriterion
standard.Consultationwiththelocalmicrobiologylaboratoryisessential,because
processingrequiresspecializedtechniques.Urineisthemostreliablebodyfluidto
studybecausetheurinecontainsleptospiresfromtheonsetofclinicalsymptoms
untilatleastthethirdweekofinfection.
Otherbodyfluidscontaintheorganism,butthewindowofopportunitytoisolate
themisshorter.BloodandCSFmayproducepositiveculturesduringthefirst710
daysofsymptoms.
Tissues(ie,liver,muscle,kidney,skin,eyes)arealsosourcesofidentificationofthe
leptospiresbutareobviouslymorecomplicatedtoacquire.Isolationofleptospires
canbedifficultandtimeconsuming,involvingreferencelaboratoriesandoften
takingseveralmonthstocomplete.
Moreoften,pairedacuteandconvalescentserumspecimensareusedtoconfirm
thediagnosis.Again,thisisadelayedmeansofconfirmationbecausetheacute
seraarecollected12weeksafteronsetofsymptoms,andtheconvalescentsera
arecollected2weeksafterward.
Antileptospireantibodiesinthesesamplesaredetectedusingthemicroscopic
agglutinationtest(MAT).TheCentersforDiseaseControlandPrevention(CDC)
laboratoryinAtlanta,Georgia,performstheMATusing23leptospireantigens.A4
foldriseinMATtiterbetweenacuteandconvalescentserawithanyofthese
antigensconfirmsthediagnosisofleptospirosis.
Fasterlaboratorymethodsmaystronglysuggestthediagnosisofleptospirosis,but
theymaybenomorereadilyavailablethantheCDClaboratoryinAtlanta.Asingle
MATtiterof1:800onanyseraoridentificationofspirochetesondarkfield
microscopy,whenaccompaniedbytheappropriateclinicalscenario,isstrongly
suggestive.
Insuspectedleptospirosis,furtherlaboratorystudiesshouldberoutinelyperformed
todeterminetheextentandseverityoforganinvolvementaftertheacutephaseof
illness.Acompletebloodcellcount(CBC)isnecessary.Findingsongeneral
laboratorystudiesareasfollows:
Inpatientswithmilddisease,elevatederythrocytesedimentationratesand
peripheralleukocytosis(3,00026,000x109/L)withaleftshiftarenoted
Significantanemiaduetopulmonaryandgastrointestinalhemorrhagecan
occur
Theplateletcountmaybediminishedasacomponentofdisseminated
intravascularcoagulation(DIC)
levelsofbloodureanitrogenandserumcreatininemaybeprofoundly
elevatedintheanuricoroliguricphase
Serumcreatinekinaselevels(MMfraction)areoftenelevatedinpatients
withmuscularinvolvement.
Coagulationtimesmaybeprolongedinpatientswithhepaticdysfunction
and/orDICOnliverfunctiontesting,serumbilirubinlevelselevateaspartof
theobstructivediseaseduetocapillaritisintheliver.levelsofhepatocellular
transaminasesareelevatedlessoftenandlesssignificantly(usually<200
U/L).Jaundiceandbilirubinemiadisproportionaltohepatocellulardamageis
commoninleptospirosisalkalinephosphataselevelsmaybeelevated10
fold.
Onurinalysis,proteinuriamaybepresent.Leukocytes,erythrocytes,hyalinecasts,
andgranularcastsmaybepresentintheurinarysediment.
AnalysisoftheCSFisusefulonlyinexcludingothercausesofbacterialmeningitis.
WhentheCNSbecomesinvolvedinleptospirosis,polymorphonuclearleukocytes
initiallypredominateandarelaterreplacedbymonocytes.CSFproteinmaybe
normalorelevated,whereasglucoselevelsremainnormal.CSFpressureisnormal,
butalumbarpuncturecanrelievetheheadache.Leptospiresareroutinelyisolated
fromtheCSF,butthisfindingdoesnotchangemanagementofthedisease.
Imagingstudiesareusefulindeterminingtheextentandseverityoforgan
involvement.Thismayincludechestradiographytoevaluatelungdiseaseand
biliarytractultrasonographyinsuspectedacalculouscholecystitis.
Electrocardiographic(ECG)abnormalitiesarecommonduringtheleptospiremic
phaseofWeilsyndrome.Inseverecases,congestiveheartfailureandcardiogenic

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shockmayoccur.

Culture
Isolatingtheorganismbycultureallowsdefinitivediagnosis.Leptospiresremain
viableinanticoagulatedbloodforaslongas11dayshence,specimenscanbe
mailedtoareferencelaboratoryforculture.Theinfectingserovarcanbeisolated
onlybyculture.
Bloodculturesmaybenegativeifdrawntooearlyortoolate.Leptospiresmaynot
bedetectedintheblooduntil4daysaftertheonsetofsymptoms(714dafter
exposure).Oncetheimmunesystemisactivated,bloodculturesmayagainbecome
negative.Leptospiresmaybeisolatedfromthecerebrospinalfluid(CSF)withinthe
first10days.
Leptospiresmaybeisolatedfromtheurineforseveralweeksaftertheinitial
infection.Insomepatients,urineculturesmayremainpositiveformonthsoryears
aftertheonsetofillness.Positiveurineculturesmaytakeaslongas8weeksto
grow.

MicroscopicAgglutinationTesting
Microscopicagglutinationtesting(MAT)usesabatteryofantigenstakenfrom
common(frequentlylocallyendemic)leptospireserovars.MATisavailableonlyat
referencelaboratories,suchastheCentersforDiseaseControlandPrevention
(CDC).
Inapatientwithclinicalfindingsconsistentwiththedisease,asingletiterexceeding
1:200orserialtitersexceeding1:100suggestleptospirosishowever,neitheris
diagnostic.A4foldriseintiterbetweenacuteandconvalescentspecimensis
consideredapositiveresult.Theantibodyresponsedoesnotreachdetectablelevels
untilthesecondweekofillness,anditcanbeaffectedbytreatment.
FalsenegativeMATfindingsmayresultfromtestingasinglespecimenobtained
beforetheimmunephaseofdisease.Testaccuracyisalsoaffectedbyappropriate
selectionofantigensforthebattery,necessitatingdiscussionwiththelaboratory
aboutwhichserovarsaresuspectedorpredominateintheregionwherethecase
originated.FalsepositiveMATresultsmayoccurwithcasesofLegionellainfection,
Lymedisease,andsyphilis.

OtherTests
Screeningtestsforleptospirosis,whichareeasytoperformandprovideresults
relativelyrapidly,includethemacroscopicslideagglutinationtest,thePatocslide
agglutinationtest,themicrocapsuleagglutinationtest,latexagglutinationtests,
dipsticktests,andtheindirecthemagglutinationtest.Confirmationofscreeningtest
results(positiveornegative)isadvisable,however,preferablywithMAT. [40]
AnimmunoglobulinM(IgM)enzymelinkedimmunoabsorbentassay(ELISA)has
beendeveloped.TheELISAusesabroadlyreactiveantigenandisastandard
serologicprocedure,asistheMAT. [41]BecauseitdetectsIgM,itmaybeusefulfor
diagnosisofnewinfectionswithin35days.Positiveresultsshouldbereferredfor
confirmatorytesting.
Nucleicacidamplification(polymerasechainreaction[PCR])basedtechniques
havebeendevelopedtodiagnoseleptospirosis.PCRcanconfirmthediagnosis
rapidlyduringtheearlyphaseofthedisease,whenleptospiresmaybepresentand
beforeantibodytitersaredetectable,butitrequiresadequateinfrastructuresuchas
appropriateequipment,laboratoryspace,andskilledpersonnel.Inaddition,PCR
basedtechniquesareunabletoidentifytheinfectingserovar,whichreducetheir
epidemiologicandpublichealthvalue.
Darkfieldexaminationofbloodorurinehasbeenusedtoidentifyleptospires.
However,thistechniquecannotberecommended,asitfrequentlyleadsto
misdiagnosis.

ChestRadiography
Themostcommonabnormalityonchestradiographyisbilateraldiffuseairspace
disease.Chestradiographymayalsorevealcardiomegalyandpulmonaryedema
duetomyocarditis.Inpatientswithalveolarhemorrhageduetopulmonary
capillaritis,thelungparenchymamaycontainmultiplepatchyinfiltrates.

HistologicFindings
Shortlyafterinoculationandduringtheincubationperiod,leptospiresactively
replicateintheliver.Theleptospiresthendisseminatethroughoutthebodyand
infectmultipletissues.
Silverstainingandimmunofluorescencecanidentifyleptospiresintheliver,spleen,
kidney,CNS,muscles,andheart.Duringtheacutephaseofleptospirosis,histology
revealstheseorganismswithoutmuchinflammatoryinfiltrate.Inadditiontothe
findingofleptospiresduringhistologicexamination,thepathologiceffectsof
leptospiraltoxinsarealsoapparent.Seetheimagebelow.

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LeptospirosisWorkup:ApproachConsiderations,Culture,MicroscopicAgglutinationTesting

Silverstain,liver,fatalhumanleptospirosis.(Thisimageisinthepublicdomainandthusfreeof
anycopyrightrestrictions.CourtesyoftheCentersforDiseaseControl/Dr.MartinHicklin)

Leptospirosismaybeseenasaninfectivesystemicvasculitis. [18]Leptospiraltoxins
breakdownendothelialcellmembranesofcapillaries.Thistoxinmediatedprocess
allowsforextravasationofbloodandleptospiresfrombloodvesselsintothe
supportedparenchyma.Secondarily,becausethecapillariesarenolonger
functional,ischemiaandcelldeathcanoccur.Laterininfection,mononuclearcells
predominateintheareasofthisfocalcellnecrosis.
Leptospirescanbeidentifiedinimmunologicallyprivilegedsites,suchasrenal
tubules,CNS,andtheanteriorchamberoftheeyes,forweekstomonthsafterthe
initialinfection.Innonhumananimals,theintendedhostsofinfection,the
leptospiresestablishresidenceintheseimmunologicallyprivilegedsites.Provided
thattheanimalsurvivestheinitialinfection,achroniccarrierstateisthen
established,andhistologyrevealsleptospiresatthesesitesforyearsafterinitial
infection.
Treatment&Management

ContributorInformationandDisclosures
Author
SandraGGompf,MD,FACP,FIDSAAssociateProfessorofInfectiousDiseasesandInternationalMedicine,
UniversityofSouthFloridaCollegeofMedicineChief,InfectiousDiseasesSection,Director,Occupational
HealthandInfectionControlPrograms,JamesAHaleyVeteransHospital
SandraGGompf,MD,FACP,FIDSAisamemberofthefollowingmedicalsocieties:AmericanCollegeof
Physicians,InfectiousDiseasesSocietyofAmerica
Disclosure:Nothingtodisclose.
Coauthor(s)
JudithGreenMcKenzie,MD,MPH,FACP,FACOEMAssociateProfessor,DirectorofClinicalPractice,
OccupationalMedicineResidencyDirector,UniversityofPennsylvaniaSchoolofMedicine
JudithGreenMcKenzie,MD,MPH,FACP,FACOEMisamemberofthefollowingmedicalsocieties:American
CollegeofPhysicians,AmericanCollegeofPreventiveMedicine,NationalMedicalAssociation,American
CollegeofOccupationalandEnvironmentalMedicine
Disclosure:Nothingtodisclose.
AnaPaulaVelez,MDAssistantProfessorofMedicine,DivisionofInfectiousDiseaseandInternational
Medicine,UniversityofSouthFloridaCollegeofMedicineandJamesAHaleyVeteransAffairsMedicalCenter
AttendingPhysician,MoffittCancerCenter
AnaPaulaVelez,MDisamemberofthefollowingmedicalsocieties:AmericanCollegeofPhysiciansAmerican
SocietyofInternalMedicine,AmericanMedicalAssociation,InfectiousDiseasesSocietyofAmerica
Disclosure:Nothingtodisclose.
ChiefEditor
MichaelStuartBronze,MDDavidRossBoydProfessorandChairman,DepartmentofMedicine,StewartG
WolfEndowedChairinInternalMedicine,DepartmentofMedicine,UniversityofOklahomaHealthScience
CenterMasteroftheAmericanCollegeofPhysiciansFellow,InfectiousDiseasesSocietyofAmerica
MichaelStuartBronze,MDisamemberofthefollowingmedicalsocieties:AlphaOmegaAlpha,American
MedicalAssociation,OklahomaStateMedicalAssociation,SouthernSocietyforClinicalInvestigation,
AssociationofProfessorsofMedicine,AmericanCollegeofPhysicians,InfectiousDiseasesSocietyofAmerica
Disclosure:Nothingtodisclose.
Acknowledgements
DeniseDemers,MD,FAAPAssistantProfessorofPediatrics,UniformedServicesUniversityoftheHealth
SciencesAttendingPhysician,DivisionofPediatricInfectiousDiseases,DepartmentofPediatrics,TriplerArmy
MedicalCenter
Disclosure:Nothingtodisclose.
JuanDDiaz,DOFellowinInfectiousDiseases,UniversityofSouthFloridaCollegeofMedicine,TampaGeneral
Hospital,andJamesAHaleyVeteransHospital
Disclosure:Nothingtodisclose.
JosephDomachowske,MDProfessorofPediatrics,MicrobiologyandImmunology,DepartmentofPediatrics,
DivisionofInfectiousDiseases,StateUniversityofNewYorkUpstateMedicalUniversity
JosephDomachowske,MDisamemberofthefollowingmedicalsocieties:AlphaOmegaAlpha,American
AcademyofPediatrics,AmericanSocietyforMicrobiology,InfectiousDiseasesSocietyofAmerica,Pediatric
InfectiousDiseasesSociety,andPhiBetaKappa

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Disclosure:Nothingtodisclose.
PatrickWHickey,MD,FAAPAssistantProfessorofPediatricsandPreventiveMedicine,UniformedServices
UniversityoftheHealthSciencesConsultingStaff,DepartmentofPediatrics,DivisionofPediatricInfectious
Disease,WalterReedArmyMedicalCenter
PatrickWHickey,MD,FAAPisamemberofthefollowingmedicalsocieties:AlphaOmegaAlpha,American
AcademyofPediatrics,AmericanSocietyofTropicalMedicineandHygiene,InfectiousDiseasesSocietyof
America,InternationalSocietyofTravelMedicine,andPediatricInfectiousDiseasesSociety
Disclosure:Nothingtodisclose.
EdmondAHookerII,MD,DrPH,FAAEMAssistantProfessor,DepartmentofEmergencyMedicine,University
ofCincinnatiCollegeofMedicineAssociateProfessor,DepartmentofHealthServicesAdministration,Xavier
University
EdmondAHookerII,MD,DrPH,FAAEMisamemberofthefollowingmedicalsocieties:AmericanAcademyof
EmergencyMedicine,AmericanPublicHealthAssociation,SocietyforAcademicEmergencyMedicine,and
SouthernMedicalAssociation
Disclosure:Nothingtodisclose.
MatthewRJezior,MDFellow,DepartmentofCardiology,WalterReedMedicalCenter
Disclosure:Nothingtodisclose.
MariaDMileno,MDAssociateProfessorofMedicine,DivisionofInfectiousDiseases,TheWarrenAlpert
MedicalSchoolofBrownUniversity
MariaDMileno,MDisamemberofthefollowingmedicalsocieties:AlphaOmegaAlpha,AmericanCollegeof
Physicians,AmericanSocietyofTropicalMedicineandHygiene,InfectiousDiseasesSocietyofAmerica,
InternationalSocietyofTravelMedicine,andSigmaXi
Disclosure:Nothingtodisclose.
JosephTMorris,MDChiefofInfectiousDiseaseService,MadiganArmyMedicalCenterAssistantProfessor,
DepartmentofInternalMedicine,UniformedServicesUniversityoftheHealthSciences
Disclosure:Nothingtodisclose.
GaryJNoel,MDProfessor,DepartmentofPediatrics,WeillCornellMedicalCollegeAttendingPediatrician,
NewYorkPresbyterianHospital
GaryJNoel,MDisamemberofthefollowingmedicalsocieties:PediatricInfectiousDiseasesSociety
Disclosure:Nothingtodisclose.
CecilyKPeterson,MDProgramDirector,ClinicalFaculty,DepartmentofMedicine,MadiganArmyMedical
Center
Disclosure:Nothingtodisclose.
CharlesVSanders,MDEdgarHullProfessorandChairman,DepartmentofInternalMedicine,Professorof
Microbiology,ImmunologyandParasitology,LouisianaStateUniversitySchoolofMedicineatNewOrleans
MedicalDirector,MedicineHospitalCenter,CharityHospitalandMedicalCenterofLouisianaatNewOrleans
ConsultingStaff,OchsnerMedicalCenter
CharlesVSanders,MDisamemberofthefollowingmedicalsocieties:AllianceforthePrudentUseof
Antibiotics,AlphaOmegaAlpha,AmericanAssociationfortheAdvancementofScience,AmericanAssociation
ofUniversityProfessors,AmericanClinicalandClimatologicalAssociation,AmericanCollegeofPhysician
Executives,AmericanCollegeofPhysicians,AmericanFederationforMedicalResearch,AmericanFoundation
forAIDSResearch,AmericanGeriatricsSociety,AmericanLungAssociation,AmericanMedicalAssociation,
AmericanSocietyforMicrobiology,AmericanThoracicSociety,AmericanVenerealDiseaseAssociation,
AssociationforProfessionalsinInfectionControlandEpidemiology,AssociationofAmericanMedicalColleges,
AssociationofAmericanPhysicians,AssociationofProfessorsofMedicine,InfectiousDiseaseSocietyfor
ObstetricsandGynecology,InfectiousDiseasesSocietyofAmerica,LouisianaStateMedicalSociety,Orleans
ParishMedicalSociety,RoyalSocietyofMedicine,SigmaXi,SocietyofGeneralInternalMedicine,
SoutheasternClinicalClub,SouthernMedicalAssociation,SouthernSocietyforClinicalInvestigation,and
SouthwesternAssociationofClinicalMicrobiology
Disclosure:Nothingtodisclose.
WilliamHShoff,MD,DTM&HDirector,PENNTravelMedicineAssociateProfessor,DepartmentofEmergency
Medicine,HospitaloftheUniversityofPennsylvania,UniversityofPennsylvaniaSchoolofMedicine
WilliamHShoff,MD,DTM&Hisamemberofthefollowingmedicalsocieties:AmericanCollegeofPhysicians,
AmericanSocietyofTropicalMedicineandHygiene,InternationalSocietyofTravelMedicine,Societyfor
AcademicEmergencyMedicine,andWildernessMedicalSociety
Disclosure:Nothingtodisclose.
RussellWSteele,MDHead,DivisionofPediatricInfectiousDiseases,OchsnerChildren'sHealthCenter
ClinicalProfessor,DepartmentofPediatrics,TulaneUniversitySchoolofMedicine
RussellWSteele,MDisamemberofthefollowingmedicalsocieties:AmericanAcademyofPediatrics,
AmericanAssociationofImmunologists,AmericanPediatricSociety,AmericanSocietyforMicrobiology,
InfectiousDiseasesSocietyofAmerica,LouisianaStateMedicalSociety,PediatricInfectiousDiseasesSociety,
SocietyforPediatricResearch,andSouthernMedicalAssociation
Disclosure:Nothingtodisclose.
FranciscoTalavera,PharmD,PhDAdjunctAssistantProfessor,UniversityofNebraskaMedicalCenterCollege
ofPharmacyEditorinChief,MedscapeDrugReference
Disclosure:MedscapeSalaryEmployment
Jeter(Jay)PritchardTaylorIII,MDComplianceOfficer,AttendingPhysician,EmergencyMedicineResidency,
DepartmentofEmergencyMedicine,PalmettoHealthRichland,UniversityofSouthCarolinaSchoolofMedicine
MedicalDirector,DepartmentofEmergencyMedicine,PalmettoHealthBaptist
Jeter(Jay)PritchardTaylorIII,MDisamemberofthefollowingmedicalsocieties:AmericanAcademyof

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EmergencyMedicine,AmericanCollegeofEmergencyPhysicians,AmericanMedicalAssociation,andSociety
forAcademicEmergencyMedicine
Disclosure:Nothingtodisclose.
MaryLWindle,PharmDAdjunctAssociateProfessor,UniversityofNebraskaMedicalCenterCollegeof
PharmacyEditorinChief,MedscapeDrugReference
Disclosure:Nothingtodisclose.

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