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10/15/08
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Rickettsia,Ehrlichia,Anaplasma,&Borrelia
RachelJ.Gordon,MD,MPHAssistantProfessorofClinicalMedicineandEpidemiology
Vector-borneInfections• Vector– Ananimal,mostoftenanarthropod,whichpicksupapathogenandtransmitsittoasusceptibleindividual.
• Reservoir– anecologicalnichewhereapathogenlivesandmultiples(canserveasasourceofinfection)
• Host– Anorganismthatisinfectedwithorisfeduponbyaparasiticorpathogenicorganism
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Case1• It’sJuneinOklahoma.A12YOboydevelopsfeverandrash.• Hewasbittenbyatick10daysago.• Fivedayslaterhedevelopedthesuddenonsetoffever,chills,severeheadache,andmusclepain.• Hethendevelopedarashthatstartedonhiswristsandanklesandsubsequentlyspreadinwardtocoverhiswholebody.• Hepresentsinmulti-organsystemfailureanddiesintheemergencyroombeforeantibioticscanbeadministered.
Case1• ImmunohistochemistryonaskinbiopsyrevealsRickettsiarickettsii
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RockyMountainSpottedFever(RMSF)
• CausedbyR.rickettsii,smallGNbacillus• ThemostsevererickettsialdiseaseinU.S.• Transmittedtohumansviatickbite(60%recallabite)• Ixodid(hardticks)areboththereservoirandvectorforRMSF– AmericandogtickorRMwoodtick,dependingonlocation
• Hosts:variousmammals--dependsontickandstageofdevelopment
TickLifecycle
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History
• 1896-RecognizedinSnakeRiverValley,Idaho• “Blackmeasles”killed100s• HowardT.Rickettsdiscoveredthecausativeagent• Rickettsdiedoftyphus(anotherRickettsialdisease)inMexicoin1910
“RockyMountain”isaMisnomer:mostcommoninSE/S.Centralstates
• AlsohaswideGeographicdistributionintheWesternhemisphere
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RMSFinNYCBorough/YR 2004 2005 2006
Manhattan 9 4 10
Bronx 3 1 10
Brooklyn 6 2 3
Queens 5 0 1
StatenIsland 0 0 0
Total 23 7 24
RMSFEpidemiology
• 90%ofcasesoccurMay—September
• Childrenareatthegreatestrisk(2/3cases<15YO)
• Exposuretodogsandresidenceinawooded/highgrassareamayincreaserisk(↑exposuretovector)
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ClinicalPresentation• After~1weekincubation:acuteonsetofflu-likesymptoms(i.e.fever,myalgias,severeheadache,malaise,nausea/vomiting)• 2-5dayslateramacularrashappearsonthewrists/ankles(rashin90-95%)• Rashspreadscentripetally(proximally)andcanbecomemaculopapular(fromedema)petechial(fromhemorrhage)w/otreatment
Late/SevereDisease• Fullbodypetechialrashwithpalm/soleinvolvement• Abdominalandjointpain• Edema,ischemia,hypovolemia,andmulti-organsystemfailure(frommicrovascularinjury)• Labs:hyponatremia,thrombocytopenia,&elevatedliverenzymelevels• Severe/fatalcasesassociatedwith:advancedage,malesex,African-American,chronicalcoholabuse,andglucose-6-phosphatedehydrogenase(G6PD)deficiency
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Pathogenesis
• IntroductionofR.rickettsiiatthebitesite• Travelsvialymphaticstothecirculationwhereitinvadesendothelialcells– OmpA/Bmediateadherence
• Theorganismisengulfed,butescapesthephagosome– PhospholipaseDandtlyClysethemembrane
• Replicationinthecytosolbybinaryfission
Pathogenesis• RickAactivateshostcellactin,whichpushesittothecellsurfaceornucleus– Extracellularrelease(tootherorgansystems)or
– Celltocellspread*• Themajorpathogeniceffectisincreasedvascularpermeabilityresultingfromthedisruptionofjunctionsbetweenendothelialcells.
• R.rickettsiiinendothelialcellsinabloodvesselwall:
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Pathogenesis
Diagnosis
• ClinicalSuspicion• Immunohistochemistryonaskinbiopsy• Serologictests(IFA)andPCRavailable– resultstaketime
• Cultureandstainingdifficultandnotrecommended
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RMSFTreatment• Doxycycline(atetracycline)• Useeveninchildren• DONOTDELAYTREATMENTwhileawaitinglaboratoryconfirmation• Orelse…
Case2• AColumbiamedicalstudenttryingtosavemoneyfindsanextra-cheaprentalintheneighborhood• Shedevelopsalittlebiteonherupperarm• 10dayslatershegetsterribleflu-likesymptoms• Adiffusemacularrashdevelopsthatbecomespapulovesicular• Shethinksit’soddthatshehasthechickenpoxagain
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Rickettsialpox
• Etiology:R.akari• Transmittedbyamitebite• Reservoir:mice• MostcommonlyrecognizedinNYC
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Rickettsialpox
• Clinicalpresentationaspercase• Regionallymphadenopathy• Diagnosisisclinical,butimmunohistochemistyonaskinbiopsymaybeused• Diseaseisself-limitedw/otreatment• Doxycyclinemaybeused
EpidemicTyphus
• R.prowazekii• Vector:humanbodylouse• Reservoir:Humans• Humansinfectedafterscratchinginfectedlousespeciesintothebite• Outbreaksoccurincrowded,unsanitaryconditions
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EpidemicTyphus
EpidemicTyphus
• Seriousillness,~1weekincubation• Fever,myalgia,severeHA,cough• Cetrifugalrash(spreadsoutward),butsparestheface,palms,soles• Multiorgansystemfailure,fatal5-40%• Brill-Zinsserdisease:reactivation(lesssevere)
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Case3• A65YOavidgardenerandgolferwholivesinWestchester,NYpresentsinJunewithfever,myalgias,arthralgias,headache,malaise,andnausea.• Labtests:leukopenia,thrombocytopenia,andelevatedliverenzymes• Doxycyclineisprescribed• PCRispositiveforAnaplasmaphagocytophilumandthereisa4-foldincreaseinconvalescentantibodytiters.
Ehrlichioses• TickborneinfectionscausedbymembersoftheAnaplamataceaefamily• EhrlichiachaffeenisiscausesHumanMonocyticEhrlichiosis(HME)• AnaplasmaphagocytophiliumcausesHumanGranulocyticAnaplasmosis(HGA)• Theseareverysmall,obligateintracellular,Gramnegativebacteriathatgenerallyhaveacoccoidappearance• Theytargeteithermonocytesorgranulocytesandarenamedaccordingly
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Morulae,Latinfor‘mulberry’
Alittlehistory• Ehrlichioses first described by vets • Human ehrlichiosis due to Ehrlichia
chaffeensis was first described in 1987 • HGA:firstrecognized1990– Wisconsinpatient– intraneutrophilic inclusions
• 1994--causative agent (Anaplasmaphagocytophilium)was recognized as distinct from E. chaffeensis
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Average annual reported HGE rate (per 100,000) by age group, in NY and CT, 1995-1997
HME--Epidemiology
• S.Central,SE,mid-Atlanticstates• Vector:Ixodesticks(hardticks)– LoneStartick(Amblyomma americanum)
• Reservoir:white-taileddeer
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HGA--Epidemiology
• NE,mid-Atlantic,UpperMidwest,PacificNWstates+internationally• Vector:Ixodesticks(hardticks)– I.scapularis(akablackleggedtickordeertick)orWesternBlackleggedtick
• Reservoir:smallmammals(esp.white-footedmice)
ClinicalPresentation
• Canbeamildillness/asymptomatictoasevere,fatalinfection(upto3%)• Immunocompromise(HIV,asplenic,onsteroids/chemotherapy)putsatriskformoreseveredisease
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ClinicalPresentation:similartorickettsialdiseases,butlesslikelytogetarash
Pathogenesis
• Stillbeingelucidated*• IntroducedviatickbiteandbindstothecellmembraneoftargetWBC• Internalizedandformclustersinsidecytoplasmicvacuoles—morulae• Keytosurvivalispreventingfusionofthephagosomewiththelysosome
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Somespecifics--PathogenesisHGA
• Msp-2bindstoPSGL-1 (CD162), a receptor on neutrophils/granulocytes
• Bacteria stay in early endosome and acquire nutrients for replication (type 4 secretion apparatus)
• Secretes one protein, AnkA, which binds to nuclear proteins (role unclear)
• Neutrophil function disrupted--including endothelial cell adhesion and transmigration, motility, degranulation, respiratory burst, and phagocytosis.
DiagnosisandTreatment
• Clinicalsuspicion(fever/flusymptoms)inendemicregionduringtickseason• PCR—acutely,diagnostictoolofchoice• Serologic—lookfor4xriseinantibodies– Mostsensitivetest
• Examinationofperipheralbloodformorulae(verylowyield)• Treatment:Doxycycline
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HMEOutbreak
• 1993Outbreakina“Golf-orientedRetirementCommunity”inTN• Wildlifereservenextdoor• 11cases• Increased risk: tick bites, exposure to
wildlife, no insect repellent, golfing, and among golfers, retrieving lost golf balls from the rough
• NEJM Volume 333:420-425; August 17, 1995
Case4• A23YOmancampinginLyme,CTgetsarashthatlookslikethis:
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Case4
• Becausehesmokesalotofmarijuana,heforgetsabouttherash.• Afterafewweeks,helookslikethis:
Case4• Hissymptomsresolvedontheirown,butafewmonthslater,hiskneelookedlikethis:
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LymeDisease• Etiology:Borreliaburgdorferi,aGramnegativespirochete• Themostcommonvector-bornediseaseintheU.S.• PredominantintheNE• Vector:Ixodestick—usuallythenymph(mustfeed24+hrs)• Reservoir:white-footedmousefornymphal/larvalticksandwhite-taileddeerforadultticks• Peaktransmission:June,July,August
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I.scapularis
• TheI.scapularisnymphalticksthatspreadB.burgdorferiareverysmall!
ClinicalPresentation• Local:erythemamigrans– Early:mayalsohavefever,flu-symptoms
• Earlyneurologicdisease:– Meningitisorradiculopathy– Cranialnervepalsy
• Cardiacdisease:– Heartblock,myopericarditis
• LateDisease:– Arthritis,CNSorPNSdisease
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Pathogenesis• B.burgdorferiinoculatedintotheskinatthebitesite,multiples,andspreadsoutwardcausingthecharacteristicrash• OspCvarianthelpsdeterminedissemination• Facilitatinghematogenousspread:– OspAbindsplasminogen– Surfaceproteinsbindingplatelet-specificintegrin
• DbpA&DbpBmediatebindingtodecorin,apeptidoglycanonthesurfaceofcollagen– BindingtocollagenmatrixinECMofjoints,heart,C/PNS
• Othersurfaceproteinsbind:– Heparan&dermatansulfate(endo/epithelialcells)– Fibronectin(anextracellularmatrixprotein)
• HostImmuneResponse
Diagnosis
• Ifthereiserythemamigrans,diagnosiscanbeclinical• Acute/convalescentantibodies• CSFexaminationmaybeindicated– Lymphocytosis,elevatedprotein,normalglucose
• Co-infectionwithHGAandbabesiamayoccur(samevector!)
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History
• 1883-Skinmanifestationsidentifiedby BuchwaldinBreslau,Germany• 1909-ArvidAfzelius,asweedish dermatologist,coinedtheterm ‘erythemamigrans’• 1920s-neurosymptomsidentified• 1930s-connectionmadebetweenEM andneurosymptoms• 1940s-illnessassociatedw/spirochetes
HistoryContinued• 1949-Firsttreatedwithpenicillin• 1970-FirstcaseofEMintheUS• 1975-Outbreakofwhatfirstappeared tobejuvenilerheumatoid arthritisin3SECTtowns includingLymeandOldLyme -HealthDeptfirstcontactedby2mothers-- Polly Morray & Judith Mensch
• 1982-SpirocheteculturedfromShelter Islandticks
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TreatmentEssentials
• Doxycycline(oralternative)forerythemamigrans• OralregimenmayalsobeusedforisolatedBell’spalsy,mildcardiacdisease,arthritis• IVCeftriaxone(3rdgencephalosporin)forheartblock,symptomaticcardiacdisease,otherPNS/CNSdisease
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CommonThemesinthisLecture
• Exposuretovector-reservoir– Timeofyear– Geographiclocation– Possiblehistoryofbite
• Clinicalpresentationofteninvolvesaflu-likeillnessandpossiblyarash• Doxycyclineisoftenthetreatmentofchoice!
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