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Rickettsia,Ehrlichia,Anaplasma,&Borrelia

RachelJ.Gordon,MD,MPHAssistantProfessorofClinicalMedicineandEpidemiology

Vector-borneInfections•  Vector– Ananimal,mostoftenanarthropod,whichpicksupapathogenandtransmitsittoasusceptibleindividual.

•  Reservoir– anecologicalnichewhereapathogenlivesandmultiples(canserveasasourceofinfection)

•  Host– Anorganismthatisinfectedwithorisfeduponbyaparasiticorpathogenicorganism

Case1•  It’sJuneinOklahoma.A12YOboydevelopsfeverandrash.•  Hewasbittenbyatick10daysago.•  Fivedayslaterhedevelopedthesuddenonsetoffever,chills,severeheadache,andmusclepain.•  Hethendevelopedarashthatstartedonhiswristsandanklesandsubsequentlyspreadinwardtocoverhiswholebody.•  Hepresentsinmulti-organsystemfailureanddiesintheemergencyroombeforeantibioticscanbeadministered.

Case1•  ImmunohistochemistryonaskinbiopsyrevealsRickettsiarickettsii

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

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)

                                                                                               

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:

Pathogenesis Diagnosis

• ClinicalSuspicion•  Immunohistochemistryonaskinbiopsy•  Serologictests(IFA)andPCRavailable– resultstaketime

• Cultureandstainingdifficultandnotrecommended

RMSFTreatment•  Doxycycline(atetracycline)•  Useeveninchildren•  DONOTDELAYTREATMENTwhileawaitinglaboratoryconfirmation•  Orelse…

Case2•  AColumbiamedicalstudenttryingtosavemoneyfindsanextra-cheaprentalintheneighborhood•  Shedevelopsalittlebiteonherupperarm•  10dayslatershegetsterribleflu-likesymptoms•  Adiffusemacularrashdevelopsthatbecomespapulovesicular•  Shethinksit’soddthatshehasthechickenpoxagain

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Thebitesiterevealsaneschar: Herhomereveals:mice!

Rickettsialpox

•  Etiology:R.akari•  Transmittedbyamitebite• Reservoir:mice• MostcommonlyrecognizedinNYC

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)

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

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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Epidemiology:Anemergingpathogen(mostcases—occurAprilto

September)

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

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

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

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:

LymeDisease•  Etiology:Borreliaburgdorferi,aGramnegativespirochete•  Themostcommonvector-bornediseaseintheU.S.•  PredominantintheNE•  Vector:Ixodestick—usuallythenymph(mustfeed24+hrs)•  Reservoir:white-footedmousefornymphal/larvalticksandwhite-taileddeerforadultticks•  Peaktransmission:June,July,August

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!)

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

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!

Preventionisthebestmedicine!Preventexposuretothevector!Usebugrepellent,protective

clothing,anddotickchecks!