Lyme disease - Wikipedia

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Lyme disease, also known as Lyme borreliosis, is a vector-borne disease caused by the Borrelia bacterium which is spread by ticks in the genus Ixodes. Lymedisease FromWikipedia,thefreeencyclopedia Jumptonavigation Jumptosearch InfectiousdiseasecausedbyBorreliabacteria,spreadbyticks Nottobeconfusedwithphytophotodermatitis,alsoknownas"limedisease". MedicalconditionLymediseaseOthernamesLymeborreliosisAnadultdeertick(mostcasesofLymearecausedbynymphalratherthanadultticks)SpecialtyInfectiousdiseaseSymptomsExpandingareaofrednessatthesiteofatickbite,fever,headache,tiredness[1]ComplicationsFacialnerveparalysis,arthritis,meningitis[1]UsualonsetAweekafterabite[1]CausesBorreliaspreadbyticks[2]DiagnosticmethodBasedonsymptoms,tickexposure,bloodtests[3]PreventionPreventionoftickbites(clothingthelimbs,DEET),doxycycline[2]MedicationDoxycycline,amoxicillin,ceftriaxone,cefuroxime[2]Frequency~476,000peryearinU.S.(2010-2018)[4][5] Lymedisease,alsoknownasLymeborreliosis,isavector-bornediseasecausedbytheBorreliabacteriumwhichisspreadbyticksinthegenusIxodes.[2][6][7]Themostcommonsignofinfectionisanexpandingredrash,knownaserythemamigrans,thatappearsatthesiteofthetickbiteaboutaweekafteritoccurred.[1]Therashistypicallyneitheritchynorpainful.[1]Approximately70–80%ofinfectedpeopledeveloparash.[1]Earlydiagnosiscanbedifficult.[8]Otherearlysymptomsmayincludefever,headache,andtiredness.[1]Ifuntreated,symptomsmayincludelossoftheabilitytomoveoneorbothsidesoftheface,jointpains,severeheadacheswithneckstiffness,orheartpalpitations,amongothers.[1]Monthstoyearslater,repeatedepisodesofjointpainandswellingmayoccur.[1]Occasionally,peopledevelopshootingpainsortinglingintheirarmsandlegs.[1]Despiteappropriatetreatment,about10to20%ofpeopledevelopjointpains,memoryproblems,andtirednessforatleastsixmonths.[1][9] LymediseaseistransmittedtohumansbythebitesofinfectedticksofthegenusIxodes.[10]IntheUnitedStates,ticksofconcernareusuallyoftheIxodesscapularistypeandmustbeattachedforatleast36hoursbeforethebacteriacanspread.[11][12]InEurope,Ixodesricinusticksmayspreadthebacteriamorequickly.[12][13]InNorthAmerica,thebacteriaBorreliaburgdorferi,B.bissettiae,andB.mayoniicauseLymedisease.[2][14][7]InEuropeandAsia,Borreliaafzelii,Borreliagarinii,B.spielmanii,and4otherspeciesalsocausethedisease.[2]Thediseasedoesnotappeartobetransmissiblebetweenpeople,byotheranimals,orthroughfood.[11]Diagnosisisbaseduponacombinationofsymptoms,historyoftickexposure,andpossiblytestingforspecificantibodiesintheblood.[3][15]Bloodtestsareoftennegativeintheearlystagesofthedisease.[2]Testingofindividualticksisnottypicallyuseful.[16] Preventionincludeseffortstopreventtickbitesbywearingclothingtocoverthearmsandlegs,andusingDEETorpicaridin-basedinsectrepellents.[2][6]Usingpesticidestoreduceticknumbersmayalsobeeffective.[2]Tickscanberemovedusingtweezers.[17]Iftheremovedtickwasfullofblood,asingledoseofdoxycyclinemaybeusedtopreventthedevelopmentofinfection,butisnotgenerallyrecommendedsincethedevelopmentofinfectionisrare.[2]Ifaninfectiondevelops,anumberofantibioticsareeffective,includingdoxycycline,amoxicillin,andcefuroxime.[2]Standardtreatmentusuallylastsfortwoorthreeweeks.[2]Somepeopledevelopafeverandmuscleandjointpainsfromtreatmentwhichmaylastforoneortwodays.[2]Inthosewhodeveloppersistentsymptoms,long-termantibiotictherapyhasnotbeenfoundtobeuseful.[2][18] LymediseaseisthemostcommondiseasespreadbyticksintheNorthernHemisphere.[19]Itisestimatedtoaffect300,000peopleayearintheUnitedStatesand65,000peopleayearinEurope.[2][20]Infectionsaremostcommoninthespringandearlysummer.[2]Lymediseasewasdiagnosedasaseparateconditionforthefirsttimein1975inLyme,Connecticut.[21]Itwasoriginallymistakenforjuvenilerheumatoidarthritis.[22]Thebacteriuminvolvedwasfirstdescribedin1981byWillyBurgdorfer.[23]Chronicsymptomsfollowingtreatmentarewelldescribedandareknownas"post-treatmentLymediseasesyndrome"(PTLDS).[18]PTLDSisdifferentfromchronicLymedisease,atermnolongersupportedbythescientificcommunityandusedindifferentwaysbydifferentgroups.[18][24]SomehealthcareprovidersclaimthatPTLDSiscausedbypersistentinfection,butthisisnotbelievedtobetruebecausenoevidenceofpersistentinfectioncanbefoundafterstandardtreatment.[25]AvaccineforLymediseasewasmarketedintheUnitedStatesbetween1998and2002,butwaswithdrawnfromthemarketduetopoorsales.[2][26][27]Researchisongoingtodevelopnewvaccines.[2] Contents 1Signsandsymptoms 1.1Earlylocalizedinfection 1.2Earlydisseminatedinfection 1.3Latedisseminatedinfection 2Cause 2.1Ticklifecycle 2.2Transmission 2.3Tick-bornecoinfections 3Pathophysiology 3.1Immunologicalstudies 4Diagnosis 4.1Laboratorytesting 4.2Imaging 4.3Differentialdiagnosis 5Prevention 5.1Tickremoval 5.2Preventiveantibiotics 5.3Gardenlandscaping 5.4Occupationalexposure 5.5Hostanimals 5.6Vaccination 6Treatment 7Prognosis 8Epidemiology 8.1Africa 8.2Asia 8.3Europe 8.3.1UnitedKingdom 8.4NorthAmerica 8.4.1Canada 8.4.2Mexico 8.4.3UnitedStates 8.5SouthAmerica 9History 10Societyandculture 10.1Controversy 11Otheranimals 11.1Pets 12References 13Furtherreading 14Externallinks Signsandsymptoms[edit] Anexpandingrashisaninitialsignofabout80%ofLymeinfections.Therashmaylooklikea"bull'seye",aspictured,inabout80%ofcasesinEuropeand20%ofcasesintheUS.[28][29][30][31] Lymediseasecanaffectmultiplebodysystemsandproduceabroadrangeofsymptoms.NoteveryonewithLymediseasehasallofthesymptoms,andmanyofthesymptomsarenotspecifictoLymediseasebutcanoccurwithotherdiseasesaswell.[32] Theincubationperiodfrominfectiontotheonsetofsymptomsisusuallyonetotwoweeksbutcanbemuchshorter(days),ormuchlonger(monthstoyears).[33]LymesymptomsmostoftenoccurfromMaytoSeptemberinthenorthernhemisphere,becausethenymphalstageofthetickisresponsibleformostcases.[33]Asymptomaticinfectionexistsbutoccursinlessthan7%ofinfectedindividualsintheUnitedStates.[34]AsymptomaticinfectionmaybemuchmorecommonamongthoseinfectedinEurope.[35] Earlylocalizedinfection[edit] Earlylocalizedinfectioncanoccurwhentheinfectionhasnotyetspreadthroughoutthebody.Onlythesitewheretheinfectionhasfirstcomeintocontactwiththeskinisaffected.Theinitialsignofabout80%ofLymeinfectionsisanerythemamigrans(EM)rashatthesiteofatickbite,oftennearskinfolds,suchasthearmpit,groin,orbackoftheknee,onthetrunk,underclothingstraps,orinchildren'shair,ears,orneck.[28][2]Mostpeoplewhogetinfecteddonotrememberseeingatickorabite.Therashappearstypicallyoneortwoweeks(range3–32days)afterthebiteandexpands2–3 cmperdayuptoadiameterof5–70 cm(median16 cm).[28][2][29]Therashisusuallycircularoroval,redorbluish,andmayhaveanelevatedordarkercenter.[2][30][31]Inabout79%ofcasesinEuropebutonly19%ofcasesinendemicareasoftheU.S.,therashgraduallyclearfromthecentertowardtheedges,possiblyforminga"bull'seye"pattern.[29][30][31]Therashmayfeelwarmbutusuallyisnotitchy,israrelytenderorpainful,andtakesuptofourweekstoresolveifuntreated.[2] TheEMrashisoftenaccompaniedbysymptomsofaviral-likeillness,includingfatigue,headache,bodyaches,fever,andchills,butusuallynotnauseaorupper-respiratoryproblems.Thesesymptomsmayalsoappearwithoutarash,orlingeraftertherashdisappears.Lymecanprogresstolaterstageswithoutthesesymptomsorarash.[2] Peoplewithhighfeverformorethantwodaysorwhoseothersymptomsofviral-likeillnessdonotimprovedespiteantibiotictreatmentforLymedisease,orwhohaveabnormallylowlevelsofwhiteorredcellsorplateletsintheblood,shouldbeinvestigatedforpossiblecoinfectionwithothertick-bornediseases,suchasehrlichiosisandbabesiosis.[36] Earlydisseminatedinfection[edit] Withindaystoweeksaftertheonsetoflocalinfection,theBorreliabacteriamayspreadthroughthelymphaticsystemorbloodstream.In10–20%ofuntreatedcases,EMrashesdevelopatsitesacrossthebodythatbearnorelationtotheoriginaltickbite.[28]Transientmusclepainsandjointpainsarealsocommon.[28] Inabout10–15%ofuntreatedpeople,Lymecausesneurologicalproblemsknownasneuroborreliosis.[37]Earlyneuroborreliosistypicallyappears4–6weeks(range1–12weeks)afterthetickbiteandinvolvessomecombinationoflymphocyticmeningitis,cranialneuritis,radiculopathyand/ormononeuritismultiplex.[36][38]Lymphocyticmeningitiscausescharacteristicchangesinthecerebrospinalfluid(CSF)andmaybeaccompaniedforseveralweeksbyvariableheadacheand,lesscommonly,usuallymildmeningitissignssuchasinabilitytoflextheneckfullyandintolerancetobrightlights,buttypicallynooronlyverylowfever.[39]Afterseveralmonths,neuroborreliosiscanalsopresentotolaryngologicalsymptoms.Upto76.5%oftheseotolaryngologicalpresentsastinnitus,themostcommonsymptom.Vertigoanddizziness(53.7%)andhearingloss(16.7%)werethenextmostcommonsymptoms.[40]Inchildren,partiallossofvisionmayalsooccur.[36]Cranialneuritisisaninflammationofcranialnerves.WhenduetoLyme,itmosttypicallycausesfacialpalsyimpairingblinking,smiling,andchewinginoneorbothsidesoftheface.Itmayalsocauseintermittentdoublevision.[36][39]Lymeradiculopathyisaninflammationofspinalnerverootsthatoftencausespainandlessoftenweakness,numbness,oralteredsensationintheareasofthebodyservedbynervesconnectedtotheaffectedroots,e.g.limb(s)orpart(s)oftrunk.Thepainisoftendescribedasunlikeanyotherpreviouslyfelt,excruciating,migrating,worseatnight,rarelysymmetrical,andoftenaccompaniedbyextremesleepdisturbance.[38][41]Mononeuritismultiplexisaninflammationcausingsimilarsymptomsinoneormoreunrelatedperipheralnerves.[37][36]Rarely,earlyneuroborreliosismayinvolveinflammationofthebrainorspinalcord,withsymptomssuchasconfusion,abnormalgait,ocularmovements,orspeech,impairedmovement,impairedmotorplanning,orshaking.[36][38] InNorthAmerica,facialpalsyisthetypicalearlyneuroborreliosispresentation,occurringin5–10%ofuntreatedpeople,inabout75%ofcasesaccompaniedbylymphocyticmeningitis.[36][42]Lymeradiculopathyisreportedhalfasfrequently,butmanycasesmaybeunrecognized.[43]InEuropeanadults,themostcommonpresentationisacombinationoflymphocyticmeningitisandradiculopathyknownasBannwarthsyndrome,accompaniedin36-89%ofcasesbyfacialpalsy.[38][41]Inthissyndrome,radicularpaintendstostartinthesamebodyregionastheinitialerythemamigransrash,iftherewasone,andprecedespossiblefacialpalsyandotherimpairedmovement.[41]Inextremecases,permanentimpairmentofmotororsensoryfunctionofthelowerlimbsmayoccur.[35]InEuropeanchildren,themostcommonmanifestationsarefacialpalsy(in55%),othercranialneuritis,andlymphocyticmeningitis(in27%).[38] Inabout4–10%ofuntreatedcasesintheU.S.and0.3–4%ofuntreatedcasesinEurope,typicallybetweenJuneandDecember,aboutonemonth(range4days-7months)afterthetickbite,theinfectionmaycauseheartcomplicationsknownasLymecarditis.[44][45]Symptomsmayincludeheartpalpitations(in69%ofpeople),dizziness,fainting,shortnessofbreath,andchestpain.[44]OthersymptomsofLymediseasemayalsobepresent,suchasEMrash,jointaches,facialpalsy,headaches,orradicularpain.[44]Insomepeople,however,carditismaybethefirstmanifestationofLymedisease.[44]Lymecarditisin19–87%ofpeopleadverselyimpactstheheart'selectricalconductionsystem,causingatrioventricularblockthatoftenmanifestsasheartrhythmsthatalternatewithinminutesbetweenabnormallyslowandabnormallyfast.[44][45]In10–15%ofpeople,Lymecausesmyocardialcomplicationssuchascardiomegaly,leftventriculardysfunction,orcongestiveheartfailure.[44] Anotherskincondition,foundinEuropebutnotinNorthAmerica,isborreliallymphocytoma,apurplishlumpthatdevelopsontheearlobe,nipple,orscrotum.[46] Latedisseminatedinfection[edit] Afterseveralmonths,untreatedorinadequatelytreatedpeoplemaygoontodevelopchronicsymptomsthataffectmanypartsofthebody,includingthejoints,nerves,brain,eyes,andheart.[citationneeded] Lymearthritisoccursinupto60%ofuntreatedpeople,typicallystartingaboutsixmonthsafterinfection.[28]Itusuallyaffectsonlyoneorafewjoints,oftenakneeorpossiblythehip,otherlargejoints,orthetemporomandibularjoint.[36][47]Thereisusuallylargejointeffusionandswelling,butonlymildormoderatepain.[36]Withouttreatment,swellingandpaintypicallyresolveovertimebutperiodicallyreturn.[36]Baker'scystsmayformandrupture.Insomecases,jointerosionoccurs.[citationneeded] Chronicneurologicsymptomsoccurinupto5%ofuntreatedpeople.[48]Aperipheralneuropathyorpolyneuropathymaydevelop,causingabnormalsensationssuchasnumbness,tinglingorburningstartingatthefeetorhandsandovertimepossiblymovingupthelimbs.Atestmayshowreducedsensationofvibrationsinthefeet.Anaffectedpersonmayfeelasifwearingastockingorglovewithoutactuallydoingso.[36] AneurologicsyndromecalledLymeencephalopathyisassociatedwithsubtlememoryandcognitivedifficulties,insomnia,ageneralsenseoffeelingunwell,andchangesinpersonality.[49]However,problemssuchasdepressionandfibromyalgiaareascommoninpeoplewithLymediseaseasinthegeneralpopulation.[50][51] Lymecancauseachronicencephalomyelitisthatresemblesmultiplesclerosis.Itmaybeprogressiveandcaninvolvecognitiveimpairment,brainfog,migraines,balanceissues,weaknessinthelegs,awkwardgait,facialpalsy,bladderproblems,vertigo,andbackpain.Inrarecases,untreatedLymediseasemaycausefrankpsychosis,whichhasbeenmisdiagnosedasschizophreniaorbipolardisorder.Panicattacksandanxietycanoccur;also,delusionalbehaviormaybeseen,includingsomatoformdelusions,sometimesaccompaniedbyadepersonalizationorderealizationsyndrome,wherethepeoplebegintofeeldetachedfromthemselvesorfromreality.[52][53] Acrodermatitischronicaatrophicans(ACA)isachronicskindisorderobservedprimarilyinEuropeamongtheelderly.[46]ACAbeginsasareddish-bluepatchofdiscoloredskin,oftenonthebacksofthehandsorfeet.Thelesionslowlyatrophiesoverseveralweeksormonths,withtheskinbecomingfirstthinandwrinkledandthen,ifuntreated,completelydryandhairless.[54] Cause[edit] Mainarticle:Lymediseasemicrobiology Deerticklifecycle Borreliabacteria,thecausativeagentofLymedisease,magnified Ixodesscapularis,theprimaryvectorofLymediseaseineasternNorthAmerica TickIxodesricinus,developmentalstages Lymediseaseiscausedbyspirochetes,spiralbacteriafromthegenusBorrelia.Spirochetesaresurroundedbypeptidoglycanandflagella,alongwithanoutermembranesimilartoGram-negativebacteria.Becauseoftheirdouble-membraneenvelope,BorreliabacteriaareoftenmistakenlydescribedasGramnegativedespitetheconsiderabledifferencesintheirenvelopecomponentsfromGram-negativebacteria.[55]TheLyme-relatedBorreliaspeciesarecollectivelyknownasBorreliaburgdorferisensulato,andshowagreatdealofgeneticdiversity.[56] B.burgdorferisensulatoisaspeciescomplexmadeupof20acceptedandthreeproposedgenospecies.EightspeciesareknowntocauseLymedisease:B.mayonii(foundinNorthAmerica),B.burgdorferisensustricto,B.bissettiae(bothfoundinNorthAmericaandEurope),B.afzelii,B.garinii,B.spielmanii,andB.lusitaniae(allfoundinEurasia).[57][58][14][7]SomestudieshavealsoproposedthatB.valaisianamaysometimesinfecthumans,butthisspeciesdoesnotseemtobeimportantcausesofdisease.[59][60] Furtherinformation:WeatherandclimateeffectsonLymediseaseexposure Ticklifecycle[edit] Therearethreestagesinthelifecycleofatick.Larva,nymph,andadult.Duringthenymphstage,ticksmostfrequentlytransmitLymediseaseandareusuallymostactiveinlatespringandearlysummerinregionswheretheclimateismild.Duringtheadultstage,Lymediseasetransmissionislesscommonduetothefactthatitislesspossibleforadulttickstobitehumansandbecausetheytendtobelargerinsizeandthereforecanbeeasilyseenandremoved.[61] Transmission[edit] Lymediseaseisclassifiedasazoonosis,asitistransmittedtohumansfromanaturalreservoiramongsmallmammalsandbirdsbyticksthatfeedonbothsetsofhosts.[62]Hard-bodiedticksofthegenusIxodesarethevectorsofLymedisease(alsothevectorforBabesia).[63]Mostinfectionsarecausedbyticksinthenymphalstage,becausetheyareverysmallandthusmayfeedforlongperiodsoftimeundetected.[62]Nymphalticksaregenerallythesizeofapoppyseedandsometimeswithadarkheadandatranslucentbody.[64]Or,thenymphaltickscanbedarker.[65](Theyoungerlarvalticksareveryrarelyinfected.[66])Althoughdeerarethepreferredhostsofadultdeerticks,andtickpopulationsaremuchlowerintheabsenceofdeer,ticksgenerallydonotacquireBorreliafromdeer,insteadtheyobtainthemfrominfectedsmallmammalssuchasthewhite-footedmouse,andoccasionallybirds.[67]AreaswhereLymeiscommonareexpanding.[68] Withinthetickmidgut,theBorrelia'soutersurfaceproteinA(OspA)bindstothetickreceptorforOspA,knownasTROSPA.Whenthetickfeeds,theBorreliadownregulatesOspAandupregulatesOspC,anothersurfaceprotein.Afterthebacteriamigratefromthemidguttothesalivaryglands,OspCbindstoSalp15,aticksalivaryproteinthatappearstohaveimmunosuppressiveeffectsthatenhanceinfection.[69]SuccessfulinfectionofthemammalianhostdependsonbacterialexpressionofOspC.[70] Tickbitesoftengounnoticedbecauseofthesmallsizeofthetickinitsnymphalstage,aswellasticksecretionsthatpreventthehostfromfeelinganyitchorpainfromthebite.However,transmissionisquiterare,withonlyabout1.2to1.4percentofrecognizedtickbitesresultinginLymedisease.[71] InEurope,themainvectorisIxodesricinus,whichisalsocalledthesheeptickorcastorbeantick.[72]InChina,Ixodespersulcatus(thetaigatick)isprobablythemostimportantvector.[73]InNorthAmerica,theblack-leggedtickordeertick(Ixodesscapularis)isthemainvectorontheEastCoast.[66] Thelonestartick(Amblyommaamericanum),whichisfoundthroughouttheSoutheasternUnitedStatesasfarwestasTexas,isunlikelytotransmittheLymediseasespirochetes,[74]thoughitmaybeimplicatedinarelatedsyndromecalledsoutherntick-associatedrashillness,whichresemblesamildformofLymedisease.[75] OntheWestCoastoftheUnitedStates,themainvectoristhewesternblack-leggedtick(Ixodespacificus).[76]ThetendencyofthistickspeciestofeedpredominantlyonhostspeciessuchastheWesternFenceLizardthatareresistanttoBorreliainfectionappearstodiminishtransmissionofLymediseaseintheWest.[77][78] Transmissioncanoccuracrosstheplacentaduringpregnancyandaswithanumberofotherspirochetaldiseases,adversepregnancyoutcomesarepossiblewithuntreatedinfection;prompttreatmentwithantibioticsreducesoreliminatesthisrisk.[79][80][81][82][83] ThereisnoscientificevidencetosupportLymediseasetransmissionviabloodtransfusion,sexualcontact,orbreastmilk.[84] Tick-bornecoinfections[edit] Mainarticle:Tick-bornedisease TicksthattransmitB.burgdorferitohumanscanalsocarryandtransmitseveralotherparasites,suchasBabesiamicrotiandAnaplasmaphagocytophilum,whichcausethediseasesbabesiosisandhumangranulocyticanaplasmosis(HGA),respectively.[85]AmongpeoplewithearlyLymedisease,dependingontheirlocation,2–12%willalsohaveHGAand2–40%willhavebabesiosis.[86]Ticksincertainregions,includingthelandsalongtheeasternBalticSea,alsotransmitvirusesthatcausetick-borneencephalitis.[87] CoinfectionscomplicateLymesymptoms,especiallydiagnosisandtreatment.ItispossibleforaticktocarryandtransmitoneofthecoinfectionsandnotBorrelia,makingdiagnosisdifficultandoftenelusive.TheCentersforDiseaseControlandPreventionstudied100ticksinruralNewJersey,andfound55%ofthetickswereinfectedwithatleastoneofthepathogens.[88] Pathophysiology[edit] B.burgdorfericanspreadthroughoutthebodyduringthecourseofthedisease,andhasbeenfoundintheskin,heart,joints,peripheralnervoussystem,andcentralnervoussystem.[70][89]ManyofthesignsandsymptomsofLymediseaseareaconsequenceoftheimmuneresponsetospirocheteinthosetissues.[48] B.burgdorferiisinjectedintotheskinbythebiteofaninfectedIxodestick.Ticksaliva,whichaccompaniesthespirocheteintotheskinduringthefeedingprocess,containssubstancesthatdisrupttheimmuneresponseatthesiteofthebite.[90]Thisprovidesaprotectiveenvironmentwherethespirochetecanestablishinfection.Thespirochetesmultiplyandmigrateoutwardwithinthedermis.ThehostinflammatoryresponsetothebacteriaintheskincausesthecharacteristiccircularEMlesion.[70]Neutrophils,however,whicharenecessarytoeliminatethespirochetesfromtheskin,failtoappearinnecessarynumbersinthedevelopingEMlesionbecauseticksalivainhibitsneutrophilfunction.Thisallowsthebacteriatosurviveandeventuallyspreadthroughoutthebody.[91] Daystoweeksfollowingthetickbite,thespirochetesspreadviathebloodstreamtojoints,heart,nervoussystem,anddistantskinsites,wheretheirpresencegivesrisetothevarietyofsymptomsofthedisseminateddisease.ThespreadofB.burgdorferiisaidedbytheattachmentofthehostproteaseplasmintothesurfaceofthespirochete.[92] Ifuntreated,thebacteriamaypersistinthebodyformonthsorevenyears,despitetheproductionofB.burgdorferiantibodiesbytheimmunesystem.[93]Thespirochetesmayavoidtheimmuneresponsebydecreasingexpressionofsurfaceproteinsthataretargetedbyantibodies,antigenicvariationoftheVlsEsurfaceprotein,inactivatingkeyimmunecomponentssuchascomplement,andhidingintheextracellularmatrix,whichmayinterferewiththefunctionofimmunefactors.[94][95] Inthebrain,B.burgdorferimayinduceastrocytestoundergoastrogliosis(proliferationfollowedbyapoptosis),whichmaycontributetoneurodysfunction.[96]Thespirochetesmayalsoinducehostcellstosecretequinolinicacid,whichstimulatestheNMDAreceptoronnervecells,whichmayaccountforthefatigueandmalaiseobservedwithLymeencephalopathy.[97]Inaddition,diffusewhitematterpathologyduringLymeencephalopathymaydisruptgraymatterconnections,andcouldaccountfordeficitsinattention,memory,visuospatialability,complexcognition,andemotionalstatus.Whitematterdiseasemayhaveagreaterpotentialforrecoverythangraymatterdisease,perhapsbecauseneuronallossislesscommon.ResolutionofMRIwhitematterhyperintensitiesafterantibiotictreatmenthasbeenobserved.[98] Tryptophan,aprecursortoserotonin,appearstobereducedwithinthecentralnervoussysteminanumberofinfectiousdiseasesthataffectthebrain,includingLyme.[99]Researchersareinvestigatingifthisneurohormonesecretionisthecauseofneuropsychiatricdisordersdevelopinginsomepeoplewithborreliosis.[100] Immunologicalstudies[edit] ExposuretotheBorreliabacteriumduringLymediseasepossiblycausesalong-livedanddamaginginflammatoryresponse,[101]aformofpathogen-inducedautoimmunedisease.[102]Theproductionofthisreactionmightbeduetoaformofmolecularmimicry,whereBorreliaavoidsbeingkilledbytheimmunesystembyresemblingnormalpartsofthebody'stissues.[103][104] Chronicsymptomsfromanautoimmunereactioncouldexplainwhysomesymptomspersistevenafterthespirocheteshavebeeneliminatedfromthebody.Thishypothesismayexplainwhychronicarthritispersistsafterantibiotictherapy,similartorheumaticfever,butitswiderapplicationiscontroversial.[105][106] Diagnosis[edit] Lymediseaseisdiagnosedbasedonsymptoms,objectivephysicalfindings(suchaserythemamigrans(EM)rash,facialpalsy,orarthritis),historyofpossibleexposuretoinfectedticks,andpossiblylaboratorytests.[2][28]PeoplewithsymptomsofearlyLymediseaseshouldhaveatotalbodyskinexaminationforEMrashesandaskedwhetherEM-typerasheshadmanifestedwithinthelast1–2months.[36]PresenceofanEMrashandrecenttickexposure(i.e.,beingoutdoorsinalikelytickhabitatwhereLymeiscommon,within30daysoftheappearanceoftherash)aresufficientforLymediagnosis;nolaboratoryconfirmationisneededorrecommended.[2][28][107][108]Mostpeoplewhogetinfecteddonotrememberatickorabite,andtheEMrashneednotlooklikeabull'seye(mostEMrashesintheU.S.donot)orbeaccompaniedbyanyothersymptoms.[2][109]IntheU.S.,LymeismostcommonintheNewEnglandandMid-AtlanticstatesandpartsofWisconsinandMinnesota,butitisexpandingintootherareas.[68]SeveralborderingareasofCanadaalsohavehighLymerisk.[110] IntheabsenceofanEMrashorhistoryoftickexposure,Lymediagnosisdependsonlaboratoryconfirmation.[63][111]ThebacteriathatcauseLymediseasearedifficulttoobservedirectlyinbodytissuesandalsodifficultandtootime-consumingtogrowinthelaboratory.[2][63]Themostwidelyusedtestslookinsteadforpresenceofantibodiesagainstthosebacteriaintheblood.[112]Apositiveantibodytestresultdoesnotbyitselfproveactiveinfectionbutcanconfirmaninfectionthatissuspectedbecauseofsymptoms,objectivefindings,andhistoryoftickexposureinaperson.[63]Becauseasmanyas5–20%ofthenormalpopulationhaveantibodiesagainstLyme,peoplewithouthistoryandsymptomssuggestiveofLymediseaseshouldnotbetestedforLymeantibodies:apositiveresultwouldlikelybefalse,possiblycausingunnecessarytreatment.[36][38] Insomecases,whenhistory,signs,andsymptomsarestronglysuggestiveofearlydisseminatedLymedisease,empirictreatmentmaybestartedandreevaluatedaslaboratorytestresultsbecomeavailable.[42][113] Laboratorytesting[edit] TestsforantibodiesinthebloodbyELISAandWesternblotisthemostwidelyusedmethodforLymediagnosis.Atwo-tieredprotocolisrecommendedbytheCentersforDiseaseControlandPrevention(CDC):thesensitiveELISAtestisperformedfirst,andifitispositiveorequivocal,thenthemorespecificWesternblotisrun.[114]Theimmunesystemtakessometimetoproduceantibodiesinquantity.AfterLymeinfectiononset,antibodiesoftypesIgMandIgGusuallycanfirstbedetectedrespectivelyat2–4weeksand4–6weeks,andpeakat6–8weeks.[115]WhenanEMrashfirstappears,detectableantibodiesmaynotbepresent.Therefore,itisrecommendedthattestingnotbeperformedanddiagnosisbebasedonthepresenceoftheEMrash.[36]Upto30daysaftersuspectedLymeinfectiononset,infectioncanbeconfirmedbydetectionofIgMorIgGantibodies;afterthat,itisrecommendedthatonlyIgGantibodiesbeconsidered.[115]ApositiveIgMandnegativeIgGtestresultafterthefirstmonthofinfectionisgenerallyindicativeofafalse-positiveresult.[116]ThenumberofIgMantibodiesusuallycollapses4–6monthsafterinfection,whileIgGantibodiescanremaindetectableforyears.[115] Othertestsmaybeusedinneuroborreliosiscases.InEurope,neuroborreliosisisusuallycausedbyBorreliagariniiandalmostalwaysinvolveslymphocyticpleocytosis,i.e.thedensitiesoflymphocytes(infection-fightingcells)andproteininthecerebrospinalfluid(CSF)typicallyrisetocharacteristicallyabnormallevels,whileglucoselevelremainsnormal.[39][36][41]Additionally,theimmunesystemproducesantibodiesagainstLymeinsidetheintrathecalspace,whichcontainstheCSF.[36][41]DemonstrationbylumbarpunctureandCSFanalysisofpleocytosisandintrathecalantibodyproductionarerequiredfordefinitediagnosisofneuroborreliosisinEurope(exceptincasesofperipheralneuropathyassociatedwithacrodermatitischronicaatrophicans,whichusuallyiscausedbyBorreliaafzeliiandconfirmedbybloodantibodytests).[38]InNorthAmerica,neuroborreliosisiscausedbyBorreliaburgdorferiandmaynotbeaccompaniedbythesameCSFsigns;theyconfirmadiagnosisofcentralnervoussystem(CNS)neuroborreliosisifpositive,butdonotexcludeitifnegative.[117]AmericanguidelinesconsiderCSFanalysisoptionalwhensymptomsappeartobeconfinedtotheperipheralnervoussystem(PNS),e.g.facialpalsywithoutovertmeningitissymptoms.[36][118]Unlikebloodandintrathecalantibodytests,CSFpleocytosistestsreverttonormalafterinfectionendsandthereforecanbeusedasobjectivemarkersoftreatmentsuccessandinformdecisionsonwhethertoretreat.[41]IninfectioninvolvingthePNS,electromyographyandnerveconductionstudiescanbeusedtomonitorobjectivelytheresponsetotreatment.[39] InLymecarditis,electrocardiogramsareusedtoevidenceheartconductionabnormalities,whileechocardiographymayshowmyocardialdysfunction.[44]BiopsyandconfirmationofBorreliacellsinmyocardialtissuemaybeusedinspecificcasesbutareusuallynotdonebecauseofriskoftheprocedure.[44] Polymerasechainreaction(PCR)testsforLymediseasehavealsobeendevelopedtodetectthegeneticmaterial(DNA)oftheLymediseasespirochete.CultureorPCRarethecurrentmeansfordetectingthepresenceoftheorganism,asserologicstudiesonlytestforantibodiesofBorrelia.PCRhastheadvantageofbeingmuchfasterthanculture.However,PCRtestsaresusceptibletofalsepositiveresults,e.g.bydetectionofdebrisofdeadBorreliacellsorspecimencontamination.[119][38]Evenwhenproperlyperformed,PCRoftenshowsfalse-negativeresultsbecausefewBorreliacellscanbefoundinbloodandcerebrospinalfluid(CSF)duringinfection.[120][38]Hence,PCRtestsarerecommendedonlyinspecialcases,e.g.diagnosisofLymearthritis,becauseitisahighlysensitivewayofdetectingospADNAinsynovialfluid.[121]AlthoughsensitivityofPCRinCSFislow,itsusemaybeconsideredwhenintrathecalantibodyproductiontestresultsaresuspectedofbeingfalselynegative,e.g.inveryearly(<6weeks)neuroborreliosisorinimmunosuppressedpeople.[38] SeveralotherformsoflaboratorytestingforLymediseaseareavailable,someofwhichhavenotbeenadequatelyvalidated.OspAantigens,shedbyliveBorreliabacteriaintourine,areapromisingtechniquebeingstudied.[122]TheuseofnanotrapparticlesfortheirdetectionisbeinglookedatandtheOspAhasbeenlinkedtoactivesymptomsofLyme.[123][124]HightitersofeitherimmunoglobulinG(IgG)orimmunoglobulinM(IgM)antibodiestoBorreliaantigensindicatedisease,butlowertiterscanbemisleading,becausetheIgMantibodiesmayremainaftertheinitialinfection,andIgGantibodiesmayremainforyears.[125] TheCDCdoesnotrecommendurineantigentests,PCRtestsonurine,immunofluorescentstainingforcell-wall-deficientformsofB.burgdorferi,andlymphocytetransformationtests.[120] Imaging[edit] Neuroimagingiscontroversialinwhetheritprovidesspecificpatternsuniquetoneuroborreliosis,butmayaidindifferentialdiagnosisandinunderstandingthepathophysiologyofthedisease.[126]Thoughcontroversial,someevidenceshowscertainneuroimagingtestscanprovidedatathatarehelpfulinthediagnosisofaperson.Magneticresonanceimaging(MRI)andsingle-photonemissioncomputedtomography(SPECT)aretwooftheteststhatcanidentifyabnormalitiesinthebrainofapersonaffectedwiththisdisease.NeuroimagingfindingsinanMRIincludelesionsintheperiventricularwhitematter,aswellasenlargedventriclesandcorticalatrophy.Thefindingsareconsideredsomewhatunexceptionalbecausethelesionshavebeenfoundtobereversiblefollowingantibiotictreatment.ImagesproducedusingSPECTshownumerousareaswhereaninsufficientamountofbloodisbeingdeliveredtothecortexandsubcorticalwhitematter.However,SPECTimagesareknowntobenonspecificbecausetheyshowaheterogeneouspatternintheimaging.TheabnormalitiesseenintheSPECTimagesareverysimilartothoseseeninpeoplewithcerebralvacuitiesandCreutzfeldt–Jakobdisease,whichmakesthemquestionable.[127] Differentialdiagnosis[edit] Communityclinicshavebeenreportedtomisdiagnose23–28%ofErythemamigrans(EM)rashesand83%ofotherobjectivemanifestationsofearlyLymedisease.[111]EMrashesareoftenmisdiagnosedasspiderbites,cellulitis,orshingles.[111]ManymisdiagnosesarecreditedtothewidespreadmisconceptionthatEMrashesshouldlooklikeabull'seye.[2]Actually,thekeydistinguishingfeaturesoftheEMrasharethespeedandextenttowhichitexpands,respectivelyupto2–3 cm/dayandadiameterofatleast5 cm,andin50%ofcasesmorethan16 cm.Therashexpandsawayfromitscenter,whichmayormaynotlookdifferentorbeseparatedbyring-likeclearingfromtherestoftherash.[28][29]ComparedtoEMrashes,spiderbitesaremorecommoninthelimbs,tendtobemorepainfulanditchyorbecomeswollen,andsomemaycausenecrosis(sinkingdarkbluepatchofdeadskin).[28][2]Cellulitismostcommonlydevelopsaroundawoundorulcer,israrelycircular,andismorelikelytobecomeswollenandtender.[28][2]EMrashesoftenappearatsitesthatareunusualforcellulitis,suchasthearmpit,groin,abdomen,orbackofknee.[28]LikeLyme,shinglesoftenbeginswithheadache,fever,andfatigue,whicharefollowedbypainornumbness.However,unlikeLyme,inshinglesthesesymptomsareusuallyfollowedbyappearanceofrashescomposedofmultiplesmallblistersalongwithanerve'sdermatome,andshinglescanalsobeconfirmedbyquicklaboratorytests.[128] FacialpalsycausedbyLymedisease(LDFP)isoftenmisdiagnosedasBell'spalsy.[42]AlthoughBell'spalsyisthemostcommontypeofone-sidedfacialpalsy(about70%ofcases),LDFPcanaccountforabout25%ofcasesoffacialpalsyinareaswhereLymediseaseiscommon.[42]ComparedtoLDFP,Bell'spalsymuchlessfrequentlyaffectsbothsidesoftheface.[42]EventhoughLDFPandBell'spalsyhavesimilarsymptomsandevolvesimilarlyifuntreated,corticosteroidtreatmentisbeneficialforBell'sPalsy,whilebeingdetrimentalforLDFP.[42]Recenthistoryofexposuretoalikelytickhabitatduringwarmermonths,EMrash,viral-likesymptomssuchasheadacheandfever,and/orpalsyinbothsidesofthefaceshouldbeevaluatedforthelikelihoodofLDFP;ifitismorethanminimal,empirictherapywithantibioticsshouldbeinitiated,withoutcorticosteroids,andreevaluateduponcompletionoflaboratorytestsforLymedisease.[42] Unlikeviralmeningitis,Lymelymphocyticmeningitistendstonotcausefever,lastlonger,andrecur.[39][36]Lymphocyticmeningitisisalsocharacterizedbypossiblyco-occurringwithEMrash,facialpalsy,orpartialvisionobstructionandhavingmuchlowerpercentageofpolymorphonuclearleukocytesinCSF.[36] Lymeradiculopathyaffectingthelimbsisoftenmisdiagnosedasaradiculopathycausedbynerverootcompression,suchassciatica.[111][129]Althoughmostcasesofradiculopathyarecompressiveandresolvewithconservativetreatment(e.g.,rest)within4–6weeks,guidelinesformanagingradiculopathyrecommendfirstevaluatingrisksofotherpossiblecausesthat,althoughlessfrequent,requireimmediatediagnosisandtreatment,includinginfectionssuchasLymeandshingles.[130]Ahistoryofoutdooractivitiesinlikelytickhabitatsinthelast3monthspossiblyfollowedbyarashorviral-likesymptoms,andcurrentheadache,othersymptomsoflymphocyticmeningitis,orfacialpalsywouldleadtosuspicionofLymediseaseandrecommendationofserologicalandlumbarpuncturetestsforconfirmation.[130] Lymeradiculopathyaffectingthetrunkcanbemisdiagnosedasmyriadotherconditions,suchasdiverticulitisandacutecoronarysyndrome.[43][111]Diagnosisoflate-stageLymediseaseisoftencomplicatedbyamultifacetedappearanceandnonspecificsymptoms,promptingonereviewertocallLymethenew"greatimitator".[131]Lymediseasemaybemisdiagnosedasmultiplesclerosis,rheumatoidarthritis,fibromyalgia,chronicfatiguesyndrome,lupus,Crohn'sdisease,HIV,orotherautoimmuneandneurodegenerativediseases.Asallpeoplewithlater-stageinfectionwillhaveapositiveantibodytest,simplebloodtestscanexcludeLymediseaseasapossiblecauseofaperson'ssymptoms.[132] Prevention[edit] Tickbitesmaybepreventedbyavoidingorreducingtimeinlikelytickhabitatsandtakingprecautionswhileinandwhengettingoutofone.[133][6] MostLymehumaninfectionsarecausedbyIxodesnymphbitesbetweenAprilandSeptember.[28][133]Ticksprefermoist,shadedlocationsinwoodlands,shrubs,tallgrassesandleaflitterorwoodpiles.[28][134]Tickdensitiestendtobehighestinwoodlands,followedbyunmaintainededgesbetweenwoodsandlawns(abouthalfashigh),ornamentalplantsandperennialgroundcover(aboutaquarter),andlawns(about30timesless).[135]Ixodeslarvaeandnymphstendtobeabundantalsowheremicenest,suchasstonewallsandwoodlogs.[135]Ixodeslarvaeandnymphstypicallywaitforpotentialhosts("quest")onleavesorgrassesclosetothegroundwithforelegsoutstretched;whenahostbrushesagainstitslimbs,thetickrapidlyclingsandclimbsonthehostlookingforaskinlocationtobite.[136]InNortheasternUnitedStates,69%oftickbitesareestimatedtohappeninresidences,11%inschoolsorcamps,9%inparksorrecreationalareas,4%atwork,3%whilehunting,and4%inotherareas.[135]Activitiesassociatedwithtickbitesaroundresidencesincludeyardwork,brushclearing,gardening,playingintheyard,andlettingintothehousedogsorcatsthatroamoutsideinwoodyorgrassyareas.[135][133]Inparks,tickbitesoftenhappenwhilehikingorcamping.[135]Walkingonamowedlawnorcenterofatrailwithouttouchingadjacentvegetationislessriskythancrawlingorsittingonalogorstonewall.[135][137]Petsshouldnotbeallowedtoroamfreelyinlikelytickhabitats.[134] Asaprecaution,CDCrecommendssoakingorsprayingclothes,shoes,andcampinggearsuchastents,backpacksandsleepingbagswith0.5%permethrinsolutionandhangingthemtodrybeforeuse.[133][138]Permethrinisodorlessandsafeforhumansbuthighlytoxictoticks.[139]Aftercrawlingonpermethrin-treatedfabricforasfewas10–20seconds,ticknymphsbecomeirritatedandfalloffordie.[139][140]Permethrin-treatedclosed-toedshoesandsocksreduceby74timesthenumberofbitesfromnymphsthatmakefirstcontactwithashoeofapersonalsowearingtreatedshorts(becausenymphsusuallyquestneartheground,thisisatypicalcontactscenario).[139]Betterprotectioncanbeachievedbytuckingpermethrin-treatedtrousers(pants)intotreatedsocksandatreatedlong-sleeveshirtintothetrouserssoastominimizegapsthroughwhichatickmightreachthewearer'sskin.[137]Light-coloredclothingmaymakeiteasiertoseeticksandremovethembeforetheybite.[137]Militaryandoutdoorworkers'uniformstreatedwithpermethrinhavebeenfoundtoreducethenumberofbitecasesby80–95%.[140]Permethrinprotectionlastsseveralweeksofwearandwashingsincustomer-treateditemsandupto70washingsforfactory-treateditems.[138]Permethrinshouldnotbeusedonhumanskin,underwearorcats.[138][141] TheEPArecommendsseveraltickrepellentsforuseonexposedskin,includingDEET,picaridin,IR3535(aderivativeofaminoacidbeta-alanine),oiloflemoneucalyptus(OLE,anaturalcompound)andOLE'sactiveingredientpara-menthane-diol(PMD).[133][142][143]Unlikepermethrin,repellentsrepelbutdonotkillticks,protectforonlyseveralhoursafterapplication,andmaybewashedoffbysweatorwater.[138]ThemostpopularrepellentisDEETintheU.S.andpicaridininEurope.[143]UnlikeDEET,picaridinisodorlessandislesslikelytoirritatetheskinorharmfabricorplastics.[143]Repellentswithhigherconcentrationmaylastlongerbutarenotmoreeffective;againstticks,20%picaridinmayworkfor8hoursvs.55–98.11%DEETfor5–6hoursor30–40%OLEfor6hours.[138][142]Repellentsshouldnotbeusedunderclothes,oneyes,mouth,woundsorcuts,oronbabiesyoungerthan2months(3yearsforOLEorPMD).[138][133]Ifsunscreenisused,repellentshouldbeappliedontopofit.[138]Repellentsshouldnotbesprayeddirectlyonaface,butshouldinsteadbesprayedonahandandthenrubbedontheface.[138] Aftercomingindoors,clothes,gearandpetsshouldbecheckedforticks.[133]Clothescanbeputintoahotdryerfor10minutestokillticks(justwashingorwarmdryerarenotenough).[133]Showeringassoonaspossible,lookingforticksovertheentirebody,andremovingthemreduceriskofinfection.[133]Unfedticknymphsarethesizeofapoppyseed,butadayortwoafterbitingandattachingthemselvestoaperson,theylooklikeasmallbloodblister.[144]Thefollowingareasshouldbecheckedespeciallycarefully:armpits,betweenlegs,backofknee,bellybutton,trunk,andinchildrenears,neckandhair.[133] Tickremoval[edit] Removalofatickusingtweezers Attachedticksshouldberemovedpromptly.Riskofinfectionincreaseswithtimeofattachment,butinNorthAmericariskofLymediseaseissmallifthetickisremovedwithin36hours.[145]CDCrecommendsinsertingafine-tippedtweezerbetweentheskinandthetick,graspingveryfirmly,andpullingtheclosedtweezerstraightawayfromtheskinwithouttwisting,jerking,squeezingorcrushingthetick.[146]Aftertickremoval,anytickpartsremainingintheskinshouldberemovedwithacleantweezer,ifpossible.[146]Thewoundandhandsshouldthenbecleanedwithalcoholorsoapandwater.[146]Thetickmaybedisposedbyplacingitinacontainerwithalcohol,sealedbag,tapeorflusheddownthetoilet.[146]Thebittenpersonshouldwritedownwhereandwhenthebitehappenedsothatthiscanbeinformedtoadoctorifthepersongetsarashorflu-likesymptomsinthefollowingseveralweeks.[146]CDCrecommendsnotusingfingers,nailpolish,petroleumjellyorheatontheticktotrytoremoveit.[146] InAustralia,wheretheAustralianparalysistickisprevalent,theAustralasianSocietyofClinicalImmunologyandAllergyrecommendsnotusingtweezerstoremoveticks,becauseifthepersonisallergic,anaphylaxiscouldresult.[147]Instead,aproductshouldbesprayedontheticktocauseittofreezeandthendropoff.[147]Adoctorwoulduseliquidnitrogen,butproductsavailablefromchemistsforfreezingwartscanbeusedinstead.[148]AnothermethodoriginatingfromAustraliaconsistsinusingabout20 cmofdentalflossorfishinglineforslowlytyinganoverhandknotbetweentheskinandthetickandthenpullingitawayfromtheskin.[149][150] Preventiveantibiotics[edit] Theriskofinfectioustransmissionincreaseswiththedurationoftickattachment.[28]Itrequiresbetween36and48hoursofattachmentforthebacteriathatcausesLymetotravelfromwithinthetickintoitssaliva.[28]IfadeertickthatissufficientlylikelytobecarryingBorreliaisfoundattachedtoapersonandremoved,andifthetickhasbeenattachedfor36hoursorisengorged,asingledoseofdoxycyclineadministeredwithinthe72hoursafterremovalmayreducetheriskofLymedisease.Itisnotgenerallyrecommendedforallpeoplebitten,asdevelopmentofinfectionisrare:about50bittenpeoplewouldhavetobetreatedthiswaytopreventonecaseoferythemamigrans(i.e.thetypicalrashfoundinabout70–80%ofpeopleinfected).[2][28] Gardenlandscaping[edit] Severallandscapingpracticesmayreduceriskoftickbitesinresidentialyards.[144][151]Thelawnshouldbekeptmowed,leaflitterandweedsremovedandgroundcoveruseavoided.[144]Woodlands,shrubs,stonewallsandwoodpilesshouldbeseparatedfromthelawnbya3-ft-widerockorwoodchipbarrier.[151]Withoutvegetationonthebarrier,tickswilltendnottocrossit;acaricidesmayalsobesprayedonittokillticks.[151]Asun-exposedtick-safezoneatleast9 ftfromthebarriershouldconcentratehumanactivityontheyard,includinganypatios,playgroundsandgardening.[151]Materialssuchaswooddecking,concrete,bricks,gravelorwoodchipsmaybeusedonthegroundunderpatiosandplaygroundssoastodiscourageticksthere.[144]An8-ft-highfencemaybeaddedtokeepdeerawayfromthetick-safezone.[151][144] Occupationalexposure[edit] OutdoorworkersareatriskofLymediseaseiftheyworkatsiteswithinfectedticks.Thisincludesconstruction,landscaping,forestry,brushclearing,landsurveying,farming,railroadwork,oilfieldwork,utilitylinework,parkorwildlifemanagement.[152][153]U.S.workersinthenortheasternandnorth-centralstatesareathighestriskofexposuretoinfectedticks.Ticksmayalsotransmitothertick-bornediseasestoworkersintheseandotherregionsofthecountry.Worksiteswithwoods,bushes,highgrassorleaflitterarelikelytohavemoreticks.Outdoorworkersshouldbemostcarefultoprotectthemselvesinthelatespringandsummerwhenyoungticksaremostactive.[154] Hostanimals[edit] Lymeandotherdeertick-bornediseasescansometimesbereducedbygreatlyreducingthedeerpopulationonwhichtheadultticksdependforfeedingandreproduction.Lymediseasecasesfellfollowingdeereradicationonanisland,Monhegan,Maine,[155]andfollowingdeercontrolinMumfordCove,Connecticut.[156]Itisworthnotingthateliminatingdeermayleadtoatemporaryincreaseintickdensity.[157] Forexample,intheU.S.,reducingthedeerpopulationtolevelsof8to10persquaremile(fromthecurrentlevelsof60ormoredeerpersquaremileintheareasofthecountrywiththehighestLymediseaserates)mayreduceticknumbersandreducethespreadofLymeandothertick-bornediseases.[158]However,suchadrasticreductionmaybeverydifficulttoimplementinmanyareas,andlowtomoderatedensitiesofdeerorotherlargemammalhostsmaycontinuetofeedsufficientadulttickstomaintainlarvaldensitiesathighlevels.Routineveterinarycontrolofticksofdomesticanimals,includinglivestock,byuseofacaricidescancontributetoreducingexposureofhumanstoticks.[citationneeded] InEurope,knownreservoirsofBorreliaburgdorferiwere9smallmammals,7medium-sizedmammalsand16speciesofbirds(includingpasserines,sea-birdsandpheasants).[159]TheseanimalsseemtotransmitspirochetestoticksandthusparticipateinthenaturalcirculationofB.burgdorferiinEurope.Thehousemouseisalsosuspectedaswellasotherspeciesofsmallrodents,particularlyinEasternEuropeandRussia.[159]"ThereservoirspeciesthatcontainthemostpathogensaretheEuropeanroedeerCapreoluscapreolus;[160]"itdoesnotappeartoserveasamajorreservoirofB.burgdorferi"thoughtJaenson&al.(1992)[161](incompetenthostforB.burgdorferiandTBEvirus)butitisimportantforfeedingtheticks,[162]asreddeerandwildboars(Susscrofa),[163]inwhichoneRickettsiaandthreeBorreliaspecieswereidentified",[160]withhighrisksofcoinfectioninroedeer.[164]Nevertheless,inthe2000s,inroedeerinEurope"twospeciesofRickettsiaandtwospeciesofBorreliawereidentified".[163] Vaccination[edit] ArecombinantvaccineagainstLymedisease,basedontheoutersurfaceproteinA(ospA)ofB.burgdorferi,wasdevelopedbySmithKlineBeecham.Inclinicaltrialsinvolvingmorethan10,000people,thevaccine,calledLYMErix,wasfoundtoconferprotectiveimmunitytoBorreliain76%ofadultsand100%ofchildrenwithonlymildormoderateandtransientadverseeffects.[165]LYMErixwasapprovedonthebasisofthesetrialsbytheFoodandDrugAdministration(FDA)on21December1998.[166] Followingapprovalofthevaccine,itsentryintoclinicalpracticewasslowforavarietyofreasons,includingitscost,whichwasoftennotreimbursedbyinsurancecompanies.[167]Subsequently,hundredsofvaccinerecipientsreportedtheyhaddevelopedautoimmuneandothersideeffects.Supportedbysomeadvocacygroups,anumberofclass-actionlawsuitswerefiledagainstGlaxoSmithKline,allegingthevaccinehadcausedthesehealthproblems.TheseclaimswereinvestigatedbytheFDAandtheCentersforDiseaseControl,whichfoundnoconnectionbetweenthevaccineandtheautoimmunecomplaints.[168] Despitethelackofevidencethatthecomplaintswerecausedbythevaccine,salesplummetedandLYMErixwaswithdrawnfromtheU.S.marketbyGlaxoSmithKlineinFebruary2002,[169]inthesettingofnegativemediacoverageandfearsofvaccinesideeffects.[168][170]ThefateofLYMErixwasdescribedinthemedicalliteratureasa"cautionarytale";[170]aneditorialinNaturecitedthewithdrawalofLYMErixasaninstanceinwhich"unfoundedpublicfearsplacepressuresonvaccinedevelopersthatgobeyondreasonablesafetyconsiderations."[26]TheoriginaldeveloperoftheOspAvaccineattheMaxPlanckInstitutetoldNature:"Thisjustshowshowirrationaltheworldcanbe ...TherewasnoscientificjustificationforthefirstOspAvaccineLYMErixbeingpulled."[168] VaccineshavebeenformulatedandapprovedforthepreventionofLymediseaseindogs.Currently,threeLymediseasevaccinesareavailable.LymeVax,formulatedbyFortDodgeLaboratories,containsintactdeadspirocheteswhichexposethehosttotheorganism.GalaxyLyme,Intervet-Schering-Plough'svaccine,targetsproteinsOspCandOspA.TheOspCantibodieskillanyofthebacteriathathavenotbeenkilledbytheOspAantibodies.CanineRecombinantLyme,formulatedbyMerial,generatesantibodiesagainsttheOspAproteinsoatickfeedingonavaccinateddogdrawsinbloodfullofanti-OspAantibodies,whichkillthespirochetesinthetick'sgutbeforetheyaretransmittedtothedog.[171] Ahexavalent(OspA)proteinsubunit-basedvaccinecandidateVLA15developedbyValnevawasgrantedfasttrackdesignationbytheU.S.FoodandDrugAdministrationin2017whichwillallowfurtherstudy.[172][173] AmRNAvaccinedesignedtocauseastrongfastimmuneresponsetoticksalivaallowedtodetectandremovetheticksfromtestanimalsbeforetheywereabletotransmittheinfectiousbacteria.[174]ThevaccinecontainsmRNAsforthebodytobuild19proteinsinticksalivawhich,byenablingquickdevelopmentoferythema(itchyredness)atthebitesite,protectsguineapigsagainstLymedisease.Italsoprotectedthetestanimalsifthetickisnotremovedifonlyonetick,butnotthree,remainattached.[175][176] Treatment[edit] Antibioticsaretheprimarytreatment.[2][28]Thespecificapproachtotheiruseisdependentontheindividualaffectedandthestageofthedisease.[28]Formostpeoplewithearlylocalizedinfection,oraladministrationofdoxycyclineiswidelyrecommendedasthefirstchoice,asitiseffectiveagainstnotonlyBorreliabacteriabutalsoavarietyofotherillnessescarriedbyticks.[28]Peopletakingdoxycyclineshouldavoidsunexposurebecauseofhigherriskofsunburns.[36]Doxycyclineiscontraindicatedinchildrenyoungerthaneightyearsofageandwomenwhoarepregnantorbreastfeeding;[28]alternativestodoxycyclineareamoxicillin,cefuroximeaxetil,andazithromycin.[28]Azithromycinisrecommendedonlyincaseofintolerancetotheotherantibiotics.[36]Thestandardtreatmentforcellulitis,cephalexin,isnotusefulforLymedisease.[36]WhenitisunclearifarashiscausedbyLymeorcellulitis,theIDSArecommendstreatmentwithcefuroximeoramoxicillin/clavulanicacid,astheseareeffectiveagainstbothinfections.[36]IndividualswithearlydisseminatedorlateLymeinfectionmayhavesymptomaticcardiacdisease,Lymearthritis,orneurologicsymptomslikefacialpalsy,radiculopathy,meningitis,orperipheralneuropathy.[28]Intravenousadministrationofceftriaxoneisrecommendedasthefirstchoiceinthesecases;[28]cefotaximeanddoxycyclineareavailableasalternatives.[28] TreatmentregimensforLymediseaserangefrom14daysinearlylocalizeddisease,to14–21daysinearlydisseminateddiseaseto14–28daysinlatedisseminateddisease.[177]NeurologiccomplicationsofLymediseasemaybetreatedwithdoxycyclineasitcanbetakenbymouthandhasalowercost,althoughinNorthAmericaevidenceofefficacyisonlyindirect.[118]Incaseoffailure,guidelinesrecommendretreatmentwithinjectableceftriaxone.[118]SeveralmonthsaftertreatmentforLymearthritis,ifjointswellingpersistsorreturns,asecondroundofantibioticsmaybeconsidered;intravenousantibioticsarepreferredforretreatmentincaseofpoorresponsetooralantibiotics.[28][36]Outsideofthat,aprolongedantibioticregimenlastingmorethan28daysisnotrecommendedasnoevidenceshowsittobeeffective.[28][178]IgMandIgGantibodylevelsmaybeelevatedforyearsevenaftersuccessfultreatmentwithantibiotics.[28]Asantibodylevelsarenotindicativeoftreatmentsuccess,testingforthemisnotrecommended.[28] Facialpalsymayresolvewithouttreatment;however,antibiotictreatmentisrecommendedtostopotherLymecomplications.[36]CorticosteroidsarenotrecommendedwhenfacialpalsyiscausedbyLymedisease.[42]Inthosewithfacialpalsy,frequentuseofartificialtearswhileawakeisrecommended,alongwithointmentandapatchortapingtheeyeclosedwhensleeping.[42][179] AboutathirdofpeoplewithLymecarditisneedatemporarypacemakeruntiltheirheartconductionabnormalityresolves,and21%needtobehospitalized.[44]Lymecarditisshouldnotbetreatedwithcorticosteroids.[44] PeoplewithLymearthritisshouldlimittheirlevelofphysicalactivitytoavoiddamagingaffectedjoints,andincaseoflimpingshouldusecrutches.[180]PainassociatedwithLymediseasemaybetreatedwithnonsteroidalanti-inflammatorydrugs(NSAIDs).[36]CorticosteroidjointinjectionsarenotrecommendedforLymearthritisthatisbeingtreatedwithantibiotics.[36][180]PeoplewithLymearthritistreatedwithintravenousantibioticsortwomonthsoforalantibioticswhocontinuetohavejointswellingtwomonthsaftertreatmentandhavenegativePCRtestforBorreliaDNAinthesynovialfluidaresaidtohaveantibiotic-refractoryLymearthritis;thisismorecommonafterinfectionbycertainBorreliastrainsinpeoplewithcertaingeneticandimmunologiccharacteristics.[36][180]Antibiotic-refractoryLymearthritismaybesymptomaticallytreatedwithNSAIDs,disease-modifyingantirheumaticdrugs(DMARDs),orarthroscopicsynovectomy.[36]PhysicaltherapyisrecommendedforadultsafterresolutionofLymearthritis.[180] Peoplereceivingtreatmentshouldbeadvisedthatreinfectionispossibleandhowtopreventit.[113] Prognosis[edit] Lymedisease'stypicalfirstsign,theerythemamigrans(EM)rash,resolveswithinseveralweeksevenwithouttreatment.[2]However,inuntreatedpeople,theinfectionoftendisseminatestothenervoussystem,heart,orjoints,possiblycausingpermanentdamagetobodytissues.[36] PeoplewhoreceiverecommendedantibiotictreatmentwithinseveraldaysofappearanceofaninitialEMrashhavethebestprospects.[111]Recoverymaynotbetotalorimmediate.ThepercentageofpeopleachievingfullrecoveryintheUnitedStatesincreasesfromabout64–71%atendoftreatmentforEMrashtoabout84–90%after30months;higherpercentagesarereportedinEurope.[181][182]Treatmentfailure,i.e.persistenceoforiginalorappearanceofnewsignsofthedisease,occursonlyinafewpeople.[181]Remainingpeopleareconsideredcuredbutcontinuetoexperiencesubjectivesymptoms,e.g.jointormusclepainsorfatigue.[183]Thesesymptomsusuallyaremildandnondisabling.[183] Peopletreatedonlyafternervoussystemmanifestationsofthediseasemayendupwithobjectiveneurologicaldeficits,inadditiontosubjectivesymptoms.[36]InEurope,anaverageof32–33monthsafterinitialLymesymptomsinpeopletreatedmostlywithdoxycycline200 mgfor14–21days,thepercentageofpeoplewithlingeringsymptomswasmuchhigheramongthosediagnosedwithneuroborreliosis(50%)thanamongthosewithonlyanEMrash(16%).[184]InanotherEuropeanstudy,5yearsaftertreatmentforneuroborreliosis,lingeringsymptomswerelesscommonamongchildren(15%)thanadults(30%),andinthelatterwaslesscommonamongthosetreatedwithin30daysofthefirstsymptom(16%)thanamongthosetreatedlater(39%);amongthosewithlingeringsymptoms,54%haddailyactivitiesrestrictedand19%wereonsickleaveorincapacitated.[185] Somedatasuggestthatabout90%ofLymefacialpalsiestreatedwithantibioticsrecoverfullyamedianof24daysafterappearingandmostoftherestrecoverwithonlymildabnormality.[186][187]However,inEurope41%ofpeopletreatedforfacialpalsyhadotherlingeringsymptomsatfollowupupto6monthslater,including28%withnumbnessoralteredsensationand14%withfatigueorconcentrationproblems.[187]Palsiesinbothsidesofthefaceareassociatedwithworseandlongertimetorecovery.[186][187]Historicaldatasuggeststhatuntreatedpeoplewithfacialpalsiesrecoveratnearlythesamerate,but88%subsequentlyhaveLymearthritis.[186][188]Otherresearchshowsthatsynkinesis(involuntarymovementofafacialmusclewhenanotheroneisvoluntarilymoved)canbecomeevidentonly6–12monthsafterfacialpalsyappearstoberesolved,asdamagednervesregrowandsometimesconnecttoincorrectmuscles.[189]Synkinesisisassociatedwithcorticosteroiduse.[189]Inlonger-termfollow-up,16–23%ofLymefacialpalsiesdonotfullyrecover.[189] InEurope,aboutaquarterofpeoplewithBannwarthsyndrome(Lymeradiculopathyandlymphocyticmeningitis)treatedwithintravenousceftriaxonefor14daysanaverageof30daysafterfirstsymptomshadtoberetreated3–6monthslaterbecauseofunsatisfactoryclinicalresponseorcontinuedobjectivemarkersofinfectionincerebrospinalfluid;after12months,64%recoveredfully,31%hadnondisablingmildorinfrequentsymptomsthatdidnotrequireregularuseofanalgesics,and5%hadsymptomsthatweredisablingorrequiredsubstantialuseofanalgesics.[41]Themostcommonlingeringnondisablingsymptomswereheadache,fatigue,alteredsensation,jointpains,memorydisturbances,malaise,radicularpain,sleepdisturbances,musclepains,andconcentrationdisturbances.Lingeringdisablingsymptomsincludedfacialpalsyandotherimpairedmovement.[41] Recoveryfromlateneuroborreliosistendstotakelongerandbelesscompletethanfromearlyneuroborreliosis,probablybecauseofirreversibleneurologicdamage.[36] AbouthalfthepeoplewithLymecarditisprogresstocompleteheartblock,butitusuallyresolvesinaweek.[44]OtherLymeheartconductionabnormalitiesresolvetypicallywithin6weeks.[44]About94%ofpeoplehavefullrecovery,but5%needapermanentpacemakerand1%endupwithpersistentheartblock(theactualpercentagemaybehigherbecauseofunrecognizedcases).[44]Lymemyocardialcomplicationsusuallyaremildandself-limiting.[44]However,insomecasesLymecarditiscanbefatal.[44] Recommendedantibiotictreatmentsareeffectiveinabout90%ofLymearthritiscases,althoughitcantakeseveralmonthsforinflammationtoresolveandasecondroundofantibioticsisoftennecessary.[36]Antibiotic-refractoryLymearthritisalsoeventuallyresolves,typicallywithin9–14months(range4months–4years);DMARDsorsynovectomycanacceleraterecovery.[180] Reinfectionisnotuncommon.InaU.S.study,6–11%ofpeopletreatedforanEMrashhadanotherEMrashwithin30months.[181]ThesecondrashtypicallyisduetoinfectionbyadifferentBorreliastrain.[190] Peoplewhohavenonspecific,subjectivesymptomssuchasfatigue,jointandmuscleaches,orcognitivedifficultiesformorethansixmonthsafterrecommendedtreatmentforLymediseasearesaidtohavepost-treatmentLymediseasesyndrome(PTLDS).Asof2016thereasonforthelingeringsymptomswasnotknown;theconditionisgenerallymanagedsimilarlytofibromyalgiaorchronicfatiguesyndrome.[191] Epidemiology[edit] CountrieswithreportedLymediseasecases. LymediseaseoccursregularlyinNorthernHemispheretemperateregions.[192] Africa[edit] InnorthernAfrica,B.burgdorferisensulatohasbeenidentifiedinMorocco,Algeria,EgyptandTunisia.[193][194][195] Lymediseaseinsub-SaharanAfricaispresentlyunknown,butevidenceindicatesitmayoccurinhumansinthisregion.TheabundanceofhostsandtickvectorswouldfavortheestablishmentofLymeinfectioninAfrica.[196]InEastAfrica,twocasesofLymediseasehavebeenreportedinKenya.[197] Asia[edit] B.burgdorferisensulato-infestedticksarebeingfoundmorefrequentlyinJapan,aswellasinnorthwestChina,Nepal,ThailandandfareasternRussia.[198][199]BorreliahasalsobeenisolatedinMongolia.[200] Europe[edit] InEurope,LymediseaseiscausedbyinfectionwithoneormorepathogenicEuropeangenospeciesofthespirochaeteB.burgdorferisensulato,mainlytransmittedbythetickIxodesricinus.[201]CasesofB.burgdorferisensulato-infectedticksarefoundpredominantlyincentralEurope,particularlyinSloveniaandAustria,buthavebeenisolatedinalmosteverycountryonthecontinent.[202]NumberofcasesinsouthernEurope,suchasItalyandPortugal,ismuchlower.[203]DiagnosedcasesinsomeWesternCountries,suchasIceland,arerising.[204] UnitedKingdom[edit] IntheUnitedKingdomthenumberoflaboratoryconfirmedcasesofLymediseasehasbeenrisingsteadilysincevoluntaryreportingwasintroducedin1986[205]when68caseswererecordedintheUKandIrelandcombined.[206]IntheUKtherewere23confirmedcasesin1988and19in1990,[207]but973in2009[205]and953in2010.[208]Provisionalfiguresforthefirst3quartersof2011showa26%increaseonthesameperiodin2010.[209] Itisthought,however,thattheactualnumberofcasesissignificantlyhigherthansuggestedbytheabovefigures,withtheUK'sHealthProtectionAgencyestimatingthattherearebetween2,000and3,000casesperyear,[208](withanaverageofaround15%oftheinfectionsacquiredoverseas[205]),whileDrDarrelHo-Yen,DirectoroftheScottishToxoplasmaReferenceLaboratoryandNationalLymeDiseaseTestingService,believesthatthenumberofconfirmedcasesshouldbemultipliedby10"totakeaccountofwronglydiagnosedcases,testsgivingfalseresults,suffererswhoweren'ttested,peoplewhoareinfectedbutnotshowingsymptoms,failurestonotifyandinfectedindividualswhodon'tconsultadoctor."[210][211] DespiteLymedisease(Borreliaburgdorferiinfection)beinganotifiablediseaseinScotland[212]sinceJanuary1990[213]whichshouldthereforebereportedonthebasisofclinicalsuspicion,itisbelievedthatmanyGPsareunawareoftherequirement.[214]Mandatoryreporting,limitedtolaboratorytestresultsonly,wasintroducedthroughouttheUKinOctober2010,undertheHealthProtection(Notification)Regulations2010.[205] AlthoughthereisagreaternumberofcasesofLymediseaseintheNewForest,SalisburyPlain,Exmoor,theSouthDowns,partsofWiltshireandBerkshire,ThetfordForest[215]andtheWestcoastandislandsofScotland,[216]infectedticksarewidespread,andcanevenbefoundintheparksofLondon.[207][217]A1989reportfoundthat25%offorestryworkersintheNewForestwereseropositive,aswerebetween2%and4–5%ofthegenerallocalpopulationofthearea.[218][219] Testsonpetdogscarriedoutthroughoutthecountryin2009indicatedthataround2.5%ofticksintheUKmaybeinfected,considerablyhigherthanpreviouslythought.[220][221]Itisthoughtthatglobalwarmingmayleadtoanincreaseintickactivityinthefuture,aswellasanincreaseintheamountoftimethatpeoplespendinpublicparks,thusincreasingtheriskofinfection.[222] NorthAmerica[edit] ManystudiesinNorthAmericahaveexaminedecologicalandenvironmentalcorrelatesofthenumberofpeopleaffectedbyLymedisease.A2005studyusingclimatesuitabilitymodellingofI.scapularisprojectedthatclimatechangewouldcauseanoverall213%increaseinsuitablevectorhabitatbytheyear2080,withnorthwardexpansionsinCanada,increasedsuitabilityinthecentralU.S.,anddecreasedsuitablehabitatandvectorretractioninthesouthernU.S.[223]A2008reviewofpublishedstudiesconcludedthatthepresenceofforestsorforestedareaswastheonlyvariablethatconsistentlyelevatedtheriskofLymediseasewhereasotherenvironmentalvariablesshowedlittleornoconcordancebetweenstudies.[224]Theauthorsarguedthatthefactorsinfluencingtickdensityandhumanriskbetweensitesarestillpoorlyunderstood,andthatfuturestudiesshouldbeconductedoverlongertimeperiods,becomemorestandardizedacrossregions,andincorporateexistingknowledgeofregionalLymediseaseecology.[224] Canada[edit] Owingtochangingclimate,therangeofticksabletocarryLymediseasehasexpandedfromalimitedareaofOntariotoincludeareasofsouthernQuebec,Manitoba,northernOntario,southernNewBrunswick,southwestNovaScotiaandlimitedpartsofSaskatchewanandAlberta,aswellasBritishColumbia.CaseshavebeenreportedasfareastastheislandofNewfoundland.[110][225][226][227]Amodel-basedpredictionbyLeightonetal.(2012)suggeststhattherangeoftheI.scapularistickwillexpandintoCanadaby46 km/yearoverthenextdecade,withwarmingclimatictemperaturesasthemaindriverofincreasedspeedofspread.[228] Mexico[edit] A2007studysuggestsBorreliaburgdorferiinfectionsareendemictoMexico,fromfourcasesreportedbetween1999and2000.[229] UnitedStates[edit] CDCmapshowingtheriskofLymediseaseintheUnitedStates,particularlyitsconcentrationintheNortheastMegalopolisandwesternWisconsin. Eachyear,approximately30,000newcasesarereportedtotheCDC;however,thisnumberislikelyunderestimated.TheCDCiscurrentlyconductingresearchonevaluationanddiagnosticsofthediseaseandpreliminaryresultssuggestthenumberofnewcasestobearound300,000.[230][231] Lymediseaseisthemostcommontick-bornediseaseinNorthAmericaandEurope,andoneofthefastest-growinginfectiousdiseasesintheUnitedStates.OfcasesreportedtotheUnitedStatesCDC,theratioofLymediseaseinfectionis7.9casesforevery100,000persons.InthetenstateswhereLymediseaseismostcommon,theaveragewas31.6casesforevery100,000personsfortheyear2005.[232][233][234] AlthoughLymediseasehasbeenreportedinallstates[230][235]about99%ofallreportedcasesareconfinedtojustfivegeographicareas(NewEngland,Mid-Atlantic,East-NorthCentral,SouthAtlantic,andWestNorth-Central).[236]New2011CDCLymecasedefinitionguidelinesareusedtodetermineconfirmedCDCsurveillancecases.[237] EffectiveJanuary2008,theCDCgivesequalweighttolaboratoryevidencefrom1apositivecultureforB.burgdorferi;2)two-tiertesting(ELISAscreeningandWesternblotconfirming);or3)single-tierIgG(oldinfection)Westernblot.[238]Previously,theCDConlyincludedlaboratoryevidencebasedon(1)and(2)intheirsurveillancecasedefinition.ThecasedefinitionnowincludestheuseofWesternblotwithoutpriorELISAscreen.[238] Thenumberofreportedcasesofthediseasehasbeenincreasing,asareendemicregionsinNorthAmerica.Forexample,B.burgdorferisensulatowaspreviouslythoughttobehinderedinitsabilitytobemaintainedinanenzooticcycleinCalifornia,becauseitwasassumedthelargelizardpopulationwoulddilutethenumberofpeopleaffectedbyB.burgdorferiinlocaltickpopulations;thishassincebeenbroughtintoquestion,assomeevidencehassuggestedlizardscanbecomeinfected.[239] ExceptforonestudyinEurope,[240]muchofthedataimplicatinglizardsisbasedonDNAdetectionofthespirocheteandhasnotdemonstratedthatlizardsareabletoinfectticksfeedinguponthem.[239][241][242][243]AssomeexperimentssuggestlizardsarerefractorytoinfectionwithBorrelia,itappearslikelytheirinvolvementintheenzooticcycleismorecomplexandspecies-specific.[78] WhileB.burgdorferiismostassociatedwithtickshostedbywhite-taileddeerandwhite-footedmice,Borreliaafzeliiismostfrequentlydetectedinrodent-feedingvectorticks,andBorreliagariniiandBorreliavalaisianaappeartobeassociatedwithbirds.BothrodentsandbirdsarecompetentreservoirhostsforB.burgdorferisensustricto.TheresistanceofagenospeciesofLymediseasespirochetestothebacteriolyticactivitiesofthealternativecomplementpathwayofvarioushostspeciesmaydetermineitsreservoirhostassociation.[citationneeded] Severalsimilarbutapparentlydistinctconditionsmayexist,causedbyvariousspeciesorsubspeciesofBorreliainNorthAmerica.AregionallyrestrictedconditionthatmayberelatedtoBorreliainfectionissoutherntick-associatedrashillness(STARI),alsoknownasMastersdisease.Amblyommaamericanum,knowncommonlyasthelone-startick,isrecognizedastheprimaryvectorforSTARI.InsomepartsofthegeographicaldistributionofSTARI,Lymediseaseisquiterare(e.g.,Arkansas),sopeopleintheseregionsexperiencingLyme-likesymptoms—especiallyiftheyfollowabitefromalone-startick—shouldconsiderSTARIasapossibility.ItisgenerallyamilderconditionthanLymeandtypicallyrespondswelltoantibiotictreatment.[244] Inrecentyearstherehavebeen5to10casesayearofadiseasesimilartoLymeoccurringinMontana.ItoccursprimarilyinpocketsalongtheYellowstoneRiverincentralMontana.Peoplehavedevelopedaredbull's-eyerasharoundatickbitefollowedbyweeksoffatigueandafever.[235] Lymediseaseeffectsarecomparableamongmalesandfemales.Awiderangeofagegroupsisaffected,thoughthenumberofcasesishighestamong10-to19-year-olds.Forunknownreasons,LymediseaseisseventimesmorecommonamongAsians.[245] SouthAmerica[edit] InSouthAmerica,tick-bornediseaserecognitionandoccurrenceisrising.InBrazil,aLyme-likediseaseknownasBaggio–Yoshinarisyndromewasidentified,causedbymicroorganismsthatdonotbelongtotheB.burgdorferisensulatocomplexandtransmittedbyticksoftheAmblyommaandRhipicephalusgenera.[246]ThefirstreportedcaseofBYSinBrazilwasmadein1992inCotia,SãoPaulo.[247] History[edit] TheevolutionaryhistoryofBorreliaburgdorferigeneticshasbeenthesubjectofrecentstudies.Onestudyhasfoundthatpriortothereforestationthataccompaniedpost-colonialfarmabandonmentinNewEnglandandthewholesalemigrationintothemid-westthatoccurredduringtheearly19thcentury,LymediseasewaspresentforthousandsofyearsinAmericaandhadspreadalongwithitstickhostsfromtheNortheasttotheMidwest.[248] JohnJosselyn,whovisitedNewEnglandin1638andagainfrom1663to1670,wrote"therebeinfinitenumbersoftickshanginguponthebushesinsummertimethatwillcleavetoman'sgarmentsandcreepintohisbreeches,eatingthemselvesinashorttimeintotheveryfleshofaman.Ihaveseenthestockingsofthosethathavegonethroughthewoodscoveredwiththem."[249] ThisisalsoconfirmedbythewritingsofPeterKalm,aSwedishbotanistwhowassenttoAmericabyLinnaeus,andwhofoundtheforestsofNewYork"abound"withtickswhenhevisitedin1749.WhenKalm'sjourneywasretraced100yearslater,theforestsweregoneandtheLymebacteriumhadprobablybecomeisolatedtoafewpocketsalongthenortheastcoast,Wisconsin,andMinnesota.[250] PerhapsthefirstdetaileddescriptionofwhatisnowknownasLymediseaseappearedinthewritingsofJohnWalkerafteravisittotheislandofJura(DeerIsland)offthewestcoastofScotlandin1764.[251]HegivesagooddescriptionbothofthesymptomsofLymedisease(with"exquisitepain[in]theinteriorpartsofthelimbs")andofthetickvectoritself,whichhedescribesasa"worm"withabodywhichis"ofareddishcolorandofacompressedshapewitharowoffeetoneachside"that"penetratestheskin".ManypeoplefromthisareaofGreatBritainemigratedtoNorthAmericabetween1717andtheendofthe18thcentury.[citationneeded] TheexaminationofpreservedmuseumspecimenshasfoundBorreliaDNAinaninfectedIxodesricinustickfromGermanythatdatesbackto1884,andfromaninfectedmousefromCapeCodthatdiedin1894.[250]The2010autopsyofÖtzitheIceman,a5,300-year-oldmummy,revealedthepresenceoftheDNAsequenceofBorreliaburgdorferimakinghimtheearliestknownhumanwithLymedisease.[252] TheearlyEuropeanstudiesofwhatisnowknownasLymediseasedescribeditsskinmanifestations.Thefirststudydatesto1883inBreslau,Germany(nowWrocław,Poland),wherephysicianAlfredBuchwalddescribedamanwhohadsufferedfor16yearswithadegenerativeskindisordernowknownasacrodermatitischronicaatrophicans.[253] Ata1909researchconference,SwedishdermatologistArvidAfzeliuspresentedastudyaboutanexpanding,ring-likelesionhehadobservedinanolderwomanfollowingthebiteofasheeptick.Henamedthelesionerythemamigrans.[253]Theskinconditionnowknownasborreliallymphocytomawasfirstdescribedin1911.[254] Themodernhistoryofmedicalunderstandingofthedisease,includingitscause,diagnosis,andtreatment,hasbeendifficult.[255] Neurologicalproblemsfollowingtickbiteswererecognizedstartinginthe1920s.FrenchphysiciansGarinandBujadouxdescribedafarmerwithapainfulsensoryradiculitisaccompaniedbymildmeningitisfollowingatickbite.Alarge,ring-shapedrashwasalsonoted,althoughthedoctorsdidnotrelateittothemeningoradiculitis.In1930,theSwedishdermatologistSvenHellerströmwasthefirsttoproposeEMandneurologicalsymptomsfollowingatickbitewererelated.[256]Inthe1940s,GermanneurologistAlfredBannwarthdescribedseveralcasesofchroniclymphocyticmeningitisandpolyradiculoneuritis,someofwhichwereaccompaniedbyerythematousskinlesions. CarlLennhoff,whoworkedattheKarolinskaInstituteinSweden,believedmanyskinconditionswerecausedbyspirochetes.In1948,heusedaspecialstaintomicroscopicallyobservewhathebelievedwerespirochetesinvarioustypesofskinlesions,includingEM.[257]Althoughhisconclusionswerelatershowntobeerroneous,interestinthestudyofspirocheteswassparked.In1949,NilsThyresson,whoalsoworkedattheKarolinskaInstitute,wasthefirsttotreatACAwithpenicillin.[258]Inthe1950s,therelationshipamongtickbite,lymphocytoma,EMandBannwarth'ssyndromewasrecognizedthroughoutEuropeleadingtothewidespreaduseofpenicillinfortreatmentinEurope.[259][260] In1970,adermatologistinWisconsinnamedRudolphScrimentirecognizedanEMlesioninapersonafterrecallingapaperbyHellerströmthathadbeenreprintedinanAmericansciencejournalin1950.ThiswasthefirstdocumentedcaseofEMintheUnitedStates.BasedontheEuropeanliterature,hetreatedthepersonwithpenicillin.[261] ThefullsyndromenowknownasLymediseasewasnotrecognizeduntilaclusterofcasesoriginallythoughttobejuvenilerheumatoidarthritiswasidentifiedinthreetownsinsoutheasternConnecticutin1975,includingthetownsLymeandOldLyme,whichgavethediseaseitspopularname.[262]ThiswasinvestigatedbyphysiciansDavidSnydmanandAllenSteereoftheEpidemicIntelligenceService,andbyothersfromYaleUniversity,includingStephenMalawista,whoiscreditedasaco-discoverofthedisease.[263]TherecognitionthatthepeopleintheUnitedStateshadEMledtotherecognitionthat"Lymearthritis"wasonemanifestationofthesametick-borneconditionknowninEurope.[264] Before1976,theelementsofB.burgdorferisensulatoinfectionwerecalledorknownastick-bornemeningopolyneuritis,Garin-Bujadouxsyndrome,Bannwarthsyndrome,Afzelius'sdisease,[265]MontaukKneeorsheeptickfever.Since1976thediseaseismostoftenreferredtoasLymedisease,[266][267]Lymeborreliosisorsimplyborreliosis.[268][269] In1980,Steere,etal.,begantotestantibioticregimensinadultswithLymedisease.[270]Inthesameyear,NewYorkStateHealthDept.epidemiologistJorgeBenachprovidedWillyBurgdorfer,aresearcherattheRockyMountainBiologicalLaboratory,withcollectionsofI.dammini[scapularis]fromShelterIsland,NewYork,aknownLyme-endemicareaaspartofanongoinginvestigationofRockyMountainspottedfever.Inexaminingtheticksforrickettsiae,Burgdorfernoticed"poorlystained,ratherlong,irregularlycoiledspirochetes."Furtherexaminationrevealedspirochetesin60%oftheticks.BurgdorfercreditedhisfamiliaritywiththeEuropeanliteratureforhisrealizationthatthespirochetesmightbethe"long-soughtcauseofECMandLymedisease."BenachsuppliedhimwithmoreticksfromShelterIslandandserafrompeoplediagnosedwithLymedisease.UniversityofTexasHealthScienceCenterresearcherAlanBarbour"offeredhisexpertisetocultureandimmunochemicallycharacterizetheorganism."Burgdorfersubsequentlyconfirmedhisdiscoverybyisolating,frompeoplewithLymedisease,spirochetesidenticaltothosefoundinticks.[271]InJune1982,hepublishedhisfindingsinScience,andthespirochetewasnamedBorreliaburgdorferiinhishonor.[272] AftertheidentificationofB.burgdorferiasthecausativeagentofLymedisease,antibioticswereselectedfortesting,guidedbyinvitroantibioticsensitivities,includingtetracyclineantibiotics,amoxicillin,cefuroximeaxetil,intravenousandintramuscularpenicillinandintravenousceftriaxone.[273][274]Themechanismofticktransmissionwasalsothesubjectofmuchdiscussion.B.burgdorferispirocheteswereidentifiedinticksalivain1987,confirmingthehypothesisthattransmissionoccurredviaticksalivaryglands.[275] Societyandculture[edit] UrbanizationandotheranthropogenicfactorscanbeimplicatedinthespreadofLymediseasetohumans.Inmanyareas,expansionofsuburbanneighborhoodshasledtogradualdeforestationofsurroundingwoodedareasandincreasedbordercontactbetweenhumansandtick-denseareas.Humanexpansionhasalsoresultedinareductionofpredatorsthathuntdeeraswellasmice,chipmunksandothersmallrodents—theprimaryreservoirsforLymedisease.Asaconsequenceofincreasedhumancontactwithhostandvector,thelikelihoodoftransmissionofthediseasehasgreatlyincreased.[276][277]Researchersareinvestigatingpossiblelinksbetweenglobalwarmingandthespreadofvector-bornediseases,includingLymedisease.[278] Controversy[edit] Mainarticle:ChronicLymedisease Theterm"chronicLymedisease"iscontroversialandnotrecognizedinthemedicalliterature,[279]andmostmedicalauthoritiesadviseagainstlong-termantibiotictreatmentforLymedisease.[36][118][280]Studieshaveshownthatmostpeoplediagnosedwith"chronicLymedisease"eitherhavenoobjectiveevidenceofpreviousorcurrentinfectionwithB.burgdorferiorarepeoplewhoshouldbeclassifiedashavingpost-treatmentLymediseasesyndrome(PTLDS),whichisdefinedascontinuingorrelapsingnon-specificsymptoms(suchasfatigue,musculoskeletalpain,andcognitivecomplaints)inapersonpreviouslytreatedforLymedisease.[281] The2008documentaryUnderOurSkinisknownforpromotingconspiracytheoriesabout"chronicLymedisease".[282] Otheranimals[edit] Pets[edit] PreventionofLymediseaseisanimportantstepinkeepingdogssafeinendemicareas.Preventioneducationandanumberofpreventivemeasuresareavailable.First,fordogownerswholivenearorwhooftenfrequenttick-infestedareas,routinevaccinationsoftheirdogsisanimportantstep.[283] Anothercrucialpreventivemeasureistheuseofpersistentacaricides,suchastopicalrepellentsorpesticidesthatcontaintriazapentadienes(Amitraz),phenylpyrazoles(Fipronil),orpermethrin(pyrethroids).[284]TheseacaricidestargetprimarilytheadultstagesofLyme-carryingticksandreducethenumberofreproductivelyactiveticksintheenvironment.[283]Formulationsoftheseingredientsareavailableinavarietyoftopicalforms,includingspot-ons,sprays,powders,impregnatedcollars,solutions,andshampoos.[284] Examinationofadogforticksafterbeinginatick-infestedareaisanimportantprecautionarymeasuretotakeinthepreventionofLymedisease.Keyspotstoexamineincludethehead,neck,andears.[285] Indogs,aseriouslong-termprognosismayresultinglomerulardisease,[286]whichisacategoryofkidneydamagethatmaycausechronickidneydisease.[171]Dogsmayalsoexperiencechronicjointdiseaseifthediseaseisleftuntreated.However,themajorityofcasesofLymediseaseindogsresultincompleterecoverywith,andsometimeswithout,treatmentwithantibiotics.[287][verificationneeded]Inrarecases,Lymediseasecanbefataltobothhumansanddogs.[288] References[edit] ^abcdefghijk"SignsandSymptomsofLymeDisease".cdc.gov.11January2013.Archivedfromtheoriginalon16January2013.Retrieved2March2015. ^abcdefghijklmnopqrstuvwxyzaaabacadaeafagShapiroED(May2014)."Clinicalpractice.Lymedisease"(PDF).TheNewEnglandJournalofMedicine.370(18):1724–1731.doi:10.1056/NEJMcp1314325.PMC 4487875.PMID 24785207.Archivedfromtheoriginal(PDF)on21August2016.Retrieved5July2016. ^ab"LymeDiseaseDiagnosisandTesting".cdc.gov.10January2013.Archivedfromtheoriginalon2March2015.Retrieved2March2015. ^"ConcernaboutLymedisease|CDC".13January2021. 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Barbour,AlanG.(2015).Lymedisease:whyit'sspreading,howitmakesyousick,andwhattodoaboutit.Baltimore.ISBN 9781421417219. Halperin,JohnJay,ed.(2018).Lymedisease:anevidence-basedapproach(2nd ed.).Wallingford,Oxfordshire,UK:CABI.ISBN 978-1786392077. Radolf,JustinD.;Samuels,D.Scott,eds.(2021).Lymediseaseandrelapsingfeverspirochetes:genomics,molecularbiology,hostinteractionsanddiseasepathogenesis.Poole,UK:Caister.ISBN 978-1913652616. Externallinks[edit] WikimediaCommonshasmediarelatedtoBorreliosis. LymediseaseorganizationsatCurlie CDC-LymeDisease LymeDiseaseTests–LabTestsOnline NIH–LymeDisease NICEGuidelines–LymeDisease ClassificationDICD-10:A69.2ICD-9-CM:088.81MeSH:D008193DiseasesDB:1531ExternalresourcesMedlinePlus:001319PatientUK:LymediseaseScholia:Q201989 vteTick-bornediseasesandinfestationsDiseasesBacterialinfectionsRickettsiales Anaplasmosis Boutonneusefever Ehrlichiosis(Humangranulocytic,Humanmonocytotropic,HumanE.ewingiiinfection) Scrubtyphus Spottedfeverrickettsiosis PacificCoasttickfever Americantickbitefever rickettsialpox RockyMountainspottedfever) Spirochaete Baggio–Yoshinarisyndrome Lymedisease Relapsingfeverborreliosis Thiotrichales Tularemia Viralinfections Bhanjavirus Bourbonvirus Coloradotickfever Crimean–Congohemorrhagicfever Heartlandbandavirus Kemerovotickborneviralfever KyasanurForestdisease Omskhemorrhagicfever Powassanencephalitis Severefeverwiththrombocytopeniasyndrome Teteorthobunyavirus Tick-borneencephalitis Protozoaninfections Babesiosis Otherdiseases Tickparalysis Alpha-galallergy Southerntick-associatedrashillness Infestations Tickinfestation SpeciesandbitesAmblyomma Amblyommaamericanum Amblyommacajennense Amblyommatriguttatum Dermacentor Dermacentorandersoni Dermacentorvariabilis Ixodes Ixodescornuatus Ixodesholocyclus Ixodespacificus Ixodesricinus Ixodesscapularis Ornithodoros Ornithodorosgurneyi Ornithodoroshermsi Ornithodorosmoubata Other Rhipicephalussanguineus vteBacterialdiseasesduetogramnegativenon-proteobacteria(BV4)SpirochaeteSpirochaetaceaeTreponema Treponemapallidum Syphilis/bejel Yaws Treponemacarateum(Pinta) Treponemadenticola Borrelia Borreliaburgdorferi/Borreliaafzelii Lymedisease Erythemamigrans Neuroborreliosis Borreliarecurrentis(Lousebornerelapsingfever) Borreliahermsii/Borreliaduttoni/Borreliaparkeri(Tickbornerelapsingfever) LeptospiraceaeLeptospira Leptospirainterrogans(Leptospirosis) ChlamydiaceaeChlamydia Chlamydiapsittaci(Psittacosis) Chlamydiapneumoniae Chlamydiatrachomatis Chlamydia Lymphogranulomavenereum Trachoma Bacteroidetes Bacteroidesfragilis Tannerellaforsythia Capnocytophagacanimorsus Porphyromonasgingivalis Prevotellaintermedia Fusobacteria Fusobacteriumnecrophorum(Lemierre'ssyndrome) Fusobacteriumnucleatum Fusobacteriumpolymorphum Streptobacillusmoniliformis(Rat-bitefever/Haverhillfever) vteBacterialskindiseaseGram+veFirmicutes Staphylococcus Staphylococcalscaldedskinsyndrome Impetigo Toxicshocksyndrome Streptococcus Impetigo CutaneousgroupBstreptococcalinfection Streptococcalintertrigo CutaneousStreptococcusiniaeinfection Erysipelas/Chronicrecurrenterysipelas Scarletfever Corynebacterium Erythrasma Listeriosis Clostridium Gasgangrene Dermatitisgangrenosa Mycoplasma ErysipeloidofRosenbach Actinobacteria Mycobacterium-related:Aquariumgranuloma Borderlinelepromatousleprosy Borderlineleprosy Borderlinetuberculoidleprosy Buruliulcer Erythemainduratum Histoidleprosy Lepromatousleprosy Leprosy Lichenscrofulosorum Lupusvulgaris Miliarytuberculosis Mycobacteriumavium-intracellularecomplexinfection Mycobacteriumhaemophiluminfection Mycobacteriumkansasiiinfection Papulonecrotictuberculid Primaryinoculationtuberculosis Rapidgrowingmycobacteriuminfection Scrofuloderma Tuberculosiscutisorificialis Tuberculosisverrucosacutis Tuberculouscellulitis Tuberculousgumma Tuberculoidleprosy Cutaneousactinomycosis Nocardiosis Cutaneousdiphtheriainfection Arcanobacteriumhaemolyticuminfection GroupJKcorynebacteriumsepsis Gram-veProteobacteria α:Endemictyphus Epidemictyphus Scrubtyphus NorthAsianticktyphus Queenslandticktyphus Flyingsquirreltyphus Trenchfever Bacillaryangiomatosis Africantickbitefever Americantickbitefever Rickettsiaaeschlimanniiinfection Rickettsialpox RockyMountainspottedfever Humangranulocytotropicanaplasmosis Humanmonocytotropicehrlichiosis Flea-bornespottedfever Japanesespottedfever Mediterraneanspottedfever FlindersIslandspottedfever Verrugaperuana Brill–Zinsserdisease Brucellosis Cat-scratchdisease Oroyafever Ehrlichiosisewingiiinfection β:Gonococcemia/Gonorrhea/Primarygonococcaldermatitis Melioidosis CutaneousPasteurellahemolyticainfection Meningococcemia Glanders Chromobacteriosisinfection γ:Pasteurellosis Tularemia Vibriovulnificus Rhinoscleroma Haemophilusinfluenzaecellulitis Pseudomonalpyoderma/Pseudomonashot-footsyndrome/Hottubfolliculitis/Ecthymagangrenosum/Greennailsyndrome Qfever Salmonellosis Shigellosis Plague Granulomainguinale Chancroid Aeromonasinfection ε:Helicobactercellulitis Other Syphilid Syphilis Chancre Yaws Pinta Bejel Chlamydiainfection Leptospirosis Rat-bitefever Lymedisease Lymphogranulomavenereum Unspecifiedpathogen Abscess Periapicalabscess Boil/furuncle Hospitalfurunculosis Carbuncle Cellulitis Paronychia/Pyogenicparonychia Perianalcellulitis Acutelymphadenitis Pilonidalcyst Pyoderma Folliculitis Superficialpustularfolliculitis Sycosisvulgaris Pimple Ecthyma Pittedkeratolysis Trichomycosisaxillaris Necrotizingfascitis Gangrene Chronicunderminingburrowingulcers Fourniergangrene Elephantiasisnostras Blisteringdistaldactylitis Botryomycosis Malakoplakia Gram-negativefolliculitis Gram-negativetoewebinfection Pyomyositis Blastomycosis-likepyoderma Bullousimpetigo Chroniclymphangitis Recurrenttoxin-mediatedperinealerythema Tick-bornelymphadenopathy Tropicalulcer AuthoritycontrolGeneral IntegratedAuthorityFile(Germany) Nationallibraries France(data) UnitedStates Retrievedfrom"https://en.wikipedia.org/w/index.php?title=Lyme_disease&oldid=1062811059" 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