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ReviewPathogenicfree-livingamoebae:Epidemiologyandclinicalreview`nes:revuee´pide´miologiqueetcliniqueLesamibeslibrespathogeH.Trabelsi,F.Dendana,A.Sellami,H.Sellami,F.Cheikhrouhou,S.Neji,F.Makni,A.Ayadi*Fungalandparasiticmolecularbiologylaboratory,SchoolofMedicineSfax,UniversityofSfax,MagidaBoulilaStreet,3029Sfax,TunisiaARTICLEINFOABSTRACTArticlehistory:
Received27May2011Accepted2March2012AvailableonlinexxxKeywords:Acanthamoebaspp.NaegleriafowleriBalamuthiamandrillarisSappiniasp.EpidemiologyEcologyHumaninfectionsFree-livingamoebaearewidelydistributedinsoilandwater.Smallnumberofthemwasimplicatedinhumandisease:Acanthamoebaspp.,Naegleriafowleri,BalamuthiamandrillarisandSappiniadiploidea.Someoftheinfectionswereopportunistic,occurringmainlyinimmunocompromisedhosts(AcanthamoebaandBalamuthiaencephalitis)whileothersarenonopportunistic(Acanthamoebakeratitis,NaegleriameningoencephalitisandsomecasesofBalamuthiaencephalitis).Although,thenumberofinfectionscausedbytheseamoebaeislow,theirdiagnosiswasstilldifficulttoconfirmandsotherewasahighermortality,particularly,associatedwithencephalitis.Inthisreview,wepresentsomeinformationaboutepidemiology,ecologyandthetypesofdiseasescausedbythesepathogensamoebae.ß2012ElsevierMassonSAS.Allrightsreserved.´SUME´RE´s:MotscleAcanthamoebaspp.NaegleriafowleriBalamuthiamandrillarisSappiniasp.´pide´miologieE´EcologieInfectionshumaines´sdansl’eauetlesol.QuatregenresLesamibeslibressontdesprotozoairesquisontlargementdistribue´senpathologiehumaine:Acanthamoebaspp.,Naegleriafowleri,Balamuthiamandrillarisetsontimplique´esparcesamibessontopportunistes,survenantSappiniadiploidea.Certainesinfectionscause´prime´s(ence´phalitesa`AcanthamoebaetBalamuthia)alorsqueessentiellementchezlesimmunode´ratitesa`Acanthamoeba,meningoence´phalitea`Naegleriaetcertainesd’autressontnonopportunistes(ke´lenombrere´duitdecesinfections,leurdiagnosticreste,encore,´phalitesbalamuthiennes).Malgreence`confirmerexpliquantlamortalite´e´leve´e,associe´eparticulie`rementauxence´phalites.Dansdifficilea´tudionscertainesparticularite´se´pide´miologiques,e´cologiquesetcliniquesconcernantcetterevue,nouse`nes.cesamibeslibrespathoge´serve´s.ß2012ElsevierMassonSAS.Tousdroitsre1.IntroductionFree-livingamoebae(FLA)areubiquitousandopportunisticprotozoawidelydistributedinnature.Theycouldbefoundinsoil,dust,air,seawater,drinkingwater,swimmingpools,sewage,eyewashsolutions,contactlens,dialysisunitsanddentaltreatmentunits[1–6].AmongtheseFLA,onlyfourgenerasuchasAcanthamoeba,Naegleria,BalamuthiaandSappiniaareresponsi-bleforopportunisticandnonopportunisticinfectionsinhumansandotheranimals[7,8].Acanthamoebaspp.haveanassociationwithhumandisease,suchasgranulomatousamoebicencephalitis(GAE),cutaneouslesions,nasopharyngeal,pulmonaryandkidney*Correspondingauthor.E-mailaddress:ali.ayadi@rns.tn(A.Ayadi).infections,primarilyinimmunocompromisedpatients;theyalsocauseamoebickeratitisinimmunocompetentpersons.Balamuthiamandrillaris,acloserelativeofAcanthamoeba,causesskin,lunginfectionsandafatalGAEmostlyinimmunocompetentchildren.Naegleriafowlericausesanon-opportunisticprimaryamoebicmeningoencephalitis(PAM)inhealthychildrenandyoungadults.Sappiniasp.hasbeenreported,onlyonce,fromabraininfectioninahealthyman[9].TheseFLAmayalsobecarriersofpathogenicbacteriasuchasLegionellaspp.,Vibriospp.andListeriaspp.[10–12].ThetaxonomyofFLAwasrevisedseveraltimes,reflectingnewdatafromgenomicsequencingstudies[13,14].Anewtaxonomicclassificationbasedonmorphologic,biochemicalandmolecularapproacheswasproposedbytheInternationalSocietyofProto-zoologists.Thefour-pathogenFLAhasbeenclassifiedundertwo‘‘SuperGroups’’.Therefore,AcanthamoebaandBalamuthiawere0369-8114/$–seefrontmatterß2012ElsevierMassonSAS.Allrightsreserved.doi:10.1016/j.patbio.2012.03.002Pleasecitethisarticleinpressas:TrabelsiH,etal.Pathogenicfree-livingamoebae:Epidemiologyandclinicalreview.PatholBiol(Paris)(2012),doi:10.1016/j.patbio.2012.03.002GModel
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2H.Trabelsietal./PathologieBiologiexxx(2012)xxx–xxxclassifiedunderSuperGroupAmoebozoa:Acanthamoebidae;N.fowleriunderSuperGroupExcavata:Heterolobosia:Vahlk-ampfiidae;andSappiniaunderSuperGroupAmoebozoa:Flabelli-nea:Thecamoebidae[15].group3:hascysts(<19mm)withglobularorovoidendocystsandsmoothorwavyectocysts.Thisgroupincludesfivespecies(A.palestinensis,A.culbertsoni,A.royreba,A.lenticulataandA.pustulosa).2.Acanthamoebaspecies2.1.Epidemiology,ecologyandgrowthinvitroAcanthamoebaisthemostcommonamoebaeandhasawidedistributioninnature.Itisanopportunisticamphizoicprotozoan,whichcanbefoundinsoil,airandwatersamples[16].Itcansurviveinbrackish,freshandseawater,beachsands,sewage,flowerpotsoils,homeaquaria,humidifiers,heating,hospitalenvironment,dentalunits,dialysisunit,contactlens...[7].Itwasalsoisolatedfromvegetables,someanimals(fishes,reptiles,amphibians,dogs,monkeys,birds...),pulmonarysecretions,maxillarysinusandstoolsamples[17].Acanthamoebacantolerateawiderangeofosmolarity,temperature,salinityandpHconditions,allowingthemtosurviveindistilledwater,tissueculture,mammalianbodyfluid.Itcansurviveat378Candathigherbodytemperatures.So,someAcanthamoebaspeciescancausehumaninfectionssuchas:A.castellanii,A.culbertsoni,A.hatchetti,A.healyi,A.astroonyxix,A.divionensisandA.polyphaga[7].Otherspeciesmaybethermo-tolerantbutnonpathogenic.Acanthamoebahastwostagesduringitslifecycle:avegetative¨testage(8–40mm)andadormantcyststage(8–ortrophozoı¨temorphologyischaracterizedbythepresence29mm).Trophozoıofasinglenucleusandafineacanthopodiaprojectingoutwardfromthesurfaceofthebody.Theacanthopodiaallowsparasiteadhesiontosurfaces,cellularmovementsandcapturingpray.¨tefeedonbacteria,algae,yeastorsmallorganicparticlesTrophozoıandoccursbybinaryfission[18].Thisinfectiousandinvasiveformcannotsurvivealongtimeonanadverseenvironmentalcondition(lackoffood,extremesintemperatureandpH,increasedosmolarityorhypo-osmolarity...)anddifferentiateintouninucle-atecystwithadouble-walledstructure(endo-andectocyst).Thisresistantformpossessespores,whichareusedtomonitorenvironmentalchanges.Itisprotectedfromdesiccation,starvationandavarietyofchemicalandphysicianagents[19].Cystshavebeenknowntosurviveinvitroforgreaterorequalto20years[20].Withreturnofoptimalconditionsforgrowth,cystsgerminatetogiverisetotrophicforms.Infact,morethan24speciesofAcanthamoebawereidentifiedbasedonmorphologicalcriteria[16,21].Thesespeciesareassignedintothreegroupsbasedontheirmorphologyandcystsize:However,thisclassificationwasconsideredunreliablesincethereisvariationincystmorphologycausedbycultureconditions.Recently,identificationshaverelieduponsequencingoftheamoebae18SrRNAgenes.Basedonsequencevariation,17differentgenotypes(T1–T17)ofAcanthamoebahavebeenestablished:T1-T12[13],T13[22],T14[23],T15[24],T16[25]andT17[26].Eachgenotypeexhibits5%ormoresequencedivergencebetweendifferentgenotypes.However,thepathogenicityofAcanthamoebacouldbelimitedtosomegenotypesandthemajorityofhumaninfectionshavebeenassociatedwiththeT4genotype[18].AcanthamoebaserveashostsforalargenumberofpathogenicbacteriaincludingLegionellaspp.,Vibriocholerae,Burkholderiacepacia,Listeriamonocytogenes,EscherichiacoliO157,Mycobacteri-umbovis,Mycobacteriumavium[11,27–32].Approximately,20to24%ofclinicalandenvironmentalisolatesofAcanthamoebaharborintracellularbacteria[33].Moreover,Acanthamoebacanharborecho-virus[7].Recently,amimiviruswasdiscoveredinA.polyphaga[34].Inaddition,itisknownthatCoxsackievirusandadenoviruscaninfectAcanthamoeba[35].Theintracellularlocalizationsofthesemicroorganismsprotectthemfromadverseconditionsandallowbacteriatoevadehostdefenses,toresisttoantibioticsactionsandtoincreaseitsvirulence[36].Also,biofilmsformedinaqueousenvironments(intravenouscatheters,contactlens,sclerabuckles,dentalunits...)areknowntobeareservoirofalargenumberofmicroorganisms.TheyplayanimportantroleinthepathogenesisofAcanthamoeba,particularly,inkeratitisinfections.Theyprovidetheparasiteanattractivenicheandanabundantnutrient.LaboratorycultivationofAcanthamoebaisrealizedonnon-nutrientagarmediumseededwithGram-negativebacteria,whicharepreferablynotencapsulatedorpigmented(E.coliorEnterobacter¨teforms.Platesareaerogenes)toallowforgrowthoftrophozoıincubatedat308Cuntiltrophozoiteshavetransformedintocysts[18].Theuseofnon-nutrientagarplatescoveredwithbacteriaisrecommendedforisolationofamoebaebothfromclinicalandenvironmentalsamples.Acanthamoebacan,also,begrowninbacteria-free(axenic)conditionsinanenrichedculturemediummodified(peptone,yeastextract,glucoseandmineralstrace)containingantibiotics(penicillin,streptomycin).Platesareincuba-tedat308Cforupto48hours.Moreover,Acanthamoebacanbeculturedonmammaliancellculturesoronachemicallydefinedmedium[37].group1:thisgroupincludesfourspecies(A.astronyxis,A.comandoni,A.echinulataandA.tubiashi).Thesespeciesarecharacterizedbylargetrophozoites,whileinthecystformsectocystandendocystarewidelyseparatedandexhibitthefollowingproperties:fewerthansixarmswithaveragediameterofcystsgreaterorequalto18mm–A.astronyxis,sixto10armsandaveragediameterofcystsgreaterorequalto25.6mm–A.comandoni,12–14armsandaveragediameterofcystsgreaterorequalto25mm–A.echinulata,Averagediameterofcystsgreaterorequalto22.6mm–A.tubiashi;group2:ectocystsmaybethick,thinandendocystsmaybepolygonal,triangularorroundwithameandiameteroflessthan18mm.Thisgroupisthemostabundantinnatureandincludes11species(A.mauritanensis,A.castellanii,A.polyphaga,A.quina,A.divionensis,A.triangularis,A.lugdunensis,A.griffini,A.rhysodes,A.paradivionensisandA.hatchetti);2.2.HumaninfectionsSeveralspeciesofAcanthamoebacancauseGAE,nasopharyn-gealandcutaneousacanthamoebiasistypicallyinimmunocom-promisedpatientsandapainfulkeratitismostlyincontact-lenswearers.However,consideringthemanyopportunitiesforcontactwithamoebae,Acanthamoebainfectionsarerarelyencounteredinhumansandanimals[7].Chappeletal.[38]showedthatmorethan80%ofnormalhumanpopulationshaveAcanthamoebaantibodies.Therefore,Acanthamoebapathogenicitywastheresultantofseveralprocesses,whichmustoccurtogetheranddependsonitscapacityofmucousadhesionandtissuemigration.2.2.1.SystemicinfectionsSystemicinfectionsincludeGAE,nasopharyngealandcutane-ouslesions.CutaneousornasopharyngealinfectionscanevolveintoGAEasamoebaearecarriedtothecentralnervoussystem(CNS)bythecirculatorysystem.Pleasecitethisarticleinpressas:TrabelsiH,etal.Pathogenicfree-livingamoebae:Epidemiologyandclinicalreview.PatholBiol(Paris)(2012),doi:10.1016/j.patbio.2012.03.002GModel
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2.2.1.1.Granulomatousamoebicencephalitis.GAEisrelativelyrare.Todate,approximately150caseshavebeendescribedworldwide.BecauseoftheproblemsinrecognizingGAE,itispossiblethatothercasesoccurredbutwereundiagnosedormisdiagnosed.InFrance,asingleandfatalcaseofAcanthamoebalenticulataGAE,withextracerebraldissemination,inahearttransplantpatientwasreported[39].GAEisanopportunisticandfataldisease,whichaffectsimmunocompromisedordebilitatedhosts(particularlypatientswithHIV/AIDS,diabeticorhaveundergoneorgantransplantation).However,fewcasesofGAEweredescribedfromindividualswithoutsignsofimmunodepression[17].Thewaysofentryincludethelowerrespiratorytractandskinlesionsfollowedbyhematogenousspread.AcanthamoebaentryintotheCNSmostlikelyoccursthroughtheblood-brainbarrier,particularly,throughtheendothelialliningofcerebralcapillaries[40,41].Infewcases,pathogensthatreachthecerebrospinalfluids(CSF)enterbythechoroidplexus.AffectedorgansotherthantheCNSmayincludethesubcutaneoustissue,skin,liver,lungs,kidneys,adrenalglands,pancreas,prostate,lymphnodesandbonemarrow,whichfurthersuggesthematogenousspread[18].ThecutaneousandrespiratoryinfectionsmaydevelopoverseveralmonthsbuttheinvolvementoftheCNScangivefatalconsequenceswithindaysorweeks.Thepathogenicmechanismsuntilnowareunclear.Thelesionsweremostobservedinthebasalganglia,midbrain,brainstemandcerebralhemisphereswithcharacteristiclesionsintheCNSparenchymaresultinginchronicgranulomatousencephalitis.Themicroscopicfindingsofthepost-mortembiopsiesrevealamoebaetrophozoitesandcysts,predominantlyintheperivascularspacesintheparenchy-ma[18].Thenecroticphaseiscausedbyactivelyfeedingtrophozoiteorinflammatoryprocessessuchasthereleaseofcytokines.GAEisaninsidiousinfectionanddevelopasachronicdiseasespanningfromseveralweekstomonths[7,8].Theprodromalperiodisunknown.Clinicalsymptomsarevariousandassociate:subtleheadache,fever,behavioralchanges,hemiparesis,lethargy,stiffnick,aphasia,ataxia,vomiting,nausea,visualdisturbances,increasedintracranialpressure,andinthelaterstagelossofconsciousness,seizures,comaanddeath.Often,palsywithnumbnessresultinginfacialasymmetrycanbeobserved[17,18].Thetemporalandparietallobesarethemostaffectedtissues.Magneticresonanceimaging(MRI)andcomputedtomography(CT)scansofthebrainshowring-enhancinglesionsorlowdensityabnormalitiesmimickingasingleormultiplespacesoccupyingmass,respectively[42].CSFexaminationgenerallyrevealspleocytosiswithlymphocyticpredominance,increasedproteinconcentrationanddecreasedglucoseconcentration[36].AcanthamoebatrophozoitesandcystscanbedetectedinbraintissueorCSFbybothlightandelectronmicroscopy.Histologicalstaining,suchashematoxylin-eosin(H&E),PeriodicAcidShiff,Gomori’smethenaminesilverortrichrome,canbeusedtoidentifycystsinbraintissuebiopsyorautopsy[43].AcanthamoebacanbedetectedinCSFsedimentstainedwithGiemsa[44].Also,PCRanalysisofDNAextractedfrombiopsymaterialwasdeveloped.Thistechniquemayprovideamorerapiddiagnosis,maybeusefultodistinguishamoebicencephalitiscausedbyAcanthamoebafromB.mandrillarisorN.fowleriandmayofferanopportunityforearliertreatment[45].CurrenttherapeuticagentsforGAE,givenintravenously,includeacombinationofpentamidineisethionate,ketoconazole,sulfadiazine,fluconazole,amphotericinB,azithromycin,itracona-zoleorrifampicin,whichrarelyleadtoasuccessfulprognosis[42].Therefore,amoebicencephalitisisalmostfatalbecauseofdifficultyanddelayindiagnosisthediseaseandlackofoptimalantimicro-bialtherapy[46].Recently,miltefosinehasbeenshowntohaveamoebicidalactivity.Indeed,ithasbeensuccessfullyusedtotreatapatientwithdisseminatedacanthamoebiasis[47].2.2.1.2.Cutaneousacanthamoebiasis.Cutaneousacanthamoebiasisisarareopportunisticinfectioninimmunocompromisedpatients,particularly,inHIVinfectedpatients.ThefirstcaseofcutaneousAcanthamoebainfectioninanAIDSpatientwasreportedin1986[48].Characteristiclesionswerenodules,pustules,papulesandskinulcerationsthatcontainAcanthamoebatrophozoitesandcysts.Themostaffectedsitesoflesionsaretheface,trunkandextremities.Theyarerareinhealthyindividuals.Inimmunocom-promisedpatients,theyarearouteofentryintothebloodstream,followedbythehematogenousspreadtodifferenttissues.TheinvolvementofCNSleadstodeathwithinweeks[49].Positivediagnosiswasobtainedbybiopsyvisualizingnumerousamoebictrophozoitesandcystsinanecroticulcerationwithamixedinflammatorycellinfiltrate.Inaddition,freshtissueshouldbecultivatedontoagarplatesseededwithE.coliorE.aerogenes.Treatmentofcutaneousacanthamoebiasis,withoutCNSinvolvement,includetopicalapplicationsofchlorhexidinegluco-nateandketoconazolecreaminadditiontopentamidineisethionate,ketoconazole,sulfadiazine,flucytosine,fluconazole,oritraconazolethathavesuccessfultherapeuticresults[17].2.2.2.AcanthamoebakeratitisAcanthamoebakeratitis(AK)isacornealmicrobialinfection,whichmostly,developinimmunocompetentpersons.Themainriskfactorsarewearingcontactlensforextendedperiodoftime,cornealtrauma,nonsterilecontactlensrinsing,biofilmformationoncontactlensandswimmingincontaminatedwaterwhilewearingcontactlens.Typically,onlyoneeyeisinvolvedbutbilateralkeratitishasalsobeenreported.Acanthamoebatransmis-sionintothecorneaisdependentonitsvirulenceandthephysiologicalstateofthecornea.Infact,cornealtraumatismisaprerequisiteinkeratitisinnoncontactlenswearsandforindividualswithAK,abrasionofthecorneaisimplicatedin85%ofwearcontactlens.Inrecentyears,thenumberofAKcaseshasbeenincreasingindevelopingcountriescorrelatingtotheincreasednumberofcontactlenswearers.TheestimatednumberofAKis1.36casespermillionscontactlenswearsintheUnitedStates,against17to21casespermillioninEngland[50].InFrance,AKisrarewithonecaseper30,000contactlenswearsbuttheirincidenceisconstantlyincreasing[51].Acanthamoebamustbepresentinthetrophozoitestagetobindtohumancornealepithelialcells.Recentstudieshaveindicatedthatcystsareanineffectivestage[52].WhentrophozoitesformsofAcanthamoebaadheretothecornealepithelium,theyproduceavarietyofproteases,whichfacilitatecornealinvasion,resultinginparasite-mediatedcytolysisofthecornea[53].Theinfectioncausesdestructionofthecornealepitheliumandstroma,infiltra-tionofinflammatorycellsandeventually,formationofdesceme-tocoeleandperforation.Limbitisandscleritiscanalsooccurbyasecondaryimmunologicalreactionorbydirectspreadofinfectionfromthecornea[54].TheclinicalmanifestationsofAKstartwithredness,epiphora,lacrimation,diptosis,conjonctivalhyperhemia,foreignbodysensation,painandphotophobia.Epithelialirregularitiesandopacitiescanbeearlyobservedbuttheyarenon-specificsigns.Insomecases,theepitheliumcanbecompletelyintact.Pseudo-dentriticepitheliallesionrepresentsoneofthefirstsignsofAK.Atthisstage,lesionsmaymimicherpessimplexkeratitis[55].Thecornealsensitivitycanbedecreased,whichremovesthedifferen-tialdiagnosisfromherpessimplex.Inafurtherstageofthedisease,therearestromalabnormalitieslikenummularinfiltratesandPleasecitethisarticleinpressas:TrabelsiH,etal.Pathogenicfree-livingamoebae:Epidemiologyandclinicalreview.PatholBiol(Paris)(2012),doi:10.1016/j.patbio.2012.03.002GModel
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4H.Trabelsietal./PathologieBiologiexxx(2012)xxx–xxxradialkeratoneuritis.Thiskeratoneuritisischaracterizedbyliner,radial,branchinginfiltratesoftheparasitealongthecornealnervesintotheanteriorstromawithanteriorchamberreactionleadingtohypopyonin39%[56].AringshapedstromalinfiltrateisacharacteristicofadvancedinfectionandisnearlypathognomonicforAK.Inthelaterstageofdisease,ifnotdiagnosedearlyandtreatedaggressively,manycomplicationscanoccur:cornealepitheliumulceration,perforation,lossofvisualacuityandeventuallyblindnessandenucleation.Accordingtosomestudies,asymptomaticcarriageincontactslensisnotuncommon,infact,upto8%ofasymptomaticsubjectsorpatientswithoutAKhadcontactlenspositiveAcanthamoebaculture[57].Theamoebaeareonthecontactlensbutdonotinvadethecornea.So,AKdiagnosisisnotconfirmedbytheonlyisolationofAcanthamoebafromcontactlens.Itisdiagnosedbymicroscopicexaminationofcornealscrapingorcornealbiopsy.Thecultureofcornealscraping,biopsyorlenscasesallowsisolationandidentificationoftheamoebae.Theconfocalmicroscopycanbeahelpfulandnoninvasivemethodforthediagnosis.Recently,PCRhasbeenfoundtobemoresensitivediagnostictestthanculture.Soitcouldbeparticularlyusefulinconfirmingtheclinicaldiagnosisinculturenegativepatients[55].TheresistanceofAcanthamoebacyststoanti-microbialsisthemaindifficultyintreatingAK.Infact,Acanthamoebamaypersistintheencystedformformonthsandmayreactivateaftertherapydiscontinuation.Severalvarietiesofdrugscanbeusedincludingchlorhexidine,polyhexamethylenebiguanide,propamidine,isethionate,dibromopropamidineisethionate,neomycin,paro-momycin,polymixinB,clotrimazole,anditraconazole[46].Topicalapplicationofsteroidsiscommon,bothtorelievepainandtolesseninflammation,particularlyfollowingkeratoplasty[7].LikeAcanthamoeba,N.fowlericanharborintracellularbacteriasuchasLegionellapneumophila[17].TheisolationofN.fowleriisperformedonnon-nutrientagarplatescoatedat458Cwithbacteria(preferablynon-mucoidstrains),suchasE.coli,E.aerogenesorKlebsiellapneumonia.Inaddition,N.fowlericanbegrowninanaxenicmediumorinachemicallydefinedmedium,likeAcanthamoebaandBalamuthia[37].3.2.Clinicalmanifestations3.Naegleriafowleri3.1.Epidemiology,lifecycleandgrowthinvitroAmongthe30speciesofNaegleria,onlyonespecies,N.fowleri,wasknownpathogencausinghumanPAM.Itisafree-livingameoboflagellateworldwidedisturbedinsoilandwater.Itissensitivetosomeenvironmentalconditionssuchasdrying,pHextremesandcannotsurviveinseawater[7].N.fowleriisthermophilicanditwasabletogrowattemperatureupto458C.Itcanbefoundinlakes,freshwater,swimmingpools,aquaria,sewage,irrigationcanals,ponds,hotsprings,thermallypollutedstreamsandrivers.ItwasalsoisolatedfromthenasalmucosaofhealthyasymptomaticchildrenandfromnasalpassagesofpatientswithPAM[58].PathogenicstrainsofNaegleriacanalsobegrownintissuecultureat378C,producingeffectthatvarieswiththevirulenceoftheisolate[59].ThelifecycleofNaegleriaincludesamoeboidtrophozoite(10–25mm)andresistantcyststage(8–20mm)withatransitorypear-shapedflagellatestage(10–16mm).Thetrophozoiteisanactiveformthatconstantlychangesinsizeandshape.Itfeedsonbacteriaandotherorganicmatterandundergoesasexualreplication.Theamoeboidformtransformsintoflagellateformthatusuallyhastwoflagellaatthebroadendwhenplacedindistilledwaterordeprivedofnutrients,butitwillconvertbackintotheamoeboidformwhenconditionsarefavorable.Thisstageallowsthedispersionoftheamoebaeinthesoilorinwaterhabitat.Theamoeboidtrophozoiteformcanalsoencystwhenthegrowthconditionsbecomeadverseandthefoodsupplydiminishes.Cystsare,generally,sphericalanddoublewalledwithfinepores.Allstagesarecharacterizedbyasinglenucleuswithalargekaryosomebutnotperipheralchromatin.Onlytheamoeboidformsarefoundintissues.3.2.1.PrimaryamoeboicmeningoencephalitisPAMduetoN.fowlerihasaworldwidedistribution.Morethan300caseshavebeenreportedinternationallymostlyintheUnitedStates,AustraliaandEurope[60].InFrance,thefirstcaseoffatalPAMcausedbyN.fowleriinanimmunocompetent9-year-oldboywasreported[61].PAMisafatalinfectionoftheCNS,whichusually,occursinhealthychildrenandyoungadults.Itoccurs,typicallyinhotsummer,duringrecreationalactivitiesinpollutedwarmfreshwater.N.fowlerientersthebodythroughthenasalpassages.The¨tepenetratestheolfactorymucosaandmigratesalongtrophozoıtheolfactorynerve,crossingthecribriformplateuntilreachingtheolfactorybulbsoftheCNS[62].Withintheolfactorybulbs,Naegleriainduceanintenseinflammatoryresponseassociatedwithlyticnecrosishemorrhagesurroundedbypurulentexudates.Theyarealsoseveralnumeroussuperficialhemorrhagicareasinthecortex.Mostofthelesionswereobservedaroundthebaseoftheorbitofrontalandtemporallobe,baseofthebrain,hypothala-mus,midbrain,pons,medullaoblongata,andtheupperportionofthespinalcord.Indeed,thefrontalandtheolfactorylobesofthebrainaretheinitialtargetsofamoebicdestructionbecauseoftheirproximitytothepointofentranceofamoebaeintotheCNS[7].PAMisafulminateinfectionthatoccurs1to2daysafterexposure.Itincludessevereheadache,nausea,vomiting,fever(38.5–418C),behavioralabnormalitiesandnuckalrigiditywithkerningandBrudzinskisigns.Later,photophobiaandcranialnervepalsiesthatmayindicatebrainedemaandherniationcanbeobserved.Intracranialpressureisusuallyraisedto600mmH2Oorhigher[17].Cardiacrhythmabnormalitiesandmyocardialnecrosishavebeenfoundinsomecases[40].Increasedintracranialpressureandherniationareusuallythecauseofdeath[8,39].Intheadvancedstage,theredbloodcellnumberincreasestoashighas24,600mmÀ3.Thewhitebloodcellcount,predominantlypolymor-phonuclearleukocytes(PMN),alsomayvaryfrom300cellsmmÀ3toashighas26,000mmÀ3.Theproteinconcentrationmayrangefrom100mgper100mLto1000mgper100mL,andglucosemaybe10mgper100mLorlower[8,40].Therapiddiagnosisisobtainedbymicroscopicexamination,preferablyphasecontrast,offreshlydrawnCSF,tovisualizemotileamoebae.Trophozoites,ifpresent,canbeidentifiedbyGiemsaorWrightstainsofCSFsmears.Scansofthebraincanshowobliterationofthecisternaearoundthemidbrainandthesubarachnoidspaceoverthecerebralhemispheres.Markeddiffuseenhancementintheseregionsmaybeseenafteradministrationofintravenouscontrastmedium[8,40].IntreatingPAM,thedrugofchoiceistheantifungalpolyeneantibioticamphotericinB(AMB).Infact,Naegleriaarehighlysensitivetothisdrug,withaminimalamoebicidalconcentrationof0.026to0.078mg/mL[63].Thistreatmentmustbestartedearlyinordertobeeffective.4.Balamuthiamandrillaris4.1.Epidemiology,lifecycleandgrowthinvitroB.mandrillarisistheonlyspeciesofBalamuthiaknowntocauseinfectionsinhumansandanimals.ItisknowntocausePleasecitethisarticleinpressas:TrabelsiH,etal.Pathogenicfree-livingamoebae:Epidemiologyandclinicalreview.PatholBiol(Paris)(2012),doi:10.1016/j.patbio.2012.03.002GModel
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seriouscutaneousinfectionsandfatalencephalitisinvolvingtheCNS[64].UnlikeAcanthamoeba,whichiswidelydistributedintheenvironment,B.mandrillarisispresentinsoilandisdifficulttoisolateandtoculture[65].Thisparasitecannotbeculturedonanagarplatecoatedwithgram-negativebacteriabecauseunlikemostamoebae,B.mandrillarisdoesnotfeedonbacteria.However,amoebicgrowthrequirestheuseoftissueculturecellsasafoodsource[17].Thelifecyclecomprisesatrophicamoeboidstage(50–60mm)largerthanthatofAcanthamoebaandNaegleriaandacyststage(12–30mm)withtriple-layeredwalllackingpores.Thetrophozo-iteispleomorphicand,usually,uninucleatewithavesicularnucleusthatcontainsalargeandcentrallynucleolus.Cystsarealsouninucleateandmoreorlessspherical.Theymaybefoundinthebrain,eyes,skin,lungsandotherorgans[66,67].Recently,ithasbeenshownthatBalamuthiamaybehostsforpathogenicmicroorganismssuchasLegionella[68].Inaddition,Micheletal.[69]haveshownthatB.mandrillarissupportedthegrowthofSimkanianegevensis,aChlamydialikebacterium,butlosttheabilitytoformcysts.isethionate,sulfadiazine,clarithromycin,fluconazoleandflucyto-sine[74,75].5.Sappiniasp.4.2.BalamuthiaamoebicencephalitisBalamuthiacausesencephalitisinfectionssimilartoGAEandoccurs,particularly,inimmunocompromisedhosts(HIVpatients,intravenousdrugusers,debilitedpatients).Ithasbeenalsoreportedfromimmunocompetentindividuals,especiallyyoungchildrenandolderindividuals[17].Balamuthiaamoebicencepha-litis(BAE)hasbeenalsodiagnosedinanimals,includingahorse,asheepanddogs,butmostofteninnon-humanprimates[7].SomecasesofBAEhavenorelationtoseasonalchangesandmayoccuratanytimeoftheyear.Portalofentryisskinlesionscontaminatedbysoil,orcyststransportedbycurrentairtotherespiratorytract.PathogenicmechanismsofinfectionscausedbyB.mandrillarisareunclear.Thisamoebaisexquisitelyencephalotropicandcytopathic,causingextensivebraintissuedamage[70].SomerecentstudieshaveindicatedthatBalamuthiainduceshumanbrainmicrovascu-larendotheliumcellstoreleaseapleotropiccytokineIL6,whichplayaroleininitiatingearlyinflammatoryresponse[71].Furthermore,Balamuthiamaycausethedegradationoftheextracellularmatrixbyametalloproteaseactivity[72].ThediseaseprofileandpathologyofBalamuthiainfectionaresimilartothoseofAcanthamoeba.Theinfectionischronicandthetimebetweentheappearanceofskinlesionsandneurologicalsymptomsmayrangefrom1monthtoabout2years.Symptomsofthecerebralinfectionincludeheadache,photophobia,fever,personalitychange,stiffneck,cerebellarataxia,hemiparesis,aphasiaandseizures.Amoebaemaydisseminatetootherorganssuchaskidney,adrenalglands,pancreas,thyroidandlungbutarenotgenerallyfoundintheCSF[7].Scanscanshowthepresenceoffocalenhancinglesions,cysticlesions,edemaandhydrocephalus,whichmaymimicabrainabscess,braintumor,orintracerebralhematoma[17];thismakesdifficulttheidentificationoftheopportunisticamoebae.Biologically,CSFproteinsandleukocyteswereelevated,glucoselevelwasnormalordecreased.Actually,PCRwasusedtoconfirmthepresenceofBalamuthiainBAEandtocorroborateimmunoflu-orescentantibodiesdiagnosisinclinicalserumsamples[73].Biopsyandhistopathologicexaminationofbraintissuewillconfirmpremortemdiagnosis.However,mostdiagnosisofBAEismadeinpost-mortembyHandEorimmunofluorescencestainingofbraintissue.Indeed,among100casesreported,onlythreesurvivorsareknown,twoinCalifornia[74]andoneinNew-York[75].Theyaretreatedwithacombinationofpentamidine,ThegenusSappiniacomprisestwodistinctspecies,S.pedataandS.diploidea.Thisfree-livingamoebaiswidelydistributedintheenvironmentandhasbeenisolatedfromsoil,freshwater,mammalianfeces,forestlitter,elk,bison,cattleandtherectumoflizard[17].Thelifecycleofthisparasitehastwostages,atrophozoiteandacyst.Thetrophozoiteform(40–80mm)ischaracterizedbythepresenceoftwotightlyopposednuclei,amonopodiallocomotion,andacellsurfacewithoutanysub-pseudopodialprojections.Thecysts(18–25mm)arecharacterizedbytheformationofbicellularcystsasaresultoftwocopulatingtrophozoites,latertransformingintounicellularbinucleatecysts[76].Theyaredouble-walledandhavenuclearpores.Somecellsharbourendocytobioticbacteriaincytoplasmaticvacuoles.Cystscansurvivepassagethroughthestomachwithitsgastricfluid,buttheirintestinalpresenceisnotsynonymofinfection[7].Sappiniasp.hasnotbeenshowntobelethalinhumansorexperimentalanimalsanditwasneverimplicatedinpathologybeforethediscoveryofasinglecaseofencephalitiscausedbythisamoebaoccurredinanimmunocompetentyoungmanwhosurvivedtheinfection[9,77].InthiscasedescribedbyGelmanetal.[9,77],thebraininfectioncausedbySappiniamaydevelopfromanearliersinusinfection.Thesymptomsincludeunconsciousness,seizure,nausea,vomiting,bifrontalheadaches,photophobiaandblurryvisionfor2to3days.A2cmsolitarymasswasdetectedintheposteriorlefttemporallobe.Theexcisedmassonsectioningshowednecrotizinghemorrhagicinflammationcontainingtrophozoiteforms,particu-larly,aroundthebloodvessels.Asuccessfuloutcomeinthispatientwasreportedaftersurgicalexcisionofthenecroticlesionandtreatmentforover31weekswithazithromicin,intravenouspentamidine,itraconazoleandflucytosine.TheamoebaoriginallyidentifiedasS.diploidea,wasidentifiedlaterasS.pedata,byusinganewdevelopedreal-timePCRassaysbasedon18SrRNAgenesequences[78].Amorerecentandexhaustivephylogenicstudyindicatedthatthisstrainmightinfactbeanewspecieswithinthisgenus,whichiscloselyrelatedtoS.pedatathantoS.diploidea[79].6.ConclusionFLAinfectionsareemergingdiseasesthatgained,recently,muchattention.Theseamoebaearecosmopoliteandtheyhavebeenisolatedworldwide.Theyhaveapolymorphicmorphologythatallowsthemtoadapttothevariedenvironmentalconditions.SeveralspeciescanbepathogeniccausingeitherrarebutrapidlyfatalinfectionssuchasNaegleriameningoencephalitis,ormoreinsidiousinfectionssuchasAcanthamoebakeratitisandencepha-litis.Inadditiontocausinghumandisease,FLAcanharborintracellularpathogenicandnon-pathogenicmicroorganismsandmayserveasreservoirsandvectorsofbacterialandviralinfectionsinhumans.SincethemajorityofFLAinfectionsarefatalandtheseamoebaeareimportantwaterreservoirofpathogenicbacteria,suchasL.pneumophila,thedevelopmentofmorerapiddiagnosticmethodsiswellrecommended.DisclosureofinterestTheauthorsdeclarethattheyhavenoconflictsofinterestconcerningthisarticle.Pleasecitethisarticleinpressas:TrabelsiH,etal.Pathogenicfree-livingamoebae:Epidemiologyandclinicalreview.PatholBiol(Paris)(2012),doi:10.1016/j.patbio.2012.03.002GModel
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