Anais
Brasileiros
de
Dermatologia
www.anaisdedermatologia.org.br
REVIEW
Cutaneous
manifestations
of
bartonellosis
夽,夽夽
Karina
de
Almeida
Lins
a,b,
Marina
Rovani
Drummond
a,b,
Paulo
Eduardo
Neves
Ferreira
Velho
b,c,∗aDepartmentofClinicalMedicine,SchoolofMedicalSciences,UniversidadeEstadualdeCampinas,Campinas,SP,Brazil bLaboratoryofAppliedResearchinDermatologyandBartonellaInfection,SchoolofMedicalSciences,UniversidadeEstadualde Campinas,Campinas,SP,Brazil
cDisciplineofDermatology,DepartmentofClinicalMedicine,SchoolofMedicalSciences,UniversidadeEstadualdeCampinas, Campinas,SP,Brazil
Received4June2018;accepted27February2019 Availableonline2October2019
KEYWORDS
Bartonella;
Skindiseases;
Neglecteddiseases
Abstract Bartonellosis are diseases caused by any kind of Bartonella species. The infec-tion manifestsasasymptomaticbacteremiatopotentially fataldisorders. Manyspeciesare pathogenic to humans, but three are responsible for most clinical symptoms: Bartonella bacilliformis,Bartonellaquintana,andBartonellahenselae.Peruvianwart,causedbyB. bacil-liformis,maybeindistinguishablefrombacillaryangiomatosiscausedbytheothertwospecies. Othercutaneousmanifestationsincludemaculo-papularrashintrenchfever,papulesor nod-ulesincat scratchdisease, andvasculitis (oftenassociated with endocarditis). Inaddition, febrilemorbilliformrash,purpura,urticaria,erythemanodosum,erythemamultiforme, ery-themamarginatus,granulomaannularis,leukocytoclasticvasculitis,granulomatousreactions, andangioproliferativereactionsmayoccur.Consideringthebroadspectrumofinfectionand thepotentialcomplicationsassociatedwithBartonellaspp.,theinfectionshouldbeconsidered byphysiciansmorefrequentlyamongthedifferentialdiagnosesofidiopathicconditions.Health professionalsandresearchersoftenneglectedthisdiseases.
©2019PublishedbyElsevierEspa˜na,S.L.U.onbehalfofSociedadeBrasileiradeDermatologia. ThisisanopenaccessarticleundertheCCBYlicense(http://creativecommons.org/licenses/ by/4.0/).
夽 Howtocitethisarticle:LinsKA,DrummondMR,VelhoPE.Cutaneousmanifestationsofbartonellosis.AnBrasDermatol.2019;94:594---602. 夽夽StudyconductedattheLaboratoryofAppliedResearchinDermatologyandBartonellaInfection,SchoolofMedicalSciences,
Universi-dadeEstadualdeCampinas,Campinas,SP,Brazil.
∗Correspondingauthor.
E-mail:[email protected](P.E.Velho).
https://doi.org/10.1016/j.abd.2019.09.024
0365-0596/©2019PublishedbyElsevierEspa˜na,S.L.U.onbehalfofSociedadeBrasileiradeDermatologia.Thisisanopenaccessarticle undertheCCBYlicense(http://creativecommons.org/licenses/by/4.0/).
Introduction
BartonellosisarediseasescausedbyanyBartonellaspecies.1
They are neglected, re-emergent, and distributed world-wide,affectingmainlypopulationssufferingfrompoverty, withprecarious sanitation,and thatare indirect contact witharthropodsanddomesticanimals.2,3Mostspeciescause
zoonoticdiseases.1,3
Bartonellaspp.arefastidiousGram-negativebacilli,well adaptedtoavarietyofanimalreservoirs,particularly mam-mals.Thesebacteriaarecapableofinfectingandsurviving insideerythrocytes.Theintraerythrocyticphaseallowsfora protectionnichefortheagent,resultinginaprolongedand recurrentinfection.4Thebacteriacanalsoinfect
endothe-lialcells.5
The main route of transmission of Bartonella spp. is from infected humans or animals to new hosts through blood-suckingarthropodvectors.Transmissionthrough ani-malscratcheshasbeenreportedbutitisnotcertain,since fleas are needed for transmission among cats.1,6 Recent
studiesreinforcethehypothesisthatthesebacteriacanbe transmittedthroughblood transfusion,which isa concern for people all over the world since currently thereis no preventive action against this possibility.3,7---9 In addition,
asymptomaticinfectionbyBartonellasp.hasalreadybeen detectedinblooddonors.3,8---18
Bartonellaspp.areresponsibleforabroadclinical spec-trum, from asymptomatic bacteremia to potentially fatal presentations.Althoughthemanifestationsassociatedwith bartonellosis have increased considerably over the past decades,physiciansusuallydonotconsiderthepossibilityof infectionwiththesebacteriaamongdifferentialdiagnoses, exceptincaseswithlocalizedlymphnodeenlargementor endocarditiswithnegativeculture,19,20whichsuggeststhat
bartonellosishasbeenneglectedbythemedicalcommunity, leavingmanycasesundiagnosed.
Clinical
aspects
Amongthe16speciesofBartonellathatarepathogenicto humans,threeareresponsible forthe majority ofclinical symptoms: Bartonella bacilliformis, Bartonella quintana,
andBartonellahenselae.5,21
Until 1993, B. bacilliformis was considered the only species of this genus. It is the etiologic agent of Car-rion’sdisease, previouslyknownastheonly bartonellosis.
B.bacilliformisistransmittedbythefemaleLutzomyia ver-rucarum, endemic in the Peruvian Andes and regions of EcuadorandColombia.
Reports in recent decades of outbreaks in regions of atypicalaltitudestronglysuggest epidemiologicalareasas potentialforexpansion.Currentclimatechangesassociated withhumanactivitieshavecontributedtotheresurgenceof infectionanditsexpansionintonewareas.Climatechanges affectvectordistributionand,additionally,phenomenasuch asElNi˜nohavecausedanincreaseinhumiditylevels,which favorsthe reproduction of vectors and theoccurrence of outbreaks.22,23Somestudiesenvolvinganimalstosearchfor
potentialnewhostshaveshownthatsomespeciesofapes in thejungles of SouthAmerica, such astheFeline Night Monkey(Aotusinfulatus),aresusceptibletoB.bacilliformis
infection.Thesedatawarnoftheriskofexpansionof Car-rion’sdiseaseduetothepossibleadaptation ofvectorsin areasinhabitedbytheseanimals,whichmayserveas dis-easedispersalfacilitators inneighboring endemicregions, includingBrazil.24
The disease is biphasic, with an acute phase (Oroya fever)characterizedbyfever,hemolyticanemia,and tran-sientimmunodeficiencyandachronicphase(Peruvianwart) markedbycutaneousvasoproliferativelesions.1,25
The acute phaseof the disease lasts fromone tofour weeksandseveritycanrangefrommildtofatal. Absence ofantibiotictreatment canleadtoa mortalityrateofup to88%. Thisis caused bythemassiveinvasionof erythro-cytesand initiallyleads tonon-specific symptomssuch as malaise,drowsiness,headache,chills, fever,anorexiaand myalgia, which make the patient increasingly more jaun-diced and confused. As the disease progresses, a severe hemolyticcondition,accompaniedbylymphadenopathyand hepatosplenomegaly,isestablished.Diseaseworseningcan lead to acute respiratory distress, pericardial effusion, myocarditis, endocarditis, delirium, seizures, coma and multipleorganfailure.1,9,25
After an average of two months in the acute febrile phase(which maynotoccur,particularlyin nativesofthe endemic region) the Peruvian wart appears, an eruptive cutaneous manifestation formed by angiomatous lesions, whichisoftenclinicallyandhistologicallysimilartolesions ofbacillary angiomatosis (BA). These lesionsmay present as angiomatous lesions, papules, papule-tumors, or nod-ules. They appearin patches,predominantly onthe face andextremities,andmeasure 0.2---4cmin diameter.They maypersistfor monthsor evenyears,andcanbe accom-paniedby fever,bone, and/orjointpains.The severityof theeruptionisvariableanditappearsnottoberelatedto previousantibiotictreatment.Thisisthetissuephaseof Car-rion’sdiseaseandisself-limiting.26Althoughnotfatal,ifleft
untreated,theselesionspersistaspathogenreservoirsanda sourceofcontagionthroughthevector.Thisinfectionis usu-allytreatedwithrifampicin,althoughstreptomycinisalso effectiveandwasthedrugofchoicebefore1975.Peruvian wartdoesnotrespondtotreatmentwithchloramphenicolor penicillin.Treatmentalternativesincludeciprofloxacinand azithromycinassociatedwithdeflazacort.27Itdoesnotlead
toscarring,exceptwhenthereissecondaryinfection.28,29
Histologically,Peruvianwartlesionsshowaproliferation ofendothelialcellsoftheterminalvasculatureinthedermis andsubcutis.Theacuteandchronicinflammatoryinfiltrate that accompanies the presence of B. bacilliformis in the intersticeandinside the endothelialcells is an important finding,eveninnon-ulceratedlesions.Thelesionscanhave moredifferentiatedand ectaticvessels thatareclinically andhistologically similarto pyogenic granuloma. Cellular atypiacanbeseen,particularlyinmoresolidlesions,with imperceptiblelumensandspindlecellsthatresembleKaposi sarcoma.30
B. quintana was initially associated with trench fever (TF),characterizedbyrecurrentfebrileepisodes.Currently reported in hikers, alcoholics, and AIDS patients in the United States and Europe, the disease has been consid-ered asre-emergent andis the agent implicatedin cases ofchronic bacteremia, endocarditis, andBA. Humans are theonlyknownreservoirsandthetransmissionamongthem
Figure 1 Lesions caused by cat scratches presented by a 28-year-oldmanwithBartonellasp.infectiondetectedby poly-merasechainreaction.
is through body lice, the reason why this pathogen is stronglyassociatedtounsanitaryconditionsandpoor per-sonalhygiene.31Thediseaseisalsoknownasquintanafever
orfive-dayfever, andithasanincubation periodof15---25 days.TFcanbeasymptomaticorsevere.Approximatelyhalf ofthoseaffectedexperienceasuddenonsetofflu-like symp-tomswithnorespiratorysymptomsandshortduration.High andprolongedfever can occurover severalweeks. Symp-tomsremitformanydaysandafteranasymptomaticperiod therecanbeparoxysmalclinicalexacerbationthreetofive times or more within a year.30 Eighty to 90% of patients
presentwitherythematous,maculopapularlesionsofupto 1cmonthetrunk.32Furredtongue,conjunctivalcongestion,
andmusculoskeletalpainarefrequentlyassociated.33
B.henselae isazoonoticagentwhosemain reservoiris domestic cats. Transmission between cats does not occur intheabsenceoffleas,althoughtransmissiontohumansis often associatedwith cat scratches. Fig.1 shows the cat scratchobservedina28-year-oldmanwithTypeIdiabetes, presentingwithnauseaandvomitingforthreedaysand low-eringofconsciousnessforoneday.HehadGlasgow3levelof consciousnessandsepsisofunknownorigin.Thereweretwo injuriesthatsuggestedscratchinglesions.Infectionby Bar-tonellasp.wasdetectedthroughconventionalpolymerase chainreaction(PCR)fortheinternaltranscribedspacer(ITS) regionfromabloodsample.
Contact with cats is a risk factor for B. henselae
infection.34 Cats living in warm and humid geographical
areashaveahighernumberofpotentialvectorsandhigher levelsofbacteremia(7---%---43%)andanti-B.henselae sero-prevalence(4%---81%).25,35 ThissuggeststhatBartonellasp.
infection could be more prevalent in developing tropical countries.InCampinas,SP,Brazil,90.2%ofthecatsinvolved inthestudywerepositiveforthetestdetectingthepresence ofB.henselaeDNAintheirblood.36
Besidescats, otherpetsalreadydescribedasreservoirs includeguineapigs,rabbits,anddogs.37
Tickshavebeenproventobevectors37andcontactwith
thesearthropods has been associated withBartonella sp. infection in blood donors from Hemocentro at Unicamp (Campinas,SP).34
Immunocompetent patients infected with B. henselae
candevelop catscratchdisease(CSD),characterizedby a self-limitedregionallymphadenitisassociatedwithfever.
ForBassetal.38intheirreview,CSDincidenceis
propor-tionaltothedensityofthecatpopulation,theirages,and humanexposuretotheseanimals.Theauthorsalsorelated theincidenceofthediseasetotheprevalenceanddegree ofinfestationbyfleas,Ctenocephalidesfelis,towarmand humid climates,relatedtogeographicallocationand sea-sonality, reinforcingthat thedisease is moreprevalent in tropicalregions.
Lymphadenitis follows the primary lesion, from a few daysto many weeksafter the catscratch or bite, appar-ently by the exposure of the dermis tobacteria found in thefecesoffelinefleas.Itischaracterizedbyan erythema-tous, non-pruriticpapuleonthe areaofthetrauma oron itsextremity,incaseof ascratch.In2---3daysitbecomes vesicular and crusty, remainingfor a few days and evolv-ing to a patch that can last for up to 2---3 months. The lesionpersistsfor 7---21daysor issometimes presentwith lymphnodeenlargement.Rarely,thecutaneouslesionisthe onlyclinicalmanifestation,evenwhenthereishistoryofa scratchorbite.Thepresenceoftheinoculationlesionshould bethoroughly sought inthehistory andphysical examina-tion,sinceitcanbefoundinover90%ofcases.25Afterthis
periodthere can besuperficial scarringsimilar tothat of varicella.Itmaymeasurefromafewmillimetersto1cmin diameter.30
Thehistopathology ofcutaneouslesionsmimicsthat of lymph nodes, with the formation of granulomas with a centralnecroticarea,surroundedbylymphocytesand his-tiocytesandwithaneutrophilicinfiltrate.Thepus canbe loculed,whichisimportantduringaspiration.Itdiffersfrom othergranulomatousdiseaseswiththepresenceof concur-rent microabscesses and granulomas.39 Histopathological
findingsin lymphnodescanbemistaken forthoseseen in Hodgkin’sdisease,includingcellssimilartoReed---Stenberg cells.40 Microabscesses with bacterial clusters identified
withtheWarthin---Starrystainingmaybeobserved,mainly onnewerlesions.26
Althoughrare,purpura canbeserious.41 Maculopapular
exanthem, erythema multiforme, and erythema nodosum are the cutaneous manifestations that, for Warwick,42
accompany CSD. For that author, erythema nodosum is the most frequent, to which Carithers,43 who does not
see this association asa surprise, agrees, sinceerythema nodosum appears in the course of other granulomatous diseases such as tuberculosis and sarcoidosis. Erythema nodosumcanoccurinassociationwithtypicalcasesbut usu-allyappearsassociatedwithdiffuseandnon-regionallymph nodeenlargement.44
B.henselaealsocausesawidevarietyofclinical condi-tions,suchasfeverofunknownorigin,splenicandhepatic manifestations, encephalopathies, ocular diseases, endo-carditis,etc.1
PatientsinfectedbyB.quintanaorB.henselae, particu-larlythosewhoareimmunodeficient,candevelopBA,which ischaracterizedbyangioproliferativelesions.21Specifically
in cases of B.henselae infection, theseinjuries may also beassociatedwithpeliosis,arareconditioncharacterized bysmallblood-filledcysticspacesfoundintheliver,often diagnosedonlythroughbiopsy,whichmaycauseliverfailure
Figure 2 Bacillary angiomatosis: (A) single angiomatous lesiononthethirdinterdigitoftherighthandofawoman;(B) electronmicroscopyofcutaneousfragmenttransmissionwith innumerableGram-negativebacillifeaturingintra-and extra-cellulardistribution(1200×,inset16,000×).
orruptureandmayevenbefatal.21,45Bacillarypeliosiscan
alsoaffectotherorgans.46
CutaneouslesionsarethemainmanifestationsofBAbut thediseasemaynotaffecttheskininupto45%ofcases.47
They may be solitary lesions, but, more frequently, are multiple and widespread. They may be papules, plaques, angiomatoustumors,rarelyhyperkeratotic,ornoduleswith skin-coloredsurface.Ascalingcollaretteonthebaseofthe lesionisa typicalfeature.Theyresemble pyogenic granu-loma.Theyarefriableandcanbleedeasilyandprofusely. Thepresentationofhardenedandhyperpigmentedplaques is theleastfrequent. Therearereports ofinvolvementin the oral, anal, conjunctival, gastrointestinal, and female genital mucous membranes, as well as airways. BA can be accompanied by disseminated visceral disease both in immunodeficient and immunocompetent individuals.38,48,49
Fig.2showsthecaseofasingleangiomatouslesioninthe third interdigit of the right hand of a 26-year-old woman presentingwithfever,oralcandidiasis,andweightlossfor2 months.Anti-HIVserologywasreagent. Anatomopathologi-calexaminationwascompatiblewithbacillaryangiomatosis andWarthin---Starrystainingshowedbacterialclumps. Gram-negativebacilliwereobservedthroughtheanalysisofaskin fragmentusingtransmissionelectronmicroscopy.
Differential diagnosis with Kaposi sarcoma can be clinically impossible, particularly with early sarcomatous lesions. Both diseases can occur at the same time. Any other angiomatous lesionswill be part of the differential diagnosis.26,30
Regarding histology, there are three main features: (1) angioproliferation in lobules, with vessels formed by prominentendothelialcells,withatypiaandmitosesbeing seen in areas withdense cellularity; (2)predominance of neutrophils in the inflammatory infiltrate and occasional leukocytoclasia; (3) presence of interstitial or intracellu-lar bacterial clumps found with Warthin---Starry staining, immunohistochemistry,transmissionelectronmicroscopy,or confocalmicroscopy.26,30,50
It has been suggested that the difference between the angiogenic and granulomatous response triggered by the organism observed in BA and CSD, respectively, appears to be determined by the degree of the host’s immunocompetence.51,52 The concurrence of lesions with
clinical and pathological features of CSD and BA, also reported after the use of corticosteroids, with the
Figure3 Cutaneousvasculitisonthelegofa42-year-oldman withahistoryofcatscratchesandfever,withadiagnosisofB. henselaeendocarditisconfirmedbypolymerasechainreaction, serology,andculture.
demonstration of the same agent, supports the above interpretation.53
Bartonella spp. can cause asymptomatic cyclic bac-teremiainhumansandanimals.Thischronicinfectioncan potentiallyresultinendocarditisandbefatal.1Nearly31%of
endocarditiscaseshavenegativeculturesandofthose,upto 30%arecausedbyBartonellaspp.20SixspeciesofBartonella
havebeen associatedwithendocarditis, but 95%of endo-carditiscasesfromtheseagentsarecausedbyB.quintana
orB.henselae.54Vasculitiscanoccurandevensimulate
sys-temicvasculitiswithantineutrophilcytoplasmicantibodies (ANCA)positivity(Fig.3).55Fig.3showsacaseofskin
vas-culitisseenina42-year-oldwhitemalewithahistoryofcat scratchesandfeverfor2months.Skinlesionshadappeared onhislegstwoweeksearlier.Thediagnosisofendocarditis causedbyB.henselaewasconfirmedbyserology,PCRand culture.
B. henselae can cause chronic non-specific hepatic inflammationinadultsandchildren.Itcanalsobe responsi-bleforhepaticangiomatosisandbacillarypeliosis,besides granulomatous hepatitis, with or without necrosis. Bar-tonellaspp.arenotincludedinguidelinesforthescreening ofcryptogenichepatitisanditispossiblethatpartofthe40% ofdenovohepatitiscasesthatoccurafterlivertransplants arerelatedtoinfectionbythesebacteria.56
Often identified as the clinical expression of atypical CSD, non-classic forms of the disease should be consid-ered separately, sch asmorbilliform exanthem, urticaria, erythemamarginatum,granulomaannulare, leukocytoclas-ticvasculitis.32,41 Fig.4showsacaseofannulargranuloma
ina52-year-oldwomanwhoreportedalesionsimilartothe imageatthesiteofacatscratchonherleftforearmseven yearsearlier. The lesionsspread.Shehadintense myalgia andarthralgiathatmadewalkingdifficult.Chestand abdom-inal tomography showed mediastinal and retroperitoneal multiple lymph node enlargement. She had been treated
Figure 4 Annular granuloma presented by a 52-year-old woman.B.henselae DNA was amplifiedinafragmentofthe mediastinallymphnodeandinthepatient’sblood.
Figure5 Sclerosingpanniculitiswithrecurrentanemia. Scle-rosingpanniculitisintherightlegofa32-year-oldwomanwith ahistoryofrecurrentanemia ofunknown origin.Thepatient subsequentlytestedforpositiveB.henselaeDNAinblood sam-ples.
withdeflazacort7.5mg/d, methotrexate15mg/week and hydroxychloroquine400mg/d for2years,withadiagnosis ofsarcoidosis.Theanatomopathologicalexaminationofthe skin wascompatiblewithannular granuloma. B.henselae
DNAwasamplifiedinafragmentofamediastinallymphnode andinthepatient’sblood.
Pyogranulomatous panniculitis was described in a dog whoseownerhadsimilarlesions.Bothimprovedwith treat-mentfor Bartonella sp.infection.57 The authors followed
a 32-year-old woman with sclerosing panniculitis, with a granulomatous reaction on her right leg detected dur-ing histological analysis and history of recurrent anemia of unknown origin, dependent on corticosteroids for 4 years.ElectronmicroscopyshowedGram-negativebacteria insideanerythrocyte.Hercaseimprovedwitherythromycin treatment.Withthediscontinuationoftheantibiotic ther-apy after six weeks, the lesions recurred and no longer respondedtoantibiotic therapy.Ablood sample fromthe patient was subsequently screened for B. henselae DNA, whichshowedtobepositive(Fig.5).
Cutaneous manifestations can appear whether or not associatedwithgranulomatous manifestation ontheliver,
Table 1 Idiopathicmanifestations potentiallyassociated toBartonellaspp.infection.
Prolongedfever
Recurrentorsevereanemia Hepatitis Serositis Chroniclymphadenopathy Chronicfatigue Uveitis Retinitis Neuritis
Febrilemaculopapularexanthem Purpura Urticaria Erythemanodosum Erythemamultiforme Erythemamarginatum Granulomaannulare Leukocytoclasticvasculitis Granulomatousreactions Angioproliferativereactions
spleen, heart, bones, and mesenteric and/or mediastinal lymphnodes.30
A growing number of possible immune parainfectious or post-infectious manifestations have been described in association with Bartonella spp. infection.41 Considering
the broad spectrum of the infection and the potential complications associatedtoBartonella spp., theinfection shouldbeconsideredbyphysiciansmorefrequentlyamong thedifferentialdiagnosesofidiopathicconditions.The con-ditions that shouldincludeBartonella sp. infectionin the differentialdiagnosisarelistedinTable1.
Possibilityoftransmissionbybloodtransfusion
Since Bartonella spp. can causeasymptomatic infections, theextent oftheinfection mightbeunderestimated.The worldwide seroprevalence of Bartonella sp. in humans ranges from 1.5% to77.5%.58 In a study with 437 healthy
patients from arural region in Piau, MGBrazil, the sero-prevalence was 12.8% for B. quintana and 13.7% for B. henselae.59 In another study conducted with 125 blood
donorsin RiodeJaneiro,43 (34.4%)wereseropositivefor
B.henselae.13
Asymptomatic hosts with erythrocytic infection can donate blood. Ina recent study with500 blood donors in Campinas,SP,Brazil,antibodiestoB.quintanaandB. hense-laeweredetected in 32.0%(136/500) and16.2% (78/500) ofthedonors,respectively. The samestudyfound3.2% of blooddonorswithBartonellaspp.blood infection;in1.2% of them, B. henselae bacteremia was documented inthe donatedblood.3
Blood transfusion represents a potential risk for the transmission of these bacteria. Cats were experimentally infectedwithB.henselaeandB.clarridgeiaethrough intra-venousandintramuscularinoculationwiththebloodofcats known tobe infected.60 Inaddition, transmissionthrough
transfusion has been documented in immunocompetent mice.7Astudyusingtransmissionelectron microscopyand
culturedocumentedtheabilityofB.henselaetosurvivein blood stored at 4◦C for 35 days.61 Thereare tworeports
ofthetransmissionoftheinfectiontohumansthrough acci-dentalpercutaneousinjectionwithcontaminatedblood.62,63
The actual worldwide prevalence among blood donors is unknownandroutinescreeningofdonatedbloodisnot con-ductedforthesepathogens.
Laboratorydiagnosis
There is no standard laboratory diagnosis for infections causedbyBartonellaspp.Itisincreasinglyclearthatnone of thediagnosticmethods available currentlywillconfirm
Bartonella sp.infection in allinfected immunocompetent patients,sincethisgrouphaslowbacteremia,whichmakes detection even more difficult.19 This difficulty in
labora-torydiagnosisisanothercontributingfactorforneglecting this pathogen. Nowadays, it is clear that multiple tech-niquesmustbeusedincombinationtoavoidfalse-negative results.3,64 The most common laboratory diagnostic tools
areindirectimmunofluorescence(IIF)serology,culture,or PCR.65---67
IIFis themost commonmethodbecauseofits simplic-ity.However,immunologicmethods have somelimitations such as cross-reaction among species and with multiple pathogens,whichcanleadtofalse-positiveresults.Thereis alsothepossibilityoffalse-negativeresultssincethe anti-gensfromcommercialkitsarelimitedtoafewspecies.68,69
Other factorsthat should betaken intoconsideration are theheterogeneityamongthestrainsandgenotypesof Bar-tonellaspp.,thedifferencesinanalysisparametersamong pathologists,andthesubjectivityofreadingtheresultswith IFA.Manystudieshavedemonstratedthelackofcorrelation betweenPCRandpositiveserology.64 Ingeneral,the
sero-logic test should not beused asthe only diagnostictools and,in caseof positivity,it shouldonlybe interpretedas pastexposuretoBartonellasp.Serologictestingshouldbe usedwithothertechniquessuchascultureandPCRtoassure diagnosticaccuracy.70
The use of conventional microbiologic techniques to detect and isolate Bartonella spp. is not as efficientdue to the fastidious nature of these bacteria, the low num-ber of circulating bacteria in infected organisms, and the cyclical bacteremia. Isolation requires a long incu-bation period (six to eight weeks) and special growth conditions (special culture media enriched with blood above 35◦C, in a saturated water atmosphere with 5% CO2).35,71,72 Primary isolation is rarely successful in
non-reservoirand/orimmunocompetenthosts,aswellashumans with CSD.71---74 Liquid culture of Bartonella spp. increases
detection sensitivity of infection by these bacteria via
molecularmethods.72,73,75
There isnoconsensusabout thebestprimersand con-ditionstobeusedfordetectionofBartonellaDNAthrough PCR. Besidesthe primersthatdetermine theregiontobe amplified and, therefore, the sensitivity of the reaction, thechosenPCRtechniquealsoinfluencesthesuccessofthe diagnosis.DoubleamplificationPCRcanenhancedetection sensitivity considerably, aswell as real-time PCR.35,67,75,76
Theadvantagesofdiagnosticmoleculartechniquessuchas PCRarefastresultsandthepossibilityofidentificationof
thespeciescausingtheinfection.77Nonetheless,thereare
limitations,suchasthepossibilityoffalse-positiveresults (through contaminationof previously positive samples) or false-negativeresults(duetoanamountofDNAinferiorto thedetectionthreshold).Inaddition,findingthepathogenic DNAinasample does notnecessarily guaranteeanactive infection.78,79
Histologyisnotfrequentlyusedasadiagnosticmethod butcanbeveryvaluablefor BAcases,Peruvianwart,and CSD,orwhenthereistissueinvolvement,evenifnot cuta-neous.Cutaneoushistologicfindingsweredescribedabove.
Therapeutics
Thereisnotherapeuticregimenthatguaranteeseradication ofBartonellafromtheorganism.Thiscanbeeasily demon-stratedbytheappearanceofPeruvianwartseveninpatients treatedwithantibioticsforOroyafever.Futhermore, antibi-otictreatmentdoesnotalterthecureratesinpatientswith lymphnodeenlargementcausedbyBartonellaspp.80
Sincetherearenosystematicreviewsonthistopic, treat-mentdecisionsarebasedincasereportsthattestalimited numberofpatients.Patientswithsystemicdiseasecaused byBartonella spp.shouldbetreated withgentamicinand doxycycline;chloramphenicolhasbeen proposedfor treat-ment in case of bacteremia by B.bacilliformis (Carrion’s disease). Gentamicin associated with doxycycline is con-sidered the best treatment for endocarditis and TF, and rifampicinorstreptomycincanalsobeusedtotreat Peru-vianwarts.5ErythromycinistheantibioticofchoiceforBA
andhepaticpeliosiscases;it shouldbeadministeredfora minimumoftwomonths.1
Prevention
As mentioned previously, contact with cats is the main riskfactorfortransmissionofCSDandother formsof bar-tonellosis. Flea infestations, free street access, and an environmentwithmultiplecatsarefactorsthatincreasethe likelihoodoffelineinfection.Therefore,catownersshould avoidfleainfestation,keepingthemindoorsandawayfrom straycats.TheEuropeanAdvisoryBoardonCatDiseases sug-geststhatimmunodeficientpeopleadoptcats olderthan1 yearofage,withnofleas,ingoodgeneralhealth,andthat donotcome fromsheltersor houseswithmultiple cats.81
TopreventTF,peopleshouldavoid contactwithbodylice andimprovepersonalhygiene.Carrion’sdiseasecanbe pre-ventedby the useof repellentsand clothing that protect fromsandflybitesinareaswherethediseaseisendemic.82
Besides these relevant preventive measures, dissemi-nation of information on Bartonella sp. infection to the medical community in general is necessary to avoid the occurrenceofbartonellosis.Neglectingthediseasecertainly contributestothedisseminationoftheinfectionandto inad-equatelytreatedcasesallovertheworld.
Conclusion
Bartonellosis are associated with a broad spectrum of symptoms, debilitating conditions, and potentially fatal
outcomes.Ectoparasitesareinvolvedinthetransmissionof
Bartonellasp.These diseasesarefrequentlyneglectedby healthcareprofessionalsandresearchers.Theinfectioncan beasymptomaticandhaveagreatimpactonthemorbidity of,forexample,patientswithHansen’sdisease(astriggers forType2leprosyreaction),orpatientswithsicklecell ane-mia(associatedwithpainful crisis duetovaso-occlusion), andcryptogenichepatitisorcirrhosis.Diagnosisis challeng-ing because physicians do not consider the possibility of bartonellosisand,evenwhenthisoccurs,therearetechnical andlaboratorydifficultiesforaconclusivediagnosis.There shouldbeincentivesformoreresearchrelatedtoBartonella
spp.infection.Therearelimitedresourcesforthe investi-gationoftheseagentssinceBartonellosisarenoteveninthe listofneglecteddiseasesoftheWorldHealthOrganization.83
However,thesediseasesareamenabletobeingcontrolled, prevented,andeveneradicatedwithplausibleandeffective measures.
Financial
support
DoctoralScholarshipfromCNPq159717/2013-2(Drummond, MR);Productivity Grant fromCNPq301900/2015-9(Velho, PENF).
Author’s
contribution
Karina de Almeida Lins: Approval of final version of the manuscript; conceptualization and planning of the study; compositionofthemanuscript;criticalreviewofthe liter-ature;criticalreviewofthemanuscript.
MarinaRovaniDrummond:Approvaloffinalversionofthe manuscript;compositionofthemanuscript;criticalreview oftheliterature;criticalreviewofthemanuscript.
PauloEduardoNevesFerreiraVelho:Approvaloffinal ver-sionof themanuscript;conceptualization andplanning of thestudy;compositionofthemanuscript;criticalreviewof theliterature;criticalreviewofthemanuscript.
Conflicts
of
interest
Nonedeclared.
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