Congenitally transmitted visceral leishmaniasis : report of two brazilian human cases

Brazilian Journal of Infectious Diseases

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REFERÊNCIA

MESCOUTO-BORGES, Myrlena Regina Machado et al. Congenitally transmitted visceral

leishmaniasis: report of two brazilian human cases.

​Brazilian Journal of Infectious Diseases​,

Salvador, v. 17, n. 2, p. 263-266, mar./abr. 2013. DOI: https://doi.org/10.1016/j.bjid.2012.10.017.

Disponível em:

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m=iso. Acesso em: 12 ago. 2020.

The

Brazilian

Journal

of

INFECTIOUS

DISEASES

w w w . e l s e v i e r . c o m / l o c a t e / b j i d

Case

report

Congenitally

transmitted

visceral

leishmaniasis:

report

of

two

Brazilian

human

cases

Myrlena

Regina

Machado

Mescouto-Borges

_,

_Érika

_Maués

_,

_Dorcas

_Lamounier

_Costa

_,

Maria

Cristina

da

Silva

Pranchevicius

_,

_Gustavo

_Adolfo

_Sierra

_Romero

a_{UniversidadeFederaldoTocantins,Palmas,TO,Brazil}

b_{LaboratóriodeLeishmanioses,NúcleodeMedicinaTropical,UniversidadedeBrasília,Brasília,DF,Brazil}

c_{HospitalDonaRegina,SecretariadeEstadodaSaúdedoTocantins,Palmas,TO,Brazil}

d_{InstitutodeDoenc¸asTropicaisNathanPortela,UniversidadeFederaldoPiauí,Teresina,PI,Brazil}

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Articlehistory:

Received20July2012 Accepted2October2012 Availableonline27February2013

Keywords: Congenitaltransmission Visceralleishmaniasis Leishmaniainfantum Pregnancy

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Visceralleishmaniasisisarelevantpublichealthproblemworldwide.Mostofthereported casesinLatinAmericaarefromBrazil.Hereinwereporttwohumancasesof congeni-tallytransmittedvisceralleishmaniasisintwopatientswhodevelopedsymptomsduring pregnancy.ThediagnosiswasmadebyvisualexaminationofLeishmaniaparasitesinbone marrowaspiratesofthemothersandbydetectingparasitekDNAinbonemarrowsamples ofthenewbornchildrenusingpolymerasechainreaction.

©2013 ElsevierEditoraLtda.Allrightsreserved.

Introduction

Americanvisceralleishmaniasis(AVL)isanendemicdisease causedbyLeishmaniainfantum(syn.L.chagasi),whichoccurs predominantly intropicaland subtropicalregionsofSouth America.AVListypicallytransmittedtohumansthroughthe biteofthefemalesandflyLutzomyialongipalpis.Otherroutesof transmissionhavebeenreportedinhumanssuchassharingof contaminatedneedlesamongdrugusers,1_{organtransplants}2

andcongenitaltransmission.3_{ClassicmanifestationsofAVL}

are persistent fever, weight loss, progressive anemia or pancytopenia,hypergammaglobulinemia,hepatomegalyand

∗ _{Correspondingauthorat:LaboratóriodeLeishmanioses,NúcleodeMedicinaTropical,UniversidadedeBrasília,CampusUniversitário}

DarcyRibeiro,AsaNorte,Brasília,DF,70904-970,Cx.P.04517,Brazil.

E-mailaddresses:gromero@unb.br,romgustavo@gmail.com(G.A.S.Romero).

splenomegaly.Congenitaltransmissionofvisceral leishman-iasiswasfirstreportedbyLowandCooke4inAfricaandby 2011, ninecases ofAVLwere reportedin pregnantwomen inBrazil.5–8 _{Congenitallytransmittedvisceralleishmaniasis}

hasacourseofdiseasesimilartothatacquiredbythebite ofsandflies.Themajorityofchildrenwithcongenital infec-tionpresentwiththeillnesswithinthefirstyear,buttheexact meansoftransmissionarenotyetcompletelyclear.9–11_Herein

wedescribetwocasesofAVLamongpregnantpatientswho transmittedthediseasecongenitallytotheirinfantsadmitted betweenJan2007andDec2008toDonaReginaHospital,which isatertiaryreferralcenterformaternalandinfantcareinthe cityofPalmas,Tocantins,Brazil.

1413-8670/$–seefrontmatter©2013 ElsevierEditoraLtda.Allrightsreserved. http://dx.doi.org/10.1016/j.bjid.2012.10.017

264

Pregnancy was confirmed by serum levels of ␤-human chorionicgonadotropinhormoneandbyanabdominal ultra-sound. Indirect fluorescent antibody test (IFAT) test was performedinserasamplestodetectantibodiesagainst

Leish-mania,asrecommendedbytheBrazilianMinistryofHealth12_;

bone marrow smears were stained with Giemsa to detect thepresenceofLeishmaniaamastigotes;andagenus-specific polymerasechainreaction(PCR)wasperformedusingbone marrowsamplestodetect120bpoftheconservedregionof parasite kDNA,as reported elsewhere.13 _{The bonemarrow}

aspirateswereobtainedfromthepregnantwomenduring hos-pitalizationandfromthenewbornsduringthefirstweekafter theirdelivery(Fig.1).

ThestudywasconductedinagreementwiththeNational Health Council Resolution number 196/96 which regulates researchinvolvinghumansubjectsinBrazilandtheHelsinki Declaration.Aconfidentialityagreementwas signedbythe researchers to protect the patient identity upon obtaining informationfromtheirmedicalrecords.Allpatientsortheir relatives/legal guardians signed a voluntary and informed consentformauthorizingtheuseoftheirmedicalrecords.

Case

presentation

Case1

A 24-year-old woman from the city of Itacajá, Tocantins, who was pregnant for the second time, was hospitalized withfeverabove38◦C.Duringthesixthmonthofpregnancy shereportedfeverandweightloss.Aphysicalexamination revealedmucocutaneouspallor,dyspneaandslightedemain thelower limbs. Uponreviewofthe abdominalultrasound itwas foundaposteriorplacentaofheterogeneoustexture and stage Imaturity, a 30-weekand 4-day gestational age andafetalheartrateof170beats/min,withnoevidenceof fetalhepatosplenomegaly.Becauseofacutefetaldistress,the patientunderwentacesareansection,resultinginapreterm

Fig.1–Identificationof120bpoftheconservedregionof theLeishmaniaminicircle-kDNAinbonemarrowaspirates fromnewbornsusingpolymerasechainreaction(PCR) revealedin2%agarosegelstainedwithethidiumbromide. Lane1:molecularweightladder(M);lane2:empty;lanes3 and5:bonemarrowfromnewborns1and2,respectively; lane4:negativecontrol(NC)withoutDNA;lane6:positive control(PC)consistingofculturedpromastigotesof

Leishmaniachagasi(syn.Leishmaniainfantum).

newborn.Themotherpresentedwithproductivecough,and the chestX-rayrevealed basalinfiltrationinthe righthemi thorax.Antibiotictherapywithintravenousoxacillinand cef-triaxonewereinitiatedandshereceivedapackedredblood cell transfusion.Giventhe clinical and laboratoryevidence (Table1),thepatientunderwent abonemarrowaspiration, whichrevealedthepresenceofLeishmaniaamastigotes.Thus, shewasstartedonintravenousamphotericinBdesoxycholate 1mg/kg/day. The following day; she had persistent fever, a painful surgical wound, jaundice and echimosis on her abdomen, periorbital region andarms. Then, amphotericin

Table1–Mainclinicalandlaboratoryfindingsuponhospitaladmissionandduringtreatmentoftwopregnantwomen

withAmericanvisceralleishmaniasisinBrazil.

Characteristic Case1 Case2

Onadmission 7thday post-partum Onadmission 7thday post-partum 14thday post-partum Axillarytemperature(◦C) 38.0 37.2 38.5 36.2 36.3

Spleensizeunderleftcostalmargin(cm) 10 8.5 6 4 4

Hemoglobin(g/dL) 7.3 5.2 11.0 6.0 9.6

Hematocrit(%) 22 27 33 15 28

Whitebloodcount(cells/mm3_{) 2600 6000 4643 10,200 15,300}

Plateletcount(platelets/mm3_{) 151,000 122,000 315,000 80,000 155,000}

Prothrombintime(%) 78 63 92 36 58 Totalbilirubin(mg/dL) 0.8 9.5 0.4 4.6 6.4 Directbilirubin(mg/dL) 0.5 3.2 0.12 1.1 2.2 Plasmaalbumin(g/dL) 3.8 2.2 2.7 2.2 3.0 Plasmaglobulin(g/dL) 2.6 4.9 4.2 4.7 4.5 AST(U/L) 38 179 15 64 85 ALT(U/L) 32 327 48 96 113 BUN(mg/dL) 23 28 32 27 25 Serumcreatinine(mg/dL) 0.7 0.9 0.8 0.7 0.8

Bdesoxycholatewas replacedbyanintravenous liposomal formulationofamphotericinB,3mg/kg/day,andthepatient wastransferredtoacriticalcareunit.Thepatientdevelopeda coagulationdisorder,generalizedbleedinganddied10days afterbeinghospitalized. IFATresultobtainedonadmission waspositivewithdilutiontiterof160(referencecut-off=40).

Thenewborn female weighed 1170g and was classified asextremelypremature.Herweightwasappropriateforthe estimatedgestationalage,andshehadanApgarscoreof6 and8duringthefirstand fifthminutesafterbirth, respec-tively.Withinthenext24h,shedevelopedgradeIIpulmonary hyaline membrane disease,forwhich she wasmaintained onnasalcontinuouspositiveairflowpressure.Splenomegaly and hepatomegalywere detectedonphysicalexamination. Thefollowingday,thenewborn’s tachypneaworsened,and shewas placedon mechanicalventilation.Inaddition, she was started on antimicrobial therapy with ampicillin and amikacin.After72h,thepatientdevelopedjaundiceand wors-eninganemia.Bonemarrowaspiratesmearslookingforthe presenceofLeishmaniawasnegative.Despitemultipleblood transfusions,thenewborn’serythrocyteindexescontinuedto decrease.Wethen performedaPCR testtodetect parasite kDNAusingthecellscollectedfromthebonemarrowaspirate which gave a positive result forLeishmania spp. The new-bornwasstartedontreatmentwithintravenousamphotericin Bdeoxycholate,1mg/kg/dayfor14daysmakingsatisfactory progressandbeingdischargedfromthecriticalcareunit20 daysafterbirth.

Case2

A 23-year-old woman from the city of Porto Nacional, Tocantins,whowaspregnantforthesecondtime,was hos-pitalizedwithcomplaintofintermittentfeverduringthepast 4monthsassociatedwithweakness, fatigue,vomitingand anorexia.Aphysicalexaminationofthepatientrevealed dehy-dration, weight loss and edema of the legs. She reported having suffered from eclampsia during her previous preg-nancy, and she had undergone five prenatal evaluations withnoabnormalbloodpressurelevels.Duringtheseventh monthofpregnancy, shepresented withdailyfever, lower limbedema,jaundiceandprogressiveanemia.Anultrasound test revealed a slight decrease in amniotic fluid, a poste-riorplacentaofheterogeneoustextureandstageIImaturity consistentwitha35-weekand4-daygestationalage,afetal heart rate of 169beats/min, splenomegaly and mild right hydronephrosis.Clinicalandlaboratoryfindingsaredescribed inTable1.Becauseofacutefetaldistress,itwasperformeda cesareansectionanddeliveredapreterminfantwithaweight whichwasappropriateforthegestationalage.Directanalysis ofbonemarrowsmearsfromthemotherrevealedthe

pres-enceofLeishmaniaamastigotes.Themotherwastreatedwith

intravenousliposomalamphotericinB,3mg/kg/day,IVfor7 days. However,hergeneralcondition deteriorated, as indi-catedbyaworseningofheranemia,dyspnea,toxemiaand posturalhypotension anddecrease ofprothrombinactivity. Thepatientwastransferredtotheintensivecareunitwhere sherecoveredandwasdischargedafter14days.IFATresult obtainedonadmissionwaspositivewithdilutiontiterof160 (referencecut-off=40).

Thenewbornmaleweighed2590gwhichwasappropriate forthegestationalage,andhehadanApgarscoreof3and5 forthefirstandfifthminutesoflife,respectively.Thenewborn developedacuterespiratoryfailureduetomeconium aspira-tionandrequiredmechanicalventilation.Splenomegalywas detectedonphysicalexamination.Thenewbornwas trans-ferred to theneonatal intensivecare unitand was treated withampicillinandamikacin,withnoclinicalimprovement. Suspectingvisceralleishmaniasis,weobtainedabone mar-rowaspiratelookingforLeishmaniaamastigotesbuttheresults were negative.Due tosevere anemia, herequiredmultiple blood transfusions and later, he developed jaundice being started onoxacillin and cefepimeplus intravenous liposo-malamphotericinB 3mg/kg/day. A PCRtestfor Leishmania

kDNA waspositiveonbonemarrowaspirate.Thenewborn had satisfactoryprogressand wasdischarged50daysafter birth.

Discussion

The present cases of congenitally acquired visceral leish-maniasisconstituteararecondition.During2007and2008, there were 873 visceral leishmaniasis cases in adults and children residentsin the StateofTocantins that were reg-istered inthe BrazilianNational SurveillanceSystem.Most ofthecongenitalvisceralleishmaniasisinfectionsdescribed inthe literaturefollow acoursewheretherearefewor no maternalsymptomsandwheremacroscopicchangesofthe placenta and its annexes are typically not observed. Also, ithasnotbeenpossibletoconfirmthattransplacentalfetal infection hasbeen themode oftransmissioninany ofthe casesthathavebeenreportedsofar.Eltoumetal.reported acaseofapregnantwomanwithsymptomatic leishmania-siswhosufferedamiscarriage.11_{Theauthorsproposedthat}

theparasiteenteredintothefetalcirculationduringits sep-arationfromtheplacenta orthroughdamagedareasinthe maternal–fetalbarrierbecausethemothershowednosigns ofillness.Inaddition,laboratorytestsonthe abortedfetus showed thrombosis,fibrin depositionin athirdofthe pla-centalchorionicvilli,thepresenceofamastigotesinsideand outside macrophages and the absence of aninflammatory reactioninresponsetotheparasites.Unfortunately,placenta histopathologic studies were not performedin the present cases.

In pregnantwomen, thedetection ofvisceromegalycan beimpairedbythegrowthoftheuterus.Amongthe labora-torystudiesthatpregnantwomentypicallyundergoaredirect visualization of amastigote formsin bone marrow smears anddetectionofanti-Leishmaniaserumantibodiesusingthe IFAT, where the presence ofquantifiable titersof antibod-ies higherthan 40-folddilution ofthe serum isconsidered positive. The PCR is a highly sensitive and specific tech-nique to detect Leishmania kDNA, making it an important tooltoimprovetheopportunityofearlytreatment,especially innewborns toavoidmisinterpretationofpositive serolog-ical tests due to passive transfer of maternal antibodies. Thetestsperformedonthetwopregnantwomenupontheir admission revealed that they had high titers of antibod-ies, which could cross the placental barrier. Although the

266

bonemarrowsmearswerepositiveforLeishmaniaamastigotes in the pregnant women, they were not elucidatory in the newborns.PCRamplificationofparasitekDNAinnewborn’s bonemarrowsamplessuggeststhatleishmaniasiswas verti-callytransmittedbecausetheydevelopedsignsofthedisease shortlyafterbirthand remained inthehospitaluntiltheir moreseveresymptomswereresolvedwhileonspecific anti-leishmanial treatment. The early onset of symptoms after birth rules out the possibility that the newborns acquired thediseasethroughvectortransmission.Thisresult demon-stratesthat,usingPCR,itispossibletomakeanearlydiagnosis ofleishmaniasisinthenewbornandprovideimmediate treat-mentforthemotherandfetustoavoidorminimizedisease complications.

Thereisaconcernabouttheeffectofthedrugsusedfor thetreatmentofleishmaniasisonthewell-beingofthefetus becauseclinicaltrialsdevelopedforapprovalpurposeswith drugsagainstvisceralleishmaniasisusuallyexcludepregnant women.However,arecentstudyconductedinAfricashowed ahigherincidenceofabortioninpatientstreatedwith pen-tavalentantimony.14_{Thetransplacentaltransferofantimony}

hasbeenprovedinmice,showingthatapproximately1/3of the antimonypresent in the maternalblood is transferred tothefetus.15_{Thesecondwomanwhowasdiagnosed}

ben-efitedfromtheexperiencewegained fromthefirstpatient who died earlier.Asa result, shewastreated with liposo-mal amphotericinB, which could have contributed to her favorablerecovery.BecauseAVLamongpregnantwomenis anextremelyserioushealthconcernitisreasonableto rec-ommendtreatmentwithliposomalamphotericinBbecause ithasthebestsafetyprofile.Monitoringforthepresenceof AVLinpregnantwomenlivinginendemicareasisessential fortheimplementationoftimelytreatmentandcanprevent fataloutcomes.

Conflict

of

interest

Allauthorsdeclaretohavenoconflictofinterest.

Acknowledgements

WethanktheDanielaCarvalhoLemosfortechnicalsupport. ThisstudyhadfinancialsupportfromtheBrazilianMinistry ofHealth(Process:20072029000137–MS/CNPq/CECT– N◦ 01/2006).

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