Actionable-Diagnosis-of-Neuroleptospirosis-by-Next

briefreportThenewenglandjournalofmedicinenengljmed370;25nejm.orgjune19,20142408ActionableDiagnosisofNeuroleptospirosisbyNext-GenerationSequencingMichaelR.Wilson,M.D.,SamiaN.Naccache,Ph.D.,ErikSamayoa,B.S.,C.L.S.,MarkBiagtan,M.D.,HibaBashir,M.D.,GuixiaYu,B.S.,ShahriarM.Salamat,M.D.,Ph.D.,SnehaSomasekar,B.S.,ScotFederman,B.A.,SteveMiller,M.D.,Ph.D.,RobertSokolic,M.D.,ElizabethGarabedian,R.N.,M.S.L.S.,FabioCandotti,M.D.,RebeccaH.Buckley,M.D.,KurtD.Reed,M.D.,TeresaL.Meyer,R.N.,M.S.,ChristineM.Seroogy,M.D.,ReneeGalloway,M.P.H.,SherylL.Henderson,M.D.,Ph.D.,JamesE.Gern,M.D.,JosephL.DeRisi,Ph.D.,andCharlesY.Chiu,M.D.,Ph.D.FromtheDepartmentsofBiochemistryandBiophysics(M.R.W.,J.L.D.),Neurology(M.R.W.),andLaboratoryMedicine(S.N.N.,E.S.,G.Y.,S.S.,S.F.,S.M.,C.Y.C.),andtheDepartmentofMedicine,DivisionofInfec-tiousDiseases(C.Y.C.),UniversityofCali-fornia,SanFrancisco(UCSF),andUCSF–AbbottViralDiagnosticsandDiscoveryCenter(S.N.N.,E.S.,G.Y.,S.S.,S.F.,S.M.,C.Y.C.)—bothinSanFrancisco;theDe-partmentofMedicine,DivisionofAllergyandImmunology(M.B.,H.B.,J.E.G.),andtheDepartmentsofPathologyandLabo-ratoryMedicine(S.M.S.,K.D.R.)andPe-diatrics(T.L.M.,C.M.S.,S.L.H.,J.E.G.),UniversityofWisconsin,Madison;theExperimentalTransplantationandImmu-nologyBranch,CenterforCancerResearch,NationalCancerInstitute,NationalInsti-tutesofHealth,Bethesda,MD(R.S.,E.G.,F.C.);theDepartmentsofPediatricsandImmunology,DivisionofAllergyandIm-munology,DukeUniversity,Durham,NC(R.H.B.);andtheCentersforDiseaseCon-trolandPrevention,Atlanta(R.G.).AddressreprintrequeststoDr.ChiuattheDe-partmentofLaboratoryMedicine,Univer-sityofCalifornia,SanFrancisco,185BerrySt.,Box134,SanFrancisco,CA94107,[e-mail]nJune4,2014,atNEJM.org.NEnglJMed2014;370:2408-17.DOI:10.1056/NEJMoa1401268Copyright©2014MassachusettsMedicalSociety.SUMMARYA14-year-oldboywithseverecombinedimmunodeficiencypresentedthreetimestoamedicalfacilityoveraperiodof4monthswithfeverandheadachethatpro-gressedtohydrocephalusandstatusepilepticusnecessitatingamedicallyinducedcoma.Diagnosticworkupincludingbrainbiopsywasunrevealing.Unbiasednext-generationsequencingofthecerebrospinalfluididentified475of3,063,784sequencereads(0.016%)correspondingtoleptospirainfection.Clinicalassaysforleptospirosiswerenegative.Targetedantimicrobialagentswereadministered,andthepatientwasdischargedhome32dayslaterwithastatusclosetohispremorbidcondition.Polymerase-chain-reaction(PCR)andserologictestingattheCentersforDiseaseControlandPrevention(CDC)subsequentlyconfirmedevidenceofLeptospirasantarosaiinfection.Morethanhalfthecasesofmeningoencephalitisremainun-diagnosed,despiteextensiveclinicallaboratorytesting.1-4Becausemorethan100differentinfectiousagentscancauseencephalitis,establishingadiagnosiswiththeuseofcultures,serologictests,andpathogen-specificPCRassayscanbedifficult.Unbiasednext-generationsequencinghasthepotentialtorevolutionizeourabilitytodiscoveremergingpathogens,especiallynewlyidentifiedviruses.5-8However,theusefulnessofnext-generationsequencingforthediagnosisofinfectiousdiseasesinaclinicallyrelevanttimeframeislargelyunexplored.9Weusedunbiasednext-generationsequencingtoidentifyatreatable,albeitrare,bacte-rialcauseofmeningoencephalitis.Inthiscase,theresultsofnext-generationse-quencingcontributeddirectlytoadramaticeffectonthepatient’scare,resultingultimatelyinafavorableoutcome.CASEREPORTA14-year-oldboywithseverecombinedimmunodeficiency(SCID)causedbyaden-osinedeaminasedeficiencyandpartialimmunereconstitutionafterhehadunder-gonetwohaploidenticalbonemarrowtransplantationsinitiallypresentedtotheemergencydepartmentinearlyApril2013afterhavinghadheadacheandfevers,withtemperaturesupto39.4°C,for6days(Fig.1A).Hewasadmittedtothehospi-TheNewEnglandJournalofMedicineDownloadedfromnejm.orgonMarch25,2015.Forpersonaluseonly.Nootheruseswithoutpermission.Copyright©2014MassachusettsMedicalSociety.Allrightsreserved.briefreportnengljmed370;25nejm.orgjune19,20142409talanddischarged1daylaterafterresolutionofhisfeverandheadache.Thepatient’soutpatientmedicationsincludedmonthlyinfusionsofintravenousimmuneglobu-linforhypogammaglobulinemiaandtrimetho-prim–sulfamethoxazoleoratovaquoneforprophy-laxisagainstPneumocystisjiroveciipneumonia.Hehadnoknownsickcontactsbutdidhavethreepetcats.HehadgoneonamissionarytriptoPuertoRicoduringthefirst2weeksofAugust2012(Fig.1A),whereheswaminariverandtheocean.Notably,a17-year-oldfellowtravelerhadbeenhospitalizedfor4dayswithfeverandhematuria.ThepatienthadalsovacationedinFloridainMarch2013,whereheswaminapoolataresortwheretherewereanumberofferalcats.InSeptember2012,thepatienthadpresentedtohisprimarycarephysicianwithfever,headache,andbilateralconjunctivitisthatresolvedsponta-neouslyin10days(Fig.1A).AttheendofOcto-ber2012,hehadhadphotophobiaandpainwithmovementofhislefteye.Hisophthalmologisthadprescribedeyedropsconsistingofacombi-nationofaglucocorticoid,avasoconstrictor,andanantibiotic(ciprofloxacin)foruveitis.Oneweeklater,uveitishaddevelopedinthecontralateraleyeandwastreatedinasimilarmanner.Theoph-thalmo