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CASEREPORTOpenAccessDrugreactionwitheosinophiliaandsystemicsymptomssyndromeinapatienttakingphenytoinandlevetiracetam:acasereportDavidJeffreyHall1andJasonStevenFromm2*AbstractIntroduction:Drugreactionwitheosinophiliaandsystemicsymptomssyndromeisapotentiallylife-threateninghypersensitivityreactionwithrash,fever,andinternalorganinvolvement,oftenhepatitis,occurringmostcommonlytwotoeightweeksafterinitiationofamedication.
Thepresentcaseisanexampleofsevereandpotentiallylife-threateninghepatitisasamanifestationofdrugreactionwitheosinophiliaandsystemicsymptomssyndrome.
Casepresentation:Wereportacaseofanti-epileptic-induceddrugreactionwitheosinophiliaandsystemicsymptomssyndromeinan18-year-oldAfrican-Americanmanwhopresentedwithafive-dayhistoryofrash,periorbitalandupperextremityedema,hepatitisandfever.
Laboratoryfindingsrevealedanatypicallymphocytosis,eosinophilia,andelevatedserumtransaminases.
Nodrugallergieswerereportedatthetimeofpresentation,butphenytoinandlevetiracetamtherapyhadbeeninitiatedfiveweekspriortohospitaladmissionfornew-onsetseizures.
Bothmedicationswerediscontinuedonhospitaladmission,andafterthreedaysofhigh-dosecorticosteroidtherapythepatientexperiencedresolutionofbothhissymptomsandlaboratorymarkersofinflammation.
Conclusion:Giventhesignificantmortalityattributedtodrugreactionwitheosinophiliaandsystemicsymptomssyndrome,medicalpersonnelshouldbeawareofthepotentialforthisseverehypersensitivityreactionandshouldensureclosefollow-upandofferanticipatoryguidancewhenbeginninganynewmedication,particularlyanti-epileptictherapy.
Earlyrecognitionofdrugreactionwitheosinophiliaandsystemicsymptomssyndromeandinitiationofappropriatetherapyareimperativeinlimitingmorbidity.
Keywords:Allergy,Anti-epileptic,DRESSsyndrome,Hepatitis,Hypersensitivityreaction,LevetiracetamPhenytoin,RashIntroductionDrugreactionwitheosinophiliaandsystemicsymptoms(DRESS)syndrome,alsoknownasdrug-inducedhy-persensitivitysyndrome(DIHS),isanunder-recognizedandpotentiallylife-threateninghypersensitivityreactionassociatedwithavarietyofmedications,manybeinganti-epileptics.
PatientswithDRESSsyndrometypicallypresentwithrash,swelling,fever,andsystemicmanifes-tationssuchasaseveretransaminitis[1].
Inmostcases,apatient'sface,trunk,andupperextremitiesareaffectedbyarashwhichisatfirstmorbilliformthengraduallytransitionstomaculopapular,andfinallycanprogresstoedemaoftheface,particularlyintheperiorbitalregion.
Althoughrashandeosinophiliaarecommonlyseeninhypersensitivityreactions,thedefiningcharacteristicofDRESSsyndromeisorgandysfunction,mostcommonlyoftheliver,kidneys,heart,orlungs.
Thesepatientsaretypicallyfoundtohavestartedoneofafewselectmedi-cationsinthepasttwotoeightweeks(Table1)witharo-maticanti-epilepticsbeingthemostcommonlyimplicated[2-6].
Non-aromaticanti-epilepticmedica-tionssuchasatopiramate,ethosuximide,andlevetirace-tamweretraditionallythoughttobesafer;however,arecentcasereportdescribedDRESSsyndromeinapa-tienttakingonlylevetiracetam[7].
Althoughthetruein-cidenceisunknown,DRESSsyndromehasbeen*Correspondence:jason.
fromm@medicine.
ufl.
edu2DepartmentofMedicine,UniversityofFloridaCollegeofMedicine,1600SWArcherRoad,POBox100277,Gainesville,FL32610-0277,USAFulllistofauthorinformationisavailableattheendofthearticleJOURNALOFMEDICALCASEREPORTS2013HallandFromm;licenseeBioMedCentralLtd.
ThisisanOpenAccessarticledistributedunderthetermsoftheCreativeCommonsAttributionLicense(http://creativecommons.
org/licenses/by/2.
0),whichpermitsunrestricteduse,distribution,andreproductioninanymedium,providedtheoriginalworkisproperlycited.
HallandFrommJournalofMedicalCaseReports2013,7:2http://www.
jmedicalcasereports.
com/content/7/1/2estimatedtooccurinapproximatelyoneoutof1000to10,000newusersofanti-epilepticmedicationsandismorecommonlyreportedinAfrican-Americanmen[1,8,9].
VitaminDdeficiencyhasbeenimplicatedasapossiblecontributortothepathogenesisofDRESSduetoitsprotectiveeffectsagainstinflammatoryandauto-immuneconditions,andbecausevitaminDdeficiencyoccursmorefrequentlyinpeoplewithdarkerskinphenotypes[10].
DIHSwasoriginallydescribedin1950byChaikenetal.
asatriadoffever,rash,andmulti-organfailure[11].
TheacronymDRESSwasthenputforthbyBocquetetal.
andoftenincludeshepatitis,pericarditis,interstitialnephritis,orinterstitialpneumonitis[1,12].
IsolatedelevationoflivertransaminasesisthemostcommonlaboratorymanifestationofhepatitisinDRESSsyndrome.
Inseverecasesitcanprogresstofulminantliverfailure,occurringinasmanyas10%ofcasesandaccountingfortheprinciplecauseofmortalityinpatientsaffectedbyDRESSsyndrome[1].
AlthoughthepathophysiologyofDRESSsyndromeremainsunknown,eosinophilicinfiltrationisprobablythemechanismforinvolvementoforganssuchastheliverandkidneys[2].
Promptrecognitionandremovaloftheoffendingagentisthekeytolimitingfurtherhepaticdamage,althoughhepatitismaysignificantlyworsenevenafterdiscontinuationofthedrugandmaytakemonthstoresolvecompletely.
Althoughnorandomized-controlledtherapytrialshavebeendone,corticosteroidsareutilizedinmanyreportedcases[3-5,8].
Nospecifictherapeuticregimenordosinghasbeenshowntobemorebeneficialthananother,butitisimportantthattherapyiscontin-uedforlongenoughinordertopreventthepossibilityofrelapse.
Thefollowingcasereportdemonstratesthenecessityofpromptrecognitionandinitiationofappro-priatetherapyinpreventingthepotentialsequelaeofDRESSsyndrome.
CasepresentationAn18-year-oldAfrican-Americanmanpresentedwithafive-dayhistoryofpruritic,maculopapularrashwithassociatedperiorbitalswelling,fever,andtransaminitis.
Fivedayspriortopresentationhenotedpruritisandrashoverhisextremities,whichoverthenextseveraldaysprogressedtohischest,back,andface.
Hehadahistoryofseizuresthatbegan35dayspriortothisadmissiontreatedwithphenytoinextended-releaseER100mgdailyandlevetiracetam500mgtwiceaday.
Afterinvestigation,nospecificfocusoretiologyofhisseizureshadbeenidentified.
Hehashaddecreasedverbalandreadingskillssinceearlychildhood,butdetailsabouthisdeliveryandearlydevelopmentareunclearbecausehewasadopted.
Thepatienthadnoothersignificantpastmedicalhistory,drugallergies,oralcoholuse.
Reviewofsystemswaspositivefornon-productivecough,fever,andtea-coloredurine,andnegativeforchestpain,ab-dominalpain,shortnessofbreath,nausea,vomiting,weight-loss,chills,oranyrecentalteredmentalstatus.
Onexamination,thepatientwasfebrileto40.
2°C(104.
4°F)withaheartrateof88beats/minute,respira-toryrateof18,andbloodpressureof110/55mmHg.
Thepatientwaswellnourished,welldeveloped,alertandwelloriented,andappeareduncomfortablebutnotindistress.
Afineexanthematousrashwasnotedontheface,upper,andlowerextremitiesinsun-exposedareaswithoutinvolvementoftheoralmucosa,palms,orsoles.
Therewasprofoundperiorbitaledemathatpreventedeye-opening.
Hisabdomenwassoftandnon-distendedwithnotenderness,guarding,orhepatosplenomegaly.
Nofocaldeficitswereappreciatedonneurologicalexam-ination.
Atthispointthedifferentialdiagnosisincludeddrug-inducedhypersensitivity,erythemamultiforme,toxicepidermalnecrolysis,vasculitis,anexanthemduetoviralinfectionsuchasEpstein–Barrvirus(EBV),cyto-megalovirus(CMV),andhumanimmunodeficiencyvirus(HIV),andauto-immuneconditionssuchassystemiclupuserythematosus.
Laboratoryresultsrevealedawhitebloodcellcountof7.
9thousand/mm3(normalfrom4.
0to10.
0thousand/mm3),with60%neutrophils,8.
0%lymphocytes,and4.
0%eosinophils(absolute0.
32thousand/mm[3]).
Hisfreephenytoinlevelonadmissionwas0.
4mcg/mL(therapeuticfrom1.
0to2.
0mcg/mL).
Hisbasicmetabolicpanelwaswithinnormallimits.
Hepaticfunctionpanelrevealedanaspartateaminotransferaseof778U/L(normalfrom0to37),andalanineaminotransferase(ALT)of1274U/L(normalfrom0to41).
Acetaminophenandsalicylatelevelswerebelowdetectablelimits.
EvaluationforacuteandchronichepatitiswithserologieswasnegativeforhepatitisA,B,andC.
Anextensiveworkupwasperformedincludingelectrocardiogramandechocardiogramwhichwerenegativeforabnormalities.
EBV,CMV,andHIVTable1DruggroupscommonlyassociatedwithdrugreactionwitheosinophiliaandsystemicsymptomssyndromeDrugGroups:SpecificExamples:Anticonvulsantsphenytoin,carbamazepine,phenobarbital,lamotrigine,valproateAntidepressantsdespiramine,amitriptyline,fluoxetineSulfonamides/sulfonesdapsone,sulfasalazine,trimethoprim-sulfamethoxazoleAnti-inflammatoriespiroxicam,naproxen,diclofenac,sulindac,ibuprofenAnti-infectivesabacavir,nevirapine,linezolid,doxycycline,nitrofurantoinAngiotensin-convertingenzymeinhibitorscaptopril,enalaprilBeta-blockersatenolol,celiprololHallandFrommJournalofMedicalCaseReports2013,7:2Page2of5http://www.
jmedicalcasereports.
com/content/7/1/2testingwereallnegative,asweretheresultsoftestsforantinuclearantibodies(ANA).
Thepatientwasadmittedtoourhospitalwithapresumptivediagnosisofdrug-inducedhypersensitivity.
Allmedicationswerediscontin-uedandthepatientwasmonitoredforsignsofclinicalrecovery.
Onhospitalday1,thepatient'sconditionworsenedwithincreasedfacialswellingandrashextendingtohischestandabdomen.
Hebegantoshowsignsofliversyntheticdysfunctionwithanelevatedprothombintimeandinternationalnormalizedratioaswellasanin-creasingtransaminitis.
Arepeatcompletebloodcountshowedanatypicallymphocytosisandeosinophiliaat8.
0%.
Becauseofhisdeterioratingcondition,thepatientwasstartedondexamethasone4mgorallyfourtimesdaily.
Onhospitalday2,thepatientshowedamarkedclinicalrecovery.
Despiteimprovementinthepatient'srash,hislevelsoftransaminasescontinuedtoclimb,necessitatinghepatologyconsultationtoassistwithevaluationfortransplantation.
Onhospitalday3hislevelsoftransaminasesbegantoimprove,andbyday8histransaminitishadsubstantiallyresolved(Figure1)andhewasdischargedhomeonprednisone50mgtobetakenonceadayuntilfollow-upwithahepatologist.
Follow-upfivemonthsafterdischargerevealedthatthepatientwasdoingwellwithnorecurrenceofhisrashorothersymptoms,noseizures,andnormalizationofhisserumtransaminases.
Heexperiencednoflareaftercorticosteroidtaperingorwithdrawalandtodatehasnothadanyhepaticsequelae.
DiscussionDRESSsyndromeisanoftenunder-diagnosedandunder-recognizedseveretypeIV(delayedtype)hypersensitivityreactionthatcanoccurwithanymedicationbutmostcommonlyinresponsetoaromaticanticonvulsants[1,2,6,9,10,12,13].
Likemostsevereallergicreactions,DRESSsyndromeinvolvesrash,diffuseswelling,aswellaseosinophilia[1,2,11,14].
ThehallmarkofDRESSsyn-drome,however,isthepresenceofsystemicmanifesta-tionssuchasinflammationoftheliver,kidneys,heart,orotherorgans[1,12,13].
Althoughnoformaldiagnosticcriteriahavebeenwidelyaccepted,aJapaneseworkinggroupin2007establishedasetofdiagnosticguidelinesrequiringthefollowing:first,maculopapularrashdevelop-inggreaterthanthreeweeksafterstartingadrug;second,prolongedclinicalsymptomstwoweeksafterdiscontinu-ationofthecausativedrug;third,fevergreaterthan38°C;fourth,liverabnormalities(includingALTgreaterthan100U/L);fifth,leukocyteabnormalities(eitherleukocytosisgreaterthan11*109/L,anatypicallymphocytosis,oreosinophiliagreaterthan1.
5*109/L);sixth,lymphadenop-athy;andseventh,humanherpesvirus6(HHV-6)reactiva-tion[2].
ThepatientdescribedheremetallofthesedescribedcriteriaforadiagnosisofDRESS.
Althoughhehadnopalpablelymphadenopathy,anabdominalcom-putedtomographyscanconfirmedprofoundretrope-ritoneallymphnodeenlargement.
Finally,aqualitativedeoxyribonucleicacid(DNA)assayrevealedthepresenceofHHV-6typeBinthepatient'sblood,indicatingthereactivationofHHV-6associatedwiththepatient'sDRESSsyndrome[2,15,16].
Alternatively,Kardaunetal.
oftheSevereCutaneousAdverseReactions(RegiSCAR)studygrouppublishedascoringsystemin2007whichhasalsobeenwidelyusedtoevaluatepotentialcasesofDRESSsyndrome[14].
Thecriteriaforthissysteminclude:first,fevergreaterthan38.
5°C;second,enlargedlymphnodes;third,eosino-philia;fourth,atypicallymphocytosis;fifth,skininvolve-ment;sixth,organinvolvement;seventh,resolutiongreaterthan15days;andeighth,evaluationofothercauses(ANA,bloodcultures,serologyforhepatitisAvirus,hepatitisBvirus,hepatitisCvirus,andchlamydiaand/ormycoplasma).
Usingthisscoringsystem,afinalscoreoflessthantwoindicatesnocase,afinalscoreofbetweentwoandthreeindicatesapossiblecase,afinalscoreofbetweenfourandfiveindicatesaprobablecase,andafinalscoreofgreaterthanfiveindicatesadefinitecase.
Thepatientinthiscasereporthadascoreofsixpoints(oneeachforlymphadenopathy,eosinophilia,atypicallymphocytosis,skinrashsuggestiveofDRESS,liverinvolvement,andevaluationofotherpotentialcauses),indicatinga'definitecase'ofDRESSpertheRegiSCARscoringguidelines.
Animportantquestiontoconsideriswhichmedicationwasactuallythesourceofthepatient'sreaction,ashehadbeenstartedonphenytoinandlevetiracetamwithindaysofeachotherduetorecurringseizuresonphenytoinFigure1Serummeasurementsofalanineaminotransferase(ALT)andaspartateaminotransferase(AST)duringthepatient'sadmission.
Normalreferencerangesarefrom0to41U/LforALTandfrom0to37U/LforAST.
Day0(*)representsthedayofadmissionanddiscontinuationofphenytoin.
CorticosteroidtherapywasbegunonDay2(**).
HallandFrommJournalofMedicalCaseReports2013,7:2Page3of5http://www.
jmedicalcasereports.
com/content/7/1/2alone.
AlthoughDRESSwasoriginallydescribedinresponsetophenytoinandithasbeenoneofthemostcommoncausativemedications,Gómez-Zorrillaetal.
publishedacasereportearlierthisyear(2012)ofapatientpresentingwithDRESSsyndromewhotooknomedica-tionsotherthanlevetiracetam[6,7,11].
Ifthepatientweretoagainrequireanticonvulsanttherapy,itwouldbeprudenttoavoiduseofbothphenytoinandlevetiracetam,andtooptinsteadforanalternativenon-aromaticanticonvulsant.
PromptrecognitionoftheadversedrugreactionanddiscontinuationofoffendingmedicationareimperativestepsinlimitingtheprogressionofDRESSsyndrome.
PharmacologicaltreatmentofDRESSsyndromehastodatenotbeenstudiedwithrandomizedcontrolledtrialsandinsteadhasbeenestablishedonthebasisofcasereportsandretrospectiveanalysis.
Systemiccorticoste-roidshavebecomeamainstayoftherapyinseverecasesandoftenproducemarkedimprovementinclinicalsymptomsandlaboratorymeasuresinjustafewdaysaftertheinitiationoftreatment[3-5,8].
Ifsymptomscontinuetoprogressdespitetheuseofcorticosteroids,otheroptionsincludeintravenousimmunoglobulin(IVIG)and/orplasmapheresis[6].
TheFrenchSocietyofDermatologypublishedareportin2010outliningaconsensusontherapeuticmana-gementofDRESS[17].
Theyrecommendtheuseofsystemiccorticosteroidsatadoseequivalenttoonemg/kg/dayofprednisoneinpatientswithanysignofseverityincluding:transaminasesgreaterthanfivetimesnormal,renalinvolvement,pneumonia,hemophagocytosis,orcardiacinvolvement.
TheyfurtherrecommendtheuseofIVIGatadoseoftwog/kgoverfivedaysforapatientwithlife-threateningsignssuchasrenalfailureorres-piratoryfailure.
Inaddition,theyproposetheuseofsteroidsincombinationwithganciclovirinpatientswithsignsofseverityandconfirmationofamajorviralreacti-vationofHHV-6.
However,becauseanti-HHV-6im-munoglobulinGtitersarenotcurrentlywidelyavailableinallhospitalsandlaboratories,resultsoftentakeseve-raldaysorweekstoconfirmviralreactivation.
BecausetimeisanimportantfactorinthetreatmentofDRESS,itisnotrecommendedtodelaydefinitivetherapyinordertoconfirmamajorviralreactivation.
Furtherstudyandrandomizedcontrolledtrialsoftheseandotherpotentialpharmacologictherapieswillbeimpor-tantinestablishingastandardofcareandtoimproveunderstandingofhowbesttotreatpatientsaffectedbyDRESSsyndrome.
ConclusionGiventhesignificantmortalityattributedtoDRESSsyndrome,cliniciansshouldbeawareofthepotentialforthisseverehypersensitivityreactionparticularlyinstartinganynewanti-epilepticmedication.
Inpatientspresentingwithskinrashandsystemicabnormalitiesafterarecentchangeinmedications,physiciansshouldconsiderDRESSsyndromeasapossiblediagnosisandswitchtomoreaggressivetherapyifremovaloftheoffendingagentdoesnotresultinclinicalimprovement.
FurtherstudyofpotentialpharmacologicaltherapiesiswarrantedgiventhesignificantmorbidityassociatedwithDRESSsyndrome.
ConsentWritteninformedconsentwasobtainedfromthepatientandhislegalguardianforpublicationofthiscasereportandanyaccompanyingimages.
Acopyofthewrittencon-sentisavailableforreviewbytheEditor-in-Chiefofthisjournal.
CompetinginterestsTheauthorsdeclarethattheyhavenocompetinginterests.
Authors'contributionsDHanalyzedandinterpretedthedataregardingthepatient'sconditionandwrotethefirstdraftofthemanuscript.
JFexaminedandadministeredtreatmenttothepatientandwasamajorcontributorinwritingandeditingthemanuscript.
Bothauthorsreadandapprovedthefinalmanuscript.
Authordetails1CollegeofMedicine,UniversityofFloridaCollegeofMedicine,1600SWArcherRoad,POBox100277,Gainesville,FL32610-0277,USA.
2DepartmentofMedicine,UniversityofFloridaCollegeofMedicine,1600SWArcherRoad,POBox100277,Gainesville,FL32610-0277,USA.
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doi:10.
1186/1752-1947-7-2Citethisarticleas:HallandFromm:Drugreactionwitheosinophiliaandsystemicsymptomssyndromeinapatienttakingphenytoinandlevetiracetam:acasereport.
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