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Drug-inducedhypersensitivitysyndrome(DIHS)2021/3/131HISTORYDrug-InducedHypersensitivitySyndrome(DIHS),wasfirstrecognizedin19

50byChaiken,inapatientusinganticonvulsant.Later,SaItzsteindescribedthiskindofdrugreactionaspseudolymphomaInthe1960swith

thedevelopmentofcarbamazepine,thediseasenamedantispasmodicsyndromeinadditiontoanticonvulsants,diaphenylsulfone(DDS).allopurinol(别嘌醇),salaz

osulfapyridine(柳氮磺胺吡啶)anddapsone(氨苯砜)canalsocauseDIHS2021/3/1322021/3/1332021/3/134DefitionDrug-InducedHypersensitivityS

yndrome(DIHS)isasevereandraresystemicreactiontriggeredbyadrug(usuallyanantiepilepticdrug).accompaniedbyfever,lymphadenopathy,hepatitis,hematologi

cabnormalitieswitheosinophiliaandatypicallymphocytes,andmayinvolveotherorganswitheosinophilicinfiltration,causingdamagetoseveralsystems,esp

eciallytothekidneys,heart,lungs,andpancreasischaracterizedbylateonset,infectiousmononucleosis-likesymptoms,andherpesvirus6(HHV-6)

reactivation.2021/3/135EtiopathogenesisDrug:deficiencyorabnormalityoftheepoxidehydroxylaseenzyme(环氧酶羟化酶)thatd

etoxifiesthemetabolitesofaromaticamineanticonvulsants(metabolicpathway)Herpesvirus:associatedsequentialreactivationofhe

rpesvirusfamily.(Recently,accumulatingevidencesuggeststhatotherHHVs,suchasHSV,EBV,HHV-7andCMVmightbereactivatedduringthecourseo

fDIHS)Gene:NAT2andcertainhumanleukocyteantigen(HLA)alleles(immuneresponse)2021/3/136Clinicalmanifestationsi

ncubationperiod(2-6weeks)Fever,：oftenhigh(38.5-40oC)Rash:Maculopapularrashdeveloping＞3weeksafterst

artingtherapywithalimitednumberofdrugs.Thecutaneouseruptionconsistsofamorbilliformrash,whichisalsocommoninotherlessse

veredrugreactionsandbothpresentationsareindistinguishableTheface,uppertrunkandupperextremitiesareinitia

llyaffected,withsubsequentprogressiontothelowerextremities.Lymphadenopathy(>2mm)2021/3/137Themaculopapulareruptionlaterbecomesinfiltratedwith

edematousfollicularaccentuat-ion.Swellingoftheface,withmarkedperiorbitalinvolvement.Vesiclesmayariseandfinevesiclesbyedemaofthedermiscanbepresent.N

onecrosisoftheepidermislikeTENoccurs,exceptinrarecasesofoverlappingDRESS/DIHSandTEN.Smallsterileperifollicularpustulesandnonfolli

cularpustulesmayappear,whicharedifferentfromacutegeneralizedexanthematouspustulosis,anddoesnotpredominateo

nthemainfoldsoftheskin..Overtimetherashbecomespurplish,sharplylowerlimbsandtheresolutionisscaling.Anotherformofpresentationisapictur

eofexfoliativedermatitis,whichmaybeassociatedwithmucosalinvolvement,suchascheilitis,erosions,pharygitisandenanthematousenlarged→2021/3/1

38Varioushematologicabnormalities:Leukocytosismaybehigh,upuntil11,000leukocytes/mm3,andeosinophiliareachesvalueshighert

han1500/mm3Hepatitis：hepatomegaly.ALT/ASTincreased.hepaticnecrosisMultiorganinvolvement:myocarditis/myositis,pericarditis,int

erstitialnephritis(11%ofcases),necrotizinggranulomatousvasculitisinkidney,braininvolvement(encephalitisormeningitis),colitisandthyroiditis.the

mortalityrateisabout10%to20%,mainlydiedofseverehepatitis√2021/3/139Myocarditismaydevelopatthebeginni

ngofthesyndromeorupto40daysafterinstallation.Sym-ptomsincludeheartfailure,chestpain,suddentachycardia,dyspnea,andhypotensionin

earlyDRESS/DIHS.Renalinvolvementoccursinabout11%ofcases,beingparticularlyevidentincasesarisingfromtheuse

ofallopurinol.Therewasanincreaseinserumcreatinineandureaanddecreasedcreatinineclearance.InurineItests,increasedcontentofeosinophilscandeobserved.

Neurologicalcomplicationsincludemeningitisandence-phalitis.occursabout2to4weeksafteronsetofthedrugreac

tionpulmonaryinvolvementisrarelyreportedinDRESS/DIHS2021/3/1310Gastrointestinalbleedingmaybeanabrupt

complicationc-ausedbyulcerscausedbyCMVEspeciallyincasesrelatedtoadvancedage,renalimpairment,jaundiceandhepatitiswithreactivationofCM

V.Incontrast,caseswherethereisareactivationofEpstein-Barrvirus(EBV)seemstohavelessaseverecourse,buta

remorelikelytohavelaterdevelopment(usuallyafterseveralyears)ofautoimmunediseasessuchasdiabetesmellitustype

1andautoimmunehypothyroidism2021/3/1311AuxiliaryexaminationCompletebloodcount,ALT,AST,totalbilirrubin,GGT,

alkalinephosphatase,sodium,potassium,creatinineandcreatinineclearance,24hurineproteinandurinaryeosinophilcount,CPK,LDH,ferritin,t

riglycerides,calciumandPTH,bloodglucose,TAPandTTPA,lipase,proteinelectrophore-sis,creactiveprotein,quantit

ativePCRforHHV-6,7,EBVandCMV,bloodculture,anti-nuclearfactor。2021/3/1312Diagnosticcaiteria2021/3/13132021/3/1314服用苯妥英钠药物史发热：以中高热为主，体温最高

可达40.8oC皮疹：颜面部、躯干、四肢可见散在或弥漫分布的红色斑丘疹，高出皮面，压之不褪色，伴瘙痒，无脱屑与水泡。淋巴结肿大：颈部可扪与数枚直径约2.0-3.0cm的淋巴结腋下可扪与1-2枚直径约1.5-2.0c

m的淋巴结腹股沟区可扪与1-2直径约1.5-2.0cm的淋巴结2021/3/1315肝炎：肝大：入院时肋下12cm，剑突下11cm10.15肋下8cm，剑突下8.5cm肝功：2021/3/1316辅助检查血常规：血氨、乳酸EB-PCR:2.22*106血、痰、咽拭子、骨髓培养：

阴性心肌标志物、免疫术前全套胸部平片、心脏彩超、胸腹部B超2021/3/1317Score=62021/3/1318DifferentialdiagnoseSJS(Johnson综合征)⁄TEN(大疱性表皮松解坏死

型药疹)SJS⁄TENisdiagnosedbycharacteristicskinandmucosalmanifestations,butnotbyorganinvolvement.However,DIHSisdiagnosedbasedonitscharacteristiccli

nicalcourse,multipleorganinvolvementanddetectionofherpesvirusreactivationTheonsetofSJS⁄TENwaswithin3weeksafterthesta

rtofdrugadministrationin67%ofcases,Incontrast,DIHSdevelopedat2–6weeksin80%ofcases,andoccurredmostfrequentlyat4-5weeks.2021/3/

1319ComplicationHemophagocyticsyndrome(HPS):canrarelybeobser-vedinthecourseofDRESS/DIHS.HPSisassociatedwithandtriggeredbyvariousconditions,

includingviralinfections,particularlyEBV,malignanttu-mors,orautoimmunediseases.WheninthecourseoftheDRESS/DIHS,HPSusuallyoccur

stwoweeksaftertheonsetofdrugeruption.Thereisadecreaseinwhitebloodcellsandplateletsthatisdetectedsimultane

ouslywiththeelevationoflactatedehydrogenase(LDH).Bonemarrowaspiraterevealedhemophagocytosisfiguresin

anincreasednumberofmacrophages.2021/3/1320Theincidenceofthissyndromeisestimatedtovaryfromonecaseamong1,000to10,000t

hemortalityrateisabout10%to20%aspecifictherapymaybenecessary2021/3/1321Treatmentsystemiccorticosteroids(doseequa

ltoorgreaterthan1to1.5mg/kg/dayofprednisoneorequivalent)withmarkedimprovementofsymptomsandlaboratoryparameters,butseveraldaysafte

rthestartoftreatment.Systemiccorticosteroidsshouldhavetheirdosereduced,aftertheclinicalandlaboratorycontrolofthedisease,slowlyover6-8week

sinordertopreventarecurrenceofthesymptomsofthedisease.Abruptdeteriorationofvarioussymptomsisobservedwhenthewithdrawalisacciden

talorbyrapidreductionofthedosesofcorticosteroids.2021/3/1322TREATMENTItshouldberememberedthattheimmunosuppressivetherapiesm

ayincreasetheriskofinfectiouscomplicationsandsepsis.Physiciansshouldalsopayattentiontoaproperbalancebetweentheneedsofcor

ticosteroidsforreliefofsymptomsandclinicalsignsandtheirpossiblenegativeinterferenceonviralload.Attention:Specialattentionshouldbegiventoaposs

iblereactivationofCMV/EBV,especiallyinpatientswithsevereDRESS/DIHS.themonitoringofliverfunctiontestsshouldbeperforme

dandappropriatetestsorderedtoruleouttheinvolvementofotherorganslikelungs,thyroidandheart.2021/3/1323HighdosesofIVIG:havetwoimmunologicaleffects:(i

)compensatesforthedecreaseinconcentrationofimmunoglobulinsinthepatient’sbloodandthedefectsoftheimmuneprotectionagainstHHV-6(ii

)highdosesofIVIGhaveananti-inflammatoryeffectthatcanregulateimmuneresponses,asseeninthetreatmentofautoimmunediseases.2021/3/1324plasmaexchange:esp

eciallywithlowimmuneorseverecasesofinfectionandunfavorableimpactofGCtherapyandGCineffectiveinpatientswithseveresho

cktherapy,canbeinconjunctionwithIVIG.OnceadayOr3timesinarow2021/3/1325CsA:CsAcaninhibitmonocytesandmacrophagesgeneratedTNF-alpha.ObstaclestoTc

ells,IL-2receptorexpressionandtranscriptionalregulationfactornuclearfactor-KBandinhibitTcellactivation,preventapoptosisinducedmolecularCD9

5(ras)andCD95ligand(FasL)mRNAexpression.CSAtooutbreaksofCD8+CTLcaninhibitproliferationandcolony.ThedramaticprogressinsevereDHS,SJS/toxicnecrosisl

oosesolution,andaccompaniedbyaweakenedimmunesystemorcasesofsevereinfectionandunfavorableimpactofGCtherapycangiveCsAtreatment

,treatmentamountforevery3-5mg/kg,with8to12d,thenreducingsequenceuntilthedrugwithdrawal.2021/3/13261.激素甲强龙：10mg/Kg*d*3d,减量为5mg/Kg*d*4

，2.5mg/Kg*d*2d2.血浆置换：10.15、10.17进行2次3.免疫球蛋白：10.14IVIG：12.5mg10.15IVIG：17.5mg2021/3/1327经过上述治疗，现患儿无发热、皮疹已退。复查肝功：ALT：167、AST：118。肝肋下8cm，

剑突下8.5cm。血常规：WBC：31.07，L：0.5，N：0.4，嗜酸：0.08，HB：90。肺部病变较前有所吸收、心肌标志物阴性2021/3/1328谢谢大家2021/3/1329