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Drug-inducedhypersensitivitysyndrome(DIHS)2021/3/131HISTORYDrug-InducedHypersensitivitySyndrome(DIHS),wasfirstrecognizedin1950byChaiken,inap

atientusinganticonvulsant.Later,SaItzsteindescribedthiskindofdrugreactionaspseudolymphomaInthe1960swiththedevelopmen

tofcarbamazepine,thediseasenamedantispasmodicsyndromeinadditiontoanticonvulsants,diaphenylsulfone(DDS).allopurino

l(别嘌醇),salazosulfapyridine(柳氮磺胺吡啶)anddapsone(氨苯砜)canalsocauseDIHS2021/3/1322021/3/1332021/3/134DefitionDrug-InducedHypersensiti

vitySyndrome(DIHS)isasevereandraresystemicreactiontriggeredbyadrug(usuallyanantiepilepticdrug).accompaniedbyfever,lymphadenopathy,hepatitis,he

matologicabnormalitieswitheosinophiliaandatypicallymphocytes,andmayinvolveotherorganswitheosinophilicinfiltration,causingdam

agetoseveralsystems,especiallytothekidneys,heart,lungs,andpancreasischaracterizedbylateonset,infectiousmononucleosis-likesymptoms,andherpesvirus6(HH

V-6)reactivation.2021/3/135EtiopathogenesisDrug:deficiencyorabnormalityoftheepoxidehydroxylaseenzyme(环氧酶羟化酶)thatdetoxifiesth

emetabolitesofaromaticamineanticonvulsants(metabolicpathway)Herpesvirus:associatedsequentialreactivationofherpesvirusfamily.(Recently,accu

mulatingevidencesuggeststhatotherHHVs,suchasHSV,EBV,HHV-7andCMVmightbereactivatedduringthecourseofDIHS)Gene:NAT2a

ndcertainhumanleukocyteantigen(HLA)alleles(immuneresponse)2021/3/136Clinicalmanifestationsincubationperiod(2-6weeks)Feve

r,：oftenhigh(38.5-40oC)Rash:Maculopapularrashdeveloping＞3weeksafterstartingtherapywithalimitednumberof

drugs.Thecutaneouseruptionconsistsofamorbilliformrash,whichisalsocommoninotherlessseveredrugreactionsandbothpresentationsareindistinguishableThe

face,uppertrunkandupperextremitiesareinitiallyaffected,withsubsequentprogressiontothelowerextremities.Lymphadenopathy(>2mm)2021/3/137Themacu

lopapulareruptionlaterbecomesinfiltratedwithedematousfollicularaccentuat-ion.Swellingoftheface,withmarkedperiorbitalinvolvement.Vesiclesmaya

riseandfinevesiclesbyedemaofthedermiscanbepresent.NonecrosisoftheepidermislikeTENoccurs,exceptinrarecasesofov

erlappingDRESS/DIHSandTEN.Smallsterileperifollicularpustulesandnonfollicularpustulesmayappear,whichare

differentfromacutegeneralizedexanthematouspustulosis,anddoesnotpredominateonthemainfoldsoftheskin..Overtimetherashbecomespurp

lish,sharplylowerlimbsandtheresolutionisscaling.Anotherformofpresentationisapictureofexfoliativedermatitis,whichmaybeas

sociatedwithmucosalinvolvement,suchascheilitis,erosions,pharygitisandenanthematousenlarged→2021/3/138Variou

shematologicabnormalities:Leukocytosismaybehigh,upuntil11,000leukocytes/mm3,andeosinophiliareachesvalueshigherthan1500/mm3Hepatitis：hepatomegaly

.ALT/ASTincreased.hepaticnecrosisMultiorganinvolvement:myocarditis/myositis,pericarditis,interstitia

lnephritis(11%ofcases),necrotizinggranulomatousvasculitisinkidney,braininvolvement(encephalitisormeningitis),colitisandthyroiditi

s.themortalityrateisabout10%to20%,mainlydiedofseverehepatitis√2021/3/139Myocarditismaydevelopatthebeginni

ngofthesyndromeorupto40daysafterinstallation.Sym-ptomsincludeheartfailure,chestpain,suddentachycardia,dyspnea,andhypotensioninearlyDRESS/

DIHS.Renalinvolvementoccursinabout11%ofcases,beingparticularlyevidentincasesarisingfromtheuseofallopurinol.Therew

asanincreaseinserumcreatinineandureaanddecreasedcreatinineclearance.InurineItests,increasedcontentofeosinophilscandeobserved.Neurologicalcompli

cationsincludemeningitisandence-phalitis.occursabout2to4weeksafteronsetofthedrugreactionpulmonaryinvolvementisrarelyreportedinDRESS/DIHS

2021/3/1310Gastrointestinalbleedingmaybeanabruptcomplicationc-ausedbyulcerscausedbyCMVEspeciallyincasesrelatedtoa

dvancedage,renalimpairment,jaundiceandhepatitiswithreactivationofCMV.Incontrast,caseswherethereisareactivat

ionofEpstein-Barrvirus(EBV)seemstohavelessaseverecourse,butaremorelikelytohavelaterdevelopment(usuallya

fterseveralyears)ofautoimmunediseasessuchasdiabetesmellitustype1andautoimmunehypothyroidism2021/3/1311Auxiliaryexamina

tionCompletebloodcount,ALT,AST,totalbilirrubin,GGT,alkalinephosphatase,sodium,potassium,creatinineandc

reatinineclearance,24hurineproteinandurinaryeosinophilcount,CPK,LDH,ferritin,triglycerides,calciumandPTH,bloodg

lucose,TAPandTTPA,lipase,proteinelectrophore-sis,creactiveprotein,quantitativePCRforHHV-6,7,EBVandCMV,bl

oodculture,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1.5-2.0cm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⁄TENisdiagnosedbycharacteristicskinandmucosalmanifest

ations,butnotbyorganinvolvement.However,DIHSisdiagnosedbasedonitscharacteristicclinicalcourse,multipleorganinvolvementandd

etectionofherpesvirusreactivationTheonsetofSJS⁄TENwaswithin3weeksafterthestartofdrugadministrationin67%ofcases,In

contrast,DIHSdevelopedat2–6weeksin80%ofcases,andoccurredmostfrequentlyat4-5weeks.2021/3/1319ComplicationHemophagocyticsyndrome(HPS):canrare

lybeobser-vedinthecourseofDRESS/DIHS.HPSisassociatedwithandtriggeredbyvariousconditions,includingviralinfections,parti

cularlyEBV,malignanttu-mors,orautoimmunediseases.WheninthecourseoftheDRESS/DIHS,HPSusuallyoccurstwoweeksafterth

eonsetofdrugeruption.Thereisadecreaseinwhitebloodcellsandplateletsthatisdetectedsimultaneouslywiththeelevationoflactatedehydrogenase(LDH).Bonemarrow

aspiraterevealedhemophagocytosisfiguresinanincreasednumberofmacrophages.2021/3/1320Theincidenceofthissyndromeisestimatedtovaryfromonecaseamo

ng1,000to10,000themortalityrateisabout10%to20%aspecifictherapymaybenecessary2021/3/1321Treatmentsystemiccorticoster

oids(doseequaltoorgreaterthan1to1.5mg/kg/dayofprednisoneorequivalent)withmarkedimprovementofsymptomsandla

boratoryparameters,butseveraldaysafterthestartoftreatment.Systemiccorticosteroidsshouldhavetheirdosereduced,aftertheclinicalandlabora

torycontrolofthedisease,slowlyover6-8weeksinordertopreventarecurrenceofthesymptomsofthedisease.Abruptdeteriorationofvarioussymptomsisob

servedwhenthewithdrawalisaccidentalorbyrapidreductionofthedosesofcorticosteroids.2021/3/1322TREATMENTItshouldberemembe

redthattheimmunosuppressivetherapiesmayincreasetheriskofinfectiouscomplicationsandsepsis.Physiciansshouldalsopayattentiontoaproperbala

ncebetweentheneedsofcorticosteroidsforreliefofsymptomsandclinicalsignsandtheirpossiblenegativeinterferenceonviralload.

Attention:SpecialattentionshouldbegiventoapossiblereactivationofCMV/EBV,especiallyinpatientswithsevereDRESS/DIHS.themonitoringofliverfunctiontestssh

ouldbeperformedandappropriatetestsorderedtoruleouttheinvolvementofotherorganslikelungs,thyroidandheart.2021/3/1323HighdosesofIVIG:havetwoimmunologi

caleffects:(i)compensatesforthedecreaseinconcentrationofimmunoglobulinsinthepatient’sbloodandthedefects

oftheimmuneprotectionagainstHHV-6(ii)highdosesofIVIGhaveananti-inflammatoryeffectthatcanregulateimmuneresponses,as

seeninthetreatmentofautoimmunediseases.2021/3/1324plasmaexchange:especiallywithlowimmuneorseverecasesofinfectionandunf

avorableimpactofGCtherapyandGCineffectiveinpatientswithsevereshocktherapy,canbeinconjunctionwithIVIG.Once

adayOr3timesinarow2021/3/1325CsA:CsAcaninhibitmonocytesandmacrophagesgeneratedTNF-alpha.ObstaclestoTcells,IL

-2receptorexpressionandtranscriptionalregulationfactornuclearfactor-KBandinhibitTcellactivation,preventapoptosisinducedmolec

ularCD95(ras)andCD95ligand(FasL)mRNAexpression.CSAtooutbreaksofCD8+CTLcaninhibitproliferationandcolony.ThedramaticprogressinsevereDHS,SJS

/toxicnecrosisloosesolution,andaccompaniedbyaweakenedimmunesystemorcasesofsevereinfectionandunfavorableimpactofGCtherapycangiveCsAtreatment,treatmen

tamountforevery3-5mg/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