药物超敏反应综合征PPT课件

.,1,学习,汇报者：涂金伟,.,2,Drug-inducedhypersensitivitysyndrome(DIHS),.,3,HISTORY,Drug-InducedHypersensitivitySyndrome(DIHS),wasfirstrecognizedin1950byChaiken,inapatientusinganticonvulsant.Later,SaItzsteindescribedthiskindofdrugreactionaspseudolymphomaInthe1960swiththedevelopmentofcarbamazepine,thediseasenamedantispasmodicsyndromeinadditiontoanticonvulsants,diaphenylsulfone(DDS).allopurinol(别嘌醇),salazosulfapyridine(柳氮磺胺吡啶)anddapsone(氨苯砜)canalsocauseDIHS,.,4,.,5,.,6,Defition,Drug-InducedHypersensitivitySyndrome(DIHS)isasevereandraresystemicreactiontriggeredbyadrug(usuallyanantiepilepticdrug).accompaniedbyfever,lymphadenopathy,hepatitis,hematologicabnormalitieswitheosinophiliaandatypicallymphocytes,andmayinvolveotherorganswitheosinophilicinfiltration,causingdamagetoseveralsystems,especiallytothekidneys,heart,lungs,andpancreasischaracterizedbylateonset,infectiousmononucleosis-likesymptoms,andherpesvirus6(HHV-6)reactivation.,.,7,Etiopathogenesis,Drug:deficiencyorabnormalityoftheepoxidehydroxylaseenzyme(环氧酶羟化酶)thatdetoxifiesthemetabolitesofaromaticamineanticonvulsants(metabolicpathway)Herpesvirus:associatedsequentialreactivationofherpesvirusfamily.(Recently,accumulatingevidencesuggeststhatotherHHVs,suchasHSV,EBV,HHV-7andCMVmightbereactivatedduringthecourseofDIHS)Gene:NAT2andcertainhumanleukocyteantigen(HLA)alleles(immuneresponse),.,8,Clinicalmanifestations,incubationperiod(2-6weeks)Fever,：oftenhigh(38.5-40oC)Rash:Maculopapularrashdeveloping3weeksafterstartingtherapywithalimitednumberofdrugs.Thecutaneouseruptionconsistsofamorbilliformrash,whichisalsocommoninotherlessseveredrugreactionsandbothpresentationsareindistinguishableTheface,uppertrunkandupperextremitiesareinitiallyaffected,withsubsequentprogressiontothelowerextremities.Lymphadenopathy(2mm),.,9,Themaculopapulareruptionlaterbecomesinfiltratedwithedematousfollicularaccentuat-ion.Swellingoftheface,withmarkedperiorbitalinvolvement.Vesiclesmayariseandfinevesiclesbyedemaofthedermiscanbepresent.NonecrosisoftheepidermislikeTENoccurs,exceptinrarecasesofoverlappingDRESS/DIHSandTEN.Smallsterileperifollicularpustulesandnonfollicularpustulesmayappear,whicharedifferentfromacutegeneralizedexanthematouspustulosis,anddoesnotpredominateonthemainfoldsoftheskin.Overtimetherashbecomespurplish,sharplylowerlimbsandtheresolutionisscaling.Anotherformofpresentationisapictureofexfoliativedermatitis,whichmaybeassociatedwithmucosalinvolvement,suchascheilitis,erosions,pharygitisandenanthematousenlarged,.,10,Varioushematologicabnormalities:Leukocytosismaybehigh,upuntil11,000leukocytes/mm3,andeosinophiliareachesvalueshigherthan1500/mm3Hepatitis：hepatomegaly.ALT/ASTincreased.hepaticnecrosisMultiorganinvolvement:myocarditis/myositis,pericarditis,interstitialnephritis(11%ofcases),necrotizinggranulomatousvasculitisinkidney,braininvolvement(encephalitisormeningitis),colitisandthyroiditis.themortalityrateisabout10%to20%,mainlydiedofseverehepatitis,.,11,Myocarditismaydevelopatthebeginningofthesyndromeorupto40daysafterinstallation.Sym-ptomsincludeheartfailure,chestpain,suddentachycardia,dyspnea,andhypotensioninearlyDRESS/DIHS.Renalinvolvementoccursinabout11%ofcases,beingparticularlyevidentincasesarisingfromtheuseofallopurinol.Therewasanincreaseinserumcreatinineandureaanddecreasedcreatinineclearance.InurineItests,increasedcontentofeosinophilscandeobserved.Neurologicalcomplicationsincludemeningitisandence-phalitis.occursabout2to4weeksafteronsetofthedrugreactionpulmonaryinvolvementisrarelyreportedinDRESS/DIHS,.,12,Gastrointestinalbleedingmaybeanabruptcomplicationc-ausedbyulcerscausedbyCMVEspeciallyincasesrelatedtoadvancedage,renalimpairment,jaundiceandhepatitiswithreactivationofCMV.Incontrast,caseswherethereisareactivationofEpstein-Barrvirus(EBV)seemstohavelessaseverecourse,butaremorelikelytohavelaterdevelopment(usuallyafterseveralyears)ofautoimmunediseasessuchasdiabetesmellitustype1andautoimmunehypothyroidism,.,13,Auxiliaryexamination,Completebloodcount,ALT,AST,totalbilirrubin,GGT,alkalinephosphatase,sodium,potassium,creatinineandcreatinineclearance,24hurineproteinandurinaryeosinophilcount,CPK,LDH,ferritin,triglycerides,calciumandPTH,bloodglucose,TAPandTTPA,lipase,proteinelectrophore-sis,creactiveprotein,quantitativePCRforHHV-6,7,EBVandCMV,bloodculture,anti-nuclearfactor。,.,14,Diagnosticcaiteria,.,15,.,16,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，无脱屑及水泡。淋巴结肿大：颈部可扪及数枚直径约2.0-3.0cm的淋巴结腋下可扪及1-2枚直径约1.5-2.0cm的淋巴结腹股沟区可扪及1-2直径约1.5-2.0cm的淋巴结,.,17,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：,.,18,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,.,19,Score=6,.,20,Differentialdiagnose,SJS(Johnson综合征)TEN(大疱性表皮松解坏死型药疹)SJSTENisdiagnosedbycharacteristicskinandmucosalmanifestations,butnotbyorganinvolvement.However,DIHSisdiagnosedbasedonitscharacteristicclinicalcourse,multipleorganinvolvementanddetectionofherpesvirusreactivationTheonsetofSJSTENwaswithin3weeksafterthestartofdrugadministrationin67%ofcases,Incontrast,DIHSdevelopedat26weeksin80%ofcases,andoccurredmostfrequentlyat4-5weeks.,.,21,Complication,Hemophagocyticsyndrome(HPS):canrarelybeobser-vedinthecourseofDRESS/DIHS.HPSisassociatedwithandtriggeredbyvariousconditions,includingviralinfections,particularlyEBV,malignanttu-mors,orautoimmunediseases.WheninthecourseoftheDRESS/DIHS,HPSusuallyoccurstwoweeksaftertheonsetofdrugeruption.Thereisadecreaseinwhitebloodcellsandplateletsthatisdetectedsimultaneouslywiththeelevationoflactatedehydrogenase(LDH).Bonemarrowaspiraterevealedhemophagocytosisfiguresinanincreasednumberofmacrophages.,.,22,Theincidenceofthissyndromeisestimatedtovaryfromonecaseamong1,000to10,000themortalityrateisabout10%to20%aspecifictherapymaybenecessary,.,23,Treatment,systemiccorticosteroids(doseequaltoorgreaterthan1to1.5mg/kg/dayofprednisoneorequivalent)withmarkedimprovementofsymptomsandlaboratoryparameters,butseveraldaysafterthestartoftreatment.Systemiccorticosteroidsshouldhavetheirdosereduced,aftertheclinicalandlaboratorycontrolofthedisease,slowlyover6-8weeksinordertopreventarecurrenceofthesymptomsofthedisease.Abruptdeteriorationofvarioussymptomsisobservedwhenthewithdrawalisaccidentalorbyrapidreductionofthedosesofcorticosteroids.,.,24,TREATMENT,Itshouldberememberedthattheimmunosuppressivetherapiesmayincreasetheriskofinfectiouscomplicationsandsepsis.Physiciansshouldalsopayattentiontoaproperbalancebetweentheneedsofcorticosteroidsforreliefofsymptomsandclinicalsignsandtheirpossiblenegativeinterferenceonviralload.Attention:SpecialattentionshouldbegiventoapossiblereactivationofCMV/EBV,especiallyinpatientswithsevereDRESS/DIHS.themonitoringofliverfunctiontestsshouldbeperformedandappropriatetestsorderedtoruleouttheinvolvementofotherorganslikelungs,thyroidandheart.,.,25,HighdosesofIVIG:havetwoimmunologicaleffects:(i)compensatesforthedecreaseinconcentrationofimmunoglobulinsinthepatientsbloodandthedefectsoftheimmuneprotectionagainstHHV-6(ii)highdosesofIVIGhaveananti-inflammatoryeffectthatcanregulateimmuneresponses,asseeninthetreatmentofautoimmunediseases.,.,26,plasmaexchange:especiallywithlowimmuneorseverecasesofinfectionandunfavorableimpactofGCtherapyandGCineffectiveinpatientswithsevereshocktherapy,canbeinconjunctionwithIVIG.OnceadayOr3timesinarow,.,27,CsA:CsAcaninhibit