药物超敏反应综合征ppt课件

学习 1 Drug inducedhypersensitivitysyndrome DIHS 2 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 3 4 5 Defition Drug InducedHypersensitivitySyndrome DIHS isasevereandraresystemicreactiontriggeredbyadrug usuallyanantiepilepticdrug accompaniedbyfever lymphadenopathy hepatitis hematologicabnormalitieswitheosinophiliaandatypicallymphocytes andmayinvolveotherorganswitheosinophilicinfiltration causingdamagetoseveralsystems especiallytothekidneys heart lungs andpancreasischaracterizedbylateonset infectiousmononucleosis likesymptoms andherpesvirus6 HHV 6 reactivation 6 Etiopathogenesis Drug deficiencyorabnormalityoftheepoxidehydroxylaseenzyme 环氧酶羟化酶 thatdetoxifiesthemetabolitesofaromaticamineanticonvulsants metabolicpathway Herpesvirus associatedsequentialreactivationofherpesvirusfamily Recently accumulatingevidencesuggeststhatotherHHVs suchasHSV EBV HHV 7andCMVmightbereactivatedduringthecourseofDIHS Gene NAT2andcertainhumanleukocyteantigen HLA alleles immuneresponse 7 Clinicalmanifestations incubationperiod 2 6weeks Fever oftenhigh 38 5 40oC Rash Maculopapularrashdeveloping 3weeksafterstartingtherapywithalimitednumberofdrugs Thecutaneouseruptionconsistsofamorbilliformrash whichisalsocommoninotherlessseveredrugreactionsandbothpresentationsareindistinguishableTheface uppertrunkandupperextremitiesareinitiallyaffected withsubsequentprogressiontothelowerextremities Lymphadenopathy 2mm 8 Themaculopapulareruptionlaterbecomesinfiltratedwithedematousfollicularaccentuat ion Swellingoftheface withmarkedperiorbitalinvolvement Vesiclesmayariseandfinevesiclesbyedemaofthedermiscanbepresent NonecrosisoftheepidermislikeTENoccurs exceptinrarecasesofoverlappingDRESS DIHSandTEN Smallsterileperifollicularpustulesandnonfollicularpustulesmayappear whicharedifferentfromacutegeneralizedexanthematouspustulosis anddoesnotpredominateonthemainfoldsoftheskin Overtimetherashbecomespurplish sharplylowerlimbsandtheresolutionisscaling Anotherformofpresentationisapictureofexfoliativedermatitis whichmaybeassociatedwithmucosalinvolvement suchascheilitis erosions pharygitisandenanthematousenlarged 9 Varioushematologicabnormalities Leukocytosismaybehigh upuntil11 000leukocytes mm3 andeosinophiliareachesvalueshigherthan1500 mm3Hepatitis hepatomegaly ALT ASTincreased hepaticnecrosisMultiorganinvolvement myocarditis myositis pericarditis interstitialnephritis 11 ofcases necrotizinggranulomatousvasculitisinkidney braininvolvement encephalitisormeningitis colitisandthyroiditis themortalityrateisabout10 to20 mainlydiedofseverehepatitis 10 Myocarditismaydevelopatthebeginningofthesyndromeorupto40daysafterinstallation Sym ptomsincludeheartfailure chestpain suddentachycardia dyspnea andhypotensioninearlyDRESS DIHS Renalinvolvementoccursinabout11 ofcases beingparticularlyevidentincasesarisingfromtheuseofallopurinol Therewasanincreaseinserumcreatinineandureaanddecreasedcreatinineclearance InurineItests increasedcontentofeosinophilscandeobserved Neurologicalcomplicationsincludemeningitisandence phalitis occursabout2to4weeksafteronsetofthedrugreactionpulmonaryinvolvementisrarelyreportedinDRESS DIHS 11 Gastrointestinalbleedingmaybeanabruptcomplicationc ausedbyulcerscausedbyCMVEspeciallyincasesrelatedtoadvancedage renalimpairment jaundiceandhepatitiswithreactivationofCMV Incontrast caseswherethereisareactivationofEpstein Barrvirus EBV seemstohavelessaseverecourse butaremorelikelytohavelaterdevelopment usuallyafterseveralyears ofautoimmunediseasessuchasdiabetesmellitustype1andautoimmunehypothyroidism 12 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 13 Diagnosticcaiteria 14 15 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 16 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 17 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 18 Score 6 19 Differentialdiagnose SJS Johnson综合征 TEN 大疱性表皮松解坏死型药疹 SJS TENisdiagnosedbycharacteristicskinandmucosalmanifestations butnotbyorganinvolvement However DIHSisdiagnosedbasedonitscharacteristicclinicalcourse multipleorganinvolvementanddetectionofherpesvirusreactivationTheonsetofSJS TENwaswithin3weeksafterthestartofdrugadministrationin67 ofcases Incontrast DIHSdevelopedat2 6weeksin80 ofcases andoccurredmostfrequentlyat4 5weeks 20 Complication Hemophagocyticsyndrome HPS canrarelybeobser vedinthecourseofDRESS DIHS HPSisassociatedwithandtriggeredbyvariousconditions includingviralinfections particularlyEBV malignanttu mors orautoimmunediseases WheninthecourseoftheDRESS DIHS HPSusuallyoccurstwoweeksaftertheonsetofdrugeruption Thereisadecreaseinwhitebloodcellsandplateletsthatisdetectedsimultaneouslywiththeelevationoflactatedehydrogenase LDH Bonemarrowaspiraterevealedhemophagocytosisfiguresinanincreasednumberofmacrophages 21 Theincidenceofthissyndromeisestimatedtovaryfromonecaseamong1 000to10 000themortalityrateisabout10 to20 aspecifictherapymaybenecessary 22 Treatment systemiccorticosteroids doseequaltoorgreaterthan1to1 5mg kg dayofprednisoneorequivalent withmarkedimprovementofsymptomsandlaboratoryparameters butseveraldaysafterthestartoftreatment Systemiccorticosteroidsshouldhavetheirdosereduced aftertheclinicalandlaboratorycontrolofthedisease slowlyover6 8weeksinordertopreventarecurrenceofthesymptomsofthedisease Abruptdeteriorationofvarioussymptomsisobservedwhenthewithdrawalisaccidentalorbyrapidreductionofthedosesofcorticosteroids 23 TREATMENT Itshouldberememberedthattheimmunosuppressivetherapiesmayincreasetheriskofinfectiouscomplicationsandsepsis Physiciansshouldalsopayattentiontoaproperbalancebetweentheneedsofcorticosteroidsforreliefofsymptomsandclinicalsignsandtheirpossiblenegativeinterferenceonviralload Attention SpecialattentionshouldbegiventoapossiblereactivationofCMV EBV especiallyinpatientswithsevereDRESS DIHS themonitoringofliverfunctiontestsshouldbeperformedandappropriatetestsorderedtoruleouttheinvolvementofotherorganslikelungs thyroidandheart 24 HighdosesofIVIG havetwoimmunologicaleffects i compensatesforthedecreaseinconcentrationofimmunoglobulinsinthepatient sbloodandthedefectsoftheimmuneprotectionagainstHHV 6 ii highdosesofIVIGhaveananti inflammatoryeffectthatcanregulateimmuneresponses asseeninthetreatmentofautoimmunediseases 25 plasmaexchange especiallywithlowimmuneorseverecasesofinfectionandunfavorableimpactofGCtherapyandGCineffectiveinpatientswithsevereshocktherapy canbeinconjunctionwithIVIG OnceadayOr3timesinarow 26 CsA CsAcaninhibitmonocytesandmacrophagesgeneratedTNF alpha ObstaclestoTcells IL 2receptorexpressionandtranscriptionalregulationfactornuclearfactor KBandinhibitTcellactivation preventapoptosisinducedmolecularCD95 ras andCD95ligand FasL mRNAexpression CSAtooutbreaksofCD8 CTLcaninhibitproliferationandcolony ThedramaticprogressinsevereDHS SJS toxicnecrosisloosesolution andaccompaniedbyaweakenedimmunesystemorcasesofsevereinfectionandunfavorableimpactofGCtherapycangiveCsAtreatment treatmentamountforevery3 5mg kg with8to12d thenreducingsequenceuntilthedrugwithdrawal 27 1 激素甲强龙 10mg Kg d 3d 减量为5mg Kg d 4 2 5mg Kg d 2d2 血浆置换 10 15 10 17进行2次3 免疫球蛋白 10 14IVIG 12 5mg10 15IVIG 17 5mg 28 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 29 谢 谢 大 家 30