藥物超敏反應綜合征

學習1編輯pptDrug-inducedhypersensitivitysyndrome(DIHS)2編輯pptHISTORYDrug-InducedHypersensitivitySyndrome(DIHS),wasfirstrecognizedin1950byChaiken,inapatientusinganticonvulsant.Later,SaItzsteindescribedthiskindofdrugreactionaspseudolymphomaInthe1960swiththedevelopmentofcarbamazepine,thediseasenamedantispasmodicsyndromeinadditiontoanticonvulsants,diaphenylsulfone(DDS).allopurinol(別嘌醇),salazosulfapyridine(柳氮磺胺吡啶)anddapsone(氨苯砜)canalsocauseDIHS3編輯ppt4編輯ppt5編輯pptDefitionDrug-InducedHypersensitivitySyndrome(DIHS)isasevereandraresystemicreactiontriggeredbyadrug(usuallyanantiepilepticdrug).accompaniedbyfever,lymphadenopathy,hepatitis,hematologicabnormalitieswitheosinophiliaandatypicallymphocytes,andmayinvolveotherorganswitheosinophilicinfiltration,causingdamagetoseveralsystems,especiallytothekidneys,heart,lungs,andpancreasischaracterizedbylateonset,infectiousmononucleosis-likesymptoms,andherpesvirus6(HHV-6)reactivation.6編輯pptEtiopathogenesisDrug:deficiencyorabnormalityoftheepoxidehydroxylaseenzyme(環(huán)氧酶羥化酶)thatdetoxifiesthemetabolitesofaromaticamineanticonvulsants(metabolicpathway)Herpesvirus:associatedsequentialreactivationofherpesvirusfamily.(Recently,accumulatingevidencesuggeststhatotherHHVs,suchasHSV,EBV,HHV-7andCMVmightbereactivatedduringthecourseofDIHS)Gene:NAT2andcertainhumanleukocyteantigen(HLA)alleles(immuneresponse)7編輯pptClinicalmanifestationsincubationperiod(2-6weeks)Fever,：oftenhigh(38.5-40oC)Rash:Maculopapularrashdeveloping＞3weeksafterstartingtherapywithalimitednumberofdrugs.Thecutaneouseruptionconsistsofamorbilliformrash,whichisalsocommoninotherlessseveredrugreactionsandbothpresentationsareindistinguishableTheface,uppertrunkandupperextremitiesareinitiallyaffected,withsubsequentprogressiontothelowerextremities.Lymphadenopathy(>2mm)8編輯pptThemaculopapulareruptionlaterbecomesinfiltratedwithedematousfollicularaccentuat-ion.Swellingoftheface,withmarkedperiorbitalinvolvement.Vesiclesmayariseandfinevesiclesbyedemaofthedermiscanbepresent.NonecrosisoftheepidermislikeTENoccurs,exceptinrarecasesofoverlappingDRESS/DIHSandTEN.Smallsterileperifollicularpustulesandnonfollicularpustulesmayappear,whicharedifferentfromacutegeneralizedexanthematouspustulosis,anddoesnotpredominateonthemainfoldsoftheskin..Overtimetherashbecomespurplish,sharplylowerlimbsandtheresolutionisscaling.Anotherformofpresentationisapictureofexfoliativedermatitis,whichmaybeassociatedwithmucosalinvolvement,suchascheilitis,erosions,pharygitisandenanthematousenlarged→9編輯pptVarioushematologicabnormalities:Leukocytosismaybehigh,upuntil11,000leukocytes/mm3,andeosinophiliareachesvalueshigherthan1500/mm3Hepatitis：hepatomegaly.ALT/ASTincreased.hepaticnecrosisMultiorganinvolvement:myocarditis/myositis,pericarditis,interstitial

nephritis

(11%ofcases),necrotizinggranulomatousvasculitisinkidney,brain

involvement(encephalitisormeningitis),colitisandthyroiditis.themortalityrateisabout10%to20%,mainlydiedofseverehepatitis

√10編輯pptMyocarditismaydevelopatthebeginningofthesyndromeorupto40daysafterinstallation.Sym-ptomsincludeheartfailure,chestpain,suddentachycardia,dyspnea,andhypotensioninearlyDRESS/DIHS.Renalinvolvementoccursinabout11%ofcases,beingparticularlyevidentincasesarisingfromtheuseofallopurinol.Therewasanincreaseinserumcreatinineandureaanddecreasedcreatinineclearance.InurineItests,increasedcontentofeosinophilscandeobserved.Neurologicalcomplicationsincludemeningitisandence-phalitis.occursabout2to4weeksafteronsetofthedrugreactionpulmonaryinvolvementisrarelyreportedinDRESS/DIHS11編輯pptGastrointestinalbleedingmaybeanabruptcomplicationc-ausedbyulcerscausedbyCMV

Especiallyincasesrelatedtoadvancedage,renalimpairment,jaundiceandhepatitiswithreactivationofCMV.Incontrast,caseswherethereisareactivationofEpstein-Barrvirus(EBV)seemstohavelessaseverecourse,butaremorelikelytohavelaterdevelopment(usuallyafterseveralyears)ofautoimmunediseasessuchasdiabetesmellitustype1andautoimmunehypothyroidism12編輯pptAuxiliaryexaminationCompletebloodcount,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編輯pptDiagnosticcaiteria14編輯ppt15編輯ppt服用苯妥英鈉藥物史發(fā)熱：以中高熱為主，體溫最高可達40.8oC皮疹：顏面部、軀干、四肢可見散在或彌漫分布的紅色斑丘疹，高出皮面，壓之不褪色，伴瘙癢，無脫屑及水泡。淋巴結腫大：頸部可捫及數枚直徑約2.0-3.0cm的淋巴結腋下可捫及1-2枚直徑約1.5-2.0cm的淋巴結腹股溝區(qū)可捫及1-2直徑約1.5-2.0cm的淋巴結

16編輯ppt肝炎：肝大：入院時肋下12cm，劍突下11cm10.15肋下8cm，劍突下8.5cm肝功：

17編輯ppt輔助檢查血常規(guī)：血氨、乳酸EB-PCR:2.22*106血、痰、咽拭子、骨髓培養(yǎng)：陰性心肌標志物、免疫術前全套胸部平片、心臟彩超、胸腹部B超18編輯ppt

Score=619編輯pptDifferentialdiagnoseSJS(Johnson綜合征)?TEN(大皰性表皮松解壞死型藥疹)SJS?TENisdiagnosedbycharacteristicskinandmucosalmanifestations,butnotbyorganinvolvement.However,DIHSisdiagnosedbasedonitscharacteristicclinicalcourse,multipleorganinvolvementanddetectionofherpesvirusreactivationTheonsetofSJS?TENwaswithin3weeksafterthestartofdrugadministrationin67%ofcases,Incontrast,DIHSdevelopedat2–6weeksin80%ofcases,andoccurredmostfrequentlyat4-5weeks.20編輯pptComplicationHemophagocyticsyndrome(HPS):canrarelybeobser-vedinthecourseofDRESS/DIHS.HPSisassociatedwithandtriggeredbyvariousconditions,includingviralinfections,particularlyEBV,malignanttu-mors,orautoimmunediseases.WheninthecourseoftheDRESS/DIHS,HPSusuallyoccurstwoweeksaftertheonsetofdrugeruption.Thereisadecreaseinwhitebloodcellsandplateletsthatisdetectedsimultaneouslywiththeelevationoflactatedehydrogenase(LDH).Bonemarrowaspiraterevealedhemophagocytosisfiguresinanincreasednumberofmacrophages.21編輯pptTheincidenceofthissyndromeisestimatedtovaryfromonecaseamong1,000to10,000themortalityrateisabout10%to20%aspecifictherapymaybenecessary22編輯pptTreatmentsystemiccorticosteroids(doseequaltoorgreaterthan1to1.5mg/kg/dayofprednisoneorequivalent)withmarkedimprovementofsymptomsandlaboratoryparameters,butseveraldaysafterthestartoftreatment.Systemiccorticosteroidsshouldhavetheirdosereduced,aftertheclinicalandlaboratorycontrolofthedisease,slowlyover6-8weeksinordertopreventarecurrenceofthesymptomsofthedisease.Abruptdeteriorationofvarioussymptomsisobservedwhenthewithdrawalisaccidentalorbyrapidreductionofthedosesofcorticosteroids.23編輯pptTREATMENTItshouldberememberedthattheimmunosuppressivetherapiesmayincreasetheriskofinfectiouscomplicationsandsepsis.Physiciansshouldalsopayattentiontoaproperbalancebetweentheneedsofcorticosteroidsforreliefofsymptomsandclinicalsignsandtheirpossiblenegativeinterferenceonviralload.Attention:SpecialattentionshouldbegiventoapossiblereactivationofCMV/EBV,especiallyinpatientswithsevereDRESS/DIHS.themonitoringofliverfunctiontestsshouldbeperformedandappropriatetestsorderedtoruleouttheinvolvementofotherorganslikelungs,thyroidandheart.24編輯pptHighdosesofIVIG:havetwoimmunologicaleffects:(i)compensatesforthedecreaseinconcentrationofimmunoglobulinsinthepatient’sbloodandthedefectsoftheimmuneprotectionagainstHHV-6(ii)highdosesofIVIGhaveananti-inflammatoryeffectthatcanregulateimmuneresponses,asseeninthetreatmentofautoimmunediseases.25編輯pptplasmaexchange:especiallywithlowimmuneorseverecasesofinfectionandunfavorableimpactofGCtherapyandGCineffectiveinpatientswithsevereshocktherapy,canbeinconjunctionwithIVIG.OnceadayOr3timesinarow26編輯pptCsA:CsAcaninhibitmonocytesandmacrophagesgeneratedT