药物过敏诊断与管理PPT课件.ppt

药物过敏的诊断与管理,DiagnosisandManagementonDrugAllergy,1,.,Allergy2014;69:420437,药物过敏的国际共识,2,Allergy2017;72:10061021.,食物过敏、药物过敏和严重过敏反应的精准医学,3,DrugadversereactionsAdversedrugreactionsAdversereactiontodrugDrugAllergyDrughypersensitivityreactions(DHRs),Allergy2014;69:420437,TERMS,4,DenitionandclassicationsofDHRsPathogenesisandpathophysiologyClinicalpresentationsDiagnosisBiologicaltestsPrinciplesofdrugallergymanagementDHRs=Drughypersensitivityreactions,Allergy2014;69:420437,CONTENTS,5,DenitionandclassicationsofDrughypersensitivityreactions（DHRs）,药物超敏反应的定义和分型,6,.,DHRs的定义,DenitionDrughypersensitivityreactions(DHRs)aretheadverseeffectsofpharmaceuticalformulations(includingactivedrugsandexcipients)thatclinicallyresembleallergy(Box1).,DHRs是临床上类似于过敏反应的药物不良表现。药物过敏反应是证明有确切的免疫机制的DHRs（药物特异性抗体或T-cell介导）当可疑DrugAllergy时，DHRs是最合适的术语。15%ofalladversedrugreactionsDHRsaffectmorethan7%ofthegeneralpopulation,7,DHRs的分型,ClassicationsDHRs表现多种多样（异质性的）Clinically,DHRscanbeclassifiedas:临床分型,速发型DHRs,非速发型DHRs,Mechanistically,DHRscanbedefinedasallergicandnonallergic.,机制上分型：过敏性，非过敏性,8,PathogenesisandpathophysiologyofDHR,DHRs的发病机制和病理生理学,9,.,Pathogenesisandpathophysiology,Immune/allergic/andnonimmune/nonallergicDHRsImmediateallergicDHRs/Nonimmediate/delayedallergicDHRsChemicalbasisofdrugallergies1.thehaptenhypothesis2.Analternativehypothesis(thepharmacologicalinteractionwithimmunereceptor(p-i)concept)3.Pharmaco-andimmunogeneticbasisofdrugallergiesRoleofvirusesinthepathogenesisofDHRs,10,ClinicalpresentationsofDHRs,DHRs的临床表现,11,.,ImmediateDHRs：,AcuteanddelayedmanifestationsofDHRs,Urticaria荨麻诊Angioedema血管性水肿Rhinitis鼻炎Conjunctivitis结膜炎Bronchospasm支气管痉挛gastrointestinalsymptoms(nausea,vomiting,diarrhea)anaphylaxis,whichcanleadtocardiovascularcollapse(anaphylacticshock)严重过敏反应,Allergy2014;69:420437,12,NonimmediateDHRs（skinwithvariablecutaneoussymptoms）,Delayedurticaria迟发型荨麻疹Maculopapulareruptions斑丘疹性红皮病Fixeddrugeruptions(FDE)固定性药疹Vasculitis血管炎blisteringdiseases：皮肤水疱疾病TEN（toxicepidermalnecrolysis）中毒性表皮坏死松解症SJS（Stevens-Johnsonsyndrome史蒂文斯约翰逊综合征Generalizedbullousfixeddrugeruptions泛发性固定性药疹AGEP（acutegeneralizedexanthematouspustulosis)急性泛发性脓疱病Drugreactionwitheosinophiliaandsystemicsymptoms(DRESS)嗜酸细胞增高伴全身症状的药物反应Symmetricaldrug-relatedintertriginousandflexuralexanthemas(SDRIFE)对称性药物相关的擦烂性和皱着部皮疹（是一种最新的病名）,13,Internalorganscanbeaffectedeitheraloneorwithcutaneoussymptoms(HSS/DRESS/DiHS,vasculitis,SJS/TEN),hepatitis肝炎renalfailure肾衰pneumonitis肺炎anemia贫血症neutropenia中性白细胞减少症thrombocytopenia血小板减少Vasculitis血管炎Drug-inducedhypersensitivitysydrome,DIHS,14,青霉素、解热镇痛类、巴比妥类及磺胺类药物，尤其是半合成青霉素(氨苄青霉素和羟氨苄青霉素)多引起该型药疹。麻疹样药疹为散在或密集、红色针头至米粒大的斑疹或斑丘疹，对称分布，可泛发全身，以躯干为多，类似麻疹，严重者可伴发小出血点。,1、麻疹样药疹,重度麻疹样的药疹,轻度麻疹样的药疹,15,2、猩红热样药疹,猩红热样药疹初起为小片红斑，从面、颈、上肢、躯干向下发展，于23日内可遍布全身，并相互融合，伴面部四肢肿胀，酷似猩红热的皮疹，尤以皱褶部位及四肢屈侧更为明显。,16,3、固定性药疹,解热镇痛类、磺胺类或巴比妥类等引起。皮疹多见于口唇、口周、龟头等皮肤粘膜交界处，手足背及躯干亦可发生。皮疹为圆形或类圆形的水肿性暗紫红色斑疹，直径约l4cm，常为一个，偶可数个，边界清楚，绕以红晕，轻度瘙痒，一般不伴周身症状。,痢特灵引起的固定性药疹,17,4、荨麻疹型药疹,多由血清制品(如破伤风或狂犬病疫苗)、痢特灵、青霉素等引起。临床表现与急性荨麻疹相似，但持续时间较长，同时可伴有血清病样症状，如发热、关节疼痛、淋巴结肿大、血管性水肿甚至蛋白尿等。若致敏药物排泄十分缓慢，或因生活或工作中不断接触微量致敏原，可表现为慢性荨麻疹。,18,5、湿疹型药疹,接触或外用青霉素、链霉素、磺胺类及奎宁等药物引起接触性皮炎，可出现湿疹样皮疹。皮疹为大小不等红斑、丘疹、丘疱疹及水疱，常融合成片,泛发全身，可有糜烂、渗出、脱屑等，全身症状常较轻，病程相对较长。,19,湿疹型药疹,Robertsetal.JInfect.2005Jun;50(5):375-81.,20,6、紫癜型药疹,多由抗生素类、巴比妥盐、眠尔通、利尿药、奎宁等引起。可通过II型变态反应引起血小板减少性紫癜，或III型变态反应出现血管炎而产生紫癜。轻者双侧小腿出现红色瘀点或瘀斑，散在或密集分布，可略微隆起，压之不褪色。有时可伴发风团或中心发生小水疱或血疱。重者四肢躯干均可累及，可伴有关节肿痛、腹痛、血尿、便血等，甚至有粘膜出血、贫血等。,21,7、多形红斑型药疹,多由磺胺类、解热镇痛类及巴比妥类等引起。临床表现与多形红斑相似，皮损为豌豆至蚕豆大圆形或椭圆形水肿性红斑、丘疹，境界清楚，中心呈紫红色，虹膜现象阳性，常有水疱。多对称分布于四肢伸侧、躯干，伴有瘙痒，常累及口腔及外生殖器粘膜，可伴疼痛。皮疹可泛发全身，在红斑、丘疹、水疱的基础上出现大疱、糜烂及渗出，尤其在口腔、眼部、肛门、外生殖器等腔口部位出现红斑、糜烂，疼痛剧烈。可伴高热、外周血白细胞可升高、肝肾功能损害及继发感染等，称为重症多形红斑型药疹，为重型药疹之一，病情凶险，可导致死亡。,22,多形性红斑,渗出性多形红斑,SJS,水肿性红斑、丘疹，境界清楚，中心呈紫红色，虹膜现象阳性，常有水疱。多对称分布于四肢伸侧、躯干，伴有瘙痒，糜烂及渗出，常累及口腔及外生殖器粘膜,23,多形性红斑,渗出性多形红斑,斯-约二氏综合征,Stevens-Johnsonsyndrome(SJS),ClinRevAllergyImmunol.2018Feb;54(1):147-176.,24,8、大疱性表皮松解型药疹,常由磺胺类、解热镇痛类、抗生素类、巴比妥类等引起。是病情严重的药疹之一，起病急骤，部分病例开始时似多形红斑或固定型药疹，皮损为弥漫性紫红或暗红色斑片，迅速波及全身。红斑处出现大小不等的松弛性水疱或大疱，尼氏征阳性，稍受外力即成糜烂面，可形成大面积的表皮坏死松解。呈暗灰色的坏死表皮覆于糜烂面上，可伴大面积的糜烂及大量渗出，似浅表的II度烫伤，触痛明显。全身中毒症状较重，伴高热、乏力、恶心、呕吐、腹泻等症状。口腔、颊粘膜、眼结膜、呼吸道、胃肠道粘膜也可糜烂、溃疡。严重者常因继发感染、肝肾功能衰竭、电解质紊乱、内脏出血、蛋白尿甚至氮质血症等而死亡。,25,中毒性表皮坏死松解症(TEN),（大疱性表皮松解型药疹）,红斑处出现大小不等的松弛性水疱或大疱尼氏征阳性，稍受外力即成糜烂面可形成大面积的表皮坏死松解呈暗灰色的坏死表皮覆于糜烂面上可伴大面积的糜烂及大量渗出似浅表的II度烫伤，触痛明显,ClinRevAllergyImmunol.2018Feb;54(1):147-176.,26,多形性红斑,渗出性多形红斑,斯-约二氏综合征/中毒性表皮坏死松解症(SJS/TEN),27,9、剥脱性皮炎型药疹,磺胺类、巴比妥类、抗癫痫药(如苯妥英钠、卡马西平等)、解热镇痛类、抗生素等药引起。药疹多是长期用药后发生。皮损初呈麻疹样或猩红热样，逐渐加重融合成全身弥漫性潮红、肿胀，尤以面部及手足为重，可有丘疱疹或水疱，伴糜烂、少量渗出。23周左右，皮肤红肿渐消退，全身出现大量鳞片状或落叶状脱屑，手足部则呈手套或袜套状剥脱。头发、指(趾)甲可脱落(病愈可再生)。口唇和口腔粘膜红肿，或出现水疱、糜烂，疼痛而影响进食。眼结膜充血、水肿、畏光、分泌物增多，重时可发生角膜溃疡。全身浅表淋巴结常肿大，可伴有支气管肺炎、药物性肝炎、外周血白细胞可显著增高或降低，甚至出现粒细胞缺乏。该型药疹病程较长，如未及时停用致敏药物及积极治疗，严重者常因全身衰竭或继发感染而死亡。,28,剥脱性皮炎型药疹,29,Danger/severitysignsofDHRsDHRs的危险/严重信号（征兆）,Acompletehistoryofthedrugstaken(types,doses,durationAdetaileddescriptionofthesymptomsandsigns(types,onset,localization,andevolution),Acompleteexaminationoftheskinandthemucousmembranes(includingthemouth,eyes,andgenitals)Asearchfordanger/severitysigns,whichincludeclinicalsymptomsaswellassomelaboratoryparameters(Fig.2),30,Multipledrughypersensitivitysyndrome多种药物超敏反应综合症（MDHS）,MDHS：drugallergiestotwoormorechemicallydifferentdrugs（二种或多种不同化学成分的药物）theprevalenceofMDHsrangesfrom1%to10%T-cellactivationbydifferentcompoundshasbeenclearlydemonstratedinMDHsMDHS与以下药物反应的区别：cross-reactivity(duetostructuralsimilarities,commonmetabolicpathways,orpharmacologicmechanisms)areupreactions(exacerbationofanexistingdrugallergybytheearlyswitchoftherapytoanoveldrug)multipledrugintolerancesyndrome,Allergy2014;69:420437,31,ThediagnosisofDHRs,药物超敏反应的诊断,32,.,ThediagnosisofDHRs,Thediagnosisisindeedbasedonhistory,onclinicalmanifestations,andifpossible,oninvivotestsandsomeinvitrobiologicaltests(Fig.3)EvaluationoftheclinicalhistoryClinicalmanifestationsPharmacovigilancealgorithmsSkintestsreliableinvitrotestsDrugprovocationtest(DPT),药物超敏反应的诊断,33,.,Suspicionofdrughypersensitivity,.,Evaluationoftheclinicalhistory(ENDAquestionnaire),Drugprovocationtest*,Results,Provendrughypersensitivity,Nodrughypersensitivity,Therapeuticalapproach*,Provendrugallergy,Possibledrughypersensitivity?.,Skintestsavailable*?,Drugprovocationtestavailable*?,yes,NO,yes,Nodrughypersensitivity,NEGATIVE,POSITIVE,Results,POSITIVE,yes,No,NEGATIVE,*Intheabsenceofcontraindications*Ifnoalternativeisavailable,Fig.3FlowchartwhenassessingDHRs(adaptedfromwithpermission).,*Currentlyavailablebiologicalteststodiagnosedrugallergylacksensitivity.,评估药物超敏反应的流程图,No,34,BiomarkerstestofDHRs,药物超敏反应的生物学标记物检测,35,.,SPT和sIgE（I型DHR)IgMorIgG(drug-inducedcytopenia,typeDHRstovaccinesorallergiestodextrans(右旋糖苷；葡聚糖）BAT-嗜碱细胞活化试验basophilhistaminereleaseassay-嗜碱细胞组胺释放试验CD63andCD203c（flowcytometry，流式细胞仪）Mediators：Tryptase（类胰蛋白酶）,higherlevelsduringdruganaphylaxis）Cells:granzymeBandgranulysin颗粒酶、颗粒酶溶素CD3+CD4+Tcells,IFN-r(SJS)LTT（Lymphocytetransformationtests）淋巴细胞转换试验Patchtesting：maculopapularrashes,flexuralexanthems,fixeddrugeruptions,andAGEP.DrughasbeenfoundfrequentlytobepositiveinpatientswithrecenthistoriesofDRESSandSJShistamineortryptase（CAPFEIA）组胺或类胰蛋白酶suldopeptideleukotrienesproducedinvitro-硫基肽白三烯,BiomarkerstestsofDHRs,36,Coombstest（抗人球蛋白试验）invitrohemolysistest,determinationofcomplementfactorsandcirculatingimmunecomplexes(溶血试验、补体、免疫复合物）AssaysinvolvingTcells(lymphocytetransformation/activationtests)（淋巴细胞转换/激化试验）Searchingforgeneticmarkers：基因标记HLAmarkerspatchtesting（人类白细胞抗原标记物斑贴试验）HLAalleleandthesusceptibilitytospecicformsofDHRshavebeenrecentlydiscovered(HLA等位基因）HLA-B*5701expressionandDRESS-predictivetestingstrategiesverysuccessfulpredictivestrategyofabacavir（阿巴卡伟）HLA-B*1502-drugcarbamazepine（卡马西平）中国人10-15%HLA-B*5801-Allopurind(别嘌呤)中国人9-11%HLA-A*3101-carbamazepine北欧人2-5%,Fordrug-inducedtypeandallergicreactions,37,Principlesofdrugallergymanagement,药物过敏反应的管理准则,38,.,Principlesofdrugallergymanagement,Acutedrugreactions急性药物反应快速、准确处理Anaphylaxis，停止任何可疑的药物。Individualpreventivemeasures个体化预防措施填写详尽的文件报告、用药前和手术前询问病人的过敏史建立电子档案DPT必须在医院进行缓慢注射术前用药和预防性应用类固醇类或抗组胺药物。Generalpreventivemeasures常规的预防措施AdeclarationtotheCommitteeonSafetyofMedicineReports.向医药安全委员会报告,39,应该在高度专业化的中心、专家团队、抢救药物、设备完善及时发现、及时救治AnaphylaxisAnadrenalineautoinjectorandanexposureactionplandescribingfeaturesofbothmildandworseningreactions,andhowtoinjectadrenaline.AntihistaminesDrugdesensitization,J.L.Turnbulletal.Review:foodallergiesandintolerances2014AlimentPharmacolTher,JAllergyClinImmunol2015;136：556-68.,Principlesofdrugallergymanagement,40,西替利嗪(cetirizine)仙特敏、适迪、赛特赞10mg1/d氯雷他定(loratadine)开瑞坦（克敏能、百为坦）10mg1/d美喹他嗪(mequitazine)波丽玛郎、甲喹酚嗪5mg2/d咪唑斯汀(mizolastine)皿治林10mg1/d依巴斯汀(ebastine)开思亭10mg1/d氮卓斯汀(azelastine)爱赛平2mg1/d左西替利嗪(Levocetirizine)优泽TM5mg1/d地氯雷他定(deloratadine)地衡塞5mg1/d盐酸非索非那定莱多菲30mg/儿童,60mg/成人1-2/d(fexofenadineHCI),药名商品名剂型与剂量,新一代抗组胺药：Anti-histamines,41,用药前应仔细询问患者的药物过敏史及症状。应按规定的药物进行皮肤试验。皮试液浓度为：青霉素500U/ml，链霉素5mg/m1，普鲁卡因0.25，破伤风抗毒素1:10，用量均为0.1ml。避免乱用药物。对过敏体质者，注意复方制剂中含有的已知过敏药物。注意药疹的早期症状。如突然出现瘙痒、红斑、发热等反应，应立即停用一切可疑药物，密切观察，及时处理。已确诊为药疹者，应将致敏药物记人病历首页，或建立患者药物禁忌卡片。嘱患者牢记，每次看病时应告诉医生勿用该药。,药物过敏的预防,42,Conclusions,ThediagnosisofDHRsisoftenchallengingandrequiresthesamecarefulapproach,nomatterwhichspecificdrugisinvolved.Provocationtestsarethegoldstandardfordeterminingcurrenttolerance,butrequireexpertise,carryacertainamountofrisk,andarelimited.Newandvalidatedbiologicaltestsfordiagnosis,availabletoallclinicians,arenecessaryinordertoimprovecareforthesepatients.HLAtypinghasprovidedanimportanttoolfordetectingsusceptiblepatientpopulations.CollaborativebasicresearchintothepathophysiologyofDHRshouldbeintensi