药物过敏诊断与管理.ppt

,单击此处编辑母版标题样式,*,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,药物过敏的诊断与管理,Diagnosis and Management on,D,rug,A,llergy,主讲人：苏梦可,Allergy 2014;69:420437,药物过敏的国际共识,Allergy 2017;72:10061021.,食物过敏、药物过敏和严重过敏反应的精准医学,Drug adverse reactions,Adverse drug reactions,Adverse reaction to drug,Drug Allergy,Drug hypersensitivity reactions,(,DHRs),Allergy 2014;69:420437,TERMS,Denition and classications of DHRs,Pathogenesis and pathophysiology,Clinical presentations,Diagnosis,Biological tests,Principles of drug allergy management,DHRs,=,Drug hypersensitivity reactions,Allergy 2014;69:420437,CONTENTS,Denition and classications of,Drug hypersensitivity reactions,（,DHRs,）,药物超敏反应的定义和分型,DHRs,的定义,Denition,Drug hypersensitivity reactions(,DHRs,)are the adverse effects of pharmaceutical formulations(including active drugs and excipients)that clinically resemble allergy (Box 1).,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,Drug Allergy,时，,DHRs,是最合适的术语。,15%,of all adverse drug reactions,DHRs affect more than,7%,of,the general population,DHRs,的分型,Classications,DHRs,表现多种多样（异质性的）,Clinically,DHRs can be classified as:,临床分型,速发型,DHRs,非速发型,DHRs,Mechanistically,DHRs can be defined as allergic and nonallergic.,机制上分型：,过敏性，非过敏性,Pathogenesis and pathophysiology of DHR,DHRs,的,发病机制和病理生理学,Pathogenesis and pathophysiology,Immune/allergic/,and nonimmune/nonallergic DHRs,Immediate allergic DHRs/Nonimmediate/delayed allergic DHRs,Chemical basis of drug allergies,1.,the hapten hypothesis,2.An alternative hypothesis(the pharmacological interaction with immune receptor(p-i)concept),3.Pharmaco-and immunogenetic basis of drug allergies,Role of viruses in the pathogenesis of DHRs,Clinical presentations of DHRs,DHRs,的临床表现,Immediate DHRs,：,Acute and delayed manifestations of DHRs,Urticaria,荨麻诊,Angioedema,血管性水肿,Rhinitis,鼻炎,Conjunctivitis,结膜炎,Bronchospasm,支气管痉挛,gastrointestinal symptoms(nausea,vomiting,diarrhea),anaphylaxis,which can lead to cardiovascular collapse(,anaphylactic shock,),严重过敏反应,Allergy 2014;69:420437,Nonimmediate DHRs,（,skin with variable cutaneous symptoms,）,Delayed urticaria,迟发型荨麻疹,Maculopapular eruptions,斑丘疹性红皮病,Fixed drug eruptions(FDE),固定性药疹,Vasculitis,血管炎,blistering diseases,：,皮肤水疱疾病,TEN,（,toxic epidermal necrolysis,）,中毒性表皮坏死松解症,SJS,（,Stevens-Johnsonsyndrome,史蒂文斯,约翰逊综合征,Generalized bullous fixed drug eruptions,泛发性固定性药疹,AGEP,（,acute generalized exanthematous pustulosis),急性泛发性脓疱病,Drug reaction with eosinophilia and systemic symptoms(DRESS),嗜酸细胞增高伴全身症状的药物反应,Symmetrical drug-related intertriginous and flexural exanthemas(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）,Internal organs can be affected either alone or with cutaneous symptoms(HSS/DRESS/DiHS,vasculitis,SJS/TEN,),hepatitis,肝炎,renal failure,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-induced hypersensitivity sydrome,DIHS,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,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,2,3,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。,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,l,4cm,，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,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。,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。,湿疹型药疹,Roberts et al.J Infect.2005 Jun;50(5):375-81.,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。,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。,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,多形性红斑,渗出性多形红斑,斯,-,约二氏综合征,Stevens-Johnson syndrome(SJS),Clin Rev Allergy Immunol.2018 Feb;54(1):147-176.,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。,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,Clin Rev Allergy Immunol.2018 Feb;54(1):147-176.,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),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。,2,3,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。,剥脱性皮炎型药疹,Danger/severity signs of DHRs DHRs,的危险,/,严重信号（征兆）,A complete history of the drugs taken(types,doses,duration,A detailed description of the symptoms and signs(types,onset,localization,and evolution),A complete examination of the skin and the mucous membranes(including the mouth,eyes,and genitals),A search for danger/severity signs,which include clinical symptoms as well as some laboratory parameters(Fig.2),Multiple drug hypersensitivity syndrome,多种药物超敏反应综合症,（,MDHS,）,MDHS,：,drug allergies to two or more chemically different drugs,（,二种或多种不同化学成分的药物）,the prevalence of MDHs ranges from 1%to 10%,T-cell activation by different compounds has been clearly,demonstrated in MDHs,MDHS,与以下药物反应的区别：,cross-reactivity(due to structural similarities,common metabolic pathways,or pharmacologic mechanisms),areup reactions(exacerbation of an existing drug allergy by the early switch of therapy to a novel drug),multiple drug intolerance syndrome,Allergy 2014;69:420437,The diagnosis of DHRs,药物超敏反应的诊断,The diagnosis of DHRs,The diagnosis is indeed based on history,on clinical,manifestations,and if possible,on in vivo tests and,some in vitro biological tests(Fig.3),Evaluation of the clinical history,Clinical manifestations Pharmacovigilance algorithms,Skin tests,reliable in vitro tests,Drug provocation test(DPT),药物超敏反应的诊断,.,Suspicion of,drug hypersensitivity,.,Evaluation of the clinical history (ENDA questionnaire),Drug provocation test*,Results,Proven drug hypersensitivity,No drug hypersensitivity,Therapeutical,approach*,Proven,drug allergy,Possible drug,hypersensitivity?.,Skin tests,available*?,Drug provocation,test available*?,yes,NO,yes,No drug hypersensitivity,NEGATIVE,POSITIVE,Results,POSITIVE,yes,No,NEGATIVE,*In the absence of contraindications,*If no alternative is available,Fig.3 Flow chart when assessing DHRs(adapted from with permission).,*Currently available biological tests to diagnose drug,allergy lack sensitivity.,评估药物超敏,反应的流程图,No,Biomarkers,test of DHRs,药物超敏反应的生物学标记物检测,SPT,和,sIgE,（,I,型,DHR),IgM or,IgG(,drug-induced,cytopenia,type DHRs to vaccines or allergies to dextrans(,右旋糖苷；葡聚糖）,BAT,-,嗜碱细胞活化试验,basophil histamine release assay-,嗜碱细胞组胺释放试验,CD63,and,CD203c,（,flow cytometry,，流式细胞仪）,Mediators,：,Tryptase,（,类胰蛋白酶）,higher levels during drug anaphylaxis,）,Cells:,granzyme B and granulysin,颗粒酶、颗粒酶溶素,CD3+CD4+T cells,IFN-r(SJS),LTT,（,Lymphocyte transformation tests,）淋巴细胞转换试验,Patch testing,：,maculopapular rashes,flexural exanthems,fixed drug eruptions,and AGEP.Drug has been found frequently to be positive in patients with recent histories of DRESS and SJS,histamine or tryptase,（,CAP FEIA,）组胺或类胰蛋白酶,suldopeptide leukotrienes produced in vitro-,硫基肽白三烯,Biomarkers,tests of DHRs,Coombs test,（抗人球蛋白试验）,in vitro hemolysis test,determination of complement factors and circulating immune complexes(,溶血试验、补体、免疫复合物）,Assays involving T cells(lymphocyte transformation/activation tests),（淋巴细胞转换,/,激化试验）,Searching for genetic markers,：,基因标记,HLA markers patch testing,（人类白细胞抗原标记物斑贴试验）,HLA allele,and the susceptibility to specic forms of DHRs have been recently discovered (HLA,等位基因）,HLA-B*5701,expression and DRESS-predictive testing strategies,very successful predictive strategy of abacavir,（阿巴卡伟）,HLA-B*1502,-drug carbamazepine,（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%,For drug-induced type,and,allergic reactions,Principles of drug allergy management,药物过敏反应的管理准则,Principles of drug allergy management,Acute drug reactions,急性药物反应,快速、准确处理,Anaphylaxis,，停止任何可疑的药物。,Individual preventive measures,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。,General preventive measures,常规的预防措施,A declaration to the Committee on Safety of Medicine Reports.,向医药安全委员会报告,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,Anaphylaxis,An adrenaline autoinjector,and an exposure action plan describing features of both mild and worsening reactions,and,how to inject adrenaline.,Antihistamines,Drug desensitization,J.L.Turnbull et al.,Review:food allergies and intolerances,2014 Aliment Pharmacol Ther,J Allergy Clin Immunol 2015;136,：,556-68.,Principles of drug allergy management,西替利嗪,(,cetirizine),仙特敏,、适迪、赛特赞,10 mg 1/d,氯雷他定,(,loratadine),开瑞坦（克敏能、百为坦）,10 mg 1/d,美喹他嗪,(mequitazine),波丽玛郎、甲喹酚嗪,5 mg 2/d,咪唑斯,汀,(mizolastine),皿治林,10 mg 1/d,依巴斯汀,(,ebastine),开思亭,10 mg 1/d,氮卓斯汀,(,azelastine),爱赛平,2mg 1/d,左西替利嗪,(Levocetirizine),优泽,TM,5mg,1/d,地氯雷他定,(,deloratadine),地衡塞,5 mg 1/d,盐酸非索非那定 莱多菲,30mg/,儿童,60 mg/,成人,1-2/d,(fexofenadine HCI),药名 商品名 剂型与剂量,新一代抗组胺药：,Anti-histamines,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,Conclusions,The diagnosis of DHRs is often challenging and requires the,same careful approach,no matter which specific drug is,involved.,Provocation tests are the gold standard for determining current tolerance,but require expertise,carry a certain amount,of risk,and are limited.,New and validated,biological tests for diagnosis,available to all clinicians,are,necessary in order to improve care for these patients.,HLA typing has provided an important tool for,detecting susceptible patient populations.,Collaborative basic research into the pathophysiology of DHR should be intensified in order to better understand this complex set of diseases by drug and mediated(or not)by the immune system.,Conclusions,结论,DHRs,的诊断常常具有挑战性，需要严格谨慎的诊断方法和标准。,开发新的、更有价值的生物学检测手段诊断药物过敏。,HLA,型提供了检测易感人群的重要工具,DHR,的基础研究和病理生理学相结合，将更好的掌握由药物引起和是（或不是）由免疫系统介导的这种复杂的病症。,International Consensus on drug allergy,Allergy 2014;69:420437,Drug hypersensitivity in children:report from the pediatric task force of the EAACI Drug Allergy Interest Group,Allergy 2016;71:149161,.,Drug allergy:diagnosis and management of drug allergy in adults,children and young people;a look at NICE guidance,BMJ,2016,Guideline review,A retrospective study of DRESS-drug reaction with eosinophilia and systemic symptoms.,Psychiatr.Pol.2017;51(6):10791093,Precision medicine in allergic diseasefood allergy,drug allergy,and anaphylaxisPRACTALL document of the European Academy of Allergy and Clinical Immunology and the American Academy of Allergy,Asthma and Immunology,Allergy 2017;72:10061021,.,Pro and Contra:Provocation Tests in Drug Hypersensitivity,Int J Mol Sci 2017;4:187,Current Perspectives on Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis.Clin Rev Allergy Immunol.2018;54(1):147-17,参考文献,6.,后面内容直接删除就行,资料可以编辑修改使用,资料可以编辑修改使用,主要经营：网络软件设计、图文设计制作、发布广告等,公司秉着以优质的服务对待每一位客户，做到让客户满意！,致力于数据挖掘，合同简历、论文写作、,PPT,设计、计划书、策划案、学习课件、各类模板等方方面面，打造全网一站式需求,感谢您的观看和下载,The user can demonstrate on a projector or computer,or print the presentation and make it into a film to be used in a wider field,