重症感染患者生物标记物的临床价值.ppt

1 重症感染患者生物标记物的临床价值 解放军总医院全军呼吸病研究所解立新 2 什么是生物标记物 Biomarkers 生物标志物 Biomarker 这一概念首次出现于美国国家研究委员会 NRC 在1983年出版的红皮书 联邦政府风险评估 中它是指可以标记系统 器官 组织 细胞及亚细胞结构或功能的改变或可能发生的改变的生化指标 具有非常广泛的用途目前 生物标志物广泛用于疾病诊断 判断疾病分期或者用来评价新药或新疗法在目标人群中的安全性及有效性随着高通量全基因组学 蛋白组学 代谢组学技术的迅猛发展 有望发现更多更好的新的生物标记物目前临床常规用于感染的如 WBC ESR PCT CRP IL 6等 3 理想的生物标记物 能够明确鉴别感染与非感染 Sepsisvs SIRS 能够动态评价疾病严重程度和预后期望能够鉴别细菌 真菌 病毒在鉴别肺部感染方面具有独特的优势能够指导抗菌药物的合理应用 有这样理想的生物标记物吗 4 Biomarkersforpneumonia Potentialbiomarkerspresentedthebiologicalstateofpneumonia ClinicaChimicaActa419 2013 19 25 5 Biomarkersrelatedtosepsis C1q complementcomponent1qsubcomponent HMGB1 high mobilitygroupproteinB1 NEcell nuroendocrinecell PAI 1 plasminogenactivatorinhibitor 1 PAMPs pathogenassociatedmolecularpatterns PTX3 pentraxin relatedprotein3 RAGE receptorofadvancedglycationendproducts sRAGE solublereceptorofadvancedglycationendproductsTLR4 Toll likereceptor4 CurrOpinInfectDis2012 25 328 336 6 Biomarkersrelatedtosepsis JournalofInfection 2010 60 409 416 7 Procalcitoninasadiagnosticmarker DiagnMicrobiolInfectDis 2012 73 3 221 7 8 Procalcitoninasadiagnosticmarkerforsepsis LancetInfectDis2013 13 426 35 PCT Sensitivityof0 77 95 CI0 72 0 81 Specificityof0 79 95 CI0 74 0 84 ROCwas0 85 95 CI0 81 0 88 Procalcitoninisahelpfulbiomarkerforearlydiagnosisofsepsisincriticallyillpatients Nevertheless theresultsofthetestmustbeinterpretedcarefullyinthecontextofmedicalhistory physicalexamination andmicrobiologicalassessment 9 SurvivingSepsis2012 Useoflowprocalcitoninlevelsorsimilarbiomarkerstoassisttheclinicianinthediscontinuationofempiricantibioticsinpatientswhoinitiallyappearedseptic buthavenosubsequentevidenceofinfection grade2C Norecommendationcanbegivenfortheuseofthesemarkerstodistinguishbetweensevereinfectionandotheracuteinflammatorystates CritCareMed2013 41 580 637 10 Diagnosingnon infectiousfever CurrentOpinioninCriticalCare2007 13 578 585 11 Diagnosingnon infectiousfever FMF familialMediterraneanfever JournalofInfection 2010 60 409 416 12 Diagnosingnon infectiousfever OverviewoftheClinicalValueofSepsisParameters CurrentMedicinalChemistry 2008 15 581 587 I Tratio Theratioofimmature totalneutrophilsLBP lipopolysaccharidebindingprotein 13 Diagnosingnon infectiousfever FengL etal PLoSONE 2012 7 e38400ZhangJ etal BMCInfectiousDiseases2011 11 53 结论 PCT CRP和WBC在鉴别ICU患者Sepsis和SIRS方面诊断价值不大 CRP及PCT水平在severesepsis与sepsis或者SIRS组间差异无统计学意义 14 Diagnosingnon infectiousfever SuLX etal MediatorsInflamm 2013 969875 结论 PCT CRP在鉴别ICU患者Sepsis和SIRS方面具有一定的价值 15 Diagnosingnon infectiousfever CRP 13 19 8 03vs 9 55 6 52mg dL P 0 033 WBC 12 98 7 58vs 11 3 5 01 109 L P 0 264 PCT 2 39 8 1 vs 2 71 25 ng ml P 0 693 结论 PCT CRP和WBC在鉴别ICU患者因菌血症导致的新的发热方面没有诊断价值 SuLX etal BMCInfectiousDiseases2012 12 157 16 Biomarkersforpneumonia Biomarkersinrespiratoryinfectionsforthedetectionofaclinicallyrelevantbacterialinfection ExpertRev Respir Med 6 2 203 214 2012 17 Biomarkersforpneumonia Conclusion TheevidenceforthebenefitsofPOCCRPmeasurementinLRTIpatientsinprimarycareislimited contradictoryanddoesnotsupportitsusetoguidetreatmentdecisionsyet EvaluatingtheevidencefortheimplementationofC reactiveproteinmeasurementinadultpatientswithsuspectedlowerrespiratorytractinfectioninprimarycare asystematicreview FamilyPractice2012 29 383 393 18 Biomarkersforpneumonia Clinicalusefulnessofprocalcitonin PCT andC reactiveprotein CRP inpatientswithcommunity acquiredpneumonia EurJInternMed 2011Oct 22 5 460 5 19 Biomarkersforpneumonia Clinicalusefulnessofprocalcitonin PCT andC reactiveprotein CRP inpatientswithcommunity acquiredpneumonia EurJInternMed 2011Oct 22 5 460 5 PCThowevercarriessomeadditionaladvantagesoverCRP suchasthegreaterspecificityforinfectionsandamorenarrowrangeofnormalconcentrations 20 ComparisonsofclinicaldataofpatientswithVAPondayofconfirmationandpatientswithoutVAPonday7inICU 结论 对于VAP的诊断 WBC敏感性最高 CPIS评分特异性最强 SuLX etal AMJCritCare 2012 21 6 e110 e119 Biomarkersforpneumonia 21 DiscriminatingPathogens OverviewoftheClinicalValueofSepsisParameters CurrentMedicinalChemistry 2008 15 581 587 I Tratio Theratioofimmature totalneutrophilsLBP lipopolysaccharidebindingprotein 22 DiscriminatingPathogens Combinationofbiomarkersforthediscriminationbetweenbacterialandvirallowerrespiratorytractinfections JournalofInfection 2012 65 490e495 23 DiscriminatingPathogens Combinationofbiomarkersforthediscriminationbetweenbacterialandvirallowerrespiratorytractinfections JournalofInfection 2012 65 490e495 24 DiscriminatingPathogens Mixedviral bacterialCAP BMCPulmonaryMedicine2014 14 123 mixed viral bacterial 25 DiscriminatingPathogens Cutoffvaluesforthedifferentiationbetweeninfectiousandnoninfectiouscausesofinflammation CritCareClin27 2011 253 263 26 DiscriminatingPathogens UseofSerumProcalcitonintoDetectBacterialInfectioninPatientsWithAutoimmuneDiseases Conclusion ProcalcitoninhashigherdiagnosticvaluethanCRPforthedetectionofbacterialsepsisinpatientswithautoimmunedisease andthetestforprocalcitoninismorespecificthansensitive ArthritisRheum 2012 64 9 3034 42 27 PredictingSeverity OverviewoftheClinicalValueofSepsisParameters CurrentMedicinalChemistry 2008 15 581 587 I Tratio Theratioofimmature totalneutrophilsLBP lipopolysaccharidebindingprotein 28 PredictingSeverity Chest 2012 141 4 1063 73 29 PredictingSeverity Chest 2012 141 4 1063 73 30 PredictingSeverity FengL etal PLoSONE 2012 7 e38400ZhangJ etal BMCInfectiousDiseases2011 11 53 结论 PCT和CRP在鉴别ICUSepsis患者严重程度方面有一定价值 31 Predictingprognosis 结论 在预测ICUSepsis患者死亡预后方面PCT有一定价值 WangH etal SHOCK 2012 37 3 263 267 32 PredictingPrognosis 结论 动态评价ICUSepsis患者死亡预后方面PCT有一定价值 SOFA更佳 FengL etal PLoSONE 2012 7 e38400 PredictingPrognosis CritCare 2014 OnpeerReview TheelevatedPCTlevelwasariskfactorofdeath 33 34 GuidingAntibioticTherapy CurrOpinCritCare2013 19 453 460 35 GuidingAntibioticTherapy CurrOpinCritCare2013 19 453 460 36 GuidingAntibioticTherapy IntensiveCareMed 2012 38 940 949 Durationofantibiotictherapyforthefirstepisodeofinfection p 0 000 37 GuidingAntibioticTherapy IntensiveCareMed 2012 38 940 949 28 daysmortality p 0 906 38 Procalcitoninguidedantibiotictherapyalgorithmscouldhelpinreducingthedurationofantimicrobialadministrationwithouthavinganegativeimpactonsurvival AnESICMsystematicreviewandmeta analysisofprocalcitonin guidedantibiotictherapyalgorithmsinadultcriticallyillpatients IntensiveCareMed 2012 38 940 949 GuidingAntibioticTherapy 39 SurvivingSepsis2012 Useoflowprocalcitoninlevelsorsimilarbiomarkerstoassisttheclinicianinthediscontinuationofempiricantibioticsinpatientswhoinitiallyappearedseptic buthavenosubsequentevidenceofinfection grade2C Norecommendationcanbegivenfortheuseofthesemarkerstodistinguishbetweensevereinfectionandotheracuteinflammatorystates CritCareMed2013 41 580 637 40 PCTforguidanceofantibiotictherapy CurrOpinInfectDis2013 26 159 167 PSI 肺炎严重程度指数 Pneumoniaseverityindex 41 PCTforguidanceofantibiotictherapy CurrOpinInfectDis2013 26 159 167 PSI 肺炎严重程度指数 Pneumoniaseverityindex 42 PCTforguidanceofantibiotictherapy CurrOpinInfectDis2013 26 159 167 PSI 肺炎严重程度指数 Pneumoniaseverityindex 43 PCTforguidanceofantibiotictherapy PCTistheonlybiomarkerthathasbeenextensivelystudiedsofartohelpdecision makingindiscontinuingantibiotictherapyinadultsPCTbemeasuredtohelppredictinfection however availabledataareinsufficienttodecideoninitiatingantibioticsbasedonPCTlevelsInadultpatientssuspectedofcommunity acquiredLRTI withholdingantibiotictherapywhentheserumPCTlevelislow 0 25ng mL InpatientshavingnosocomialLRTI dataareinsufficienttorecommendinitiatingtherapybasedonasinglePCTlevelorevenrepeatedmeasurements AnnalsofIntensiveCare2013 3 21 44 PCTforguidanceofantibiotictherapy ForICUpatientssuspectedofcommunity acquiredinfection wedonotrecommendusingathresholdserumPCTvaluetohelpthedecisiontoinitiateantibiotictherapyDataareinsufficienttorecommendusingPCTserumkineticsforthedecisiontoinitiateantibiotictherapyinpatientssuspectedofICU acquiredinfectionInnon immunocompromisedout orin patientstreatedforRTI antibioticscanbediscontinuedifthePCTlevelatday3is80 90 whetherornotmicrobiologicaldocumentationhasbeenobtained AnnalsofIntensiveCare2013 3 21 45 PCTforguidanceofantibiotictherapy ICUpatientswhohavenonbacteremicsepsisfromaknownsiteofinfection antibioticscanbestoppedifthePCTlevelatday3is80 relativetothehighestlevelrecorded irrespectiveoftheseverityoftheinfectiousepisodeInbacteremicpatients aminimaldurationoftherapyof5daysisrecommended AnnalsofIntensiveCare2013 3 21 46 应用全基因组学 蛋白组学 代谢组学 贯穿组学等最新生物信息学技术 筛选对重症感染患者早期诊断 严重程度和预后评价等方面具有临床价值的新的生物标记物 可能是未来寻找新的biomarker 揭示感染发生 发展机制的有效手段我们发现血sTREM 1 可溶性髓系细胞表达触发受体 1 sCD163 miR 15a miR 16 miR 574 5p miR 193b miR 483 5p VitaminD bindingprotein等具有临床价值的新的生物标记物 JTraumaAcuteCareSurg 2013 74 3 940 945 PLoSONE 2013 8 1 e54237 ClinChemLabMed2012 50 8 1423 1428 PLoSONE 20127 7 e38400 SHOCK 2012 37 3 263 267 BMCInfectDis 2011 11 53 NewBiomarkers 47 鉴别Sepsis和SIRS 感染与非感染 sTREM 1具有明显的优势 诊断的准确性最好 明显优于现有的WBC PCT CRP ESR Il 6和sCD163等指标应用多元回归分析 sTREM 1是唯一能够鉴别感染与非感染的生物标记物 PLoSONE 20127 7 e38400 MediatInlmamm 2013 969875 NewBiomarkers 48 鉴别Sepsis和SIRS 感染与非感染 我们研究发现血清miR 15a在鉴别Sepsis和SIRS方面也同样具有很好的价值 ClinChemLabMed2012 50 8 1423 1428 NewBiomarkers 49 早期鉴别疾病严重程度我们的研究证明sTREM 1在早期判断疾病严重程度方面明显优于目前诊断价值最高的PCT ROCcurve高达0 9 MediatInlmamm 2013 969875 BMCInfectDis 2011 11 53 NewBiomarkers 50 对疾病预后的评价 我们研究发现血清miR 574 5p早期对重症患者死亡预后的评价甚至优于目前评价价值最好的SOFA 序贯脏器衰竭评分 评分 特异性高达96 15 动态评价患者死亡预后 sCD163则更具有临床价值 SHOCK 2012 37 3 263 267 MediatInlmamm 2013 969875 NewBiomarkers 51 临床肺部感染评分 CPIS 在诊断呼吸机相关肺炎特异性最高早期预警 48h 重症患者继发急性肾功能不全 AKI 尿液sTREM 1诊断价值高于现有的BUN sCr CCr等指标 CritCare 2011 15 R250 BMCInfectDis 2012