生物标记物在重症感染的临床价值

重症感染患者生物标记物的临床价值1什么是生物标记物(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2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？3Biomarkersfor

pneumoniaPotentialbiomarkerspresentedthebiologicalstateof

pneumoniaClinicaChimicaActa419(2013)

19–2545Biomarkersrelatedto

sepsisC1q:complementcomponent1qsubcomponent;HMGB1:high-mobilitygroupprotein

B1;NEcell:nuroendocrinecell;PAI-1:plasminogenactivatorinhibitor-1;PAMPs:pathogenassociatedmolecular

patterns;PTX3:pentraxin-relatedprotein3;RAGE:receptorofadvancedglycationendproducts;sRAGE:solublereceptorofadvancedglycationendproductsTLR4:Toll-likereceptor

4;CurrOpinInfectDis2012,

25:328–336Biomarkersrelatedto

sepsis6Biomarkersrelatedto

sepsisJournalofInfection(2010)60,

409-41678Procalcitoninasadiagnostic

markerDiagnMicrobiolInfectDis.

2012;73(3):221-7LancetInfectDis2013;13:

4926–35ProcalcitoninasadiagnosticmarkerforsepsisPCT:Sensitivityof0·77(95%CI0·72–0·81)Specificityof0·79(95%CI0·74–0·84).ROCwas0·85(95%CI

0·81–0·88)Procalcitoninisahelpfulbiomarkerforearlydiagnosisofsepsisincriticallyill

patients.Nevertheless,theresultsofthetestmustbeinterpretedcarefullyinthecontextofmedicalhistory,physicalexamination,andmicrobiological

assessment.

Useoflowprocalcitoninlevelsorsimilarbiomarkerstoassist

theclinicianinthediscontinuationofempiricantibioticsin

patientswhoinitiallyappearedseptic,buthavenosubsequent

evidenceofinfection

(grade

2C).

Norecommendation

canbegivenfortheuseofthesemarkerstodistinguishbetweensevereinfectionandotheracuteinflammatory

statesCritCareMed2013;

41:580–63710SurvivingSepsis

201211Diagnosingnon-infectious

feverCurrentOpinioninCriticalCare2007,

13:578–585JournalofInfection(2010)60,

4091-4216Diagnosingnon-infectious

feverFMF:familialMediterranean

feverDiagnosingnon-infectious

feverOverviewoftheClinicalValueofSepsis

Parameters13I/Tratio:Theratioofimmature:totalneutrophilsLBP：

lipopolysaccharidebindingproteinCurrentMedicinalChemistry,2008,15,

581-587Diagnosingnon-infectious

feverFengL,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severe

sepsis

与sepsis或者SIRS组间差异无统计学意义1415Diagnosingnon-infectious

feverSuLX,etal.Mediators

Inflamm.2013:969875.结论：PCT、CRP在鉴别ICU患者Sepsis和SIRS方面具有一定的价值16Diagnosingnon-infectious

feverCRP：13.19±8.03vs.9.55±6.52mg/dL,P

<0.033WBC：12.98±7.58vs.11.3±5.01×109/L,P=

0.264PCT：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,

12:157ExpertRev.Respir.Med.6(2),203–214(20121)

7Biomarkersfor

pneumoniaBiomarkersinrespiratoryinfectionsforthedetectionofaclinicallyrelevantbacterial

infectionFamilyPractice2012;

29:383–39318Biomarkersfor

pneumoniaEvaluatingtheevidencefortheimplementationofC-reactiveproteinmeasurementinadultpatientswithsuspectedlowerrespiratorytractinfectioninprimarycare:asystematic

review.

Conclusion.TheevidenceforthebenefitsofPOCCRPmeasurementinLRTIpatientsinprimarycareislimited,contradictoryanddoesnotsupportitsusetoguidetreatmentdecisions

yet.Biomarkersfor

pneumoniaClinicalusefulnessofprocalcitonin(PCT)andC-reactiveprotein(CRP)inpatientswithcommunity-acquired

pneumoniaEurJInternMed.2011

Oct;22(5):460-5.19Biomarkersfor

pneumoniaClinicalusefulnessofprocalcitonin(PCT)andC-reactiveprotein(CRP)inpatientswithcommunity-acquired

pneumoniaPCThowevercarriessomeadditionaladvantagesoverCRP,suchasthegreaterspecificityforinfectionsandamorenarrowrangeofnormalconcentrationsEurJInternMed.2011

Oct;22(5):460-5.20ComparisonsofclinicaldataofpatientswithVAPondayofconfirmationandpatientswithoutVAPonday7in

ICU结论：对于VAP的诊断，WBC敏感性最高，CPIS评分特异性最强21SuLX,etal.AMJCritCare.2012,

21(6)：e110-e119Biomarkersfor

pneumoniaDiscriminating

PathogensOverviewoftheClinicalValueofSepsis

ParametersI/Tratio:Theratioofimmature:totalneutrophilsLBP：

lipopolysaccharidebindingproteinCurrentMedicinalChemistry,2008,15,

581-58722Discriminating

PathogensCombinationofbiomarkersforthediscriminationbetweenbacterialandvirallowerrespiratorytract

infections23JournalofInfection(2012)65,

490e495Discriminating

PathogensCombinationofbiomarkersforthediscriminationbetweenbacterialandvirallowerrespiratorytract

infections24JournalofInfection(2012)65,

490e495Discriminating

PathogensMixedviral-bacterial

CAPBMCPulmonary

Medicine2014,

14:123mixed

(viral-bacterial)25Discriminating

PathogensCutoffvaluesforthedifferentiationbetweeninfectiousandnoninfectiouscausesof

inflammation26CritCareClin27(2011)

253–26327Discriminating

PathogensUseofSerumProcalcitonintoDetectBacterialInfectioninPatientsWithAutoimmune

DiseasesConclusion.ProcalcitoninhashigherdiagnosticvaluethanCRPforthedetectionofbacterial

sepsisinpatientswithautoimmunedisease,andthetestforprocalcitoninismorespecificthan

sensitive.ArthritisRheum.

2012;64(9):3034-42.Predicting

SeverityOverviewoftheClinicalValueofSepsis

ParametersI/Tratio:Theratioofimmature:totalneutrophilsLBP：

lipopolysaccharidebindingproteinCurrentMedicinalChemistry,2008,15,

581-58728Predicting

SeverityChest.

2012;141(4):1063-73.29Predicting

SeverityChest.

2012;141(4):1063-73.30Predicting

Severity临床指标Sepsis(n=

15)Severesepsis(n=

29)Septicshock(n=

8)P值CRP

(mg/dl)10.60

(11.50)9.40(14.70)13.65(9.48)0.711PCT

(ng/ml)0.21(2.50)1.05(11.29)11.78(44.4)0.075SOFA评分2.9±

2.15.9±

3.111.6±

2.90.000FengL,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AUC标准误P值95%置信区间下限上限CRP0.63310.056610.02260.52210.7441PCT0.64770.064230.02400.52180.7736SOFA0.70070.051850.00060.59900.8023sCD163CRPPCTSOFA0.00.20.40.60.81.00.0 0.2 0.4 0.6 0.8 1.01-

SpecificitySensitivity31Predicting

prognosisVariableAUC(95%CI)P-valueCutoff

pointSensitivitySpecificitySOFA

score0.813(0.721,0.906)P<0.0014.5000.8820.571APECHEⅡ0.807(0.712,0.902)P<0.00117.500.9110.595CRP0.569(0.438,0.701)P=0.30113.450.3240.857结论：在预测ICU

Sepsis患者死亡预后方面PCT有一定价值WangH,etal.SHOCK.2012;

37(3):263-267PCT0.715(0.597,0.833)P=0.0016.2800.5590.81032Predicting

Prognosis结论：动态评价ICU

Sepsis患者死亡预后方面PCT有一定价值，SOFA更佳FengL,etal.PLoSONE.2012,

7:e3840033Predicting

PrognosisTheelevatedPCTlevelwasariskfactorof

deathRespirology.2015,Onpeer

R3e4view2015-8-182015-8-1835CurrOpinCritCare2013,

19:453–46035GuidingAntibiotic

TherapyCurrOpinCritCare2013,

19:453–46036GuidingAntibiotic

TherapyGuidingAntibiotic

TherapyDurationofantibiotictherapyforthefirstepisodeof

infectionIntensiveCareMed(2012)

38:940–9493794937p=

0.000GuidingAntibiotic

Therapy28-days

mortalityIntensiveCareMed(2012)

38:940–9493894938p=

0.906AnESICMsystematicreviewandmeta-analysisofprocalcitonin-guidedantibiotictherapyalgorithmsinadultcriticallyill

patients

Procalcitoninguidedantibiotictherapyalgorithmscouldhelpinreducingthedurationofantimicrobialadministrationwithouthavinganegativeimpacton

survivalGuidingAntibiotic

TherapyIntensiveCareMed(2012)

38:940–9493994939

Useoflowprocalcitoninlevelsorsimilarbiomarkerstoassist

theclinicianinthediscontinuationofempiricantibioticsin

patientswhoinitiallyappearedseptic,buthavenosubsequent

evidenceofinfection

(grade

2C).

Norecommendation

canbegivenfortheuseofthesemarkerstodistinguishbetweensevereinfectionandotheracuteinflammatory

statesCritCareMed2013;

41:580–63740SurvivingSepsis

2012PSI：肺炎严重程度指数（Pneumonia

severity

index）CurrOpinInfectDis2013,

26:159–16471PCTforguidanceofantibiotic

therapy42PCTforguidanceofantibiotic

therapyCurrOpinInfectDis2013,

26:159–167PSI：肺炎严重程度指数（Pneumonia

severity

index）CurrOpinInfectDis2013,

26:15493–167PCTforguidanceofantibiotic

therapyPSI：肺炎严重程度指数（Pneumonia

severity

index）PCTforguidanceofantibiotic

therapy

PCTistheonlybiomarkerthathasbeenextensivelystudiedsofartohelpdecision-makingindiscontinuingantibiotictherapyin

adults

PCTbemeasuredtohelppredictinfection;however,availabledataareinsufficienttodecideoninitiatingantibioticsbasedonPCT

levels

Inadultpatientssuspectedofcommunity-acquiredLRTI,withholdingantibiotictherapywhentheserumPCT

levelislow(<0.25ng/mL)

InpatientshavingnosocomialLRTI,dataareinsufficienttorecommendinitiatingtherapybasedonasinglePCTlevelorevenrepeated

measurementsAnnalsofIntensiveCare2013,

3:24144PCTforguidanceofantibiotic

therapy

ForICUpatientssuspectedofcommunity-acquiredinfection,wedonotrecommendusingathresholdserumPCTvaluetohelpthedecisiontoinitiateantibiotic

therapy

DataareinsufficienttorecommendusingPCTserumkineticsforthedecisiontoinitiateantibiotictherapyinpatientssuspectedofICU-acquired

infection

Innon-immunocompromisedout-orin-patientstreatedforRTI,antibioticscanbediscontinuedifthePCTlevelatday3is<0.25ng/mLorhasdecreasedby>80-90%,whetherornotmicrobiologicaldocumentationhasbeen

obtainedAnnalsofIntensiveCare2013,

3:24154PCTforguidanceofantibiotic

therapy

ICUpatientswhohavenonbacteremicsepsisfromaknownsiteofinfection,antibioticscanbestoppedifthePCTlevelatday3is<0.5ng/mLorhasdecreasedby>80%relativetothehighestlevelrecorded,irrespectiveoftheseverityoftheinfectious

episode

Inbacteremicpatients,aminimaldurationoftherapyof5daysisrecommendedAnnalsofIntensiveCare2013,

3:24164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、

Vitamin

D-binding

protein等具有临床价值的新的生物标记物47JTraumaAcuteCareSurg.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;11:53NewBiomarkers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..NewBiomarkers48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):1423-142849NewBiomarkers50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，ROC

curve高达0.9BMCInfectDis.

2011;11:53.MediatInlmamm.

2013;969875.NewBiomarkers51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 BMCI