生物標(biāo)記物在重癥感染的臨床價值

重癥感染患者生物標(biāo)記物的臨床價值1什么是生物標(biāo)記物(Biomarkers)

生物標(biāo)志物（Biomarker）這一概念首次出現(xiàn)于美國國家研究委員會（NRC）在1983年出版的紅皮書《聯(lián)邦政府風(fēng)險評估》中

它是指可以標(biāo)記系統(tǒng)、器官、組織、細(xì)胞及亞細(xì)胞結(jié)構(gòu)或功能的改變或可能發(fā)生的改變的生化指標(biāo)，具有非常廣泛的用途

目前，生物標(biāo)志物廣泛用于疾病診斷、判斷疾病分期或者用來評價新藥或新療法在目標(biāo)人群中的安全性及有效性

隨著高通量全基因組學(xué)、蛋白組學(xué)、代謝組學(xué)技術(shù)的迅猛發(fā)展，有望發(fā)現(xiàn)更多更好的新的生物標(biāo)記物

目前臨床常規(guī)用于感染的如：WBC，ESR，PCT，CRP，IL-6等2理想的生物標(biāo)記物

能夠明確鑒別感染與非感染（Sepsisvs.SIRS）

能夠動態(tài)評價疾病嚴(yán)重程度和預(yù)后

期望能夠鑒別細(xì)菌、真菌、病毒

在鑒別肺部感染方面具有獨特的優(yōu)勢

能夠指導(dǎo)抗菌藥物的合理應(yīng)用

-------------有這樣理想的生物標(biāo)記物嗎？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結(jié)論：PCT、CRP和WBC在鑒別ICU患者Sepsis和SIRS方面診斷價值不大CRP及PCT水平在severe

sepsis

與sepsis或者SIRS組間差異無統(tǒng)計學(xué)意義1415Diagnosingnon-infectious

feverSuLX,etal.Mediators

Inflamm.2013:969875.結(jié)論：PCT、CRP在鑒別ICU患者Sepsis和SIRS方面具有一定的價值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結(jié)論：PCT，CRP和WBC在鑒別ICU患者因菌血癥導(dǎo)致的新的發(fā)熱方面沒有診斷價值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結(jié)論：對于VAP的診斷，WBC敏感性最高，CPIS評分特異性最強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臨床指標(biāo)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評分2.9±

2.15.9±

3.111.6±

2.90.000FengL,etal.PLoSONE.2012,

7:e38400ZhangJ,etal.BMCInfectiousDiseases2011,

11:53結(jié)論：PCT和CRP在鑒別ICUSepsis患者嚴(yán)重程度方面有一定價值A(chǔ)UC標(biāo)準(zhǔn)誤P值95%置信區(qū)間下限上限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結(jié)論：在預(yù)測ICU

Sepsis患者死亡預(yù)后方面PCT有一定價值WangH,etal.SHOCK.2012;

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

Prognosis結(jié)論：動態(tài)評價ICU

Sepsis患者死亡預(yù)后方面PCT有一定價值，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：肺炎嚴(yán)重程度指數(shù)（Pneumonia

severity

index）CurrOpinInfectDis2013,

26:159–16471PCTforguidanceofantibiotic

therapy42PCTforguidanceofantibiotic

therapyCurrOpinInfectDis2013,

26:159–167PSI：肺炎嚴(yán)重程度指數(shù)（Pneumonia

severity

index）CurrOpinInfectDis2013,

26:15493–167PCTforguidanceofantibiotic

therapyPSI：肺炎嚴(yán)重程度指數(shù)（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應(yīng)用全基因組學(xué)、蛋白組學(xué)、代謝組學(xué)、貫穿組學(xué)等最新生物信息學(xué)技術(shù)，篩選對重癥感染患者早期診斷、嚴(yán)重程度和預(yù)后評價等方面具有臨床價值的新的生物標(biāo)記物，可能是未來尋找新的biomarker、揭示感染發(fā)生、發(fā)展機制的有效手段我們發(fā)現(xiàn)血sTREM-1（可溶性髓系細(xì)胞表達(dá)觸發(fā)受體-1）、sCD163、miR-15a、miR-16、miR-574-5p、

miR-193b、

miR-483-5p、

Vitamin

D-binding

protein等具有臨床價值的新的生物標(biāo)記物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鑒別Sepsis和SIRS（感染與非感染）：sTREM-1具有明顯的優(yōu)勢，診斷的準(zhǔn)確性最好，明顯優(yōu)于現(xiàn)有的WBC、PCT、CRP、ESR、Il-6和sCD163等指標(biāo)應(yīng)用多元回歸分析，sTREM-1是唯一能夠鑒別感染與非感染的生物標(biāo)記物PLoSONE.20127(7):e38400；MediatInlmamm.

2013:969875..NewBiomarkers48鑒別Sepsis和SIRS（感染與非感染）：– 我們研究發(fā)現(xiàn)血清miR-15a在鑒別Sepsis和SIRS方面也同樣具有很好的價值ClinChemLabMed2012;50(8):1423-142849NewBiomarkers50早期鑒別疾病嚴(yán)重程度– 我們的研究證明sTREM-1在早期判斷疾病嚴(yán)重程度方面明顯優(yōu)于目前診斷價值最高的PCT，ROC

curve高達(dá)0.9BMCInfectDis.

2011;11:53.MediatInlmamm.

2013;969875.NewBiomarkers51對疾病預(yù)后的評價：我們研究發(fā)現(xiàn)血清miR-574-5p早期對重癥患者死亡預(yù)后的評價甚至優(yōu)于目前評價價值最好的SOFA（序貫臟器衰竭評分）評分，特異性高達(dá)96.15%動態(tài)評價患者死亡預(yù)后，sCD163則更具有臨床價值SHOCK.2012;

37(3):263-267.MediatInlmamm.2013;

969875.NewBiomarkers臨床肺部感染評分（CPIS）在診斷呼吸機相關(guān)肺炎特異性最高早期預(yù)警（48h）重癥患者繼發(fā)急性腎功能不全（AKI），尿液sTREM-1診斷價值高于現(xiàn)有的BUN、sCr、CCr等指標(biāo)CritCare.

2011;

15:R250 BMCI