《呼吸类医学交流课件：FENO在哮喘诊断和治疗中的作用》由会员分享，可在线阅读，更多相关《呼吸类医学交流课件：FENO在哮喘诊断和治疗中的作用（37页珍藏版）》请在金锄头文库上搜索。
1、FENO在哮喘诊断和治疗中的作用FeNOintheDiagnosisandTreatmentofAsthma中国哮喘联盟专家工作组无创气道炎症技术临床应用中国专家共识ChineseExpertConsensusontheclinicalapplicationofthetechnologyfornon-invasivedetectionofairwayinflammationnNO内源性调节分子n合成由一系列酶调节NO合成酶(NOS)n由iNOS产生的NO主要由支气管壁上皮细胞生成nTh2/过敏性气道炎症通常伴随呼出气NO的增高，通常和嗜酸粒细胞性炎症相关呼出气一氧化氮(FeNO)的产生TheF
2、ormationofFractionalConcentrationofExhaledNO(FeNO)nEndogenousregulatorymoleculesnSynthesisregulatedbyaseriesofenzymesregulateNOsynthase(NOS)nNOproducedbyInducibleNitricOxideSynthase(iNOS)ismainlygeneratedbybronchialepithelialcellnTh2/allergicairwayinflammation,oftenalongwiththeincreaseofexhaledNO,is
3、relevanttoeosinophilinflammation呼出一氧化氮测定系统TheMeasurementofExhaledNitricOxide历时7年研发、7500万欧元投资拥有32项国际专利技术国际业界公认技术“金标准”05美国医学产品设计金奖美国FDA唯一批准上市品牌国家药监局同类唯一批准品牌国际太空站太空医学研究采用10上海世博会发明专利展品敏感、精确、重复性极好无需校对、无需维护全面的软、硬件质量控制(QC)数以百计论文证实其良好性能欧盟国家正常值调查指定仪器美国人正常值调查指定仪器中国人正常值调查指定仪器国内外著名机构和权威肯定对哮喘的诊断价值鉴别气道炎症类型及预测ICS反
4、应性FeNO策略管理哮喘-进一步降低恶化率FeNO在哮喘诊断和治疗中的作用FeNOintheDiagnosisandTreatmentofAsthmaTheDiagnosticValuetoAsthmaIdentifythetypeofairwayinflammationandpredicttheresponsetoICSFeNOstrategytomanageasthma-furtherreducedeteriorationrateOlinetal.,Chest,2006Smithetal.,AJRCCM,200416Figuresinblue=medianand95%C.I.Figures
5、inorange=meanandS.D.528618部分哮喘病人为非EOS气道炎症,用FeNO来诊断哮喘其敏感性及特异性不可能是100%Forsomeasthmapatientswithnon-EOSairwayinflammation,thesensitivityandspecificityofFeNOtodiagnoseasthmacantbe100%健康人和未经治疗的哮喘患者FeNO值范围ThevaluerangeofFeNOinhealthypeopleandpatientswithuntreatedasthma2200“Healthy”Untreatedasthmappb临床试验结果
6、不一致；研究一：以FeNO大于15ppb作为诊断哮喘的预测值，特异性90%，阳性率91%；研究二：以FeNO大于19ppb作为诊断阈值，特异性85.2%，敏感性52.4%；研究三：以FeNO大于20ppb作为诊断阈值，特异性61%，敏感性49%；如果取50ppb作为诊断阈值，特异性96%，敏感性19%。AndrewD.Smith,JanO.Cowan,SueFilsell,etal,.Thorax,2005;60:383388.。LievenJ.DupontMD,PhD;MauritsG.Chest2003;123;751-756SchneiderA,TilemannL,Schermer，et
7、al.RespirRes.2009;10:15.AndrewD.Smith,JanO.Cowan,SueFilsell,etal,AmJRespirCritCareMed2004,169:473-478NBerkman,AAvital,RBreuer,EBardach,etal.Thorax,2005;60:383388.FeNO诊断哮喘的临床价值TheclinicalvalueofusingFeNOtodiagnoseasthmaDiscrepantresultsbetweenclinicaltrialsStudyI:FeNO15ppbaspredictivevalueofdiagnosin
8、gasthma,specificity90%,positiverate91%;StudyII:FeNO19ppbastestingthreshold,specificity85.2%,sensitivity52.4%StudyIII:FeNO20ppbastestingthreshold,specificity61%,sensitivity49%;ifuse50ppbastestingthreshold,specificity96%,sensitivity19%.Andrew D. Smith, Am J Respir Crit Care Med 2004 FeNO对哮喘的诊断价值Thedia
9、gnosticvalueofFeNOforasthmal日本：以22ppb为截断值，诊断哮喘的敏感性为90.8%，特异性为83.9%，但过敏性鼻炎和吸烟可显著影响测定结果，故对吸烟者和鼻炎患者诊断最佳截断值为18和28ppb；l刘春涛等：以FeNO36.5ppb为阈值，诊断哮喘的敏感性、特异性、阳性预测值、阴性预测值和准确度分别为79.2%、94.3%、92.7%、83.3%和87.13%；l沙莉等：儿童哮喘选取17.9ppb为诊断界点时，FeNO有很好的阴性预测值，但阳性预测值仅为56.33%KazutoMatsunaga1,TsunahikoHirano1,KeiichiroAllergo
10、logyInternational.2011;60:331-337任旭斌，刘春涛等.中国呼吸与危重监护杂志，2009.8：322-326。沙莉，曹玲，马煜,等.FeNO诊断哮喘的临床价值TheclinicalvalueofFeNOforasthmalJapan:222ppbascut-offvalue,thesensitivityandspecificityofasthmadiagnosisis90.8%and83.9%;whilethebestcut-offvaluesforsmokersandrhinitispatientsare18ppband28ppbduebecauseallergi
11、crhinitisandsmokingcansignificantlyaffectthedeterminationresultslLiuChuntao,etal.:eNO36.5ppbasthresholdvalue,sensitivity79.2%,specificity94.3%,positivepredictivevalue92.7%,negativepredictivevalue83.3%andaccuracy87.13%lShaLi,etal.:choose17.9ppbasDiagnosticpointforpediatricasthma,negativepredictiveval
12、ueofFeNOisexcellent;whilepositivepredictivevalueisonly56.33%哮喘与非哮喘患者FeNO测定结果任旭斌，刘春涛等.中国呼吸与危重监护杂志，2009.8（4），322-326哮喘组FeNO高于非哮喘组，P36.5ppb定义为哮喘的诊断标准，计算出敏感度为92.7，特异度为83.3%，阳性预测值79.17，阴性预测值94.34%DefineFeNO36.5asthediagnosiscriteriaofasthma,sensitivity92.7%,specificity83.3%,positivepredictivevalue79.17%,
13、negativepredictivevalue94.34%FeNO诊断哮喘的临床价值TheclinicalvalueofFeNOforasthmadiagnosis临床意义：对临床症状不典型，支气管激发试验阴性或弱阳性患者，如FeNO增高，可按哮喘治疗，治疗后症状显著改善，FeNO明显下降，可明确哮喘诊断Clinicalsignificance:forpatientswithatypicalclinicalsymptoms,negativeorweakpositiveresultsinbronchialprovocationtest,ifFeNOisseentorise,itisfinetoc
14、ommenceasthmatreatmentonpatients;ifsymptomssignificantlyimproveaftertreatmentandFeNOdecreaseaswell,thediagnosisofasthmacanbeconfirmed.ATS指南：FeNO可用于辅助哮喘诊断ATSGuidelines:FeNOmaybeusedtoaidthediagnosisofasthma目前诊断与监测哮喘的主要方法:l临床表现：反复发作喘息、咳嗽、气促、胸闷、哮鸣音l肺功能：FEV1、PEF激发试验、舒张试验ATS2011WesuggestthatFeNOmaybeused
15、tosupportthediagnosisofasthmainsituationsinwhichobjectiveevidenceisneeded(weakrecommendation,moderatequalityofevidence)我们建议，在需要客观证据的情况下可使用FeNO支持哮喘诊断（一般推荐，证据质量中等）Atpresent,themainmethodofdiagnosingandmonitoringasthma:lClinicalmanifestation:recurrentgasp,cough,shortnessofbreath,chesttightness,wheezing
16、lPulmonaryfunction:FEV1、PEFprovocationtest,dilationtestThereisanoverlapofFeNOrangebetweenhealthypeopleandasthmapatients,therefore,itisdifficulttosetanormalreferencevalueofFENOAsthmaticairwayinflammationhasdifferentphenotypes,about50%60%iseosinophilasthma.ForothertypesandpatientstreatedwithInhaledste
17、roids,FeNOmightgivenegativeresult,whichisthemainlimitationofusingFeNOtodiagnoseasthmaDifferentstudiesusedifferentthresholdorcut-offvalues.Thehigherthresholdis,thehigherthespecificityandthelowerthesensitivity,viseverseThelevelofFeNOmayindicatethepossibilityofasthmadiagnosis.ThehighlevelandlowlevelofF
18、eNOhavedifferentdiagnosticvalue.Forpatientswithtypicalasthmasymptoms,TheriseofFeNOlevelislikelytoprovidesupportingevidenceforasthmadiagnosisratherthanconclusiveevidengce.TheextremelylowFeNOlevelhashighvalueinrulingoutasthmaManyfactorsmayaffectFeNOlevel,suchasheredity,age,gender,atopicstatus,weight,h
19、eight,smokingstatusanddiet,etc.DweikRA,BoggsPB,ErzurumSC,etal.AnofficialATSclinicalpracticeguideline:interpretationofexhalednitricoxidelevels(FENO)forclinicalapplications.AmJRespirCritCareMed.2011Sep1;184(5):602-15ShawDE,BerryMA,ThomasM,etal.AmJRespirCritCareMed2007;176:231237AroraR,ThornbladeCE,Dau
20、byPA,.AllergyAsthmaProc2006;27:493498.DeykinA,MassaroAF,CoulstonE,.AmJRespirCritCareMed2000;161:12371240.DupontLJ,DemedtsMG,VerledenGM.Chest2003;123:751756.OlinAC,RosengrenA,ThelleDS.Chest2006;130:13191325.。FeNO诊断价值评价TheEvaluationontheDiagnosticValueofFeNOl正常人和哮喘患者的FeNO水平存在一定范围的重叠，因此很难设定一个FeNO的正常预计值
21、l哮喘气道炎症有不同的表型，大约有50%60%的哮喘属于嗜酸粒细胞性，对于其他类型的气道炎症，以及已经接受吸入类固醇治疗的患者中，FeNO可能出现阴性结果，这是FeNO在哮喘诊断中的主要局限性l在不同的研究中，采用的诊断阈值（Threshold）或截断值（cutoff）不完全相同。阈值越高，则诊断的特异性越高，敏感性越低，反之亦然lFeNO水平的高低可以提示诊断哮喘可能性的大小，高水平和低水平的FeNO诊断价值不一样，对于具有典型哮喘症状的患者，FeNO水平升高更多的是提供哮喘诊断的支持性证据，而非结论性证据。而极低水平的FeNO具有较高的排除哮喘的价值l遗传、年龄、性别、特应性状态、体重和身
22、高、当前吸烟状态以及饮食等可以影响FeNO水平lFeNO应当结合临床症状和其他实验室检查，目前不推荐单独作为诊断哮喘的常规临床工具l对于具有某些临床特征的人群，FeNO检测仍然具有较高的诊断价值，如早年发病、具有特应质的个体，高水平的FeNO强烈提示哮喘的诊断，而低水平的FeNO通常可以排除哮喘。l对具有上述特征的非特异性呼吸道症状患者（如不明原因胸闷、咳嗽），推荐FeNO作为初筛手段l哮喘的完整诊断不仅要确认是否为哮喘，还包括评估哮喘的严重程度和控制水平，未来有可能还包括哮喘的表型（临床和炎症表型），对此FeNO检测具有独特的优势中国专家共识（草案）指出ChineseExpertConsen
23、sus(Draft)lItisrecommendedtouseFeNOalongwithclinicalsymptomsandotherlaboratoryexaminations.DonotrecommendusingFeNOonlyastheroutineclinicaltooltodiagnoseasthmalForsomegroupswithcertainclinicalfeatures,FeNOdetectionstillhashigherdiagnosticvalueforpatientswithearlyonsetandatoty.HighlevelofFeNOstronglyi
24、ndicatesdiagnosisofasthma;whilelowlevelofFeNOmayruleoutasthma.lRecommendFeNOastheEarlyscreeningmethodforpatientswithnon-specificrespiratorysymptoms(suchasunexplainedchesttightnessandcough)lThecompletediagnosisofasthmacontainsasthmaconfirmation,butalsotheassessmentofseverityandcontrollevelofasthma,mo
25、reover,thephenotypesofasthma(clinicalandInflammatoryphenotype)inthefuture.FeNOhasuniqueadvantagesinthisfield.FeNO:气道炎症的生物标记物FeNO:thebiomarkerofairwayinflammation对哮喘的诊断价值鉴别气道炎症类型及预测ICS反应性FeNO策略管理哮喘-进一步降低恶化率TheDiagnosticValuetoAsthmaIdentifythetypeofairwayinflammationandpredicttheresponsetoICSFeNOstra
26、tegytomanageasthma-furtherreducedeteriorationrate低FeNO水平LowFeNOlevel中度/增加的FeNO水平*Moderate/IncreasedFeNOlevel*高FeNO水平HighFeNOlevel成人25ppb儿童25-50ppb儿童20-35ppb成人50ppb儿童35ppb不太可能是嗜酸性细胞炎症unlikelytobeeosinophilinflammation极可能是嗜酸性细胞炎症highlylikelytobeeosinophilinflammation对ICS治疗反应性不太可能unlikelytorespondtoICS
27、treatment对ICS治疗反应性很有可能highlylikelytorespondtoICStreatment2011美国胸科学会（ATS）FeNO指南2011ATSFeNOGuidelines*Increasingdefinedas40%increasefrompreviousstableFeNOlevel.Chroniccoughand/orwheezeand/orshortnessofbreathfor6weeks.Forexample,rhinosinusitis,bronchiectasis,primaryciliarydyskinesia,anxiety-hyperventil
28、ation,cardiacdisease,GERD,orvocalcorddysfunction.Dweiketal.AmJRespirCritCareMed.2011;184(5):602-615.3,SmithAD,CowanJO,FilsellS,etal.Diagnosingasthma.Comparisonsbetweenexhalednitricoxidemeasurementsandconventionaltests.AmjRespirCritCareMed2004;169:473-84,SmithAD,CowanJO,BrassettKP,etal.Exhalednitrico
29、xide.Apredictorofsteroidresponse.AmJRespirCritCareMed2005;172:453e9EMD/000585/00NPV92%PPV82% 47“Normal”CutpointforsteroidresponsivenessppbFigureingreen=optimumcutpoint160200NosteroidresponsivenessNPVs85-95%SteroidresponsivenessPPVs75-85%Olinetal.,Chest,2006Smithetal.,AJRCCM,2005Pijnenburgetal.,Thora
30、x,2005FeNO值47ppb的病人对激素的治疗反应性高PatientswithFeNO47ppbhavehighresponsetohormonetherapySmithetal.AJRCCM,2005FeNO47病人ICS治疗后症状、肺功能及AHR均显著改善Thesymptoms,lungfunctionandAHRimprovesignificantlyinpatientswithFeNO47afterICStreatmentPC20AMP(doublingdoseshift)CompositesymptomscoreFEV1(percentchange)BaselineFENO(pp
31、b)4747Peakflow(percentchange)N=52FeNO值具有很高的阴性排除价值TaylorJBreathRes2012低FeNO值的疑似患者，对激素的反应性的可能性很低SuspectedpatientswithlowFeNOvalueareveryunlikelytorespondtohormoneFeNO具有很高的阴性预测值FeNOhasveryhighnegativepredictivevalue第一次随访对未控制的患者:增加fluticasone到1000g/天治疗增加salmeterol治疗第二次随访(一个月后)对未控制的患者:开始口服激素治疗30mg/天第三次随访
32、(二个月后)研究结束未控制患者数(ACT20)得到控制的患者数(ACT20)第一次随访1020第二次随访6537第三次随访4937+16=53PerezdeLlanoetal.,ERJ,2010FeNO测定对难治性哮喘患者FeNO可以预测增加激素是否获益Forpatientswithintractableasthma,FeNOmaypredictwhetherincreasinghormoneisbeneficialornotPerezdeLlanoetal.,ERJ,2010BaselineFeNO(cutpoint,ppb)Sensitivity(%)Specificity(%)PPV(%
33、)NPV(%)2090817892259085829230889188913578918684407094908145689490795043948568难治性哮喘患者FeNO30ppb即使增加口服激素剂量临床也无明显改善Forpatientswithintractableasthma,whenFeNO 10 ppb 20%2011ATSCourtesyofProf.J.deJongste,NLFeNOFEV1FeNO比其它指标能更快反映抗炎治疗有效性FeNOisfastertoindicatetheeffectivenessofanti-inflammationtreatmentthanot
34、herindicators单次使用ICS后不同时点FeNO的动态变化ThedynamicchangeofFeNOatdifferenttimepointsaftersingle-useICS时间基线1小时3小时24小时48小时72小时FeNO值108.557.8116.458.8115.956.8105.557.192.344.178.856.0单次使用ICS后72小时FeNO的动态变化ThedynamicchangeofFeNOwithin72hoursaftersingle-useICS时间(周）基线1234FeNO（ppb）109.552.37010.26932.4669.86015.1
35、N=32使用布地奈德/福莫特罗一月FeNO的动态变化ThedynamicchangeofFeNOwithinonemonthafterBudesonide/Fomoteroladministration小结SummarylFeNO值低对于初诊病人：排除嗜酸性气道炎症，提示患者从ICS治疗中获益可能性低经过ICS治疗的病人：如果病人FeNO值处于低水平，病人从增加激素剂量的治疗中获益可能性低lFeNO值高对于初诊病人：极可能是嗜酸性气道炎症，提示患者从ICS治疗中获益可能性大经过ICS治疗的病人：如果病人依然处于高水平，提示患者继续增加激素剂量的治疗中获益可能性大*排除长期ICS治疗，FeNO处
36、于中高水平，但稳定的病人lFeNOlevellowForfirst-visitpatients:ruleouteosinophilicairwayinflammation,indicatepatientsareunlikelytobenefitfromICStreatmentForpatientsevertreatedwithICS:ifFeNOlevelremainslow,patientsareunlikelytobenefitfromincreasinghormonedoseslFeNOlevelhighForfirst-visitpatients:Itislikelytobeeosin
37、ophilicairwayinflammation,whichindicatespatientsarelikelytobenefitfromICStreatmentForpatientsevertreatedwithICS:IfFeNOstillremainshighlevel,whichindicatespatientsarehighlikelytobenefitfromincreasinghormonedoses*Excludepatientwhoreceivedlong-termICStreatmentbutstillwithmoderateandhighlevelofFeNOFeNO:
38、气道炎症的生物标记物FeNO:thebiomarkerofairwayinflammation对哮喘的诊断价值鉴别气道炎症类型及预测ICS反应性FeNO策略管理哮喘-进一步降低恶化率TheDiagnosticValuetoAsthmaIdentifythetypeofairwayinflammationandpredicttheresponsetoICSFeNOstrategytomanageasthma-furtherreducedeteriorationrate依据FeNO指导抗炎药物调整策略Toadjustanti-inflammationmedicationaccordingtoFeN
39、Olevel52周主要结果比较MainOutcomesParametersover52weeksFeNO组较临床组：急性发作、非预约访视、1次急性发作的%、非预约访视的%均明显减少FeNO策略组较对照组急性发作率减少约50%FeNOgroupvs.Clinicalgroup：Numberofexacerbations,non-bookedvisits,1exacerbation%,non-bookedvisits%significantlydecreasedThepercentageofincidenceofexacerbationinFeNOgroupdecreasedatabout50%c
40、omparedtocontrolgroupFeNOStrategyControlStrategyStudyExacerbationRateTotalNo.PatientsExacerbationRateTotalNo.PatientsWeightRelativeRate(95%CI)Shaw20070.33520.425122.1%0.79(0.43,1.44)Smith20050.49460.9488.1%0.54(0.20,1.46)Powell20110.2881110.61510944.8%0.50(0.33,0.76)Combined0.312090.58208100.0%0.56(
41、0.42,0.74)RR0.10.20.51.02510FavorsFeNOFavorsControl恶化率降低47%Deteriorationratereduced47%Donohue,J.F.andN.Jain.Exhalednitricoxidetopredictcorticosteroidresponsivenessandreduceasthmaexacerbationrates.RespiratoryMedicine,2013.107(7):p.943-952综合3个研究，显示与传统临床管理方法相比，FeNO指导的管理组哮喘急性发作率降低47%3studiesshowtheexace
42、rbationrateofFeNOstrategygroupis47%lowercomparedtoconventionalclinicalmanagement.ICS剂量在FeNO管理组和对照组基本相同，或者倾向于FeNO策略组更低ICSdoseissimilarbetweenFeNOgroupandcontrolgroup,orslightlylowerinFeNOgroup.降低成人哮喘急性发作发生率的Meta分析MetaAnalysisofReducingIncidenceofAsthmaexacerbationinAdultsAsthmamanagementinpregnancy(M
43、AP)studyFeNO策略管理孕妇哮喘患者的双盲、随机、对照研究Powelletal.Lancet.2011;378(9795):983-990.Powelletal.Lancet.2011;378(9795):983-990.研究设计ResearchdesignFeNO16-29ppbICS1step29ppbNochangeNochangeICS1stepICS1stepACQ1.51.5ACQ1.5ACQACQ1.5ICS剂量调整NochangeLABA1stepLABA1stepNochangeLABA剂量调整NochangeACQNAFeNO策略组调整方案依据FeNO和ACQ评分A
44、djustmentplanofFeNOstrategygroupbasedonFeNOandACQscore对照组调整方案依据ACQ评分AdjustmentplanofControlgroupbasedonACQscoreACQ评分1.5Dosechangesbasedonclinicalassessmentfortheclinicalalgorithm(control)FeNO较常规策略管理妊娠哮喘患者更有效降低急性发作率，减少吸入激素用量FeNOcanreduceexacerbationrateanddecreasetheinhaledhormonedoseinpatientswithpr
45、egnancyasthmamoreeffectivelycomparedtoconventionalcontrolstrategy7550150Time,weeksExacerbations,nPowelletal.Lancet.2011;378(9795):983-990.Controlgroup(n=109)FeNOgroup0510152025900800700600500VisitMeanICSdose,g/dControlgroup(n=109)FeNOgroup(n=111)123456P=0.043更少的激素吸入量降低疾病的急性加重FeNO组急性发作率为25%，对照组急性加重率为
46、41%(P=0.011)NNT=6;每6个基于FeNO策略治疗的患者，有1名哮喘未急性发作ExacerbationrateinFeNOgroupis25%;whileexacerbationrateincontrolgroupis41%（P=0.100)NNT=6;Inevery6patientsreceivedFeNOstrategytreatment,oneofthemhasnoexacerbation与对照组(17%)相比，新生儿住院时间显著减少(8%;P=0.046)lFeNO水平与气道嗜酸粒细胞性炎症有关，从理论上讲，基于FeNO的哮喘治疗策略应当是一项理想的方法，但目前研究取得的结
47、果并不一致。l对近期公开发表的使用FeNO指导哮喘治疗的随机对照临床试验进行系统性评估后发现，其结果的不一致主要与方法学的差异有关l采用更合理的截断值/决策值，排除依从性和混杂因素的影响，有可能取得更加理想的结果。l根据某一个体FeNO的动态变化调整治疗可能是更合理的策略基于FeNO的哮喘治疗策略：评价TheasthmatreatmentbasedonFeNO:EvaluationlThelevelofFeNOisrelevanttoeosinophilinflammation.Theoratically,theasthmatreatmentbasedonFeNOissupposedtobea
48、nidealmethod;however,currentresearchresultsdidntsupportthis.lSystemicevaluationontherecentpublishedrandomizedcontrolledtrialsofasthmatreatmentbasedonFeNOhasfoundthatthediscrepancyofresultsismainlyduetothedifferencesinmethodologylRulingouttheinfluencesofcomplianceandconfoundingfactors,usingmoreappropriatecutoffvalue/decisionvaluemaybringinmoreidealresults.lToadjusttreatmentaccordingtothedynamicchangeofonecertainFeNOmaybeamoreappropriatestrategy
