FeNO-对哮喘等疾病治疗上的应用

FeNO的监测

—不仅是诊断更有助于治疗北京大学第一医院王广发1EurRespirJ2006;28:264–267炎症是慢性气道疾病的核心ABC

D

SimpsonetalRespirology2006;11:54-61A.NeutrophilicB.EosinophilicC.MixedcellularityD.Paucigranular气道炎症类型不同疾病炎症类型存在差异不同炎症类型治疗方法可能不同不同的炎症类型预后可能不同4气道炎症监测的意义气道炎症是慢性气道炎症性疾病的核心可反映疾病早期的改变——用于早期干预可用于监测疾病的活动情况及疗效随访可用于临床的诊断与鉴别诊断用于气道炎症性疾病的科学研究特殊人群具有显著的临床价值小儿不能完成肺功能的患者监测气道炎症的方法血液或尿液支气管粘膜活检支气管肺泡灌洗液诱导痰液分析新的方法：呼出气监测间接反映敏感性差创伤性大费时费力直接无创快捷敏感可重复呼出气的组成气相：CO2、O2、NO、CO等液相通过蒸发效应在正常体温下可以挥发的物质水、可挥发性有机物、过氧化氢等潮气呼吸时形成呼出气颗粒密度：<0.1~4个/cm3平均直径<0.3mm通过湍流或气流偏移形成难以挥发又不溶于水的物质白三烯B4(LT-B4)和前列腺素等无挥发性又易溶于水的物质主要包括蛋白质，分子量＜65KDNO检测具有现实的应用价值与炎症类型密切相关—嗜酸细胞性炎症与炎症的活动度及治疗相关有市场可用的产品技术发展将使检测将更加容易—儿童、老年人7Newmethodforsingle-breathfractionofexhalednitricoxidemeasurementwithimprovedfeasibilityinpreschoolchildrenwithasthmaSixty-threechildrenaged3-10

yearsperformedFeNOmeasurementswithahand-heldelectrochemicaldevicewithanewlydevelopedflow-controlunit.Exhaledairwassimultaneouslysampledtoachemiluminescenceanalyzertomeasuretimetosteady-stateNOlevel81%ofthechildrenachievedatleastoneapprovedmeasurement.>4

years:successratewas96%Timetosteady-state[NO](medianandinterquartilerange):2.5

s(2.4-3.5)attheageof3-4

years3.5

s(2.7-3.8)attheageof5-6

years8Heijkenskjöld-RentzhogCetal.PediatrAllergyImmunol.2015Jul16.doi:10.1111/pai.12447.[Epubaheadofprint]9哮喘患者呼出气一氧化氮(FeNO)含量显著升高(KharitonovSA,PeterBarnesetal,AMJRespCritCareMed1996)FeNO与支气管粘膜活检有良好的相关性FeNO和气道高反应性之间的关系R=-0.65

P<.001DupontLJetal.AmJRespirCritCareMed.1998;157(3)(pt1):894-898.FeNOreflectsAHRinsteroid-naivepatients(N=104)withmildasthmaExhaledNO(ppb)0.010.111010100PC20histamine(mg/mL)FeNO:abetterdiagnosticindicatorforevaluatingwheezeandAHRinpreschoolchildren.apopulation-based,cross-sectionalstudywith561childrenaged5-6yearsChildrenwhohadwheezeorAHRhadhigherFeNOlevelsneitherIOSnorspirometryFeNOwasassociatedwithAHRIOSorspirometryparametersshowednoassociation.FeNOwaspositivelycorrelatedwithadose-responseslopeformethacholineneitherIOSnorspirometry12LeeJWetal.JAsthma.2015Aug19:1-6.[Epubaheadofprint]FeNO显示嗜酸性细胞哮喘患者对激素的反应更好Berryetal.Thorax.2007;62(12):1043-1049.Noneosinophilicasthma(n=11)WeekMeanFeNO,ppb0088PlaceboP=0.14Eosinophilicasthma(n=12)0088P=0.72Meanmethacholine

PC20,mg/mLPlaceboMometasone400µg/d900102030405060708000Week88P=0.003PlaceboP=0.010088PlaceboMometasone400µg/dMometasone400µg/dMometasone400µg/d900102030405060708000.511.522.500.511.522.5FeNO协助判断对激素治疗的反应性FeNO的预测准确性显著高于传统方式FigurereprintedfromSmithetalwithpermissionoftheAmericanThoracicSociety.Copyright©2011AmericanThoracicSociety.*Steroidresponse(fluticasone500µg/dfor4weeks)definedasFEV1increaseof≥12%orincreaseinmeanmorningpeakflow(overprevious7days)of≥15%.†PositivebronchodilatorresponsedefinedasFEV1increaseof≥12%frombaseline15minutesafteralbuterolinhalation.Smithetal.AmJRespirCritCareMed.2005;172(4):453-459.

FeNOFEV1bronchodilatorresponse†Sensitivity00.250.500.751.001.000.750.500.250N=52patientswithundiagnosedrespiratorysymptoms1-SpecificityEMD/000585/00

FeNO较比其它指标能更快反映ICS的有效性CourtesyofProf.J.deJongste,NLFeNOFEV1“FeNO显示在预测激素的反应性的一致性优于肺量测定，舒张试验，峰流速变化以及气道激发试验"Dweiketal.AmJRespirCritCareMed.2011;184(5):602-615.TheCombinedImpactofFeNOandSputumEosinophilsMonitoringinAsthmaTreatment:AProspectiveCohortStudy.TocompareasthmacontrolinagroupofpatientswhosetreatmentwasbasedonFENOandsputumeosinophils(interventiongroup)withagroupinwhomtreatmentwasbasedonclinicalscore(controlgroup).Randomizedparallel-grouplongitudinal24-monthstudyincluding5visitsevery6months.PARTICIPANTS:Fourteenpatientswitheosinophilicasthmapergroupwereincluded.RESULTS:Intheinterventiongroup:exacerbationrate/patient/yearwasreducedat12months(0.82)(-73%)and,toagreaterextentat24months(0.5)(-84%)comparedwithbaseline(3.21,p<0.01).Inthecontrolgroup,asignificantreductioninexacerbationrate/patient/yearwasonlyobservedbetweenmonth12(3.0)and24(2.0,-33%,p<0.01).At24months,exacerbationratewaslower(-75%)intheintervention(0.5)thaninthecontrolgroup(2.0,p<0.05).16MalerbaM,etal.CurrPharmDes.2015Jul10.[Epubaheadofprint]2011年ATS:FeNO临床指南在慢性气道炎症疾病中，使用FeNO检测：

鉴别气道炎症类型（嗜酸粒细胞性气道炎症诊断中使用FeNO）

确定该个体对皮质类固醇治疗产生反应的可能性(可能因气道炎症而出现慢性呼吸道症状的个体中使用FeNO检测确定其对皮质类胆固醇治疗反应的可能性）

低

FeNO水平中度/增加的

FeNO水平*高FeNO水平成人

<25ppb

儿童

<20ppb成人>25-50ppb儿童>20-35ppb成人

>50ppb儿童

>35ppb不太可能是嗜酸性细胞炎症极可能是嗜酸性细胞炎症对ICS治疗反应性不太可能对ICS治疗反应性很有可能2011年ATS

FeNO指南*Increasingdefinedas>40%increasefrompreviousstableFeNOlevel.†Chroniccoughand/orwheezeand/orshortnessofbreathfor

>6weeks.‡Forexample,rhinosinusitis,bronchiectasis,primaryciliarydyskinesia,anxiety-hyperventilation,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.Exhalednitricoxide.Apredictorofsteroidresponse.AmJRespirCritCareMed2005;172:453e9NPV92%₃PPV82%₄Fractionalexhalednitricoxideandforcedexpiratoryflowbetween25%and75%ofvitalcapacityinchildrenwithcontrolledasthma.JY.Yoon,etal.KoreanJPediatr.2012;55(9):330-3366周后观察结果临床控制好的病人是否还能从加大激素治疗中获益？结果:FeNO进一步下降,小气道功能改善FeNO差异：慢性咳嗽是否有嗜酸性气道炎症PachecoA,etal.Gastroesophagealreflux,airwayeosinophilicinflammationandchroniccough.Respirology.2011;16:994–9.FeNO:变应性咳嗽和CVA、EB的差别Respirology.2008May;13(3):359-64FeNO预测慢性咳嗽对ICS的反应性Hahn,P.Y.,T.Y.Morgenthaler,andK.G.Lim,Useofexhalednitricoxideinpredictingresponsetoinhaledcorticosteroidsforchroniccough.MayoClinProc,2007.82(11):p.1350-5.FeNO中、高水平的慢性咳嗽患者，ICS治疗获益更佳中、高FeNO水平的慢性咳嗽患者在经过激素治疗后，其症状患者的数目和FeNO水平下降明显优于低FeNO水平患者症状的缓解FeNO对EB有很高的阴性预测值OhMJetal.Exhalednitricoxidemeasurementisusefulfortheexclusionofnonasthmaticeosinophilicbronchitisinpatientswithchroniccough.Chest.2008Nov;134(5):990-5.FeNO的值<31.7ppb:诊断为非EB的预测值为95%FeNO区分慢性咳嗽病因的最佳判断值FeNO>33ppb区分CVAEBvs.

GERD的敏感性为92%，特异性为88%RespirMed.2015Aug;109(8):970-4.FeNO可以在不明原因的慢咳患者中对经验性使用激素提供指导Hsu,J.Y.,C.Y.Wang,Y.W.Cheng,andM.C.Chou,Optimalvalueoffractionalexhalednitricoxideininhaledcorticosteroidtreatmentforpatientswithchroniccoughofunknowncause.JChinMedAssoc,2013.76(1):p.15-9.FeNO>30ppb分组中、高水平FeNO的COPD患者激素治疗后FEV1改善明显，获益更大COPD与FeNOCOPD与FeNOCOPD稳定期和急性加重期可出现嗜酸细胞性炎症FeNO的水平与支气管舒张剂和糖皮质激素的反应有关FeNO可