FeNO-對哮喘等疾病治療上的應用

FeNO的監(jiān)測

—不僅是診斷更有助于治療北京大學第一醫(yī)院王廣發(fā)1EurRespirJ2006;28:264–267炎癥是慢性氣道疾病的核心ABC

D

SimpsonetalRespirology2006;11:54-61A.NeutrophilicB.EosinophilicC.MixedcellularityD.Paucigranular氣道炎癥類型不同疾病炎癥類型存在差異不同炎癥類型治療方法可能不同不同的炎癥類型預后可能不同4氣道炎癥監(jiān)測的意義氣道炎癥是慢性氣道炎癥性疾病的核心可反映疾病早期的改變——用于早期干預可用于監(jiān)測疾病的活動情況及療效隨訪可用于臨床的診斷與鑒別診斷用于氣道炎癥性疾病的科學研究特殊人群具有顯著的臨床價值小兒不能完成肺功能的患者監(jiān)測氣道炎癥的方法血液或尿液支氣管粘膜活檢支氣管肺泡灌洗液誘導痰液分析新的方法：呼出氣監(jiān)測間接反映敏感性差創(chuàng)傷性大費時費力直接無創(chuàng)快捷敏感可重復呼出氣的組成氣相：CO2、O2、NO、CO等液相通過蒸發(fā)效應在正常體溫下可以揮發(fā)的物質水、可揮發(fā)性有機物、過氧化氫等潮氣呼吸時形成呼出氣顆粒密度：<0.1~4個/cm3平均直徑<0.3mm通過湍流或氣流偏移形成難以揮發(fā)又不溶于水的物質白三烯B4(LT-B4)和前列腺素等無揮發(fā)性又易溶于水的物質主要包括蛋白質，分子量＜65KDNO檢測具有現(xiàn)實的應用價值與炎癥類型密切相關—嗜酸細胞性炎癥與炎癥的活動度及治療相關有市場可用的產(chǎn)品技術發(fā)展將使檢測將更加容易—兒童、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

years8Heijkenskj?ld-RentzhogCetal.PediatrAllergyImmunol.2015Jul16.doi:10.1111/pai.12447.[Epubaheadofprint]9哮喘患者呼出氣一氧化氮(FeNO)含量顯著升高(KharitonovSA,PeterBarnesetal,AMJRespCritCareMed1996)FeNO與支氣管粘膜活檢有良好的相關性FeNO和氣道高反應性之間的關系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顯示嗜酸性細胞哮喘患者對激素的反應更好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協(xié)助判斷對激素治療的反應性FeNO的預測準確性顯著高于傳統(tǒng)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較比其它指標能更快反映ICS的有效性CourtesyofProf.J.deJongste,NLFeNOFEV1“FeNO顯示在預測激素的反應性的一致性優(yōu)于肺量測定，舒張試驗，峰流速變化以及氣道激發(fā)試驗"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臨床指南在慢性氣道炎癥疾病中，使用FeNO檢測：

鑒別氣道炎癥類型（嗜酸粒細胞性氣道炎癥診斷中使用FeNO）

確定該個體對皮質類固醇治療產(chǎn)生反應的可能性(可能因氣道炎癥而出現(xiàn)慢性呼吸道癥狀的個體中使用FeNO檢測確定其對皮質類膽固醇治療反應的可能性）

低

FeNO水平中度/增加的

FeNO水平*高FeNO水平成人

<25ppb

兒童

<20ppb成人>25-50ppb兒童>20-35ppb成人

>50ppb兒童

>35ppb不太可能是嗜酸性細胞炎癥極可能是嗜酸性細胞炎癥對ICS治療反應性不太可能對ICS治療反應性很有可能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%?PPV82%?Fractionalexhalednitricoxideandforcedexpiratoryflowbetween25%and75%ofvitalcapacityinchildrenwithcontrolledasthma.JY.Yoon,etal.KoreanJPediatr.2012;55(9):330-3366周后觀察結果臨床控制好的病人是否還能從加大激素治療中獲益？結果:FeNO進一步下降,小氣道功能改善FeNO差異：慢性咳嗽是否有嗜酸性氣道炎癥PachecoA,etal.Gastroesophagealreflux,airwayeosinophilicinflammationandchroniccough.Respirology.2011;16:994–9.FeNO:變應性咳嗽和CVA、EB的差別Respirology.2008May;13(3):359-64FeNO預測慢性咳嗽對ICS的反應性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治療獲益更佳中、高FeNO水平的慢性咳嗽患者在經(jīng)過激素治療后，其癥狀患者的數(shù)目和FeNO水平下降明顯優(yōu)于低FeNO水平患者癥狀的緩解FeNO對EB有很高的陰性預測值OhMJetal.Exhalednitricoxidemeasurementisusefulfortheexclusionofnonasthmaticeosinophilicbronchitisinpatientswithchroniccough.Chest.2008Nov;134(5):990-5.FeNO的值<31.7ppb:診斷為非EB的預測值為95%FeNO區(qū)分慢性咳嗽病因的最佳判斷值FeNO>33ppb區(qū)分CVAEBvs.

GERD的敏感性為92%，特異性為88%RespirMed.2015Aug;109(8):970-4.FeNO可以在不明原因的慢咳患者中對經(jīng)驗性使用激素提供指導Hsu,J.Y.,C.Y.Wang,Y.W.Cheng,andM.C.Chou,Optimalvalueoffractionalexhalednitricoxideininhaledcorticosteroidtreatmentforpatientswithchroniccoughofunknowncause.JChinMedAssoc,2013.76(1):p.15-9.FeNO>30ppb分組中、高水平FeNO的COPD患者激素治療后FEV1改善明顯，獲益更大COPD與FeNOCOPD與FeNOCOPD穩(wěn)定期和急性加重期可出現(xiàn)嗜酸細胞性炎癥FeNO的水平與支氣管舒張劑和糖皮質激素的反應有關FeNO可