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一氧化氮呼氣測(cè)定的 臨床意義和應(yīng)用,,僅供醫(yī)療專業(yè)人士參考 審批編號(hào)：415.126,022 有效期：2015.9.22-2016.9.21,Eur Respir J 2006; 28: 264–267,炎癥是慢性氣道疾病的核心,氣道疾病共同點(diǎn)： 癥狀 氣流受限 氣道高反應(yīng),正常的支氣管,有炎癥的支氣管,我們需要…… 氣道炎癥 的生物標(biāo)記物幫助診斷監(jiān)測(cè),潛在病理學(xué)問(wèn)題 嗜酸細(xì)胞或者非嗜酸細(xì)胞 ? 氣道高反應(yīng)性 ?,氣道炎癥疾病面臨的問(wèn)題,臨床診斷 是咳嗽？ 哮喘? COPD？ 其他氣道炎癥疾??？,對(duì)治療的反應(yīng)性 對(duì)ICS 治療反應(yīng)好嗎？ (開始治療 / 增加劑量 / 減少劑量 )? 對(duì)白三烯受體拮抗劑反應(yīng)好嗎？,A,B,C,D,Simpson et al Respirology 2006; 11: 54-61,A. Neutrophilic B. Eosinophilic C. Mixed cellularity D. Paucigranular,氣道炎癥類型,氣道炎癥評(píng)估,傳統(tǒng)評(píng)估方式： 癥狀 病史 肺功能,炎癥評(píng)估 有創(chuàng)： 支氣管粘膜活檢 支氣管肺泡灌洗 無(wú)創(chuàng)： 誘導(dǎo)痰 激發(fā)試驗(yàn) FeNO,內(nèi) 容,一、FeNO 預(yù)測(cè)哮喘患者對(duì)ICS的反應(yīng)性 二、FeNO 在慢性咳嗽診斷的作用,FeNO - Th2驅(qū)動(dòng)的炎癥標(biāo)記物 方便快捷 預(yù)測(cè)患者對(duì)ICS的反應(yīng)性,氣道過(guò)敏性炎癥 – Th2驅(qū)動(dòng),嗜酸性細(xì)胞：靠近管腔，基底膜，和破壞相關(guān) 肥大細(xì)胞：靠近肺部的神經(jīng)，和AHR相關(guān),Allergy Asthma Immunol Res. 2010 Apr;2(2):87-101,Nat Med. 2012 May 4;18(5):716-25,,FeNO 顯示嗜酸性細(xì)胞哮喘患者對(duì)激素的反應(yīng)更佳,Berry et al. Thorax. 2007;62(12):1043-1049.,Noneosinophilic asthma (n=11),,,,,,,Week,Mean FeNO, ppb,0,0,8,8,Placebo,,P=0.14,Eosinophilic asthma (n=12),0,0,8,8,P=0.72,,,,,Mean methacholine PC20, mg/mL,,Placebo,Mometasone 400 μg/d,,,,90,,,,,,,,,,,,,,,,,0,10,20,30,40,50,60,70,80,0,0,Week,8,8,P=0.003,Placebo,,P=0.01,,,,,,,0,0,8,8,Placebo,,Mometasone 400 μg/d,Mometasone 400 μg/d,Mometasone 400 μg/d,90,,,,,,,,,,,,,0,10,20,30,40,50,60,70,80,,,,,,,,,0,0.5,1,1.5,2,2.5,,,,,,,,,0,0.5,1,1.5,2,2.5,FeNO 協(xié)助判斷對(duì)激素治療的反應(yīng)性*,FeNO的預(yù)測(cè)準(zhǔn)確性 顯著高于傳統(tǒng)方式,Figure reprinted from Smith et al with permission of the American Thoracic Society. Copyright ? 2011 American Thoracic Society. *Steroid response (fluticasone 500 μg/d for 4 weeks) defined as FEV1 increase of ≥12% or increase in mean morning peak flow (over previous 7 days) of ≥15%. ?Positive bronchodilator response defined as FEV1 increase of ≥12% from baseline 15 minutes after albuterol inhalation. Smith et al. Am J Respir Crit Care Med. 2005;172(4):453-459.,,FeNO,,,FEV1 bronchodilator response?,Sensitivity,0,0.25,0.50,0.75,1.00,1.00,0.75,0.50,0.25,0,,,,,,,,,,,,N=52 patients with undiagnosed respiratory symptoms,,1-Specificity,,,FeNO 易于早期發(fā)現(xiàn)ICS的依從性差,Mean FeNO levels were significantly reduced in patients with good ICS adherence* FEV1 levels were not substantially different among adherence groups,SD, standard deviation. *Adherence determined by calculating number of doses taken per day/doses prescribed x 100. Good, moderate, and poor adherence defined as 75% adherence, 50% to 75% adherence, or 50% adherence to prescribed medication, respectively. Delgado-Corcoran et al. Pediatr Crit Care Med. 2004;5(1):48-52.,1,P=0.001,,P=0.013,,FeNO較比其它指標(biāo)能更快反應(yīng)ICS的有效性,Courtesy of Prof. J. de Jongste, NL,,“FeNO 顯示在預(yù)測(cè)激素的反應(yīng)性的一致性優(yōu)于肺量測(cè)定，舒張?jiān)囼?yàn)，峰流速變化以及氣道激發(fā)試驗(yàn)“,Dweik et al. Am J Respir Crit Care Med. 2011;184(5):602-615.,FeNO值具有很高的陰性排除價(jià)值,Taylor J Breath Res 2012,,低FeNO值的患者，對(duì)激素治療有反應(yīng)的可能性低,2011年ATS:FeNO臨床指南,在慢性氣道炎癥疾病中，使用FeNO檢測(cè) 鑒別氣道炎癥類型 （嗜酸粒細(xì)胞性氣道炎癥診斷中使用FeNO） 確定該個(gè)體對(duì)皮質(zhì)類固醇治療產(chǎn)生反應(yīng)的可能性 (可能因氣道炎癥而出現(xiàn)慢性呼吸道癥狀的個(gè)體中使用FeNO檢測(cè)確定其對(duì)皮質(zhì)類膽固醇治療反應(yīng)的可能性）,,,,,,對(duì)ICS治療反應(yīng)性 不太可能,對(duì)ICS治療反應(yīng)性 很有可能,2011美國(guó)胸科學(xué)會(huì)（ATS）FeNO指南,*Increasing defined as 40% increase from previous stable FeNO level. ?Chronic cough and/or wheeze and/or shortness of breath for 6 weeks. ?For example, rhinosinusitis, bronchiectasis, primary ciliary dyskinesia, anxiety-hyperventilation, cardiac disease, GERD, or vocal cord dysfunction. Dweik et al. Am J Respir Crit Care Med. 2011;184(5):602-615. 3, Smith AD, Cowan JO, Filsell S, et al. Diagnosing asthma. Comparisons between exhaled nitric oxide measurements and conventional tests. Am j Respir Crit Care Med 2004;169:473-8 4, Smith AD, Cowan JO, Brassett KP, et al. Exhaled nitric oxide. A predictor of steroid response. Am J Respir Crit Care Med 2005;172:453e9,NPV 92% ?,PPV 82% ?,,,,,47,,,,,,Cut point for steroid responsiveness,ppb,Figure in green = optimum cut point,,16,,,,0,200,No steroid responsiveness NPVs 85-95%,Steroid responsiveness PPVs 75-85%,Olin et al., Chest, 2006 Smith et al., AJRCCM, 2005 Pijnenburg et al., Thorax, 2005,FeNO值47ppb的病人對(duì)激素的治療反應(yīng)性高,,Increased FENO predicts steroid responsiveness in patients with non-specific respiratory symptoms,PC20 AMP (doubling dose shift),Composite symptom score,FEV1 (percent change),Baseline FENO (ppb),15,15-47,47,Peak flow (percent change),Smith et al. AJRCCM, 2005,FeNO47病人ICS治療后 癥狀、肺功能及AHR均顯著改善,N=52,,已經(jīng)使用ICS治療的病人， 如果還沒有得到控制，增加ICS劑量對(duì)患者是否獲益?,FeNO仍然可以預(yù)測(cè) 增加ICS劑量對(duì)患者是否獲益,Perez de Llano et al., ERJ, 2010,FeNO測(cè)定,已經(jīng)使用ICS治療的病人,,Perez de Llano et al., ERJ, 2010,,經(jīng)過(guò)ICS治療的哮喘患者FeNO30ppb， 即使繼續(xù)增加口服激素治療，其臨床獲益可能性低,臨床控制好的病人， 是否還能從加大激素治療中獲益？,哮喘管理目標(biāo)：達(dá)到并維持哮喘控制,Fractional exhaled nitric oxide and forced expiratory flow between 25% and 75% of vital capacity in children with controlled asthma. JY. Yoon, et al. Korean J Pediatr. 2012;55(9):330-336,,6周后觀察結(jié)果,結(jié)果：小氣道功能改善, FeNO進(jìn)一步下降,,小 結(jié),FeNO值低 對(duì)于初診哮喘病人： 排除嗜酸性氣道炎癥，提示患者從ICS治療中獲益可能性低 經(jīng)過(guò)ICS治療的哮喘病人： 如果FeNO值低，病人從增加激素劑量的治療中獲益可能性低 FeNO值高 對(duì)于初診哮喘病人： 極可能是嗜酸性氣道炎癥，提示患者從ICS治療中獲益可能性大 經(jīng)過(guò)ICS治療的哮喘病人： 如果病人依然處于高水平，提示患者繼續(xù)增加激素劑量的治療中獲益 可能性大,二、FeNO 在慢性咳嗽中的診斷價(jià)值,26,慢性咳嗽各種癥狀和病因重疊使診斷困難,,,,,,,,,,,C,E,G,,,,A,,B,,,,,,,,,,,,,,,,,,,慢性咳嗽的常規(guī)診斷措施,病史(癥狀特點(diǎn)，職業(yè)，用藥與治療經(jīng)過(guò)，環(huán)境等) 體檢(包括五官科等) 胸片/鼻竇片 肺功能(通氣，激發(fā)，擴(kuò)張，彌散等) 誘導(dǎo)痰 支氣管鏡 食道pH值監(jiān)測(cè) 特殊檢查(咳嗽敏感試驗(yàn)等),病因?qū)W診斷流程,慢性咳嗽常見病因,,Eur Respir J 2004; 24: 481-492,痰 中 嗜 酸 粒 細(xì) 胞 (%),CVA/EB患者嗜酸粒細(xì)胞水平高于正常人群,Birring SS et al. Am J Reapir Crit Care Med, 2004; 169: 15-19,,,,,,,,,0.3,,4.2,,0.3,,,,,,,,,,,,,0,0.4,0.8,1.2,1.6,2.0,2.4,2.8,3.2,3.6,4.0,,,,,,,CVA/EB,非哮喘性慢性咳嗽,不明原因慢性咳嗽,慢性咳嗽患者氣道嗜酸粒細(xì)胞水平升高,,4.4,正常,0.3,,p0.001,未開展誘導(dǎo)痰檢查,,可能病因？,,激素治療能否有效果？,FeNO是否可以成為誘導(dǎo)痰的替代手段？,,,,16.0,2.4,199.0,,,,,26.0,,,FeNO的折點(diǎn)與痰的嗜酸性粒細(xì)胞的關(guān)系,誘導(dǎo)痰檢查的陰性排除率為85%, 意味著只有15%左右的嗜酸性氣道炎癥患者的FeNO值低于26ppb,,Olin et al., Chest, 2006 Shaw et al., AJRCCM, 2007,Symptoms?,與誘導(dǎo)痰EOS3%對(duì)比FeNO26ppb為嗜酸性氣道炎癥的可能性加大，NPV=85%,FeNO差異：慢性咳嗽是否有嗜酸性氣道炎癥,Pacheco A,et al. Gastroesophageal reflux, airway eosinophilic inflammation and chronic cough. Respirology. 2011;16:994–9.,40.5ppb,FeNO: 變應(yīng)性咳嗽和CVA、EB的差別,Respirology. 2008 May;13(3):359-64,,FeNO對(duì)EB有很高的陰性預(yù)測(cè)值,Oh MJ et al. Exhaled nitric oxide measurement is useful for the exclusion of nonasthmatic eosinophilic bronchitis in patients with chronic cough. Chest. 2008 Nov;134(5):990-5.,,FeNO預(yù)測(cè)慢性咳嗽對(duì)ICS的反應(yīng)性,,Hahn, P.Y., T.Y. Morgenthaler, and K.G. Lim, Use of exhaled nitric oxide in predicting response to inhaled corticosteroids for chronic cough. Mayo Clin Proc, 2007. 82(11): p. 1350-5.,FeNO可以在不明原因的慢咳患者中 對(duì)經(jīng)驗(yàn)性使用激素提供指導(dǎo),Hsu, J.Y., C.Y. Wang, Y.W. Cheng, and M.C. Chou, Optimal value of fractional exhaled nitric oxide in inhaled corticosteroid treatment for patients with chronic cough of unknown cause. J Chin Med Assoc, 2013. 76(1): p. 15-9.,,,FeNO30 ppb分組,FeNO在慢性咳嗽中的診治應(yīng)用,FeNO替代誘導(dǎo)痰 在慢性咳嗽診治中的應(yīng)用,小 結(jié),FeNO可以作為慢性咳嗽病人有效的篩查手段 FeNO較高，病人被診斷為CVA或EB的可能性大，病人從ICS治療中獲益可能性大，避免激素的經(jīng)驗(yàn)性使用 FeNO測(cè)定方便快捷 對(duì)于無(wú)法開展誘導(dǎo)痰檢查的醫(yī)院，可以使用 FeNO 作為替代手段,總 結(jié),對(duì)于初診哮喘病人： FeNO值低，可以排除嗜酸性氣道炎癥； FeNO值高，極可能是嗜酸性氣道炎癥，患者從ICS治療中獲益可能性大 對(duì)于經(jīng)過(guò)ICS治療的哮喘病人： FeNO值低，該病人從增加激素劑量的治療中獲益可能性?。?FeNO值仍高，提示患者增加激素劑量獲益的 可能性大 對(duì)于慢性咳嗽病人： FeNO 測(cè)定方便快捷， 是有效的病因篩查手段，可作為誘導(dǎo)痰檢查的 替代手段,,Thanks,Thanks,