呼吸類醫(yī)學(xué)交流課件：FENO在哮喘診斷和治療中的作用

1、FENO在哮喘診斷和治療中的作用 FeNO in the Diagnosis and Treatment of Asthma 中國哮喘聯(lián)盟 專家工作組 無創(chuàng)氣道炎癥技術(shù)臨床應(yīng)用中國專家共識 Chinese Expert Consensus on the clinical application of the technology for non-invasive detection of airway inflammation n NO 內(nèi)源性調(diào)節(jié)分子 n 合成由一系列酶調(diào)節(jié) NO 合成酶 (NOS) n 由iNOS產(chǎn)生的NO主要由支氣管壁 上皮細胞生成 n Th2/過敏性氣道炎癥通常伴隨呼出

2、 氣NO的增高，通常和嗜酸粒細胞 性炎癥相關(guān) 呼出氣一氧化氮 (FeNO) 的產(chǎn)生 The Formation of Fractional Concentration of Exhaled NO (FeNO) nEndogenous regulatory molecules nSynthesis regulated by a series of enzymes regulate NO synthase (NOS) nNO produced by Inducible Nitric Oxide Synthase (iNOS) is mainly generated by bronchial epi

3、thelial cell nTh2/allergic airway inflammation, often along with the increase of exhaled NO, is relevant to eosinophil inflammation 呼出一氧化氮測定系統(tǒng) The Measurement of Exhaled Nitric Oxide 歷時7年研發(fā)、7500萬歐元投資 擁有32項國際專利技術(shù) 國際業(yè)界公認技術(shù)“金標(biāo)準(zhǔn)” 05美國醫(yī)學(xué)產(chǎn)品設(shè)計金獎 美國FDA唯一批準(zhǔn)上市品牌 國家藥監(jiān)局同類唯一批準(zhǔn)品牌 國際太空站太空醫(yī)學(xué)研究采用 10上海世博會發(fā)明專利展品 敏感、精確

4、、重復(fù)性極好 無需校對、無需維護 全面的軟、硬件質(zhì)量控制(QC) 數(shù)以百計論文證實其良好性能 歐盟國家正常值調(diào)查指定儀器 美國人正常值調(diào)查指定儀器 中國人正常值調(diào)查指定儀器 國內(nèi)外著名機構(gòu)和權(quán)威肯定 對哮喘的診斷價值 鑒別氣道炎癥類型及預(yù)測ICS反應(yīng)性 FeNO策略管理哮喘-進一步降低惡化率 FeNO 在哮喘診斷和治療中的作用 FeNO in the Diagnosis and Treatment of Asthma The Diagnostic Value to Asthma Identify the type of airway inflammation and predict the r

5、esponse to ICS FeNO strategy to manage asthma - further reduce deterioration rate Olin et al., Chest, 2006 Smith et al., AJRCCM, 2004 16 Figures in blue = median and 95% C.I. Figures in orange = mean and S.D. 528618 部分哮喘病人為非EOS氣道炎癥, 用FeNO來診斷哮喘其敏感性及特異性不 可能是100% For some asthma patients with non-EOS a

6、irway inflammation, the sensitivity and specificity of FeNO to diagnose asthma cant be 100% 健康人和未經(jīng)治療的哮喘患者FeNO值范圍 The value range of FeNO in healthy people and patients with untreated asthma 2200 “Healthy” Untreated asthma ppb 臨床試驗結(jié)果不一致； 研究一：以FeNO 大于15ppb 作為診斷哮喘的預(yù)測值，特異性90%，陽性率91%； 研究二：以FeNO 大于19ppb 作

7、為診斷閾值，特異性85.2%，敏感性52.4%； 研究三：以FeNO 大于20ppb 作為診斷閾值，特異性61%，敏感性49%；如果取 50ppb 作為診斷閾值，特異性96%，敏感性19%。 Andrew D. Smith, Jan O. Cowan, Sue Filsell, et al,.Thorax, 2005;60:383388.。 Lieven J. Dupont MD, PhD; Maurits G. Chest 2003; 123;751-756 Schneider A, Tilemann L, Schermer，et al. Respir Res. 2009;10:15. An

8、drew D. Smith, Jan O. Cowan, Sue Filsell, et al, Am J Respir Crit Care Med 2004,169: 473-478 N Berkman, A Avital, R Breuer, E Bardach,et al.Thorax, 2005;60:383388. FeNO診斷哮喘的臨床價值 The clinical value of using FeNO to diagnose asthma Discrepant results between clinical trials Study I: FeNO 15ppb as pred

9、ictive value of diagnosing asthma, specificity 90%, positive rate 91%; Study II: FeNO 19ppb as testing threshold, specificity 85.2%, sensitivity 52.4% Study III: FeNO 20ppb as testing threshold, specificity 61%, sensitivity 49%; if use 50ppb as testing threshold, specificity 96%, sensitivity 19%. An

10、drew D. Smith, Am J Respir Crit Care Med 2004 FeNO對哮喘的診斷價值 The diagnostic value of FeNO for asthma l日本：以22ppb為截斷值，診斷哮喘的敏感性為90.8%，特異性為83.9%， 但過敏性鼻炎和吸煙可顯著影響測定結(jié)果，故對吸煙者和鼻炎患者診斷最佳 截斷值為18和28 ppb； l劉春濤等：以FeNO36.5ppb為閾值，診斷哮喘的敏感性、特異性、陽性預(yù) 測值、陰性預(yù)測值和準(zhǔn)確度分別為79.2%、94.3%、92.7%、83.3%和 87.13%； l沙莉等：兒童哮喘選取17.9ppb為診斷界點時

11、，F(xiàn)eNO有很好的陰性預(yù)測值， 但陽性預(yù)測值僅為56.33% Kazuto Matsunaga1, Tsunahiko Hirano1, Keiichiro Allergology International. 2011;60:331-337 任旭斌，劉春濤等 .中國呼吸與危重監(jiān)護雜志，2009.8：322-326。 沙莉，曹玲，馬煜,等. FeNO診斷哮喘的臨床價值 The clinical value of FeNO for asthma lJapan: 222ppb as cut-off value, the sensitivity and specificity of asthma d

12、iagnosis is 90.8% and 83.9%; while the best cut-off values for smokers and rhinitis patients are 18ppb and 28 ppb due because allergic rhinitis and smoking can significantly affect the determination results lLiu Chuntao, et al.: eNO36.5ppb as threshold value, sensitivity 79.2%, specificity 94.3%, po

13、sitive predictive value 92.7%, negative predictive value 83.3% and accuracy 87.13% lSha Li, et al.: choose 17.9ppb as Diagnostic point for pediatric asthma, negative predictive value of FeNO is excellent; while positive predictive value is only 56.33% 哮喘與非哮喘患者FeNO測定結(jié)果 任旭斌，劉春濤等 .中國呼吸與危重監(jiān)護雜志，2009.8（4）

14、，322-326 哮喘組FeNO高于非哮喘組，P36.5 ppb定義為哮喘的 診斷標(biāo)準(zhǔn)，計算出敏感度為92.7 ，特異度為83.3%，陽性預(yù)測值 79.17，陰性預(yù)測值94.34% Define FeNO36.5 as the diagnosis criteria of asthma, sensitivity 92.7%, specificity 83.3%, positive predictive value 79.17%, negative predictive value 94.34% FeNO診斷哮喘的臨床價值 The clinical value of FeNO for asthma

15、 diagnosis 臨床意義：對臨床癥狀不典型，支氣管激發(fā)試驗陰性或弱陽性患者，如FeNO增 高，可按哮喘治療，治療后癥狀顯著改善，F(xiàn)eNO明顯下降，可明確哮喘診斷 Clinical significance: for patients with atypical clinical symptoms, negative or weak positive results in bronchial provocation test, if FeNO is seen to rise, it is fine to commence asthma treatment on patients; if s

16、ymptoms significantly improve after treatment and FeNO decrease as well, the diagnosis of asthma can be confirmed. ATS指南：FeNO可用于輔助哮喘診斷 ATS Guidelines: FeNO may be used to aid the diagnosis of asthma 目前診斷與監(jiān)測哮喘的主要方法: l臨床表現(xiàn) ：反復(fù)發(fā)作喘息、咳嗽、氣促、 胸悶、哮鳴音 l肺功能：FEV1、PEF 激發(fā)試驗、舒張試驗 ATS 2011 We suggest that FeNO may

17、 be used to support the diagnosis of asthma in situations in which objective evidence is needed (weak recommendation, moderate quality of evidence) 我們建議，在需要客觀證據(jù)的情況下可使用FeNO支持哮喘診斷 （一般推薦，證據(jù)質(zhì)量中等） At present, the main method of diagnosing and monitoring asthma: lClinical manifestation: recurrent gasp, co

18、ugh, shortness of breath, chest tightness, wheezing lPulmonary function: FEV1、PEF provocation test, dilation test There is an overlap of FeNO range between healthy people and asthma patients, therefore, it is difficult to set a normal reference value of FENO Asthmatic airway inflammation has differe

19、nt phenotypes, about 50%60% is eosinophil asthma. For other types and patients treated with Inhaled steroids, FeNO might give negative result, which is the main limitation of using FeNO to diagnose asthma Different studies use different threshold or cut-off values. The higher threshold is, the highe

20、r the specificity and the lower the sensitivity, vise verse The level of FeNO may indicate the possibility of asthma diagnosis. The high level and low level of FeNO have different diagnostic value. For patients with typical asthma symptoms, The rise of FeNO level is likely to provide supporting evid

21、ence for asthma diagnosis rather than conclusive evidengce. The extremely low FeNO level has high value in ruling out asthma Many factors may affect FeNO level, such as heredity, age, gender, atopic status, weight, height, smoking status and diet, etc. Dweik RA, Boggs PB, Erzurum SC,et al. An offici

22、al ATS clinical practice guideline: interpretation of exhaled nitric oxide levels (FENO) for clinical applications. Am J Respir Crit Care Med. 2011 Sep 1;184(5):602-15 Shaw DE, Berry MA, Thomas M, et al. Am J Respir Crit Care Med 2007;176:231237 Arora R, Thornblade CE, Dauby PA,. Allergy Asthma Proc

23、 2006;27:493498. Deykin A, Massaro AF, Coulston E,. Am J Respir Crit Care Med 2000;161: 12371240. Dupont LJ, Demedts MG, Verleden GM. Chest 2003;123:751756. Olin AC, Rosengren A, Thelle DS. Chest 2006;130: 13191325.。 FeNO診斷價值評價 The Evaluation on the Diagnostic Value of FeNO l正常人和哮喘患者的FeNO水平存在一定范圍的重疊

24、，因此很難設(shè)定一個FeNO的正常預(yù)計值 l哮喘氣道炎癥有不同的表型，大約有50%60%的哮喘屬于嗜酸粒細胞性，對于其他類型的氣道炎癥， 以及已經(jīng)接受吸入類固醇治療的患者中，F(xiàn)eNO可能出現(xiàn)陰性結(jié)果，這是FeNO在哮喘診斷中的主要局 限性 l在不同的研究中，采用的診斷閾值（Threshold）或截斷值（cutoff）不完全相同。閾值越高，則診斷 的特異性越高，敏感性越低，反之亦然 lFeNO水平的高低可以提示診斷哮喘可能性的大小，高水平和低水平的FeNO診斷價值不一樣，對于具 有典型哮喘癥狀的患者，F(xiàn)eNO水平升高更多的是提供哮喘診斷的支持性證據(jù)，而非結(jié)論性證據(jù)。而極 低水平的FeNO具有較高的

25、排除哮喘的價值 l遺傳、年齡、性別、特應(yīng)性狀態(tài)、體重和身高、當(dāng)前吸煙狀態(tài)以及飲食等可以影響FeNO水平 lFeNO應(yīng)當(dāng)結(jié)合臨床癥狀和其他實驗室檢查，目前不推薦單獨作為診斷哮喘的常規(guī)臨 床工具 l對于具有某些臨床特征的人群，F(xiàn)eNO檢測仍然具有較高的診斷價值，如早年發(fā)病、 具有特應(yīng)質(zhì)的個體，高水平的FeNO強烈提示哮喘的診斷，而低水平的FeNO通?？梢?排除哮喘。 l對具有上述特征的非特異性呼吸道癥狀患者（如不明原因胸悶、咳嗽），推薦FeNO 作為初篩手段 l哮喘的完整診斷不僅要確認是否為哮喘，還包括評估哮喘的嚴(yán)重程度和控制水平，未 來有可能還包括哮喘的表型（臨床和炎癥表型），對此FeNO檢測具

26、有獨特的優(yōu)勢 中國專家共識（草案）指出 Chinese Expert Consensus (Draft) lIt is recommended to use FeNO along with clinical symptoms and other laboratory examinations. Do not recommend using FeNO only as the routine clinical tool to diagnose asthma lFor some groups with certain clinical features, FeNO detection still h

27、as higher diagnostic value for patients with early onset and atoty. High level of FeNO strongly indicates diagnosis of asthma; while low level of FeNO may rule out asthma. lRecommend FeNO as the Early screening method for patients with non-specific respiratory symptoms (such as unexplained chest tig

28、htness and cough) lThe complete diagnosis of asthma contains asthma confirmation, but also the assessment of severity and control level of asthma, moreover, the phenotypes of asthma (clinical and Inflammatory phenotype) in the future. FeNO has unique advantages in this field. FeNO: 氣道炎癥的生物標(biāo)記物 FeNO:

29、the biomarker of airway inflammation 對哮喘的診斷價值 鑒別氣道炎癥類型及預(yù)測ICS反應(yīng)性 FeNO策略管理哮喘-進一步降低惡化率 The Diagnostic Value to Asthma Identify the type of airway inflammation and predict the response to ICS FeNO strategy to manage asthma - further reduce deterioration rate 低 FeNO 水平 Low FeNO level 中度/增加的 FeNO 水平* Mode

30、rate/Increased FeNO level* 高 FeNO 水平 High FeNO level 成人 25 ppb 兒童 25-50 ppb 兒童 20-35 ppb 成人 50 ppb 兒童 35 ppb 不太可能是嗜酸性細胞炎癥 unlikely to be eosinophil inflammation 極可能是嗜酸性細胞炎癥 highly likely to be eosinophil inflammation 對ICS治療反應(yīng)性 不太可能 unlikely to respond to ICS treatment 對ICS治療反應(yīng)性 很有可能 highly likely to

31、 respond to ICS treatment 2011美國胸科學(xué)會（ATS）FeNO指南 2011 ATS FeNO Guidelines *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-hypervent

32、ilation, 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

33、, 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 EMD/000585/00 NPV 92% PPV 82% 47 “Normal” Cut point for steroid responsiveness ppb Figure in green = optimum cut point 16 0200 No steroid responsiveness NPVs 85-9

34、5% Steroid responsiveness PPVs 75-85% Olin et al., Chest, 2006 Smith et al., AJRCCM, 2005 Pijnenburg et al., Thorax, 2005 FeNO值47ppb的病人對激素的治療反應(yīng)性高 Patients with FeNO 47ppb have high response to hormone therapy Smith et al. AJRCCM, 2005 FeNO47病人ICS治療后 癥狀、肺功能及AHR均顯著改善 The symptoms, lung function and AH

35、R improve significantly in patients with FeNO47 after ICS treatment PC20 AMP (doubling dose shift) Composite symptom score FEV1 (percent change) Baseline FENO (ppb) 4747 Peak flow (percent change) N=52 FeNO值具有很高的陰性排除價值 Taylor J Breath Res 2012 低FeNO值的疑似患者，對激素的反應(yīng)性的可能性很低 Suspected patients with low Fe

36、NO value are very unlikely to respond to hormone FeNO具有很高的陰性預(yù)測值 FeNO has very high negative predictive value 第一次隨訪 對未控制的患者: 增加fluticasone到 1000g/天治療 增加salmeterol治療 第二次隨訪 (一個月后) 對未控制的患者: 開始口服激素治療 30mg/天 第三次隨訪 (二個月后) 研究結(jié)束 未控制患者數(shù) (ACT 20) 得到控制的 患者數(shù) (ACT 20) 第一次隨訪1020 第二次隨訪6537 第三次隨訪4937+16 = 53 Perez d

37、e Llano et al., ERJ, 2010 FeNO測定 對難治性哮喘患者FeNO可以預(yù)測增加激素是否獲益 For patients with intractable asthma, FeNO may predict whether increasing hormone is beneficial or not Perez de Llano et al., ERJ, 2010 Baseline FeNO (cutpoint, ppb) Sensitivity (%) Specificity (%) PPV (%) NPV (%) 2090817892 2590858292 308891

38、8891 3578918684 4070949081 4568949079 5043948568 難治性哮喘患者FeNO30ppb即使增加口服 激素劑量臨床也無明顯改善 For patients with intractable asthma, when FeNO 10 ppb 20% 2011ATS Courtesy of Prof. J. de Jongste, NL FeNO FEV1 FeNO比其它指標(biāo)能更快反映抗炎治療有效性 FeNO is faster to indicate the effectiveness of anti-inflammation treatment than

39、 other indicators 單次使用ICS后不同時點FeNO的動態(tài)變化 The dynamic change of FeNO at different time points after single-use ICS 時間 基線 1小時 3小時 24小時 48小時 72小時 FeNO值 108.557.8 116.458.8 115.956.8 105.557.1 92.344.1 78.856.0 單次使用ICS后72小時FeNO的動態(tài)變化 The dynamic change of FeNO within 72 hours after single-use ICS 時間(周）基線1

40、 2 34 FeNO（ppb）109.552.37010.26932.4669.86015.1 N=32 使用布地奈德/福莫特羅一月FeNO的動態(tài)變化 The dynamic change of FeNO within one month after Budesonide/Fomoterol administration 小 結(jié) Summary lFeNO值低 對于初診病人：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ICS治療的病人：如果病人FeNO值處于低水平，病人從增加激素劑量的治療中獲益可能性低 lFeNO值高 對于初診病人：極可能是嗜酸性氣道炎癥，提示患者從ICS治療

41、中獲益可能性大 經(jīng)過ICS治療的病人：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 *排除長期ICS治療，F(xiàn)eNO處于中高水平，但穩(wěn)定的病人 lFeNO level low For first-visit patients: rule out eosinophilic airway inflammation, indicate patients are unlikely to benefit from ICS treatment For patients ever treated with ICS: if FeNO level remains low, patients

42、 are unlikely to benefit from increasing hormone doses lFeNO level high For first-visit patients: It is likely to be eosinophilic airway inflammation, which indicates patients are likely to benefit from ICS treatment For patients ever treated with ICS: If FeNO still remains high level, which indicat

43、es patients are high likely to benefit from increasing hormone doses * Exclude patient who received long-term ICS treatment but still with moderate and high level of FeNO FeNO: 氣道炎癥的生物標(biāo)記物 FeNO: the biomarker of airway inflammation 對哮喘的診斷價值 鑒別氣道炎癥類型及預(yù)測ICS反應(yīng)性 FeNO策略管理哮喘-進一步降低惡化率 The Diagnostic Value t

44、o Asthma Identify the type of airway inflammation and predict the response to ICS FeNO strategy to manage asthma - further reduce deterioration rate 依據(jù)FeNO指導(dǎo)抗炎藥物調(diào)整策略 To adjust anti-inflammation medication according to FeNO level 52周主要結(jié)果比較 Main Outcomes Parameters over 52 weeks FeNO組較臨床組： 急性發(fā)作、非預(yù)約訪視、

45、1次急性發(fā)作的%、非預(yù)約訪視的%均明顯減少 FeNO策略組較對照組急性發(fā)作率減少約50% FeNO group vs.Clinical group： Number of exacerbations, non-booked visits, 1 exacerbation %, non-booked visits % significantly decreased The percentage of incidence of exacerbation in FeNO group decreased at about 50% compared to control group FeNO Strateg

46、yControl Strategy Study Exacerbation Rate Total No. Patients Exacerbation Rate Total No. PatientsWeight Relative Rate (95% CI) Shaw 20070.33520.425122.1%0.79 (0.43, 1.44) Smith 20050.49460.9488.1%0.54 (0.20, 1.46) Powell 20110.2881110.61510944.8%0.50 (0.33, 0.76) Combined0.312090.58208100.0%0.56 (0.

47、42, 0.74) RR 0.1 0.2 0.5 1.0 2 5 10 Favors FeNO Favors Control惡化率降低47% Deterioration rate reduced 47% Donohue, J.F. and N. Jain. Exhaled nitric oxide to predict corticosteroid responsiveness and reduce asthma exacerbation rates. Respiratory Medicine, 2013. 107(7): p.943-952 綜合3個研究，顯示與傳統(tǒng)臨床管理方法相比，F(xiàn)eNO

48、指導(dǎo)的管理組哮喘急性發(fā)作率降低47% 3 studies show the exacerbation rate of FeNO strategy group is 47% lower compared to conventional clinical management. ICS劑量在FeNO管理組和對照組基本相同，或者傾向于FeNO策略組更低 ICS dose is similar between FeNO group and control group, or slightly lower in FeNO group. 降低成人哮喘急性發(fā)作發(fā)生率的Meta分析 Meta Analysis

49、 of Reducing Incidence of Asthma exacerbation in Adults Asthma management in pregnancy (MAP) study FeNO策略管理孕婦哮喘患者的雙盲、隨機、對照研究 Powell et al. Lancet. 2011;378(9795):983-990. Powell et al. Lancet. 2011;378(9795):983-990. 研究設(shè)計 Research design FeNO 16-29ppb ICS1 step 29ppb No changeNo changeICS1 stepICS1

50、step ACQ1.5 1.5ACQ 1.5ACQ ACQ1.5 ICS劑量調(diào) 整 No change LABA 1 stepLABA 1 stepNo change LABA劑 量調(diào)整 No change ACQ NA FeNO策略組調(diào)整方案 依據(jù)FeNO和ACQ評分 Adjustment plan of FeNO strategy group based on FeNO and ACQ score 對照組調(diào)整方案 依據(jù)ACQ評分 Adjustment plan of Control group based on ACQ score ACQ評分 1.5 Dose changes based on clinical assessment for the clinical algorithm(control) FeNO較