呼出气一氧化氮分析在慢性阻塞性肺疾病中的研究进展
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摘要
呼出气一氧化氮(fractional exhaled nitric oxide,FeNO)检测是一种定量、非侵入性、简便安全的气道炎症测量方法,随着美国胸科学会/欧洲呼吸学会指南对测量技术的标准化,FeNO作为哮喘的管理工具之一,已被广泛用于临床检测以嗜酸性粒细胞浸润为主的气道炎症,评估吸入糖皮质激素的疗效。而对于慢性阻塞性肺疾病(慢阻肺)而言,虽然已开展了一些初步研究,但现有研究结论存在诸多争议和冲突,单一FeNO在慢阻肺中的临床应用价值尚难定论。然而,通过模拟肺内NO气体交换构建的NO动力学模型对FeNO进行扩展分析能够获取更多信息,有助于定位气道炎症,为慢阻肺的评估和管理增加新的维度。本文回顾近年扩展FeNO分析在气道疾病中的相关研究,归纳总结FeNO参数在慢阻肺诊疗中的研究现况。
Measurement of fractional exhaled nitric oxide(FeNO) is a quantitative, non-invasive, simple and safe method for measuring airway inflammation. With the standardization of measurement techniques in the ATS/ERS guidelines, FeNO has been widely used in asthma for detecting eosinophilic airway inflammation, monitoring and evaluating the response of inhaled corticosteroids. For chronic obstructive pulmonary disease(COPD), there are a lot of controversies and conflicts in the previous study. The value of FeNO in COPD is still unclear. Now, the modelling of NO dynamics of the lung can give more information than a single FeNO value. It is helpful to locate airway inflammation and give a new insight to the assessment and management of COPD. Based on the recent studies about extended FeNO analysis in airway diseases, this review will show the present situation of FeNO parameter in the diagnosis and treatment of COPD.
Measurement of fractional exhaled nitric oxide(FeNO) is a quantitative, non-invasive, simple and safe method for measuring airway inflammation. With the standardization of measurement techniques in the ATS/ERS guidelines, FeNO has been widely used in asthma for detecting eosinophilic airway inflammation, monitoring and evaluating the response of inhaled corticosteroids. For chronic obstructive pulmonary disease(COPD), there are a lot of controversies and conflicts in the previous study. The value of FeNO in COPD is still unclear. Now, the modelling of NO dynamics of the lung can give more information than a single FeNO value. It is helpful to locate airway inflammation and give a new insight to the assessment and management of COPD. Based on the recent studies about extended FeNO analysis in airway diseases, this review will show the present situation of FeNO parameter in the diagnosis and treatment of COPD.
引文
[1]Global Initiative for Chronic Obstructive Lung Disease(GOLD).Global strategy for the diagnosis,management,and prevention of chronic obstructive pulmonary disease(2017 report)[EB/OL].[2018-12-20]http://goldcopd.org/download/326/wms-GOLD-2017-FINAL.pdf(accessed March 19,2018).
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[3]Wang C,Xu J,Yang L,et al.Prevalence and risk factors of chronic obstructive pulmonary disease in China(the China Pulmonary Health[CPH]study):a national cross-sectional study[J].Lancet Respir Med,2018,391(10131):1706-1717.
[4]Yoon HI,Sin DD.Biomarkers of therapeutic response in patients with chronic obstructive pulmonary disease:a critical review of the literature[J].Drugs,2011,71(14):1821-1837.
[5]Han MK,Agusti A,Calverley PM,et al.Chronic obstructive pulmonary disease phenotypes:the future of COPD[J].Am JRespir Crit Care Med,2010,182(5):598-604.
[6]Rennard SI,Vestbo J.The many"small COPDs":COPD should be an orphan disease[J].Chest,2008,134(3):623-627.
[7]Gustafsson LE,Leone A,Persson M,et al.Endogenous nitric oxide is present in the exhaled air of rabbits,guinea pigs and humans[J].Biochem Biophys Res Commun,1991,181(2):852-1857.
[8]Barnes PJ,Dweik RA,Gelb AF,et al.Exhaled nitric oxide in pulmonary diseases:a comprehensive review[J].Chest,2010,138(3):682-692.
[9]Saleh D,Ernst P,Lim S,et al.Increased formation of the potent oxidant peroxynitrite in the airways of asthmatic patients is associated with induction of nitric oxide synthase:effect of inhaled glucocorticoid[J].Faseb J,1998,12(11):929-937.
[10]Brindicci C,Kharitonov S,Ito M,et al.Nitric oxide synthase isoenzyme expression and activity in peripheral lungs of COPDpatients[J].Am J Respir Crit Care Med,2010,181(1):21-30.
[11]Brindicci C,Ito K,Resta O,et al.Exhaled nitric oxide from lung periphery is increased in COPD[J].Eur Respir J,2005,26(1):52-59.
[12]Maarsingh H,Leusink J,Bos IS,et al.Arginase strongly impairs neuronal nitric oxide-mediated airway smooth muscle relaxation in allergic asthma[J].Respir Res,2006,7:6.
[13]Wang Z,Pianosi P,Keogh K,et al.The Clinical Utility of Fractional Exhaled Nitric Oxide(FeNO)in Asthma Manag ement[EB/OL].[2018-12-20]https://www.ncbi.nlm.nih.gov/books/NBK487497/
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[15]Jorres RA.Modelling the production of nitric oxide within the human airways[J].Eur Respir J,2000,16(3):555-560.
[16]George SC,Hogman M,Permutt S,et al.Modeling pulmonary nitric oxide exchange[J].J Appl Physiol,2004,96(3):831-839.
[17]Horváth I,Barnes PJ,Loukides S,et al.A European Respiratory Society technica standard:exhaled biomarkers in lung disease[J].Eur Respir J,2017,49(4).pii:1600965.
[18]H?gman M,Lehtim?ki L,Dinh-Xuan AT.Utilising exhaled nitric oxide information to enhance diagnosis and therapy of respiratory disease-current evidence for clinical practice and proposals to improve the methodology[J].Expert Rev Respir Med,2017,11(2):101-109.
[19]Antus B,Barta I,Horvath I,et al.Relationship between exhaled nitric oxide and treatment response in COPD patients with exacerbations[J].Respirology,2010,15(3):472-477.
[20]Bazeghi N,Gerds TA,Budtz-Jorgensen E,et al.Exhaled nitric oxide measure using multiple flows in clinically relevant subgroups of COPD[J].Respir Med,2011,105(9):1338-1344.
[21]de Laurentiis G,Maniscalco M,Cianciulli F,et al.Exhaled nitric oxide monitoring in COPD using a portable analyzer[J].Pulm Pharmacol Ther,2008,21(4):689-693.
[22]Roy K,Smith J,Kolsum U,et al.COPD phenotype description using principal components analysis[J].Respir Res,2009,10:41.
[23]Tilemann L,Gindner L,Meyer F,et al.Differences in local and systemic inflammatory markers in patients with obstructive airways disease[J].Prim Care Respir J,2011,20(4):407-414.
[24]Santini G,Mores N,Shohreh R,et al.Exhaled and non-exhaled non-invasive markers for assessment of respiratory inflammation in patients with stable COPD and healthy smokers[J].J Breath Res,2016,10(1):017102.
[25]H?gman M,Holmkvist T,Wegener T,et al.Extended NOanalysis applied to patients with COPD,allergic asthma and allergic rhinitis[J].Respir Med,2002,96(1):24-30.
[26]Roy K,Borrill ZL,Starkey C,et al.Use of different exhaled nitric oxide multiple flow rate models in COPD[J].Eur Respir J,2007,29(4):651-659.
[27]Feng JX,Lin Y,Lin J,et al.Relationship between fractional exhaled nitric oxide level and efficacy of inhaled corticosteroid in asthma-COPD overlap syndrome patients with different disease severity[J].J Korean Med Sci,2017,32(3):439-447.
[28]Dummer JF,Epton MJ,Cowan JO,et al.Predicting corticosteroid response in chronic obstructive pulmonary disease using exhaled nitric oxide[J].Am J Respir Crit Care Med,2009,180(9):846-852.
[29]Kunisaki KM,Rice KL,Janoff EN,et al.Exhaled nitric oxide,systemic inflammation,and the spirometric response to inhaled fluticasone propionate in severe chronic obstructive pulmonary disease:a prospective study[J].Ther Adv Respir Dis,2008,2(2):55-64.
[30]Logotheti H,Pourzitaki C,Tsaousi G,et al.The role of exhaled nitric oxide in patients with chronic obstructive pulmonary disease undergoing laparotomy surgery-the noxious study[J].Nitric Oxide,2016,61:62-68.
[31]Liu J,Sandrini A,Thurston MC,et al.Nitric oxide and exhaled breath nitrite/nitrates in chronic obstructive pulmonary disease patients[J].Respiration,2007,74(6):617-623.
[32]Kobayashi S,Hanagama M,Yamanda S,et al.Inflammatory biomarkers in asthma-COPD overlap syndrome[J].Int J Chron Obstruct Pulmon Dis,2016,11:2117-2123.
[33]Lehtim?ki L,Kankaanranta H,Saarelainen S,et al.Bronchial nitric oxide is related to symptom relief during fluticasone treatment in COPD[J].Eur Respir J,2010,35(1):72-78.
[34]Short PM,Williamson PA,Lipworth BJ.Effects of extra-fine inhaled and oral corticosteroids on alveolar nitric oxide in COPD[J].Lung,2012,190(4):395-401.
[35]Gelb AF,Flynn Taylor C,Krishnan A,et al.Central and peripheral airway sites of nitric oxide gas exchange in COPD[J].Chest,2010,137(3):575-584.
[36]Santus P,Radovanovic D,Mascetti S,et al.Effects of bronchodilation on biomarkers of peripheral airway inflamma tion in COPD[J].Pharmacol Res,2018,133:160-169.
[37]Rawy AM,Mansour AI.Fraction of exhaled nitric oxide measurement as a biomarker in asthma and COPD compared with local and systemic inflammatory markers[J].Egypt JChest Dis Tuberc,2015,64(1):13-20.
[38]Bhowmik A,Seemungal TA,Donaldson GC,et al.Effects of exacerbations and seasonality on exhaled nitric oxide in COPD[J].Eur Respir J,2005,26(6):1009-1015.
[39]Huang SY,Chou PC,Wang TY,et al.Exercise-induced changes in exhaled no differentiates asthma with or without fixed airway obstruction from COPD with dynamic hyperinflation[J].Medicine(Baltimore),2016,95(15):e3400.
[40]Rouhos A,Kainu A,Piirila P,et al.Repeatability of exhaled nitric oxide measurements in patients with COPD[J].Clin Physiol Funct Imaging,2011,31(1):26-31.
[41]Mostafavi-Pour-Manshadi SM,Naderi N,Barrecheguren M,et al.Investigating fractional exhaled nitric oxide(FeNO)in chronic obstructive pulmonary disease(COPD)and asthmaCOPD overlap(ACO):a scoping review protocol[J].BMJOpen,2017,7(12):e018954.
[42]Lu Z,Huang W,Wang L,et al.Exhaled nitric oxide in patients with chronic obstructive pulmonary disease:a systematic review and meta-analysis[J].Int J Chron Obstruct Pulmon Dis,2018,13:2695-2705.
[43]Williamson PA,Clearie K,Menzies D,et al.Assessment of smallairways disease using alveolar nitric oxide and impulse oscillometry in asthma and COPD[J].Lung,2011,189(2):121-129.
[44]Hirano T,Matsunaga K,Sugiura H,et al.Relationship between alveolar nitric oxide concentration in exhaled air and small airway function in COPD[J].J Breath Res,2013,7(4):046002.
[45]Paredi P,Kharitonov SA,Meah S,et al.A novel approach to partition central and peripheral airway nitric oxide[J].Chest,2014,145(1):113-119.
[46]Lehouck A,Carremans C,De Bent K,et al.Alveolar and bronchial exhaled nitric oxide in chronic obstructive pulmonary disease[J].Respir Med,2010,104(7):1020-1026.
[47]Chen FJ,Huang XY,Liu YL,et al.Importance of fractional exhaled nitric oxide in the differentiation of asthma COPDoverlap syndrome,asthma,and COPD[J].Int J Chron Obstruct Pulmon Dis,2016,11:2385-2390.
[48]Alcazar-Navarrete B,Romero-Palacios PJ,Ruiz-Sancho A,et al.Diagnostic performance of the measurement of nitric oxide in exhaled air in the diagnosis of COPD phenotypes[J].Nitric Oxide,2016,54:67-72.
[49]邓玎玎,周爱媛,双庆翠,等.呼出气一氧化氮测定对支气管哮喘-慢性阻塞性肺疾病重叠综合征的诊断价值[J].中华结核和呼吸杂志,2017,40(2):98-101.
[50]Goto T,Camargo CJ,Hasegawa K.Fractional exhaled nitric oxide levels in asthma-COPD overlap syndrome:analysis of the national health and nutrition examination survey,2007-2012[J].Int J Chron Obstruct Pulmon Dis,2016,11:2149-2155.
[51]Alcázar-Navarrete B,Castellano Mi?án F,Santiago Díaz P,et al.Alveolar and Bronchial Nitric Oxide in Chronic Obstructive Pulmonary Disease and Asthma-COPD Overlap[J].Arch Bronconeumol,2018,54(8):414-419.
[52]夏清,潘频华,王展,等.呼出气一氧化氮检测在支气管炎症性肺疾病中的临床应用[J].中南大学学报(医学版),2014,39(4):365-370.
[53]Antus B,Barta I.Relationship between exhaled nitric oxide and the frequency of severe acute exacerbation of COPD:3-year follow-up[J].Acta Physiol Hung,2013,100(4):469-477.
[54]Durmaz D,Goksu E,Kilic T,et al.The role of nitric oxide in predicting revisit of patients with exacerbated chronic obstructive pulmonary disease[J].J Emerg Med,2015,48(2):247-253.
[55]Lázár Z,Kelemená,Gálffy G,et al.Central and peripheral airway nitric oxide in patients with stable and exacerbated chronic obstructive pulmonary disease[J].J Breath Res,2018,12(3):036017.
[56]Chou KT,Su KC,Huang SF,et al.Exhaled nitric oxide predicts eosinophilic airway inflammation in COPD[J].Lung,2014,192(4):499-504.
[57]Gao J,Zhang M,Zhou L,et al.Correlation between fractional exhaled nitric oxide and sputum eosinophilia in exacerbations of COPD[J].Int J Chron Obstruct Pulmon Dis,2017,12:1287-1293.
[58]Soter S,Barta I,Antus B.Predicting sputum eosinophilia in exacerbations of COPD using exhaled nitric oxide[J].Inflammation,2013,36(5):1178-1185.
[59]Cosio BG,Perez de Llano L,Lopez Viňa A,et al.Th-2 signature in chronic airway diseases:towards the extinction of asthma-COPD overlap syndrome?[J].Eur Respir J,2017,49(5).pii:1602397.
[60]吉泽,潘星,姬峰,等.呼出气一氧化氮检测在哮喘-慢阻肺重叠综合征治疗中的应用价值[J].第二军医大学学报,2016,37(10):1250-1255.
[61]Akamatsu K,Matsunaga K,Sugiura H,et al.Improvement of airflow limitation by fluticasone propionate/salmeterol in chronic obstructive pulmonary disease:What is the specific marker?[J].Front Pharmacol,2011,2:36.
[2]GBD 2015 Chronic Respiratory Disease Collaborators.Global,regional,and national deaths,prevalence,disability-adjusted life years,and years lived with disability for chronic obstructive pulmonary disease and asthma,1990-2015:a systematic analysis for the Global Burden of Disease Study 2015[J].Lancet Respir Med,2017,5(9):691-706.
[3]Wang C,Xu J,Yang L,et al.Prevalence and risk factors of chronic obstructive pulmonary disease in China(the China Pulmonary Health[CPH]study):a national cross-sectional study[J].Lancet Respir Med,2018,391(10131):1706-1717.
[4]Yoon HI,Sin DD.Biomarkers of therapeutic response in patients with chronic obstructive pulmonary disease:a critical review of the literature[J].Drugs,2011,71(14):1821-1837.
[5]Han MK,Agusti A,Calverley PM,et al.Chronic obstructive pulmonary disease phenotypes:the future of COPD[J].Am JRespir Crit Care Med,2010,182(5):598-604.
[6]Rennard SI,Vestbo J.The many"small COPDs":COPD should be an orphan disease[J].Chest,2008,134(3):623-627.
[7]Gustafsson LE,Leone A,Persson M,et al.Endogenous nitric oxide is present in the exhaled air of rabbits,guinea pigs and humans[J].Biochem Biophys Res Commun,1991,181(2):852-1857.
[8]Barnes PJ,Dweik RA,Gelb AF,et al.Exhaled nitric oxide in pulmonary diseases:a comprehensive review[J].Chest,2010,138(3):682-692.
[9]Saleh D,Ernst P,Lim S,et al.Increased formation of the potent oxidant peroxynitrite in the airways of asthmatic patients is associated with induction of nitric oxide synthase:effect of inhaled glucocorticoid[J].Faseb J,1998,12(11):929-937.
[10]Brindicci C,Kharitonov S,Ito M,et al.Nitric oxide synthase isoenzyme expression and activity in peripheral lungs of COPDpatients[J].Am J Respir Crit Care Med,2010,181(1):21-30.
[11]Brindicci C,Ito K,Resta O,et al.Exhaled nitric oxide from lung periphery is increased in COPD[J].Eur Respir J,2005,26(1):52-59.
[12]Maarsingh H,Leusink J,Bos IS,et al.Arginase strongly impairs neuronal nitric oxide-mediated airway smooth muscle relaxation in allergic asthma[J].Respir Res,2006,7:6.
[13]Wang Z,Pianosi P,Keogh K,et al.The Clinical Utility of Fractional Exhaled Nitric Oxide(FeNO)in Asthma Manag ement[EB/OL].[2018-12-20]https://www.ncbi.nlm.nih.gov/books/NBK487497/
[14]Tsoukias NM,George SC.A two-compartment model of pulmonary nitric oxide exchange dynamics[J].J Appl Physiol,1998,85(2):653-666.
[15]Jorres RA.Modelling the production of nitric oxide within the human airways[J].Eur Respir J,2000,16(3):555-560.
[16]George SC,Hogman M,Permutt S,et al.Modeling pulmonary nitric oxide exchange[J].J Appl Physiol,2004,96(3):831-839.
[17]Horváth I,Barnes PJ,Loukides S,et al.A European Respiratory Society technica standard:exhaled biomarkers in lung disease[J].Eur Respir J,2017,49(4).pii:1600965.
[18]H?gman M,Lehtim?ki L,Dinh-Xuan AT.Utilising exhaled nitric oxide information to enhance diagnosis and therapy of respiratory disease-current evidence for clinical practice and proposals to improve the methodology[J].Expert Rev Respir Med,2017,11(2):101-109.
[19]Antus B,Barta I,Horvath I,et al.Relationship between exhaled nitric oxide and treatment response in COPD patients with exacerbations[J].Respirology,2010,15(3):472-477.
[20]Bazeghi N,Gerds TA,Budtz-Jorgensen E,et al.Exhaled nitric oxide measure using multiple flows in clinically relevant subgroups of COPD[J].Respir Med,2011,105(9):1338-1344.
[21]de Laurentiis G,Maniscalco M,Cianciulli F,et al.Exhaled nitric oxide monitoring in COPD using a portable analyzer[J].Pulm Pharmacol Ther,2008,21(4):689-693.
[22]Roy K,Smith J,Kolsum U,et al.COPD phenotype description using principal components analysis[J].Respir Res,2009,10:41.
[23]Tilemann L,Gindner L,Meyer F,et al.Differences in local and systemic inflammatory markers in patients with obstructive airways disease[J].Prim Care Respir J,2011,20(4):407-414.
[24]Santini G,Mores N,Shohreh R,et al.Exhaled and non-exhaled non-invasive markers for assessment of respiratory inflammation in patients with stable COPD and healthy smokers[J].J Breath Res,2016,10(1):017102.
[25]H?gman M,Holmkvist T,Wegener T,et al.Extended NOanalysis applied to patients with COPD,allergic asthma and allergic rhinitis[J].Respir Med,2002,96(1):24-30.
[26]Roy K,Borrill ZL,Starkey C,et al.Use of different exhaled nitric oxide multiple flow rate models in COPD[J].Eur Respir J,2007,29(4):651-659.
[27]Feng JX,Lin Y,Lin J,et al.Relationship between fractional exhaled nitric oxide level and efficacy of inhaled corticosteroid in asthma-COPD overlap syndrome patients with different disease severity[J].J Korean Med Sci,2017,32(3):439-447.
[28]Dummer JF,Epton MJ,Cowan JO,et al.Predicting corticosteroid response in chronic obstructive pulmonary disease using exhaled nitric oxide[J].Am J Respir Crit Care Med,2009,180(9):846-852.
[29]Kunisaki KM,Rice KL,Janoff EN,et al.Exhaled nitric oxide,systemic inflammation,and the spirometric response to inhaled fluticasone propionate in severe chronic obstructive pulmonary disease:a prospective study[J].Ther Adv Respir Dis,2008,2(2):55-64.
[30]Logotheti H,Pourzitaki C,Tsaousi G,et al.The role of exhaled nitric oxide in patients with chronic obstructive pulmonary disease undergoing laparotomy surgery-the noxious study[J].Nitric Oxide,2016,61:62-68.
[31]Liu J,Sandrini A,Thurston MC,et al.Nitric oxide and exhaled breath nitrite/nitrates in chronic obstructive pulmonary disease patients[J].Respiration,2007,74(6):617-623.
[32]Kobayashi S,Hanagama M,Yamanda S,et al.Inflammatory biomarkers in asthma-COPD overlap syndrome[J].Int J Chron Obstruct Pulmon Dis,2016,11:2117-2123.
[33]Lehtim?ki L,Kankaanranta H,Saarelainen S,et al.Bronchial nitric oxide is related to symptom relief during fluticasone treatment in COPD[J].Eur Respir J,2010,35(1):72-78.
[34]Short PM,Williamson PA,Lipworth BJ.Effects of extra-fine inhaled and oral corticosteroids on alveolar nitric oxide in COPD[J].Lung,2012,190(4):395-401.
[35]Gelb AF,Flynn Taylor C,Krishnan A,et al.Central and peripheral airway sites of nitric oxide gas exchange in COPD[J].Chest,2010,137(3):575-584.
[36]Santus P,Radovanovic D,Mascetti S,et al.Effects of bronchodilation on biomarkers of peripheral airway inflamma tion in COPD[J].Pharmacol Res,2018,133:160-169.
[37]Rawy AM,Mansour AI.Fraction of exhaled nitric oxide measurement as a biomarker in asthma and COPD compared with local and systemic inflammatory markers[J].Egypt JChest Dis Tuberc,2015,64(1):13-20.
[38]Bhowmik A,Seemungal TA,Donaldson GC,et al.Effects of exacerbations and seasonality on exhaled nitric oxide in COPD[J].Eur Respir J,2005,26(6):1009-1015.
[39]Huang SY,Chou PC,Wang TY,et al.Exercise-induced changes in exhaled no differentiates asthma with or without fixed airway obstruction from COPD with dynamic hyperinflation[J].Medicine(Baltimore),2016,95(15):e3400.
[40]Rouhos A,Kainu A,Piirila P,et al.Repeatability of exhaled nitric oxide measurements in patients with COPD[J].Clin Physiol Funct Imaging,2011,31(1):26-31.
[41]Mostafavi-Pour-Manshadi SM,Naderi N,Barrecheguren M,et al.Investigating fractional exhaled nitric oxide(FeNO)in chronic obstructive pulmonary disease(COPD)and asthmaCOPD overlap(ACO):a scoping review protocol[J].BMJOpen,2017,7(12):e018954.
[42]Lu Z,Huang W,Wang L,et al.Exhaled nitric oxide in patients with chronic obstructive pulmonary disease:a systematic review and meta-analysis[J].Int J Chron Obstruct Pulmon Dis,2018,13:2695-2705.
[43]Williamson PA,Clearie K,Menzies D,et al.Assessment of smallairways disease using alveolar nitric oxide and impulse oscillometry in asthma and COPD[J].Lung,2011,189(2):121-129.
[44]Hirano T,Matsunaga K,Sugiura H,et al.Relationship between alveolar nitric oxide concentration in exhaled air and small airway function in COPD[J].J Breath Res,2013,7(4):046002.
[45]Paredi P,Kharitonov SA,Meah S,et al.A novel approach to partition central and peripheral airway nitric oxide[J].Chest,2014,145(1):113-119.
[46]Lehouck A,Carremans C,De Bent K,et al.Alveolar and bronchial exhaled nitric oxide in chronic obstructive pulmonary disease[J].Respir Med,2010,104(7):1020-1026.
[47]Chen FJ,Huang XY,Liu YL,et al.Importance of fractional exhaled nitric oxide in the differentiation of asthma COPDoverlap syndrome,asthma,and COPD[J].Int J Chron Obstruct Pulmon Dis,2016,11:2385-2390.
[48]Alcazar-Navarrete B,Romero-Palacios PJ,Ruiz-Sancho A,et al.Diagnostic performance of the measurement of nitric oxide in exhaled air in the diagnosis of COPD phenotypes[J].Nitric Oxide,2016,54:67-72.
[49]邓玎玎,周爱媛,双庆翠,等.呼出气一氧化氮测定对支气管哮喘-慢性阻塞性肺疾病重叠综合征的诊断价值[J].中华结核和呼吸杂志,2017,40(2):98-101.
[50]Goto T,Camargo CJ,Hasegawa K.Fractional exhaled nitric oxide levels in asthma-COPD overlap syndrome:analysis of the national health and nutrition examination survey,2007-2012[J].Int J Chron Obstruct Pulmon Dis,2016,11:2149-2155.
[51]Alcázar-Navarrete B,Castellano Mi?án F,Santiago Díaz P,et al.Alveolar and Bronchial Nitric Oxide in Chronic Obstructive Pulmonary Disease and Asthma-COPD Overlap[J].Arch Bronconeumol,2018,54(8):414-419.
[52]夏清,潘频华,王展,等.呼出气一氧化氮检测在支气管炎症性肺疾病中的临床应用[J].中南大学学报(医学版),2014,39(4):365-370.
[53]Antus B,Barta I.Relationship between exhaled nitric oxide and the frequency of severe acute exacerbation of COPD:3-year follow-up[J].Acta Physiol Hung,2013,100(4):469-477.
[54]Durmaz D,Goksu E,Kilic T,et al.The role of nitric oxide in predicting revisit of patients with exacerbated chronic obstructive pulmonary disease[J].J Emerg Med,2015,48(2):247-253.
[55]Lázár Z,Kelemená,Gálffy G,et al.Central and peripheral airway nitric oxide in patients with stable and exacerbated chronic obstructive pulmonary disease[J].J Breath Res,2018,12(3):036017.
[56]Chou KT,Su KC,Huang SF,et al.Exhaled nitric oxide predicts eosinophilic airway inflammation in COPD[J].Lung,2014,192(4):499-504.
[57]Gao J,Zhang M,Zhou L,et al.Correlation between fractional exhaled nitric oxide and sputum eosinophilia in exacerbations of COPD[J].Int J Chron Obstruct Pulmon Dis,2017,12:1287-1293.
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