Fractional Exhaled Nitric Oxide (FENO) in the management of asthma: a position paper of the Italian Respiratory Society (SIP/IRS) and Italian Society of Allergy, Asthma and Clinical Immunology (SIAAIC)

Abstract

Asthma prevalence in Italy is on the rise and is estimated to be over 6% of the general population. The diagnosis of asthma can be challenging and elusive, especially in children and the last two decades has brought evidences that asthma is not a single disease but consists of various phenotypes. Symptoms can be underestimated by the patient or underreported to the clinician and physical signs can be scanty. Usual objective measures, like spirometry, are necessary but sometimes not significant. Despite proper treatment asthma can be a very severe condition (even leading to death) however new drugs have recently become available which can be very effective in its control. Since asthma is currently thought to be caused by inflammation, a direct measure of the latter can be of paramount importance.  For this purpose, the measurement of Fractional Exhaled Nitric Oxide (FENO) has been used since the early years of the current century as a non-invasive, easy-to-assess tool useful for diagnosing and managing asthma. This SIP-IRS/SIAAIC Position Paper is a narrative review which summarizes the evidence behind the usefulness of FENO in the diagnosis, management and phenotypization of asthma.

Dimensions

Altmetric

PlumX Metrics

Downloads

Download data is not yet available.

References

Global Initiative for Asthma. Accessed on: 4th July 2019. Available at: https://ginasthma.org/

Cazzola M, Puxeddu, E, Bettoncelli, G, Novelli L; Segreti A, Cricelli C, et al. The prevalence of asthma and COPD in Italy: A practice-based study. Respir Med 2011;105:386-91. DOI: https://doi.org/10.1016/j.rmed.2010.09.022

de Marco R, Cappa V, Accordini S, Rava M, Antonicelli L, Bortolami O, et al. Trends in the prevalence of asthma and allergic rhinitis in Italy between 1991 and 2010. Eur Respir J 2012;39:883-92. DOI: https://doi.org/10.1183/09031936.00061611

Baiardini I, Novakova S, Mihaicuta S, Oguzulgen IK, Canonica GW. Adherence to treatment in allergic respiratory diseases. Expert Rev Respir Med 2019;13:53-62. DOI: https://doi.org/10.1080/17476348.2019.1554438

Chung KF, Wenzel SE, Brozek JL, Bush A, Castro M, Sterk PJ, et al. International ERS/ATS guidelines on definition, evaluation and treatment of severe asthma. Eur Respir J 2014;43:343-73. DOI: https://doi.org/10.1183/09031936.00202013

Senna G, Guerriero M, Paggiaro PL, Blasi F, Caminati M, Heffler E, et al. SANI-Severe Asthma Network in Italy: a way forward to monitor severe asthma. Clin Mol Allergy 2017;15:9. DOI: https://doi.org/10.1186/s12948-017-0065-4

Heffler E, Blasi F, Latorre M, Menzella F, Paggiaro P, Pelaia G, et al. The Severe Asthma Network in Italy: Findings and perspectives. J Allergy Clin Immunol Pract 2019;7:1462-8. DOI: https://doi.org/10.1016/j.jaip.2018.10.016

Kuruvilla ME, Lee FE, Lee GB. Understanding asthma phenotypes, endotypes, and mechanisms of disease. Clin Rev Allergy Immunol 2019;56:219-33. DOI: https://doi.org/10.1007/s12016-018-8712-1

Robinson D, Humbert M, Buhl R, Cruz AA, Inoue H, Korom S, et al. Revisiting Type 2-high and Type 2-low airway inflammation in asthma: current knowledge and therapeutic implications. Clin Exp Allergy 2017;47:161-75. DOI: https://doi.org/10.1111/cea.12880

Simpson JL, Scott R, Boyle MJ, Gibson PG. Inflammatory subtypes in asthma: assessment and identification using induced sputum. Respirology 2006;11:54-61. DOI: https://doi.org/10.1111/j.1440-1843.2006.00784.x

Canonica GW, Ferrando M, Baiardini I, Puggioni F, Racca F, Passalacqua G, et al. Asthma: personalized and precision medicine. Curr Opin Allergy Clin Immunol 2018;18:51-8. DOI: https://doi.org/10.1097/ACI.0000000000000416

Corren J. New targeted therapies for uncontrolled asthma. J Allergy Clin Immunol Pract 2019;7:1394-403. DOI: https://doi.org/10.1016/j.jaip.2019.03.022

Woo SI, Lee JH, Kim H, Kang JW, Sun YH, Hahn YS. Utility of fractional exhaled nitric oxide (FENO) measurements in diagnosing asthma. Respir Med 2012;106:1103-9. DOI: https://doi.org/10.1016/j.rmed.2012.03.022

LaForce C, Brooks E, Herje N, Dorinsky P, Rickard K. Impact of exhaled nitric oxide measurements on treatment decisions in an asthma specialty clinic. Ann Allergy Asthma Immunol 2014;113:619-23. DOI: https://doi.org/10.1016/j.anai.2014.06.013

McCleverty JA. Chemistry of nitric oxide relevant to biology. Chem Rev 2004;104:403-18. DOI: https://doi.org/10.1021/cr020623q

Ford PC, Wink DA, Stanbury DM. Autoxidation kinetics of aqueous nitric oxide. FEBS Lett 1993;326:1-3. DOI: https://doi.org/10.1016/0014-5793(93)81748-O

Beckman JS, Koppenol WH. Nitric oxide, superoxide, and peroxynitrite: the good, the bad, and ugly. Am J Physiol 1996;271:C1424-37. DOI: https://doi.org/10.1152/ajpcell.1996.271.5.C1424

Kelm M, Feelisch M, Krebber T, Deussen A, Motz W, Strauer BE. Role of nitric oxide in the regulation of coronary vascular tone in hearts from hypertensive rats. Maintenance of nitric oxide-forming capacity and increased basal production of nitric oxide. Hypertension 1995;25:186-93. DOI: https://doi.org/10.1161/01.HYP.25.2.186

Maniscalco M, Sofia M, Pelaia G. Nitric oxide in upper airways inflammatory diseases. Inflamm Res 2007;56:58-69. DOI: https://doi.org/10.1007/s00011-006-6111-1

Lundberg JO, Weitzberg E, Rinder J, Rudehill A, Jansson O, Wiklund NP, et al. Calcium-independent and steroid-resistant nitric oxide synthase activity in human paranasal sinus mucosa. Eur Respir J 1996;9:1344-7. DOI: https://doi.org/10.1183/09031936.96.09071344

Grisham MB, Jourd'Heuil D, Wink DA. Nitric oxide. I. Physiological chemistry of nitric oxide and its metabolites: implications in inflammation. Am J Physiol 1999;276:G315-21. DOI: https://doi.org/10.1152/ajpgi.1999.276.2.G315

Huang H, Lavoie-Lamoureux A, Moran K, Lavoie JP. IL-4 stimulates the expression of CXCL-8, E-selectin, VEGF, and inducible nitric oxide synthase mRNA by equine pulmonary artery endothelial cells. Am J Physiol-Lung C 2007;292:L1147-L54. DOI: https://doi.org/10.1152/ajplung.00294.2006

Chibana K, Trudeau JB, Mustovitch AT, Hu H, Zhao J, Balzar S, et al. IL-13 induced increases in nitrite levels are primarily driven by increases in inducible nitric oxide synthase as compared with effects on arginases in human primary bronchial epithelial cells. Clin Exp Allergy 2008;38:936-46. DOI: https://doi.org/10.1111/j.1365-2222.2008.02969.x

Liaudet L, Soriano FG, Szabo C: Biology of nitric oxide signaling. Crit Care Med 2000;28:N37-N52. DOI: https://doi.org/10.1097/00003246-200004001-00005

Bian K, Murad F. What is next in nitric oxide research? From cardiovascular system to cancer biology. Nitric Oxide 2014;43:3-7. DOI: https://doi.org/10.1016/j.niox.2014.08.006

Maarsingh H, Zaagsma J, Meurs H. Arginase: a key enzyme in the pathophysiology of allergic asthma opening novel therapeutic perspectives. Br J Pharmacol 2009;158:652-64. DOI: https://doi.org/10.1111/j.1476-5381.2009.00374.x

Maniscalco M, Bianco A, Mazzarella G, Motta A. Recent advances on nitric oxide in the upper airways. Curr Med Chem 2016;23:2736-45. DOI: https://doi.org/10.2174/0929867323666160627115335

Gustafsson LE, Leone AM, Persson MG, Wiklund NP, Moncada S. Endogenous nitric oxide is present in the exhaled air of rabbits, guinea pigs and humans. Biochem Biophys Res Commun 1991;181:852-7. DOI: https://doi.org/10.1016/0006-291X(91)91268-H

Paiola G, Tenero L, Piacentini G. The measurement of exhaled nitric oxide in routine practice. Eur Ann Allergy Clin Immunol 2009;41:131-5.

American Thoracic Society; European Respiratory Society. ATS/ERS recommendations for standardized procedures for the online and offline measurement of exhaled lower respiratory nitric oxide and nasal nitric oxide, 2005. Am J Respir Crit Care Med 2005;171:912-30. DOI: https://doi.org/10.1164/rccm.200406-710ST

Linn WS, Berhane KT, Rappaport EB, Bastain TM, Avol EL, Gilliland FD. Relationships of online exhaled, offline exhaled and ambient nitric oxide in an epidemiologic survey of schoolchildren. J Expo Sci Environ Epidemiol 2009;19:674-81. DOI: https://doi.org/10.1038/jes.2008.64

Hsu JY, Huang WC, Huang PL, Cheng YW, Chou MC. Usefulness of offline fractional exhaled nitric oxide measurements in the elderly asthmatic patients. Allergy Asthma Proc 2013;34:434-8. DOI: https://doi.org/10.2500/aap.2013.34.3692

Maniscalco M, Lundberg JO. Hand-held nitric oxide sensor NIOX MINO(R) for the monitoring of respiratory disorders. Expert Rev Respir Med 2010;4:715-21. DOI: https://doi.org/10.1586/ers.10.67

Maniscalco M, Vitale C, Vatrella A, Molino A, Bianco A, Mazzarella G. Fractional exhaled nitric oxide-measuring devices: technology update. Med Devices (Auckl) 2016;9:151-60. DOI: https://doi.org/10.2147/MDER.S91201

Harnan SE, Tappenden P, Essat M, Gomersall T, Minton J, Wong R, et al. Measurement of exhaled nitric oxide concentration in asthma: a systematic review and economic evaluation of NIOX MINO, NIOX VERO and NObreath. Health Technol Assess 2015;19:1-330. DOI: https://doi.org/10.3310/hta19820

Molino A, Fuschillo S, Mosella M, Accardo M, Guida P, Motta A, et al. Comparison of three different exhaled nitric oxide analyzers in chronic respiratory disorders. J Breath Res 2019;13:021002. DOI: https://doi.org/10.1088/1752-7163/ab0167

Wang C, Sahay P. Breath analysis using laser spectroscopic techniques: breath biomarkers, spectral fingerprints, and detection limits. Sensors (Basel) 2009;9:8230-62. DOI: https://doi.org/10.3390/s91008230

Hunter GW, Xu JC, Biaggi-Labiosa AM, Laskowski D, Dutta PK, Mondal SP, et al. Smart sensor systems for human health breath monitoring applications. J Breath Res 2011;5:037111. DOI: https://doi.org/10.1088/1752-7155/5/3/037111

McCurdy MR, Bakhirkin Y, Wysocki G, Tittel FK. Performance of an exhaled nitric oxide and carbon dioxide sensor using quantum cascade laser-based integrated cavity output spectroscopy. J Biomed Opt 2007;12:034034. DOI: https://doi.org/10.1117/1.2747608

Mandon J, Högman M, Merkus PJFM, van Amsterdam J, Harren FJM, Cristescu SM. Exhaled nitric oxide monitoring by quantum cascade laser: comparison with chemiluminescent and electrochemical sensors. J Biomed Opt 2012;17:017003. DOI: https://doi.org/10.1117/1.JBO.17.1.017003

Lewicki R, Doty JH, Curl RF, Tittel FK, Wysocki G. Ultrasensitive detection of nitric oxide at 5.33 microm by using external cavity quantum cascade laser-based Faraday rotation spectroscopy. P Natl Acad Sci USA 2009;106:12587-92. DOI: https://doi.org/10.1073/pnas.0906291106

Shorter JH, Nelson DD, McManus JB, Zahniser MS, Sama SR, Milton DK. Clinical study of multiple breath biomarkers of asthma and COPD (NO, CO(2), CO and N(2)O) by infrared laser spectroscopy. J Breath Res 2011;5:037108. DOI: https://doi.org/10.1088/1752-7155/5/3/037108

Dweik RA, Boggs PB, Erzurum SC, Irvin CG, Leigh MW, Lundberg JO, et al. American Thoracic Society Committee on Interpretation of Exhaled Nitric Oxide Levels (FENO) for Clinical Applications. An official ATS clinical practice guideline: interpretation of exhaled nitric oxide levels (FENO) for clinical applications. Am J Respir Crit Care Med 2011;184:602-15. DOI: https://doi.org/10.1164/rccm.9120-11ST

Horváth I, Barnes PJ, Loukides S, Sterk PJ, Högman M, Olin AC, et al. A European Respiratory Society technical standard: exhaled biomarkers in lung disease. Eur Respir J 2017;49:1600965. DOI: https://doi.org/10.1183/13993003.00965-2016

Grob NM, Dweik RA. Exhaled nitric oxide in asthma. From diagnosis, to monitoring, to screening: are we there yet? Chest 2008;133:837-9.

Ahovuo-Saloranta A, Csonka P, Lehtimäki L. Basic characteristics and clinical value of FeNO in smoking asthmatics - a systematic review. J Breath Res 2019;13:034003. DOI: https://doi.org/10.1088/1752-7163/ab0ece

Haccuria A, Michils A, Michiels S, Van Muylem A. Exhaled nitric oxide: a biomarker integrating both lung function and airway inflammation changes. J Allergy Clin Immunol 2014;134:554-9. DOI: https://doi.org/10.1016/j.jaci.2013.12.1070

Malinovschi A1, Janson C, Holmkvist T, Norbäck D, Meriläinen P, Högman M. Effect of smoking on exhaled nitric oxide and flow-independent nitric oxide exchange parameters. Eur Respir J 2006;28:339-45. DOI: https://doi.org/10.1183/09031936.06.00113705

Bobrowska-Korzeniowska M, Stelmach I, Brzozowska A, Jerzyńska J, Mitał M, Stelmach W. The effect of passive smoking on exhaled nitric oxide in asthmatic children. Nitric Oxide 2019;86:48-53. DOI: https://doi.org/10.1016/j.niox.2019.01.012

Hoyt JC, Robbins RA, Habib M, Springall DR, Buttery LD, Polak JM, et al. Cigarette smoke decreases inducible nitric oxide synthase in lung epithelial cells. Exp Lung Res. 2003;29(1):17-28. DOI: https://doi.org/10.1080/01902140303759

Kovesi T, Kulka R, Dales R. Exhaled nitric oxide concentration is affected by age, height, and race in healthy 9- to 12-year-old children. Chest 2008;133:169-75. DOI: https://doi.org/10.1378/chest.07-1177

Olin A-C, Bake B, Torén K. Fraction of exhaled nitric oxide at 50 mL/s: reference values for adult lifelong never-smokers. Chest 2007;131:1852-6. DOI: https://doi.org/10.1378/chest.06-2928

Travers J, Marsh S, Aldington S, Williams M, Shirtcliffe P, Pritchard A, et al. Reference ranges for exhaled nitric oxide derived from a random community survey of adults. Am J Respir Crit Care Med 2007;176:238-42. DOI: https://doi.org/10.1164/rccm.200609-1346OC

Taylor DR, Mandhane P, Greene JM, Hancox RJ, Filsell S, McLachlan CR, et al. Factors affecting exhaled nitric oxide measurements: the effect of sex. Respir Res 2007;8:82. DOI: https://doi.org/10.1186/1465-9921-8-82

Jacinto T, Malinovschi A, Janson C, Fonseca J, Alving K. Evolution of exhaled nitric oxide levels throughout development and aging of healthy humans. J Breath Res 2015;9:036005. DOI: https://doi.org/10.1088/1752-7155/9/3/036005

Blake TL, Chang AB, Chatfield MD, Petsky HL, Rodwell LT, Brown MG, et al. Does ethnicity influence fractional exhaled nitric oxide in healthy individuals? A systematic review. Chest 2019;156:239-46. DOI: https://doi.org/10.1016/j.chest.2019.02.401

Wang D, Wang Y, Liang H, David JE, Bray CL. Race and ethnicity have significant influence on fractional exhaled nitric oxide. Ann Allergy Asthma Immunol 2018;120:272-7. DOI: https://doi.org/10.1016/j.anai.2017.11.021

Borrill Z, Clough D, Truman N, Morris J, Langley S, Singh D. A comparison of exhaled nitric oxide measurements performed using three different analysers. Respir Med 2006;100:1392-6. DOI: https://doi.org/10.1016/j.rmed.2005.11.018

Cattoni I, Guarnieri G, Tosetto A, Mason P, Scarpa MC, Saetta M, et al. Mechanisms of decrease in fractional exhaled nitric oxide during acute bronchoconstriction. Chest 2013;143:1269-76. DOI: https://doi.org/10.1378/chest.12-1374

Kharitonov SA, Gonio F, Kelly C, Meah S, Barnes PJ. Reproducibility of exhaled nitric oxide measurements in healthy and asthmatic adults and children. Eur Respir J 2003;21:433-8. DOI: https://doi.org/10.1183/09031936.03.00066903a

Olivieri M, Talamini G, Corradi M, Perbellini L, Mutti A, Tantucci C, et al. Reference values for exhaled nitric oxide (reveno) study. Respir Res 2006;7:94. DOI: https://doi.org/10.1186/1465-9921-7-94

Buchvald F, Baraldi E, Carraro S, Gaston B, De Jongste J, Pijnenburg MWH, et al. Measurements of exhaled nitric oxide in healthy subjects age 4 to 17 years. J Allergy Clin Immunol 2005;115:1130-6. DOI: https://doi.org/10.1016/j.jaci.2005.03.020

Cho HJ, Jung YH, Yang SI, Lee E, Kim HY, Seo JH, et al. Reference values and determinants of fractional concentration of exhaled nitric oxide in healthy children. Allergy Asthma Immunol Res 2014;6:169-74. DOI: https://doi.org/10.4168/aair.2014.6.2.169

Malmberg LP, Petäys T, Haahtela T, Laatikainen T, Jousilahti P, Vartiainen E, et al. Exhaled nitric oxide in healthy nonatopic school-age children: determinants and height-adjusted reference values. Pediatr Pulmonol 2006;41:635-42. DOI: https://doi.org/10.1002/ppul.20417

Olin A-C, Rosengren A, Thelle DS, Lissner L, Bake B, Torén K. Height, age, and atopy are associated with fraction of exhaled nitric oxide in a large adult general population sample. Chest 2006;130:1319-25. DOI: https://doi.org/10.1378/chest.130.5.1319

de Abreu FC, da Silva Júnior JLR, Rabahi MF. The fraction exhaled nitric oxide as a biomarker of asthma control. Biomark Insights 2019;14:1177271919826550. DOI: https://doi.org/10.1177/1177271919826550

Alvarez-Puebla MJ, Olaguibel Rivera JM, Almudevar E, Echegoyen AA, de Esteban Chocarro B, Cambra K. Cutoff point for exhaled nitric oxide corresponding to 3% sputum eosinophils. J Investig Allergol Clin Immunol 2015;25:107-11.

Ekroos H, Karjalainen J, Sarna S, Laitinen LA, Sovijarvi AR. Short-term variability of exhaled nitric oxide in young male patients with mild asthma and in healthy subjects. Respir Med 2002;96:895-900. DOI: https://doi.org/10.1053/rmed.2002.1378

Pijnenburg MW, Floor SE, Hop WC, De Jongste JC. Daily ambulatory exhaled nitric oxide measurements in asthma. Pediatr Allergy Immunol 2006;17:189-93. DOI: https://doi.org/10.1111/j.1399-3038.2006.00394.x

Massaro AF, Gaston B, Kita D, Fanta C, Stamler JS, Drazen JM. Expired nitric oxide levels during treatment of acute asthma. Am J Respir Crit Care Med 1995;152:800-3. DOI: https://doi.org/10.1164/ajrccm.152.2.7633745

Beck-Ripp J, Griese M, Arenz S, Koring C, Pasqualoni B, Bufler P. Changes of exhaled nitric oxide during steroid treatment of childhood asthma. Eur Respir J 2002;19:1015-9. DOI: https://doi.org/10.1183/09031936.02.01582001

Jones SL, Kittelson J, Cowan JO, Flannery EM, Hancox RJ, McLachlan CR, et al. The predictive value of exhaled nitric oxide measurements in assessing changes in asthma control. Am J Respir Crit Care Med 2001;164:738-43. DOI: https://doi.org/10.1164/ajrccm.164.5.2012125

Michils A, Baldassarre S, Van Muylem A. Exhaled nitric oxide and asthma control: a longitudinal study in unselected patients. Eur Respir J 2008;31:539-46. DOI: https://doi.org/10.1183/09031936.00020407

Rolla G, Malinovschi A, Badiu I, Heffler E, Petrarulo M, Bucca C, et al. The increase in exhaled NO following allergen challenge is not associated with airway acidification. Eur J Clin Invest 2011;41:411-6. DOI: https://doi.org/10.1111/j.1365-2362.2010.02423.x

Ferrazzoni S, Scarpa MC, Guarnieri G, Corradi M, Mutti A, Maestrelli P. Exhaled nitric oxide and breath condensate ph in asthmatic reactions induced by isocyanates. Chest 2009;136:155-62. DOI: https://doi.org/10.1378/chest.08-2338

George SC, Hogman M, Permutt S, Silkoff PE. Modeling pulmonary nitric oxide exchange. J Appl Physiol (1985) 2004;96:831-9. DOI: https://doi.org/10.1152/japplphysiol.00950.2003

Hogman M, Malinovschi A, Norback D, Janson C. Added value with extended NO analysis in atopy and asthma. Clin Physiol Funct Imaging 2011;31:294-9. DOI: https://doi.org/10.1111/j.1475-097X.2011.01017.x

Högman M. Extended NO analysis in health and disease. J Breath Res 2012;6:047103. DOI: https://doi.org/10.1088/1752-7155/6/4/047103

van Veen IH, Sterk PJ, Schot R, Gauw SA, Rabe KF, Bel EH. Alveolar nitric oxide versus measures of peripheral airway dysfunction in severe asthma. Eur Respir J 2006;27:951-6. DOI: https://doi.org/10.1183/09031936.06.00087905

Maniscalco M, Faraone S, Sofia M, Molino A, Vatrella A, Zedda A. Extended analysis of exhaled and nasal nitric oxide for the evaluation of chronic cough. Respir Med 2015;109:970-4. DOI: https://doi.org/10.1016/j.rmed.2015.05.016

National Institute for Health Care Excellence. NICE guideline NG80. Available at: https://www.nice.org.uk/guidance/ng80

Rupani H, Chauhan AJ. Measurement of FeNO in asthma: what the hospital doctor needs to know. Br J Hosp Med (Lond) 2019;80:99-104. DOI: https://doi.org/10.12968/hmed.2019.80.2.99

Feng-Jia C, Xin-Yan H, Geng-Peng L, Yang-Li L, Can-Mao X. Validity of fractional exhaled nitric oxide and small airway function indices in diagnosis of cough-variant asthma. J Asthma 2018;55:750-5. DOI: https://doi.org/10.1080/02770903.2017.1366509

Song WJ, Kim HJ, Shim JS, Won HK, Kang SY, Sohn KH, et al. Diagnostic accuracy of fractional exhaled nitric oxide measurement in predicting cough-variant asthma and eosinophilic bronchitis in adults with chronic cough: A systematic review and meta-analysis. J Allergy Clin Immunol 2017;140:701-9.

Saito M, Kikuchi Y, Lefor AK. School-aged asthma children with high fractional exhaled nitric oxide levels and lung dysfunction are at high risk of prolonged lung dysfunction. Asia Pac Allergy 2019;9:e8. DOI: https://doi.org/10.5415/apallergy.2019.9.e8

Zhang L, Liu S, Li M, Xu X. Diagnostic value of fractional exhaled nitric oxide in cough-variant asthma: an updated meta-analysis. J Asthma 2019. doi: 10.1080/02770903.2019.1568452. DOI: https://doi.org/10.1080/02770903.2019.1568452

Pijnenburg MW. The role of FeNO in predicting asthma. Front Pediatr 2019;7:41. DOI: https://doi.org/10.3389/fped.2019.00041

British Thoracic Society/Scottish Intercollegiate Guidelines Network. British guideline on the management of asthma. SIGN 153. 2016. Available at: https://www.sign.ac.uk/assets/sign153.pdf

Karrasch S, Linde K, Rücker G, Sommer H, Karsch-Völk M, Kleijnen J, et al. Accuracy of FENO for diagnosing asthma: a systematic review. Thorax 2017;72:109-16. DOI: https://doi.org/10.1136/thoraxjnl-2016-208704

Jackson DJ, Virnig CM, Gangnon RE, Evans MD, Roberg KA, Anderson EL, et al. Fractional exhaled nitric oxide measurements are most closely associated with allergic sensitization in school-age children. J Allergy Clin Immunol 2009;124:949-53. DOI: https://doi.org/10.1016/j.jaci.2009.07.024

Janson C, Kalm-Stephens P, Foucard T, Norbäck D, Alving K, Nordvall SL. Exhaled nitric oxide levels in school children in relation to IgE sensitisation and window pane condensation. Respir Med 2005;99:1015-21. DOI: https://doi.org/10.1016/j.rmed.2005.02.003

Malinovschi A, Janson C, Holmkvist T, Norbäck D, Meriläinen P, Högman M. IgE sensitization in relation to flow-independent nitric oxide exchange parameters. Respir Res 2006;7:92. DOI: https://doi.org/10.1186/1465-9921-7-92

Kalm-Stephens P, Nordvall L, Janson C, Neuman Å, Malinovschi A, Alving K. Elevated exhaled nitric oxide in adolescents relates to incident allergic symptoms: a prospective cohort study.J Investig Allergol Clin Immunol 2019;29:231-8. DOI: https://doi.org/10.18176/jiaci.0317

Linhares D, Jacinto T, Pereira AM, Fonseca JA. Effects of atopy and rhinitis on exhaled nitric oxide values - a systematic review. Clin Transl Allergy 2011;1:8. DOI: https://doi.org/10.1186/2045-7022-1-8

Kalpaklioglu AF, Kalkan IK. Comparison of orally exhaled nitric oxide in allergic versus nonallergic rhinitis. Am J Rhinol Allergy 2012;26:e50-4. DOI: https://doi.org/10.2500/ajra.2012.26.3717

Lopuhaä CE, Koopmans JG, Jansen HM, van der Zee JS. Similar levels of nitric oxide in exhaled air in non-asthmatic rhinitis and asthma after bronchial allergen challenge. Allergy 2003;58:300-5. DOI: https://doi.org/10.1034/j.1398-9995.2003.00075.x

Bergmann-Hug K, Wirth R, Henseler M, Helbling A, Pichler WJ, Schnyder B. Effect of natural seasonal pollen exposure and repeated nasal allergen provocations on elevation of exhaled nitric oxide. Allergy 2009;64:1629-34. DOI: https://doi.org/10.1111/j.1398-9995.2009.02087.x

Heffler E, Guida G, Marsico P, Bergia R, Bommarito L, Ferrero N, et al. Exhaled nitric oxide as a diagnostic test for asthma in rhinitic patients with asthmatic symptoms. Respir Med 2006;100:1981-7. DOI: https://doi.org/10.1016/j.rmed.2006.02.019

Rolla G, Guida G, Heffler E, Badiu I, Bommarito L, De Stefani A, et al. Diagnostic classification of persistent rhinitis and its relationship to exhaled nitric oxide and asthma: a clinical study of a consecutive series of patients. Chest 2007;131:1345-52. DOI: https://doi.org/10.1378/chest.06-2618

Ciprandi G, Gallo F, Ricciardolo FL, Cirillo I. Fractional exhaled nitric oxide: A potential biomarker in allergic rhinitis? Int Arch Allergy Immunol 2017;172:99-105. DOI: https://doi.org/10.1159/000456548

Kambaraa R, Minami T, Akazawa H, Tsuji F, Sasaki T, Inohara H, Horii A. Lower airway inflammation in eosinophilic chronic rhinosinusitis as determined by exhaled nitric oxide. Int Arch Allergy Immunol 2017;173:225-32. DOI: https://doi.org/10.1159/000479387

Guida G, Rolla G, Badiu I, Marsico P, Pizzimenti S, Bommarito L, De Stefani A, Usai A, Bugiani M, Malinovschi A, Bucca C, Heffler E. Determinants of exhaled nitric oxide in chronic rhinosinusitis. Chest 2010;137:658-64. DOI: https://doi.org/10.1378/chest.09-0667

Pavlidis S, Takahashi K, Ng Kee Kwong F, Xie J, Hoda U, et al. "T2-high" in severe asthma related to blood eosinophil, exhaled nitric oxide and serum periostin. Eur Respir J 2019;53. doi: 10.1183/13993003.00938-2018. DOI: https://doi.org/10.1183/13993003.00938-2018

Mansur AH, Srivastava S, Sahal A. Disconnect of type 2 biomarkers in severe asthma; dominated by FeNO as a predictor of exacerbations and periostin as predictor of reduced lung function. Respir Med 2018;143:31-8. DOI: https://doi.org/10.1016/j.rmed.2018.08.005

Lehtimäki L, Csonka P, Mäkinen E, Isojärvi J, Hovi SL, Ahovuo-Saloranta A. Predictive value of exhaled nitric oxide in the management of asthma: a systematic review. Eur Respir J 2016;48:706-14. DOI: https://doi.org/10.1183/13993003.00699-2016

Bates CA, Silkoff PE. Exhaled nitric oxide in asthma: From bench to bedside. J Allergy Clin Immunol 2003;111:256-62. DOI: https://doi.org/10.1067/mai.2003.103

Oka A, Hirano T, Yamaji Y, Ito K, Oishi K, Edakuni N, Kawano R, Matsunaga K. Determinants of incomplete asthma control in patients with allergic rhinitis and asthma. J Allergy Clin Immunol Pract 2017;5:160-4. DOI: https://doi.org/10.1016/j.jaip.2016.08.002

Ricciardolo FL, Sorbello V, Bellezza Fontana R, Schiavetti I, Ciprandi G. Exhaled nitric oxide in relation to asthma control: A real-life survey. Allergol Immunopathol (Madr) 2016;44:197-205. DOI: https://doi.org/10.1016/j.aller.2015.05.012

Shirai T, Furuhashi K, Suda T, Chida K. Relationship of the asthma control test with pulmonary function and exhaled nitric oxide. Ann Allergy Asthma Immunol 2008;101:608-13. DOI: https://doi.org/10.1016/S1081-1206(10)60223-2

Zeng J, Chen Z, Hu Y, Hu Q, Zhong S, Liao W. Asthma control in preschool children with small airway function as measured by IOS and fractional exhaled nitric oxide. Respir Med 2018;145:8-13. DOI: https://doi.org/10.1016/j.rmed.2018.10.009

Piacentini GL, Peroni DG, Bodini A, Bonafiglia E, Rigotti E, Baraldi E, et al. Childhood asthma control test and airway inflammation evaluation in asthmatic children. Allergy 2009;64:1753-7. DOI: https://doi.org/10.1111/j.1398-9995.2009.02068.x

Lee WY, Suh DI, Song DJ, Baek HS, Shin M, Yoo Y, et al. Asthma control test reflects not only lung function but also airway inflammation in children with stable asthma. J Asthma. 2019;10:1-6. DOI: https://doi.org/10.1080/02770903.2019.1658209

Heffler E, Pizzimenti S, Badiu I, Guida G, Ricciardolo FL, Bucca C, et al. Nasal nitric oxide is a marker of poor asthma control. J Breath Res 2013;7:026009. DOI: https://doi.org/10.1088/1752-7155/7/2/026009

Sato S, Saito J, Fukuhara A, Uematsu M, Suzuki Y, Togawa R, et al. The clinical role of fractional exhaled nitric oxide in asthma control. Ann Allergy Asthma Immunol 2017;119:541-7. DOI: https://doi.org/10.1016/j.anai.2017.09.059

Meena RK, Raj D, Lodha R, Kabra SK. Fractional exhaled nitric oxide for identification of uncontrolled asthma in children. Indian Pediatr 2016;53:307-10. DOI: https://doi.org/10.1007/s13312-016-0842-z

Mahut B, Trinquart L, Le Bourgeois M, Becquemin MH, Beydon N, Aubourg F, et al. Multicentre trial evaluating alveolar NO fraction as a marker of asthma control and severity. Allergy. 2010;65:636-44. DOI: https://doi.org/10.1111/j.1398-9995.2009.02221.x

Bernstein JA, Davis B, Alvarez-Puebla MJ, Nguyen D, Levin L, Olaguibel JM. Is exhaled nitric oxide a useful adjunctive test for assessing asthma? J Asthma 2009;46:955-60. DOI: https://doi.org/10.3109/02770900903265804

Lopes C, Fonseca J, Delgado L, Moreira A, Barros R, Moreira P, et al. Assessing asthma control: questionnaires and exhaled nitric oxide provide complementary information. Eur Respir J 2008;32:1419-20. DOI: https://doi.org/10.1183/09031936.00093008

Fielding S, Pijnenburg M, de Jongste JC, Pike KC, Roberts G, Petsky H, et al. Change in FEV1 and feno measurements as predictors of future asthma outcomes in children. Chest 2019;155:331-41. DOI: https://doi.org/10.1016/j.chest.2018.10.009

Wang Z, Pianosi P, Keogh K, Zaiem F, Alsawas M, Alahdab F, et al. The clinical utility of fractional exhaled nitric oxide (FeNO) in asthma management. Report No: 17(18)-EHC030-EF. Rockville, MD: Agency for Healthcare Research and Quality (US); 2017;. DOI: https://doi.org/10.23970/AHRQEPCCER197

Visitsunthorn N, Prottasan P, Jirapongsananuruk O, Maneechotesuwan K. Is fractional exhaled nitric oxide (FeNO) associated with asthma control in children? Asian Pac J Allergy Immunol 2014;32:218-25. DOI: https://doi.org/10.12932/AP0362.32.3.2014

Martins C, Silva D, Severo M, Rufo J, Paciência I, Madureira J, et al. Spirometry-adjusted fraction of exhaled nitric oxide increases accuracy for assessment of asthma control in children. Pediatr Allergy Immunol 2017;28:754-62. DOI: https://doi.org/10.1111/pai.12803

Michils A, Haccuria A, Michiels S, Van Muylem A. Airway calibre variation is a major determinant of exhaled nitric oxide's ability to capture asthma control. Eur Respir J 2017;50: 1700392. DOI: https://doi.org/10.1183/13993003.00392-2017

Malinovschi A, Van Muylem A, Michiels S, Michils A. FeNO as a predictor of asthma control improvement after starting inhaled steroid treatment. Nitric Oxide 2014;40:110-6. DOI: https://doi.org/10.1016/j.niox.2014.06.009

Chang DV, Teper A, Balinotti J, Castro Simonelli C, Garcia-Bournissen F, Kofman C. Exhaled nitric oxide predicts loss of asthma control in children after inhaled corticosteroids withdrawal. Pediatr Pulmonol 2019;54:537-43.

Kim JK, Jung JY, Kim H, Eom SY, Hahn YS. Combined use of fractional exhaled nitric oxide and bronchodilator response in predicting future loss of asthma control among children with atopic asthma. Respirology 2017;22:466-72. DOI: https://doi.org/10.1111/resp.12934

Matsunaga K, Hirano T, Oka A, Ito K, Edakuni N. Persistently high exhaled nitric oxide and loss of lung function in controlled asthma. Allergol Int 2016;65:266-71. DOI: https://doi.org/10.1016/j.alit.2015.12.006

Yang S, Park J, Lee YK, Kim H, Hahn YS. Association of longitudinal fractional exhaled nitric oxide measurements with asthma control in atopic children. Respir Med 2015;109:572-9. DOI: https://doi.org/10.1016/j.rmed.2015.03.003

Little SA, Chalmers GW, MacLeod KJ, McSharry C, Thomson NC. Non-invasive markers of airway inflammation as predictors of oral steroid responsiveness in asthma. Thorax 2000;55:232-4. DOI: https://doi.org/10.1136/thorax.55.3.232

McNicholl DM, Stevenson M, McGarvey LP, Heaney LG. The utility of fractional exhaled nitric oxide suppression in the identification of nonadherence in difficult asthma. Am J Respir Crit Care Med 2012;186:1102-8. DOI: https://doi.org/10.1164/rccm.201204-0587OC

Petsky HL, Cates CJ, Kew KM, Chang AB. Tailoring asthma treatment on eosinophilic markers (exhaled nitric oxide or sputum eosinophils): a systematic review and meta-analysis. Thorax 2018;73:1110-9. DOI: https://doi.org/10.1136/thoraxjnl-2018-211540

SJ, Martin RJ, King TS, Boushey HA, Cherniack RM, Chinchilli VM, et al. Significant variability in response to inhaled corticosteroids for persistent asthma. J Allergy Clin Immunol 2002;109:410-8. DOI: https://doi.org/10.1067/mai.2002.122635

Price DB, Buhl R, Chan A, Freeman D, Gardener E, Godley C, et al. Fractional exhaled nitric oxide as a predictor of response to inhaled corticosteroids in patients with non-specific respiratory symptoms and insignificant bronchodilator reversibility: a randomised controlled trial. Lancet Respir Med 2018;6:29-39. DOI: https://doi.org/10.1016/S2213-2600(17)30424-1

Cowan DC, Cowan JO, Palmay R, Williamson A, Taylor DR. Effects of steroid therapy on inflammatory cell subtypes in asthma. Thorax 2010;65:384-90. DOI: https://doi.org/10.1136/thx.2009.126722

Szefler SJ, Phillips BR, Martinez FD, Chinchilli VM, Lemanske RF, Strunk RC, et al. Characterization of within-subject responses to fluticasone and montelukast in childhood asthma. J Allergy Clin Immunol 2005;115:233-42. DOI: https://doi.org/10.1016/j.jaci.2004.11.014

Cowan DC, Taylor DR, Peterson LE, Cowan JO, Palmay R, Williamson A, et al. Biomarker-based asthma phenotypes of corticosteroid response. J Allergy Clin Immunol 2015;135:877-83. DOI: https://doi.org/10.1016/j.jaci.2014.10.026

Smith AD, Cowan JO, Brassett KP, Filsell S, McLachlan C, Monti-Sheehan G, et al. Exhaled nitric oxide: a predictor of steroid response. Am J Respir Crit Care Med 2005;172:453-9. DOI: https://doi.org/10.1164/rccm.200411-1498OC

Hoshino M, Akitsu K, Ohtawa J. Comparison between montelukast and tiotropium as add-on therapy to inhaled corticosteroids plus a long-acting β2-agonist in for patients with asthma. J Asthma 2018;13:1-9.

Fritscher LG1, Rodrigues MT, Zamel N, Chapman KR. The effect of montelukast on exhaled nitric oxide of alveolar and bronchial origin in inhaled corticosteroid-treated asthma. Respir Med 2009;103:296-300. DOI: https://doi.org/10.1016/j.rmed.2008.08.007

Davis BE, Illamperuma C, Gauvreau GM, Watson RM, O'Byrne PM, Deschesnes F, et al. Single-dose desloratadine and montelukast and allergen-induced late airway responses. Eur Respir J 2009;33:1302-8. DOI: https://doi.org/10.1183/09031936.00169008

Kononowa N, Michel S, Miedinger D, Pichler CE, Chhajed PN, Helbling A, et al. Effects of add-on montelukast on airway hyperresponsiveness in patients with well-controlled asthma - a pilot study. J Drug Assess 2013;2:49-57. DOI: https://doi.org/10.3109/21556660.2013.791300

Montuschi P, Mondino C, Koch P, Ciabattoni G, Barnes PJ, Baviera G. Effects of montelukast treatment and withdrawal on fractional exhaled nitric oxide and lung function in children with asthma. Chest 2007;132:1876-81. DOI: https://doi.org/10.1378/chest.07-1587

Moeller A, Lehmann A, Knauer N, Albisetti M, Rochat M, Johannes W. Effects of montelukast on subjective and objective outcome measures in preschool asthmatic children. Pediatr Pulmonol 2008;43:179-86. DOI: https://doi.org/10.1002/ppul.20753

Tenero L, Piazza M, Sandri M, Azzali A, Chinellato I, Peroni D, et al. Effect of montelukast on markers of airway remodeling in children with asthma. Allergy Asthma Proc 2016;37:77-83. DOI: https://doi.org/10.2500/aap.2016.37.3978

Lehtimäki L, Petäys T, Haahtela T. Montelukast is not effective in controlling allergic symptoms outside the airways: a randomised double-blind placebo-controlled crossover study. Int Arch Allergy Immunol 2009;149:150-3. DOI: https://doi.org/10.1159/000189198

Pelkonen AS, Malmström K, Sarna S, Kajosaari M, Klemola T, Malmberg LP, et al. The effect of montelukast on respiratory symptoms and lung function in wheezy infants. Eur Respir J 2013;41:664-70. DOI: https://doi.org/10.1183/09031936.00173411

Zeiger RS, Schatz M, Zhang F, Crawford WW, Kaplan MS, Roth RM, et al. Elevated exhaled nitric oxide is a clinical indicator of future uncontrolled asthma in asthmatic patients on inhaled corticosteroids. J Allergy Clin Immunol 2011;128:412-4. DOI: https://doi.org/10.1016/j.jaci.2011.06.008

Petsky HL, Kew KM, Turner C, Chang AB. Exhaled nitric oxide levels to guide treatment for adults with asthma. Cochrane Database Syst Rev 2016;9:CD011440. DOI: https://doi.org/10.1002/14651858.CD011440.pub2

Petsky HL, Kew KM, Chang AB. Exhaled nitric oxide levels to guide treatment for children with asthma. Cochrane Database Syst Rev 2016;11:CD011439. DOI: https://doi.org/10.1002/14651858.CD011439.pub2

Petsky HL, Li A, Chang AB. Tailored interventions based on sputum eosinophils versus clinical symptoms for asthma in children and adults. Cochrane Database Syst Rev 2017;8:CD005603. DOI: https://doi.org/10.1002/14651858.CD005603.pub3

Bel EH, Sousa A, Fleming L, Bush A, Chung KF, Versnel J, et al. Diagnosis and definition of severe refractory asthma: an international consensus statement from the Innovative Medicine Initiative (IMI). Thorax 2011;66:910-7. DOI: https://doi.org/10.1136/thx.2010.153643

Braido F, Baiardini I, Blasi F, Pawankar R, Canonica GW. Adherence to asthma treatments: 'we know, we intend, we advocate'. Curr Opin Allergy Clin Immunol 2015;15:49-55. DOI: https://doi.org/10.1097/ACI.0000000000000132

Delgado-Corcoran C, Kissoon N, Murphy SP, Duckworth LJ. Exhaled nitric oxide reflects asthma severity and asthma control. Pediatr Crit Care Med 2004;5:48-52. DOI: https://doi.org/10.1097/01.CCM.0000105310.00799.51

Cano-Garcinuño A, Carvajal-Urueña I, Díaz-Vázquez CA, Domínguez-Aurrecoechea B, García-Merino A, de Rodas PM, et al. Clinical correlates and determinants of airway inflammation in pediatric asthma. J Investig Allergol Clin Immunol 2010;20:303-10.

Klok T, Brand PLP. Can exhaled nitric oxide fraction predict adherence to inhaled corticosteroids in atopic and nonatopic children with asthma? J Allergy Clin Immunol Pract 2017;5:521-2. DOI: https://doi.org/10.1016/j.jaip.2016.09.038

Tsai YG, Sun HL, Chien JW, Chen CY, Lin CH, Lin CY. High exhaled nitric oxide levels correlate with nonadherence in acute asthmatic children. Ann Allergy Asthma Immunol 2017;118:521-3. DOI: https://doi.org/10.1016/j.anai.2017.01.031

Hunt E, Flynn D, MacHale E, Costello RW, Murphy DM. Reduction in exhaled nitric oxide tracks improved patient inhaler compliance in difficult asthma-a case study. Asthma 2018;55:1373-5. DOI: https://doi.org/10.1080/02770903.2017.1414237

Heaney LG, Busby J, Bradding P, Chaudhuri R, Mansur AH, Niven R, et al. remotely monitored therapy and nitric oxide suppression identifies nonadherence in severe asthma. Am J Respir Crit Care Med 2019;199:454-64. DOI: https://doi.org/10.1164/rccm.201806-1182OC

Price DB, Bosnic-Anticevich S, Pavord ID, Roche N, Halpin DMG, Bjermer L, et al. Association of elevated fractional exhaled nitric oxide concentration and blood eosinophil count with severe asthma exacerbations. Clin Transl Allergy 2019;9:41. DOI: https://doi.org/10.1186/s13601-019-0282-7

Katsara M, Donnelly D, Iqbal S, Elliott T, Everard ML. Relationship between exhaled nitric oxide levels and compliance with inhaled corticosteroids in asthmatic children. Respir Med 2006;100:1512-7. DOI: https://doi.org/10.1016/j.rmed.2006.01.012

Busby J, Holweg CTJ, Chai A, Bradding P, Cai F, Chaudhuri R, et al. Change in type-2 biomarkers and related cytokines with prednisolone in uncontrolled severe oral corticosteroid dependent asthmatics : an interventional open-label study. Thorax 2019:1-4. DOI: https://doi.org/10.1136/thoraxjnl-2018-212709

Oishi K, Hirano T, Suetake R, Ohata S, Yamaji Y, Ito K, et al. A trial of oral corticosteroids for persistent systemic and airway inflammation in severe asthma. Immun Inflamm Dis 2017:5:261-4. DOI: https://doi.org/10.1002/iid3.166

Hanania NA, Wenzel S, Rosén K, Hsieh HJ, Mosesova S, Choy DF, et al. Exploring the effects of omalizumab in allergic asthma: an analysis of biomarkers in the EXTRA study. Am J Respir Crit Care Med 2013;187:804-11. DOI: https://doi.org/10.1164/rccm.201208-1414OC

Bhutani M, Yang WH, Hébert J, de Takacsy F, Stril JL. The real world effect of omalizumab add on therapy for patients with moderate to severe allergic asthma: The ASTERIX Observational study. PLoS One 2017;12:e0183869. DOI: https://doi.org/10.1371/journal.pone.0183869

Kurokawa M, Koya T, Takeuchi H, Hayashi M, Sakagami T, Ishioka K, et al. Association of upper and lower airway eosinophilic inflammation with response to omalizumab in patients with severe asthma. J Asthma 2020;57:71-8. DOI: https://doi.org/10.1080/02770903.2018.1541357

Pasha MA, Jourd'heuil D, Jourd'heuil F, Mahon L, Romero F, Feustel PJ, et al. The effect of omalizumab on small airway inflammation as measured by exhaled nitric oxide in moderate-to-severe asthmatic patients. Allergy Asthma Proc 2014;35:241-9. DOI: https://doi.org/10.2500/aap.2014.35.3741

Pavord ID, Korn S, Howarth P, Bleecker ER, Buhl R, Keene ON, Ortega H, Chanez P. Mepolizumab for severe eosinophilic asthma (DREAM): a multicentre, double-blind, placebo-controlled trial. Lancet 2012;380:651-9. DOI: https://doi.org/10.1016/S0140-6736(12)60988-X

Farah CS, Badal T, Reed N, Rogers PG, King GG, Thamrin C, Peters MJ, Seccombe LM. Mepolizumab improves small airway function in severe eosinophilic asthma. Respir Med 2019;148:49-53. DOI: https://doi.org/10.1016/j.rmed.2019.01.016

Castro M, Corren J, Pavord ID, Maspero J, Wenzel S, Rabe KF, et al. dupilumab efficacy and safety in moderate-to-severe uncontrolled asthma. N Engl J Med 2018;378:2486-96. DOI: https://doi.org/10.1056/NEJMoa1804092

Wenzel S, Pavord ID, Rabe KF, Papi A, Fitzgerald JM, Jagerschmidt A, et al. Dupilumab shows rapid and sustained suppression of inflammatory biomarkers in asthma patients in LIBERTY ASTHMA QUEST. Eur Respir J. 2018;52:PA5005. DOI: https://doi.org/10.1183/13993003.congress-2018.PA5005

Luo J, Liu D, Liu CT. The efficacy and safety of anti-interleukin 13, a monoclonal antibody, in adult patients with asthma: A systematic review and meta-analysis. Medicine (Baltimore) 2016;95:e2556. DOI: https://doi.org/10.1097/MD.0000000000002556

Panettieri RA Jr, Sjöbring U, Péterffy A, Wessman P, Bowen K, Piper E, et al. Tralokinumab for severe, uncontrolled asthma (STRATOS 1 and STRATOS 2): two randomised, double-blind, placebo-controlled, phase 3 clinical trials. Lancet Respir Med 2018;6:511-25. DOI: https://doi.org/10.1016/S2213-2600(18)30184-X

Russell RJ, Chachi L, FitzGerald JM, Backer V, Olivenstein R, Titlestad IL, et al. Effect of tralokinumab, an interleukin-13 neutralising monoclonal antibody, on eosinophilic airway inflammation in uncontrolled moderate-to-severe asthma (MESOS): a multicentre, double-blind, randomised, placebo-controlled phase 2 trial. Lancet Respir Med 2018;6:499-510. DOI: https://doi.org/10.1016/S2213-2600(18)30201-7

Corren J, Parnes JR, Wang L, Mo M, Roseti SL, Griffiths JM, et al. Tezepelumab in adults with uncontrolled asthma. N Engl J Med 2017;377:936-46. DOI: https://doi.org/10.1056/NEJMoa1704064

Soma T, Iemura H, Naito E, Miyauchi S, Uchida Y, Nakagome K, et al. Implication of fraction of exhaled nitric oxide and blood eosinophil count in severe asthma. Allergol Int 2018;67S:S3-11. DOI: https://doi.org/10.1016/j.alit.2018.04.003

Nelson BV, Sears S, Woods J, Ling CY, Hunt J, Clapper LM, Gaston B. Expired nitric oxide as a marker for childhood asthma. J Pediatr 1997;130:423-7. DOI: https://doi.org/10.1016/S0022-3476(97)70204-X

Baraldi E, Azzolin NM, Zanconato S, Dario C, Zacchello F. Corticosteroids decrease exhaled nitric oxide in children with acute asthma. J Pediatr 1997;131:381-5. DOI: https://doi.org/10.1016/S0022-3476(97)80062-5

Baraldi E, de Jongste JC, European Respiratory Society/American Thoracic Society (ERS/ATS) Task Force. Measurement of exhaled nitric oxide in children, 2001. Eur Respir J 2002;20:223-37. DOI: https://doi.org/10.1183/09031936.02.00293102

Ferraro V, Carraro S, Bozzetto S, Zanconato S, Baraldi E. Exhaled biomarkers in childhood asthma: old and new approaches. Asthma Res Pract 2018;4:9. DOI: https://doi.org/10.1186/s40733-018-0045-6

Mahr TA, Malka J, Spahn JD. Inflammometry in pediatric asthma: a review of fractional exhaled nitric oxide in clinical practice. Allergy Asthma Proc 2013;34:210-9. DOI: https://doi.org/10.2500/aap.2013.34.3660

Cibella F, Cuttitta G, La Grutta S, Passalacqua G, Viegi G. Factors that influence exhaled nitric oxide in Italian schoolchildren. Ann Allergy Asthma Immunol 2008;101:407-12. DOI: https://doi.org/10.1016/S1081-1206(10)60318-3

Dodig S, Richter D, Zrinski-Topić R. Inflammatory markers in childhood asthma. Clin Chem Lab Med 2011;49:587-99. DOI: https://doi.org/10.1515/CCLM.2011.094

Moeller A, Carlsen KH, Sly PD, Baraldi E, Piacentini G, Pavord I, et al. Monitoring asthma in childhood: lung function, bronchial responsiveness and inflammation. Eur Respir Rev 2015;24:204-15. DOI: https://doi.org/10.1183/16000617.00003914

Oh MA, Shim JY, Jung YH, Seo JH, Young Kim H, Kwon JW, et al. Fraction of exhaled nitric oxide and wheezing phenotypes in preschool children. Pediatr Pulmonol 2013;48:563-70. DOI: https://doi.org/10.1002/ppul.22705

Caudri D, Wijga AH, Hoekstra MO, Kerkhof M, Koppelman GH, Brunekreef B, et al. Prediction of asthma in symptomatic preschool children using exhaled nitric oxide, rint and specific IgE. Thorax 2010;65:801-7. DOI: https://doi.org/10.1136/thx.2009.126912

Hervás D, Milán JM, Garde J. Differences in exhaled nitric oxide in atopic children. Allergol Immunopathol (Madr) 2008;36:331-5. DOI: https://doi.org/10.1016/S0301-0546(08)75865-8

Scott M, Raza A, Karmaus W, Mitchell F, Grundy J, Kurukulaaratchy RJ, et al. Influence of atopy and asthma on exhaled nitric oxide in an unselected birth cohort study. Thorax 2010;65:258-62. DOI: https://doi.org/10.1136/thx.2009.125443

Chinellato I, Piazza M, Peroni D, Sandri M, Chiorazzo F, Boner AL, et al. Bronchial and alveolar nitric oxide in exercise-induced bronchoconstriction in asthmatic children. Clin Exp Allergy 2012;42:1190-6. DOI: https://doi.org/10.1111/j.1365-2222.2012.03973.x

Ferrer M, Jarque A, Tosca R, Michavila A. Is it necessary to treat all asthmatic children with raised levels of exhaled nitric oxide?: treating the patient or the data. Allergol Immunopathol (Madr) 2011;39:280-3. DOI: https://doi.org/10.1016/j.aller.2010.09.005

Silvestri M, Sabatini F, Spallarossa D, Fregonese L, Battistini E, Biraghi MG, et al. Exhaled nitric oxide levels in non-allergic and allergic mono- or polysensitised children with asthma. Thorax 2001;56:857-62. DOI: https://doi.org/10.1136/thorax.56.11.857

Baraldi E, Azzolin NM, Cracco A, Zacchello F. Reference values of exhaled nitric oxide for healthy children 6-15 years old. Pediatr Pulmonol 1999;27:54-8. DOI: https://doi.org/10.1002/(SICI)1099-0496(199901)27:1<54::AID-PPUL10>3.0.CO;2-V

Ferrante G, Malizia V, Antona R, Corsello G, Grutta S. The value of FeNO measurement in childhood asthma: uncertainties and perspectives. Multidiscip Respir Med 2013;8:50. DOI: https://doi.org/10.1186/2049-6958-8-50

La Grutta S, Ferrante G, Malizia V, Cibella F, Viegi G. Environmental effects on fractional exhaled nitric oxide in allergic children. J Allergy (Cairo) 2012;2012:916926. DOI: https://doi.org/10.1155/2012/916926

Ricciardolo FL, Silvestri M, Pistorio A, Strozzi MM, Tosca MA, Bellodi SC, et al. Determinants of exhaled nitric oxide levels (FeNO) in childhood atopic asthma: evidence for neonatal respiratory distress as a factor associated with low FeNO levels. J Asthma 2010;47:810-6. DOI: https://doi.org/10.3109/02770903.2010.489245

Filippone M, Bonetto G, Corradi M, Frigo AC, Baraldi E. Evidence of unexpected oxidative stress in airways of adolescents born very pre-term. Eur Respir J 2012;40:1253-9. DOI: https://doi.org/10.1183/09031936.00185511

Moeller A, Diefenbacher C, Lehmann A, Rochat M, Brooks-Wildhaber J, Hall GL, et al. Exhaled nitric oxide distinguishes between subgroups of preschool children with respiratory symptoms. J Allergy Clin Immunol 2008;121:705-9. DOI: https://doi.org/10.1016/j.jaci.2007.11.008

Singer F, Luchsinger I, Inci D, Knauer N, Latzin P, Wildhaber JH, et al. Exhaled nitric oxide in symptomatic children at preschool age predicts later asthma. Allergy 2013;68:531-8. DOI: https://doi.org/10.1111/all.12127

Chang D, Yao W, Tiller CJ, Kisling J, Slaven JE, Yu Z, et al. Exhaled nitric oxide during infancy as a risk factor for asthma and airway hyperreactivity. Eur Respir J 2015;45:98-106. DOI: https://doi.org/10.1183/09031936.00034614

Jartti T, Wendelin-Saarenhovi M, Heinonen I, Hartiala J, Vanto T. Childhood asthma management guided by repeated FeNO measurements: a meta-analysis. Paediatr Respir Rev 2012;13:178-83. DOI: https://doi.org/10.1016/j.prrv.2011.11.002

Petsky HL, Cates CJ, Li A, Kynaston JA, Turner C, Chang AB. Tailored interventions based on exhaled nitric oxide versus clinical symptoms for asthma in children and adults. Cochrane Database Syst Rev 2009;:CD006340. DOI: https://doi.org/10.1002/14651858.CD006340.pub3

Wadsworth S, Sin D, Dorscheid D. Clinical update on the use of biomarkers of airway inflammation in the management of asthma. J Asthma Allergy 2011;4:77-86. DOI: https://doi.org/10.2147/JAA.S15081

Green RJ, Klein M, Becker P, Halkas A, Lewis H, Kitchin O, et al. Disagreement among common measures of asthma control in children. Chest 2013;143:117-22. DOI: https://doi.org/10.1378/chest.12-1070

Bodini A, Peroni D, Loiacono A, Costella S, Pigozzi R, Baraldi E, et al. Exhaled nitric oxide daily evaluation is effective in monitoring exposure to relevant allergens in asthmatic children. Chest 2007;132:1520-5. DOI: https://doi.org/10.1378/chest.07-1025

Cabral AL, Vollmer WM, Barbirotto RM, Martins MA. Exhaled nitric oxide as a predictor of exacerbation in children with moderate-to-severe asthma: a prospective, 5-month study. Ann Allergy Asthma Immunol 2009;103:206-11. DOI: https://doi.org/10.1016/S1081-1206(10)60183-4

Stern G, de Jongste J, van der Valk R, Baraldi E, Carraro S, Thamrin C, Frey U. Fluctuation phenotyping based on daily fraction of exhaled nitric oxide values in asthmatic children. J Allergy Clin Immunol 2011;128:293-300. DOI: https://doi.org/10.1016/j.jaci.2011.03.010

Gagliardo R, La Grutta S, Chanez P, Profita M, Paternò A, Cibella F, et al. Non-invasive markers of airway inflammation and remodeling in childhood asthma. Pediatr Allergy Immunol 2009;20:780-90. DOI: https://doi.org/10.1111/j.1399-3038.2009.00945.x

van der Valk RJ, Baraldi E, Stern G, Frey U, de Jongste JC. Daily exhaled nitric oxide measurements and asthma exacerbations in children. Allergy 2012;67:265-71. DOI: https://doi.org/10.1111/j.1398-9995.2011.02734.x

Chang DV, Teper A, Balinotti J, Castro Simonelli C, Garcia-Bournissen F, Kofman C. Exhaled nitric oxide predicts loss of asthma control in children after inhaled corticosteroids withdrawal. Pediatr Pulmonol 2019;54:537-43. DOI: https://doi.org/10.1002/ppul.24268

Waibel V, Ulmer H, Horak E. Assessing asthma control: symptom scores, GINA levels of asthma control, lung function, and exhaled nitric oxide. Pediatr Pulmonol 2012;47:113-118. DOI: https://doi.org/10.1002/ppul.21529

Lu Z, Huang W, Wang L, Xu N, Ding Q, Cao C. Exhaled nitric oxide in patients with chronic obstructive pulmonary disease: a systematic review and meta-analysis. Int J Chron Obstruct Pulmon Dis 2018;13:2695-705. DOI: https://doi.org/10.2147/COPD.S165780

Zietkowski Z, Kucharewicz I, Bodzenta-Lukaszyk A. The influence of inhaled corticosteroids on exhaled nitric oxide in stable chronic obstructive pulmonary disease. Respir Med 2005;99:816-24. DOI: https://doi.org/10.1016/j.rmed.2004.12.008

Dummer JF, Epton MJ, Cowan JO, Cook JM, Condliffe R, Landhuis CE, et al. Predicting corticosteroid response in chronic obstructive pulmonary disease using exhaled nitric oxide. Am J Respir Crit Care Med 2009;180:846-52. DOI: https://doi.org/10.1164/rccm.200905-0685OC

Lehtimaki L, Kankaanranta H, Saarelainen S, Annila I, Aine T, Nieminen R, et al. Bronchial nitric oxide is related to symptom relief during fluticasone treatment in COPD. Eur Respir J 2010;35:72-8. DOI: https://doi.org/10.1183/09031936.00177508

Fabbri LM, Romagnoli M, Corbetta L, Casoni G, Busljetic K, Turato G, et al. Differences in airway inflammation in patients with fixed airflow obstruction due to asthma or chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2003;167:418-24. DOI: https://doi.org/10.1164/rccm.200203-183OC

Global Initiative for Asthma, Global Initiative for Chronic Obstructive Lung Disease. Diagnosis of disease of chronic airflow limitation: Asthma, COPD, and asthma-COPD overlap syndrome (ACOS). Available at: http://www.ginasthma.org/local/uploads/files/ACOS_2015.pdf

Takayama Y, Ohnishi H, Ogasawara F, Oyama K, Kubota T, Yokoyama A. Clinical utility of fractional exhaled nitric oxide and blood eosinophils counts in the diagnosis of asthma-COPD overlap. Int J Chron Obstruct Pulmon Dis 2018;13:2525-32. DOI: https://doi.org/10.2147/COPD.S167600

Hatipoğlu U, Rubinstein I. Inflammation and obstructive sleep apnea syndrome pathogenesis: a working hypothesis. Respiration 2003;70:665-71. DOI: https://doi.org/10.1159/000075218

Duarte RLM, Rabahi MF, Oliveira-E-Sá TS, Magalhães-da-Silveira FJ, Mello FCQ, Gozal D. Fractional exhaled nitric oxide measurements and screening of obstructive sleep apnea in a sleep-laboratory setting: A cross-sectional study. Lung 2019;197:131-7. DOI: https://doi.org/10.1007/s00408-018-0190-y

Zhang D, Luo J, Qiao Y, Xiao Y, Huang R, Zhong X. Measurement of exhaled nitric oxide concentration in patients with obstructive sleep apnea: A meta-analysis. Medicine (Baltimore) 2017;96):e6429. DOI: https://doi.org/10.1097/MD.0000000000006429

Gibson PG, Dolovich J, Denburg J, Ramsdale EH, Hargreave FE. Chronic cough: eosinophilic bronchitis without asthma. Lancet 1989;1:1346-8. DOI: https://doi.org/10.1016/S0140-6736(89)92801-8

Oh MJ, Lee JY, Lee BJ, Choi DC. Exhaled nitric oxide measurement is useful for the exclusion of nonasthmatic eosinophilic bronchitis in patients with chronic cough. Chest 2008;134:990-5. DOI: https://doi.org/10.1378/chest.07-2541

Song WJ, Kim HJ, Shim JS, Won HK, Kang SY, Sohn KH, et al. Diagnostic accuracy of fractional exhaled nitric oxide measurement in predicting cough-variant asthma and eosinophilic bronchitis in adults with chronic cough: A systematic review and meta-analysis. J Allergy Clin Immunol 2017;140:701-9. DOI: https://doi.org/10.1016/j.jaci.2016.11.037

Lee JE, Rhee CK, Lim JH, Lee SM, Shim YS, Lee CT, et al. Fraction of exhaled nitric oxide in patients with acute eosinophilic pneumonia. Chest 2012;141:1267-72. DOI: https://doi.org/10.1378/chest.11-1303

Oishi K, Hirano T, Suetake R, Ohata S, Yamaji Y, Ito K, et al. Exhaled nitric oxide measurements in patients with acute-onset interstitial lung disease. J Breath Res 2017;11:036001. DOI: https://doi.org/10.1088/1752-7163/aa6c4b

Park JY, Lee T, Lee H, Lee YJ, Park JS, Cho YJ, et al. Significance of fractional exhaled nitric oxide in chronic eosinophilic pneumonia: a retrospective cohort study. BMC Pulm Med 2014;14:81. DOI: https://doi.org/10.1186/1471-2466-14-81

Lundberg JO, Farkas-Szallasi T, Weitzberg E, Rinder J, Lidholm J, Anggåard A, et al. High nitric oxide production in human paranasal sinuses. Nat Med 1995;1:370-3. DOI: https://doi.org/10.1038/nm0495-370

Alving K, Weitzberg E, Lundberg JM. Increased amount of nitric oxide in exhaled air of asthmatics. Eur Respir J 1993;6:1368-70.

Lundberg JO, Weitzberg E. Nasal nitric oxide in man. Thorax 1999;54:947-52. DOI: https://doi.org/10.1136/thx.54.10.947

Kawamoto H, Takumida M, Takeno S, Watanabe H, Fukushima N, Yajin K. Localization of nitric oxide synthase in human nasal mucosa with nasal allergy. Acta Otolaryngol Suppl. 1998;539:65-70. DOI: https://doi.org/10.1080/00016489850182161

Mancinelli RL, McKay CP. Effects of nitric oxide and nitrogen dioxide on bacterial growth. Appl Environ Microbiol 1983;46:198-202. DOI: https://doi.org/10.1128/AEM.46.1.198-202.1983

Gerlach H, Rossaint R, Pappert D, Knorr M, Falke KJ. Autoinhalation of nitric oxide after endogenous synthesis in nasopharynx. Lancet 1994;343:518-9. DOI: https://doi.org/10.1016/S0140-6736(94)91465-6

Lundberg JO. Airborne nitric oxide: inflammatory marker and aerocrine messenger in man. Acta Physiol Scand Suppl 1996;633:1-27. DOI: https://doi.org/10.1111/apha.1996.157.s633.4

Holden WE, Wilkins JP, Harris M, Milczuk HA, Giraud GD. Temperature conditioning of nasal air: effects of vasoactive agents and involvement of nitric oxide. J Appl Physiol 1999;87:1260-5. DOI: https://doi.org/10.1152/jappl.1999.87.4.1260

Lundberg JO, Lundberg JM, Settergren G, Alving K, Weitzberg E. Nitric oxide, produced in the upper airways, may act in an 'aerocrine' fashion to enhance pulmonary oxygen uptake in humans. Acta Physiol Scand 1995;155:467-8. DOI: https://doi.org/10.1111/j.1748-1716.1995.tb09998.x

Knowles MR, Daniels LA, Davis SD, Zariwala MA, Leigh MW. Primary ciliary dyskinesia. Recent advances in diagnostics, genetics, and characterization of clinical disease. Am J Respir Crit Care Med 2013;188:913-22. DOI: https://doi.org/10.1164/rccm.201301-0059CI

Corbelli R, Bringolf-Isler B, Amacher A, Sasse B, Spycher M, Hammer J. Nasal nitric oxide measurements to screen children for primary ciliary dyskinesia. Chest 2004;126:1054-9. DOI: https://doi.org/10.1378/chest.126.4.1054

Leigh MW, Hazucha MJ, Chawla KK, Baker BR, Shapiro AJ, Brown DE, et al. Standardizing nasal nitric oxide measurement as a test for primary ciliary dyskinesia. Ann Am Thorac Soc 2013;10:574-81. DOI: https://doi.org/10.1513/AnnalsATS.201305-110OC

Collins SA, Behan L, Harris A, Gove K, Lucas JS. The dangers of widespread nitric oxide screening for primary ciliary dyskinesia. Thorax 2016;71:560-1. DOI: https://doi.org/10.1136/thoraxjnl-2015-208056

Thomas SR, Kharitonov SA, Scott SF, Hodson ME, Barnes PJ. Nasal and exhaled nitric oxide is reduced in adult patients with cystic fibrosis and does not correlate with cystic fibrosis genotype. Chest 2000;117:1085-9. DOI: https://doi.org/10.1378/chest.117.4.1085

Balfour-Lynn IM, Laverty A, Dinwiddie R. Reduced upper airway nitric oxide in cystic fibrosis. Arch Dis Child 1996;75:319-22. DOI: https://doi.org/10.1136/adc.75.4.319

Duong-Quy S, Vu-Minh T, Hua-Huy T, Tang-Thi-Thao T, Le-Quang K, Tran-Thanh D, et al. Study of nasal exhaled nitric oxide levels in diagnosis of allergic rhinitis in subjects with and without asthma. J Asthma Allergy 2017;10:75-82. DOI: https://doi.org/10.2147/JAA.S129047

Bommarito L, Guida G, Heffler E, Badiu I, Nebiolo F, Usai A, De Stefani A, Rolla G. Nasal nitric oxide concentration in suspected chronic rhinosinusitis. Ann Allergy Asthma Immunol 2008;101:358-62. DOI: https://doi.org/10.1016/S1081-1206(10)60310-9

Lee JM, McKnight CL, Aves T, Yip J, Grewal AS, Gupta S. Nasal nitric oxide as a marker of sinus mucosal health in patients with nasal polyposis. Int Forum Allergy Rhinol 2015;5:894-9. DOI: https://doi.org/10.1002/alr.21598

Phillips PS, Sacks R, Marcells GN, Cohen NA, Harvey RJ. Nasal nitric oxide and sinonasal disease: a systematic review of published evidence. Otolaryngol Head Neck Surg 2011;144:159-69. DOI: https://doi.org/10.1177/0194599810392667

Maniscalco M, Sofia M, Carratu L, Higenbottam T. Effect of nitric oxide inhibition on nasal airway resistance after nasal allergen challenge in allergic rhinitis. Eur J Clin Invest 2001;31:462-6. DOI: https://doi.org/10.1046/j.1365-2362.2001.00825.x

Maniscalco M, Pelaia G, Sofia M. Exhaled nasal nitric oxide during humming: potential clinical tool in sinonasal disease? Biomark Med 2013;7:261-6. DOI: https://doi.org/10.2217/bmm.13.11

Ren L, Zhang W, Zhang Y, Zhang L. Nasal nitric oxide is correlated with nasal patency and nasal symptoms. Allergy Asthma Immunol Res 2019;11:367-80. DOI: https://doi.org/10.4168/aair.2019.11.3.367

Ragab SM, Lund VJ, Saleh HA, Scadding G. Nasal nitric oxide in objective evaluation of chronic rhinosinusitis therapy. Allergy. 2006;61(6):717-24. DOI: https://doi.org/10.1111/j.1398-9995.2006.01044.x

Liu C, Zheng M, He F, Wang X, Zhang L.Role of exhaled nasal nitric oxide in distinguishing between chronic rhinosinusitis with and without nasal polyps. Am J Rhinol Allergy 2017;31:389-94. DOI: https://doi.org/10.2500/ajra.2017.31.4480

Yoshida K, Takabayashi T, Imoto Y et al. Reduced nasal nitric oxide levels in patients with eosinophilic chronic rhinosinusitis. Allergol Int 2019;68:225-32. DOI: https://doi.org/10.1016/j.alit.2018.09.005

Weitzberg E, Lundberg JO. Humming greatly increases nasal nitric oxide. Am J Respir Crit Care Med 2002;166:144-5. DOI: https://doi.org/10.1164/rccm.200202-138BC

Maniscalco M, Weitzberg E, Sundberg J, Sofia M, Lundberg JO. Assessment of nasal and sinus nitric oxide output using single-breath humming exhalations. Eur Respir J 2003;22:323-9. DOI: https://doi.org/10.1183/09031936.03.00017903

Lundberg JO, Maniscalco M, Sofia M, Lundblad L, Weitzberg E. Humming, nitric oxide, and paranasal sinus obstruction. JAMA 2003;289:302-3. DOI: https://doi.org/10.1001/jama.289.3.302-b

Maniscalco M, Sofia M, Weitzberg E, De Laurentiis G, Stanziola A, Rossillo V, et al. Humming-induced release of nasal nitric oxide for assessment of sinus obstruction in allergic rhinitis: pilot study. Eur J Clin Invest 2004;34:555-60. DOI: https://doi.org/10.1111/j.1365-2362.2004.01384.x

Shusterman DJ, Weaver EM, Goldberg AN, Schick SF, Wong HH, Balmes JR. Pilot evaluation of the nasal nitric oxide response to humming as an index of osteomeatal patency. Am J Rhinol Allergy 2012;26:123-6. DOI: https://doi.org/10.2500/ajra.2012.26.3745

Heffler E, Marchese C, Boita M, Rolla G. Nasal nitric oxide in patients with inherited retinal dystrophies. J Investig Med 2015;63:554-7. DOI: https://doi.org/10.1097/JIM.0000000000000139

Brooks EA, Massanari M. Cost-effectiveness analysis of monitoring fractional exhaled nitric oxide (FeNO) in the management of asthma. Manage Care 2018;27:42-8.

Arnold RJG, Layton A, Massanari M. Cost impact of monitoring exhaled nitric oxide in asthma management. Allergy Asthma Proc 2018;39:338-44. DOI: https://doi.org/10.2500/aap.2018.39.4165

Sabatelli L, Seppälä U, Sastre J, Crater G. Cost-effectiveness and budget impact of routine use of fractional exhaled nitric oxide monitoring for the management of adult asthma patients in Spain. J Investig Allergol Clin Immunol 2017;27:89-97. DOI: https://doi.org/10.18176/jiaci.0103

Kuo CR, Spears M, Haughney J, Smith A, Miller J, Bradshaw T, et al. Scottish consensus statement on the role of FeNO in adult asthma. Respir Med 2019;155:54-7. DOI: https://doi.org/10.1016/j.rmed.2019.07.010

Published
2020-02-19
Info
Issue
Section
Position Papers
Keywords:
Asthma diagnosis, Asthma management, Fractional Exhaled Nitric Oxide (FENO)
Statistics
  • Abstract views: 4676

  • PDF: 1070
  • HTML: 9
How to Cite
Heffler, E., Carpagnano, G. E., Favero, E., Guida, G., Maniscalco, M., Motta, A., Paoletti, G., Rolla, G., Baraldi, E., Pezzella, V., Piacentini, G., & Nardini, S. G. (2020). Fractional Exhaled Nitric Oxide (FENO) in the management of asthma: a position paper of the Italian Respiratory Society (SIP/IRS) and Italian Society of Allergy, Asthma and Clinical Immunology (SIAAIC). Multidisciplinary Respiratory Medicine, 15. https://doi.org/10.4081/mrm.2020.36