Exhaled NO in Asthma

  • D. Robin Taylor
Part of the Allergy Frontiers book series (ALLERGY, volume 4)

The advent of exhaled nitric oxide as a biomarker for eosinophilic inflammation in airways disease provides the clinician with a tool which is complementary to conventional physiological measurements such as spirometry. Measurements are technically easy and reproducible, but because nitric oxide is present in exhaled air in health, and is affected by numerous factors other than airway inflammation such as age, smoking and atopy, interpretation needs to be cautiously related to the clinical context, notably whether or not the patient has current respiratory symptoms. Low (less than 25 ppb) and high (greater than 50 ppb) levels are of value in assessing the possibility of the need for inhaled anti-inflammatory therapy in patients with non-specific symptoms. Low levels are helpful in the management of patients with complex asthma, in whom other factors such as anxiety, obesity and gastro-esophageal reflux may give rise to discordance between the severity of symptoms and the severity of airway inflammation. Studies have failed to show significant benefits when using exhaled nitric oxide to optimize inhaled steroid therapy, but further data regarding the potential benefits in oral steroid dependent asthma are awaited.


Nitric Oxide Airway Inflammation Allergy Clin Immunol Respir Crit Occupational Asthma 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


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  1. 1.
    Sont JK, Han J, van Krieken JM, et al. Relationship between the inflammatory infiltrate in bronchial biopsy specimens and clinical severity of asthma in patients treated with inhaled steroids. Thorax 1996; 51:496–502.PubMedCrossRefGoogle Scholar
  2. 2.
    Rosi E, Ronchi MC, Grazzini M, Duranti R, Scano G. Sputum analysis, bronchial hyperresponsiveness, and airway function in asthma: results of a factor analysis. J Allergy Clin Immunol 1999; 103:232–237.PubMedCrossRefGoogle Scholar
  3. 3.
    Simpson JL, Scott R, Boyle MJ, Gibson PG. Inflammatory subtypes in asthma: assessment and identification using induced sputum. Respirology 2006; 11:54–61.PubMedCrossRefGoogle Scholar
  4. 4.
    Pavord ID, Brightling CE, Woltmann G, Wardlaw AJ. Non-eosinophilic corticosteroid unresponsive asthma. Lancet 1999; 353:2213–2214.PubMedCrossRefGoogle Scholar
  5. 5.
    Djukanovic R, Sterk PJ, Fahy J V, Hargreave FE. Standardised methodology of sputum induction and processing. Eur Respir J Suppl 2002; 37:1s–2s.PubMedCrossRefGoogle Scholar
  6. 6.
    Ricciardolo FL. Multiple roles of nitric oxide in the airways. Thorax. 2003; 58:175–182.PubMedCrossRefGoogle Scholar
  7. 7.
    Lane C, Knight D, Burgess S, et al. Epithelial inducible nitric oxide synthase activity is the major determinant of nitric oxide concentration in exhaled breath. Thorax 2004; 59:757–760.PubMedCrossRefGoogle Scholar
  8. 8.
    Lund MB, Kongerud J, Nystad W, Boe J, Harris JR. Genetic and environmental effects on exhaled nitric oxide and airway responsiveness in a population-based sample of twins. Eur Respir J 2006; 1:1.Google Scholar
  9. 9.
    Travers J. MS, Aldington S., Williams M., Shirtcliffe P., Pritchard A., Weatherall M., Beasley R. Reference ranges for exhaled nitric oxide derived from a random community survey of adults. Am J Respir Crit Care Med 2007; 176:238–242.PubMedCrossRefGoogle Scholar
  10. 10.
    Buchvald F, Baraldi E, Carraro S, et al. Measurements of exhaled nitric oxide in healthy subjects age 4 to 17 years. J Allergy Clin Immunol 2005; 115:1130–1136.PubMedCrossRefGoogle Scholar
  11. 11.
    Olin AC, Rosengren A, Thelle DS, Lissner L, Bake B, Toren K. Height, age, and atopy are associated with fraction of exhaled nitric oxide in a large adult general population sample. Chest 2006; 130:1319–1325.PubMedCrossRefGoogle Scholar
  12. 12.
    Jilma B, Kastner J, Mensik C, et al. Sex differences in concentrations of exhaled nitric oxide and plasma nitrate. Life Sci 1996; 58:469–476.PubMedCrossRefGoogle Scholar
  13. 13.
    Tsang KW, Ip SK, Leung R, et al. Exhaled nitric oxide: the effects of age, gender and body size. Lung 2001; 179:83–91.PubMedCrossRefGoogle Scholar
  14. 14.
    Olivieri M, Talamini G, Corradi M, et al. Reference values for exhaled nitric oxide (reveno) study. Respir Res 2006; 7:94.PubMedCrossRefGoogle Scholar
  15. 15.
    van Amsterdam JG, Janssen NA, de Meer G, et al. The relationship between exhaled nitric oxide and allergic sensitization in a random sample of school children. Clin Exp Allergy 2003; 33:187–191.PubMedCrossRefGoogle Scholar
  16. 16.
    Jouaville LF, Annesi-Maesano I, Nguyen LT, Bocage AS, Bedu M, Caillaud D. Interrelationships among asthma, atopy, rhinitis and exhaled nitric oxide in a population-based sample of children. Clin Exp Allergy 2003; 33:1506–1511.PubMedCrossRefGoogle Scholar
  17. 17.
    Gratziou C, Lignos M, Dassiou M, Roussos C. Influence of atopy on exhaled nitric oxide in patients with stable asthma and rhinitis. Eur Respir J 1999; 14:897–901.PubMedCrossRefGoogle Scholar
  18. 18.
    Henriksen AH, Sue-Chu M, Lingaas Holmen T, Langhammer A, Bjermer L. Exhaled and nasal NO levels in allergic rhinitis: relation to sensitization, pollen season and bronchial hyperresponsiveness. Eur Respir J 1999; 13:301–306.PubMedCrossRefGoogle Scholar
  19. 19.
    Kharitonov SA, Robbins RA, Yates D, Keatings V, Barnes PJ. Acute and chronic effects of cigarette smoking on exhaled nitric oxide. Am J Respir Crit Care Med 1995; 152:609–612.PubMedGoogle Scholar
  20. 20.
    Persson MG, Zetterstrom O, Agrenius V, Ihre E, Gustafsson LE. Single-breath nitric oxide measurements in asthmatic patients and smokers. Lancet 1994; 343:146–147.PubMedCrossRefGoogle Scholar
  21. 21.
    Payne DN, Adcock IM, Wilson NM, Oates T, Scallan M, Bush A. Relationship between exhaled nitric oxide and mucosal eosinophilic inflammation in children with difficult asthma, after treatment with oral prednisolone. Am J Respir Crit Care Med 2001; 164:1376–1381.PubMedGoogle Scholar
  22. 22.
    Jatakanon A, Lim S, Kharitonov SA, Chung KF, Barnes PJ. Correlation between exhaled nitric oxide, sputum eosinophils, and methacholine responsiveness in patients with mild asthma. Thorax 1998; 53:91–95.PubMedCrossRefGoogle Scholar
  23. 23.
    Berry MA, Shaw DE, Green RH, Brightling CE, Wardlaw AJ, Pavord ID. The use of exhaled nitric oxide concentration to identify eosinophilic airway inflammation: an observational study in adults with asthma. Clin Exp Allergy 2005; 35:1175–1179.PubMedCrossRefGoogle Scholar
  24. 24.
    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; 21:433–438.PubMedCrossRefGoogle Scholar
  25. 25.
    Dupont LJ, Rochette F, Demedts MG, Verleden GM. Exhaled nitric oxide correlates with airway hyperresponsiveness in steroid-naive patients with mild asthma. Am J Respir Crit Care Med 1998; 157:894–898.PubMedGoogle Scholar
  26. 26.
    Franklin PJ, Stick SM, Le Souef PN, Ayres JG, Turner SW. Measuring exhaled nitric oxide levels in adults: the importance of atopy and airway responsiveness. Chest 2004; 126:1540–1545.PubMedCrossRefGoogle Scholar
  27. 27.
    Steerenberg PA, Janssen NA, de Meer G, et al. Relationship between exhaled NO, respiratory symptoms, lung function, bronchial hyperresponsiveness, and blood eosinophilia in school children. Thorax 2003; 58:242–245.PubMedCrossRefGoogle Scholar
  28. 28.
    Berkman N, Avital A, Breuer R, Bardach E, Springer C, Godfrey S. Exhaled nitric oxide in the diagnosis of asthma: comparison with bronchial provocation tests. Thorax 2005; 60:383–388.PubMedCrossRefGoogle Scholar
  29. 29.
    Alving K, Weitzberg E, Lundberg JM. Increased amount of nitric oxide in exhaled air of asthmatics. Eur Respir J 1993; 6:1368–1370.PubMedGoogle Scholar
  30. 30.
    Berlyne GS, Parameswaran K, Kamada D, Efthimiadis A, Hargreave FE. A comparison of exhaled nitric oxide and induced sputum as markers of airway inflammation. J Allergy Clin Immunol 2000; 106:638–644.PubMedCrossRefGoogle Scholar
  31. 31.
    Kharitonov SA, Yates D, Springall DR, et al. Exhaled nitric oxide is increased in asthma. Chest 1995; 107:156S–157S.PubMedCrossRefGoogle Scholar
  32. 32.
    Deykin A, Massaro AF, Drazen JM, Israel E. Exhaled nitric oxide as a diagnostic test for asthma: online versus offline techniques and effect of flow rate. Am J Respir Crit Care Med 2002; 165:1597–1601.PubMedCrossRefGoogle Scholar
  33. 33.
    Malmberg LP, Pelkonen AS, Haahtela T, Turpeinen M. Exhaled nitric oxide rather than lung function distinguishes preschool children with probable asthma. Thorax 2003; 58:494–499.PubMedCrossRefGoogle Scholar
  34. 34.
    Dupont LJ, Demedts MG, Verleden GM. Prospective evaluation of the validity of exhaled nitric oxide for the diagnosis of asthma. Chest 2003; 123:751–756.PubMedCrossRefGoogle Scholar
  35. 35.
    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; 169:473–478. Epub 2003 Nov 2025.PubMedCrossRefGoogle Scholar
  36. 36.
    ATS/ERS Recommendations for Standardized Procedures for the Online and Offline Measurement of Exhaled Lower Respiratory Nitric Oxide and Nasal Nitric Oxide. Am J Respir Crit Care Med 2005; 171:912–930.Google Scholar
  37. 37.
    GINA. GINA guidelines Update 2006. 2006.
  38. 38.
    Douwes J, Gibson P, Pekkanen J, Pearce N. Non-eosinophilic asthma: importance and possible mechanisms. Thorax 2002; 57:643–648.PubMedCrossRefGoogle Scholar
  39. 39.
    Kharitonov SA, Yates D, Barnes PJ. Increased nitric oxide in exhaled air of normal human subjects with upper respiratory tract infections. Eur Respir J 1995; 8:295–297.PubMedCrossRefGoogle Scholar
  40. 40.
    de Gouw HW, Grunberg K, Schot R, Kroes AC, Dick EC, Sterk PJ. Relationship between exhaled nitric oxide and airway hyperresponsiveness following experimental rhinovirus infection in asthmatic subjects. Eur Respir J 1998; 11:126–132.PubMedCrossRefGoogle Scholar
  41. 41.
    Fabbri LM, Romagnoli M, Corbetta L, 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; 167:418–424. Epub 2002 Nov 2008.PubMedCrossRefGoogle Scholar
  42. 42.
    Brown HM. Treatment of chronic asthma with prednisolone; significance of eosinophils in the sputum. Lancet. 1958; 2:1245–1247.PubMedGoogle Scholar
  43. 43.
    Brightling CE, Ward R, Wardlaw AJ, Pavord ID. Airway inflammation, airway responsiveness and cough before and after inhaled budesonide in patients with eosinophilic bronchitis. Eur Respir J. 2000; 15:682–686.PubMedCrossRefGoogle Scholar
  44. 44.
    Brightling CE, Monteiro W, Ward R, et al. Sputum eosinophilia and short-term response to prednisolone in chronic obstructive pulmonary disease: a randomised controlled trial. Lancet 2000; 356:1480–1485.PubMedCrossRefGoogle Scholar
  45. 45.
    Meijer RJ, Postma DS, Kauffman HF, Arends LR, Koeter GH, Kerstjens HA. Accuracy of eosinophils and eosinophil cationic protein to predict steroid improvement in asthma. Clin Exp Allergy 2002; 32:1096–1103.PubMedCrossRefGoogle Scholar
  46. 46.
    Green RH, Brightling CE, Woltmann G, Parker D, Wardlaw AJ, Pavord ID. Analysis of induced sputum in adults with asthma: identification of subgroup with isolated sputum neutrophilia and poor response to inhaled corticosteroids. Thorax 2002; 57:875–879.PubMedCrossRefGoogle Scholar
  47. 47.
    Szefler SJ, Martin RJ, King TS, et al. Significant variability in response to inhaled corticosteroids for persistent asthma. J Allergy Clin Immunol 2002; 109:410–418.PubMedCrossRefGoogle Scholar
  48. 48.
    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; 55:232–234.PubMedCrossRefGoogle Scholar
  49. 49.
    Smith AD, Cowan JO, Brassett KP, et al. Exhaled Nitric Oxide: A Predictor of Steroid Response. Am J Respir Crit Care Med 2005; 18:18.Google Scholar
  50. 50.
    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; 152:800–803.PubMedGoogle Scholar
  51. 51.
    Baraldi E, Azzolin NM, Zanconato S, Dario C, Zacchello F. Corticosteroids decrease exhaled nitric oxide in children with acute asthma. J Pediatr 1997; 131:381–385.PubMedCrossRefGoogle Scholar
  52. 52.
    Baraldi E, Dario C, Ongaro R, et al. Exhaled nitric oxide concentrations during treatment of wheezing exacerbation in infants and young children. Am J Respir Crit Care Med 1999; 159:1284–1288.PubMedGoogle Scholar
  53. 53.
    Crimi E, Spanevello A, Neri M, Ind PW, Rossi GA, Brusasco V. Dissociation between airway inflammation and airway hyperresponsiveness in allergic asthma. Am J Respir Crit Care Med. 1998; 157:4–9.PubMedGoogle Scholar
  54. 54.
    Jatakanon A, Lim S, Barnes PJ. Changes in sputum eosinophils predict loss of asthma control. Am J Respir Crit Care Med 2000; 161:64–72.PubMedGoogle Scholar
  55. 55.
    Pizzichini MM, Pizzichini E, Clelland L, et al. Prednisone-dependent asthma: inflammatory indices in induced sputum. Eur Respir J. 1999; 13:15–21.PubMedCrossRefGoogle Scholar
  56. 56.
    Jayaram L, Pizzichini MM, Cook RJ, et al. Determining asthma treatment by monitoring sputum cell counts: effect on exacerbations. Eur Respir J 2006; 27:483–494.PubMedCrossRefGoogle Scholar
  57. 57.
    Green RH, Brightling CE, McKenna S, et al. Asthma exacerbations and sputum eosinophil counts: a randomised controlled trial. Lancet 2002; 360:1715–1721.PubMedCrossRefGoogle Scholar
  58. 58.
    Franklin PJ, Turner SW, Le Souef PN, Stick SM. Exhaled nitric oxide and asthma: complex interactions between atopy, airway responsiveness, and symptoms in a community population of children. Thorax 2003; 58:1048–1052.PubMedCrossRefGoogle Scholar
  59. 59.
    Strunk RC, Szefler SJ, Phillips BR, et al. Relationship of exhaled nitric oxide to clinical and inflammatory markers of persistent asthma in children. J Allergy Clin Immunol 2003; 112:883–892.PubMedCrossRefGoogle Scholar
  60. 60.
    Jones SL, Kittelson J, Cowan JO, et al. The predictive value of exhaled nitric oxide measurements in assessing changes in asthma control. Am J Respir Crit Care Med 2001; 164:738–743.PubMedGoogle Scholar
  61. 61.
    Gelb AF, Flynn Taylor C, Shinar CM, Gutierrez C, Zamel N. Role of spirometry and exhaled nitric oxide to predict exacerbations in treated asthmatics. Chest 2006; 129:1492–1499.PubMedCrossRefGoogle Scholar
  62. 62.
    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; 19:1015–1019.PubMedCrossRefGoogle Scholar
  63. 63.
    Jones SL, Herbison P, Cowan JO, et al. Exhaled NO and assessment of anti-inflammatory effects of inhaled steroid: dose-response relationship. Eur Respir J 2002; 20:601–608.PubMedCrossRefGoogle Scholar
  64. 64.
    Silkoff PE, McClean P, Spino M, Erlich L, Slutsky AS, Zamel N. Dose-response relationship and reproducibility of the fall in exhaled nitric oxide after inhaled beclomethasone dipropionate therapy in asthma patients. Chest 2001; 119:1322–1328.PubMedCrossRefGoogle Scholar
  65. 65.
    Sont JK, Willems LN, Bel EH, van Krieken JH, Vandenbroucke JP, Sterk PJ. Clinical control and histopathologic outcome of asthma when using airway hyperresponsiveness as an additional guide to long-term treatment. The AMPUL Study Group. Am J Respir Crit Care Med 1999; 159:1043–1051.Google Scholar
  66. 66.
    Pijnenburg MW, Bakker EM, Hop WC, De Jongste JC. Titrating steroids on exhaled nitric oxide in asthmatic children: a randomized controlled trial. Am J Respir Crit Care Med 2005; 23:23.Google Scholar
  67. 67.
    Shaw DE, Berry MA, Green RH, Brightling CE, Wardlaw AJ, Pavord ID. The use of exhaled nitric oxide to guide asthma management: a randomsied controlled trial. Am J Respir Crit Care Med 2007; 176;231–237.PubMedCrossRefGoogle Scholar
  68. 68.
    Smith AD, Cowan JO, Brassett KP, Herbison GP, Taylor DR. Use of exhaled nitric oxide measurements to guide treatment in chronic asthma. N Engl J Med 2005; 352:2163–2173. Epub 2005 May 2124.PubMedCrossRefGoogle Scholar
  69. 69.
    Juniper EF, O'Byrne PM, Guyatt GH, Ferrie PJ, King DR. Development and validation of a questionnaire to measure asthma control. Eur Respir J 1999; 14:902–907.PubMedCrossRefGoogle Scholar
  70. 70.
    Taylor DR. Exhaled nitric oxide: forwards, backwards or sideways? Am J Respir Crit Care Med 2007; 176:221–222.PubMedCrossRefGoogle Scholar
  71. 71.
    Berry M, Hargadon B, Morgan A, et al. Alveolar nitric oxide in adults with asthma: evidence of distal lung inflammation in refractory asthma. Eur Respir J 2005; 25:986–991.PubMedCrossRefGoogle Scholar
  72. 72.
    van Dixhoorn J, Duivenvoorden HJ. Efficacy of Nijmegen questionnaire in recognition of the hyperventilation syndrome. J Psychosom Res 1985; 29:199–206.PubMedCrossRefGoogle Scholar
  73. 73.
    Pijnenburg MW, Hofhuis W, Hop WC, De Jongste JC. Exhaled nitric oxide predicts asthma relapse in children with clinical asthma remission. Thorax 2005; 60:215–218.PubMedCrossRefGoogle Scholar
  74. 74.
    Pijnenburg MW, Bakker EM, Lever S, Hop WC, De Jongste JC. High fractional concentration of nitric oxide in exhaled air despite steroid treatment in asthmatic children. Clin Exp Allergy 2005; 35:920–925.PubMedCrossRefGoogle Scholar
  75. 75.
    Gelb AF, Taylor CF, Nussbaum E, et al. Alveolar and Airway Sites of Nitric Oxide Inflammation in Treated Asthmatics. Am J Respir Crit Care Med 2004; 30:30.Google Scholar
  76. 76.
    Zacharasiewicz A, Wilson N, Lex C, et al. Clinical use of noninvasive measurements of airway inflammation in steroid reduction in children. Am J Respir Crit Care Med 2005; 171:1077–1082. Epub 2005 Feb 1011.PubMedCrossRefGoogle Scholar
  77. 77.
    Lemiere C. The use of sputum eosinophils in the evaluation of occupational asthma. Curr Opin Allergy Clin Immunol 2004; 4:81–85.PubMedCrossRefGoogle Scholar
  78. 78.
    Girard F, Chaboillez S, Cartier A, et al. An effective strategy for diagnosing occupational asthma: use of induced sputum. Am J Respir Crit Care Med 2004; 170:845–850. Epub 2004 July 2021.PubMedCrossRefGoogle Scholar
  79. 79.
    Kharitonov SA, O'Connor BJ, Evans DJ, Barnes PJ. Allergen-induced late asthmatic reactions are associated with elevation of exhaled nitric oxide. Am J Respir Crit Care Med 1995; 151:1894–1899.PubMedGoogle Scholar
  80. 80.
    Rolla G, Di Emanuele A, Dutto L, et al. Effect of inhalation aspirin challenge on exhaled nitric oxide in patients with aspirin-inducible asthma. Allergy 2004; 59:827–832.PubMedCrossRefGoogle Scholar
  81. 81.
    Lund MB, Oksne PI, Hamre R, Kongerud J. Increased nitric oxide in exhaled air: an early marker of asthma in non-smoking aluminium potroom workers? Occup Environ Med 2000; 57:274–278.PubMedCrossRefGoogle Scholar
  82. 82.
    Olin AC, Andersson E, Andersson M, Granung G, Hagberg S, Toren K. Prevalence of asthma and exhaled nitric oxide are increased in bleachery workers exposed to ozone. Eur Respir J 2004; 23:87–92.PubMedCrossRefGoogle Scholar
  83. 83.
    Ihre E, Gyllfors P, Gustafsson LE, Kumlin M, Dahlen B. Early rise in exhaled nitric oxide and mast cell activation in repeated low-dose allergen challenge. Eur Respir J 2006; 27:1152–1159. Epub 2006 Mar 1151.PubMedCrossRefGoogle Scholar
  84. 84.
    Juniper EF, Bousquet J, Abetz L, Bateman ED. Identifying ‘well-controlled’ and ‘not well-controlled’ asthma using the asthma control questionnaire. Respir Med 2006; 100:616–621. Epub 2005 Oct 2013.PubMedCrossRefGoogle Scholar

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© Springer 2009

Authors and Affiliations

  • D. Robin Taylor
    • 1
  1. 1.Dunedin School of MedicineUniversity of OtagoDunedinNew Zealand

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