Advertisement

American Journal of Respiratory Medicine

, Volume 2, Issue 1, pp 11–19 | Cite as

Clinical Usefulness of Inflammatory Markers in Asthma

  • Peter A. B. Wark
  • Peter G. GibsonEmail author
Leading Article

Abstract

Asthma is a significant and increasing health problem. Airway inflammation and hyperresponsiveness are key pathophysiological mechanisms underlying asthma. Currently, effective treatments target these two processes and can lead to clinically important improvements in disease control. At present, decisions to initiate or modify therapy are based on symptoms and measures of airway caliber, with no direct assessment of airway inflammation or hyperresponsiveness. It is now possible to measure airway inflammation using noninvasive markers such as exhaled gases, induced sputum and serum measurements. Exhaled nitric oxide (eNO) and induced sputum eosinophils show the greatest promise as clinically useful markers of airway inflammation in asthma. Induced sputum can now be applied to the diagnosis of airway diseases, based on its ability to detect eosinophilic bronchitis in cough, and to differentiate between eosinophilic and non-eosinophilic asthma. The place of induced sputum and eNO in the ongoing monitoring of patients with asthma are now being investigated in controlled trials.

Keywords

Asthma Airway Inflammation Airway Hyperresponsiveness Eosinophil Cationic Protein Exhalation Rate 
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.

Notes

Acknowledgements

The authors’ research is supported by National Health and Medical Research Council, Australia, British Medical Association, Royal Australasian College of Physicians, Asthma NSW, and the Hunter Medical Research Institute. The authors have no conflicts of interest that are directly relevant to the content of this manuscript.

References

  1. 1.
    Chung KF. Chronic inflammation in asthma. Eur Respir Rev 1998; 8: 999–1006Google Scholar
  2. 2.
    Barnes PJ, Pedersen S. Efficacy and safety of inhaled corticosteroids in asthma. Am Rev Respir Dis 1993; 148: S1–26PubMedGoogle Scholar
  3. 3.
    Finney MJB, Anderson SD, Black JL. Terfenadine modifies airway narrowing induced by the inhalation of non-isotonic aerosols in subjects with asthma. Am Rev Respir Dis 1990; 141: 1151–7PubMedGoogle Scholar
  4. 4.
    Umeno E, McDonald DM, Nadel JA. Hypertonic saline increases vascular permeability in the rat trachea by producing neurogenic inflammation. J Clin Invest 1990; 85: 1905–8PubMedCrossRefGoogle Scholar
  5. 5.
    Davviskas E, Anderson SD, Gonda I, et al. Inhalation of hypertonic saline aerosol enhances mucociliary clearance in asthmatic and healthy subjects. Eur Respir J 1996; 9: 725–32CrossRefGoogle Scholar
  6. 6.
    Fahy J, Wong H, Lui J, et al. Comparison of samples collected by sputum induction and bronchoscopy from asthmatic and healthy subjects. Am J Respir Crit Care Med 1995; 152: 53–8PubMedGoogle Scholar
  7. 7.
    Keatings VM, Evans DJ, O’Connor BJ, et al. Cellular profiles in asthmatic airways: a comparison of induced sputum, bronchial washings and bronchoalveolar lavage fluid. Thorax 1997; 52: 372–4PubMedCrossRefGoogle Scholar
  8. 8.
    Gibson PG, Saltos N, Borgas T. Airway mast cells and eosinophils correlate with clinical severity in corticosteroid-treated asthma. J Allergy Clin Immunol 2000; 105: 752–9PubMedCrossRefGoogle Scholar
  9. 9.
    Cai Y, Carty K, Henry RL, et al. Persistence of sputum eosinophilia in children with controlled asthma compared with healthy children. Eur Respir J 1998; 11: 848–53PubMedCrossRefGoogle Scholar
  10. 10.
    Pin I, Gibson PG, Kolendowicz R, et al. Use of induced sputum cell counts to investigate airway inflammation in asthma. Thorax 1992; 47: 25–9PubMedCrossRefGoogle Scholar
  11. 11.
    Popov TA, Pizzichinini MMM, Pizzichini E, et al. Some technical factors influencing the induction of sputum for cell analysis. Eur Respir J 1995; 8: 559–65PubMedGoogle Scholar
  12. 12.
    Wark PAB, Simpson JL, Hensley MJ, et al. Safety of sputum induction with isotonic saline in adults with acute severe asthma. Clin Exp Allergy 2001; 31: 1–10CrossRefGoogle Scholar
  13. 13.
    Bacci E, Cianchetti S, Paggiaro PL, et al. Comparison between hypertonic and isotonic saline induced sputum in the evaluation of airway inflammation in subjects with moderate asthma. Clin Exp Allergy 1996; 26: 395–400CrossRefGoogle Scholar
  14. 14.
    Holz O, Jorres RA, Koschyk S, et al. Changes in sputum composition during sputum induction in healthy and asthmatic subjects. Clin Exp Allergy 1998; 28: 284–92PubMedCrossRefGoogle Scholar
  15. 15.
    Gerschman NH, Liu H, Wong HH, et al. Fractional analysis of sequential induced sputum samples during sputum induction: evidence that different lung compartments are sampled at different time points. J Allergy Clin Immunol 1999; 104: 322–8CrossRefGoogle Scholar
  16. 16.
    Pizzichini MMM, Pizzichini E, Clelland L, et al. Sputum in severe exacerbations of asthma. Kinetics of inflammatory indices after prednisone treatment. Am J Respir Crit Care Med 1997; 155: 1501–8PubMedGoogle Scholar
  17. 17.
    Gibson PG, Wlodarczyk J, Hensley MJ, et al. Epidemiological association of airway inflammation with asthma symptoms and airway hyperresponsiveness in childhood. Am J Respir Crit Care Med 1998; 158: 136–45Google Scholar
  18. 18.
    Iredale MJ, Wanklyn SA, Phillips IP, et al. Non-invasive assessment of bronchial inflammation in asthma: no correlation between eosinophilia and induced sputum and bronchial responsiveness to inhaled hypertonic saline. Clin Exp Allergy 1994; 24: 940–5PubMedCrossRefGoogle Scholar
  19. 19.
    Gibson PG, Henry RL, Thomas P. Non-invasive assessment of airway inflammation in children: induced sputum, exhaled nitric oxide, and breath condensate. Eur Respir J 2000; 16: 1008–15PubMedGoogle Scholar
  20. 20.
    Norzila MZ, Fakes K, Henry RL, et al. Interleukin-8 secretion and neutrophil recruitment accompanies induced sputum eosinophil activation in children with acute asthma. Am J Respir Crit Care Med 2000; 161: 769–74PubMedGoogle Scholar
  21. 21.
    in-’t-Veen JC, de Gouw HW, Smits HH, et al. Repeatability of cellular and soluble markers of inflammation in induced sputum from patients with asthma. Eur Respir J 1996; 9: 2441–7PubMedCrossRefGoogle Scholar
  22. 22.
    Spanevello A, Beghe B, Bianchi A, et al. Comparison of two methods of processing induced sputum: selected versus entire sputum. Am J Respir Crit Care Med 1998; 157: 665–8PubMedGoogle Scholar
  23. 23.
    Gibson PG, Girgis-Gabardo A, Morris MM, et al. Cellular characteristics of sputum from patients with asthma and chronic bronchitis. Thorax 1989; 44: 693–9PubMedCrossRefGoogle Scholar
  24. 24.
    Pizzichini E, Pizzichini MMM, Efthimiadis A, et al. Indices of airway inflammation in induced sputum: reproducibility and validity of cell and fluid phase measurements. Am J Respir Crit Care Med 1996; 154: 308–17PubMedGoogle Scholar
  25. 25.
    Belda J, Leigh R, Parameswaran K, et al. Induced sputum cell counts in healthy adults. Am J Respir Crit Care Med 2000; 161: 475–8PubMedGoogle Scholar
  26. 26.
    Pin I, Freitag AP, O’Byrne PM, et al. Changes in the cellular profile of induced sputum after allergen-induced asthmatic responses. Am J Respir Crit Care Med 1992; 145: 1265–9Google Scholar
  27. 27.
    Fahy JV, Liu J, Wong H, et al. Analysis of cellular and biochemical constituents of induced sputum after allergen challenge: a method for studying allergic airway inflammation. J Allergy Clin Immunol 1994; 93: 1031–9PubMedCrossRefGoogle Scholar
  28. 28.
    Gibson PG, Wong BJ, Hepperle MJ, et al. A research method to induce and examine a mild exacerbation of asthma by withdrawal of inhaled corticosteroid. Clin Exp Allergy 1992; 225: 525–32CrossRefGoogle Scholar
  29. 29.
    Twaddell SH, Gibson PG, Carty K, et al. Assessment of airway inflammation in children with acute asthma using induced sputum. Eur Respir J 1996; 9: 2104–8PubMedCrossRefGoogle Scholar
  30. 30.
    Lemiere C, Pizzichini MM, Balkissoon R, et al. Diagnosing occupational asthma: use of induced sputum. Eur Respir J 1999 Mar; 13(3): 482–8PubMedCrossRefGoogle Scholar
  31. 31.
    Pin I, Radford S, Kolendowicz R. Airway inflammation in symptomatic and asymptomatic children with methacholine hyperresponsiveness. Eur Respir J 1993; 6: 1249–56PubMedGoogle Scholar
  32. 32.
    Piacentini GL, Martinati L, Mingoni S, et al. Influence of allergen avoidance on eosinophilic phase of airway inflammation in children with allergic asthma. J Allergy Clin Immunol 1996; 97: 1079–84PubMedCrossRefGoogle Scholar
  33. 33.
    Ronchi MC, Piragino C, Rosi E, et al. Do sputum eosinophils and ECP relate to the severity of asthma? Eur Respir J 1997; 10: 1809–13PubMedCrossRefGoogle Scholar
  34. 34.
    Virchow JG, Holscher U, Virchow C. Sputum ECP levels correlate with parameters of airflow obstruction. Am Rev Respir Dis 1992; 146: 604–6PubMedGoogle Scholar
  35. 35.
    Louis RL. Lau C, Bron AO, et al. The relationship between airways inflammation and asthma severity. Am J Respir Crit Care Med 2000; 161: 9–16PubMedGoogle Scholar
  36. 36.
    Fahy JV, Kim KW, Liu J, et al. Prominent neutrophilic inflammation in sputum from subjects with asthma exacerbation. J Allergy Clin Immunol 1995; 95: 843–52PubMedCrossRefGoogle Scholar
  37. 37.
    Wark PAB, Johnston SL, Moric I, et al. Neutrophil degranulation and cell lysis is associated with clinical severity in virus-induced asthma. Eur Respir J. In pressGoogle Scholar
  38. 38.
    Wenzel SE, Schwartz LB, Langmack EL, et al. Evidence that severe asthma can be divided pathologically into two inflammatory subtypes with distinct physiologic and clinical characteristics. Am J Respir Crit Care Med 1999; 160: 1001–8PubMedGoogle Scholar
  39. 39.
    Pavord ID, Brightling CE, Woltmann G, et al. Non-eosinophilic corticosteroid unresponsive asthma. Lancet 1999; 353: 2213–4PubMedCrossRefGoogle Scholar
  40. 40.
    Pizzichini E, Pizzichini MM, Gibson PG, et al. Sputum eosinophilia predicts benefit from prednisone in smokers with chronic obstructive bronchitis. Am J Respir Crit Care Med 1998; 158: 1511–7PubMedGoogle Scholar
  41. 41.
    Jatakonen A, Kharitonov S, Lim S, et al. Effect of differing doses of inhaled budesonide on markers of airway inflammation in patients with mild asthma. Thorax 1999; 54: 108–14CrossRefGoogle Scholar
  42. 42.
    Lim S, Jatakonen A, Gilbey JM, et al. Effect of inhaled budesonide on lung function and airway inflammation: assessment by various inflammatory markers in mild asthma. Am J Respir Crit Care Med 1999; 159: 22–30PubMedGoogle Scholar
  43. 43.
    van Renson EL, Straathof KC, Veselic-Charvat MA, et al. Effect of inhaled steroids on airway hyperresponsiveness, sputum eosinophils, and exhaled nitric oxide levels in patients with asthma. Thorax 1999; 54: 403–8CrossRefGoogle Scholar
  44. 44.
    Gershman NH, Wong HH, Liu JT, et al. Low and high dose fluticasone propionate in asthma; effects during and after treatment. Eur Respir J 2000; 15: 11–8PubMedCrossRefGoogle Scholar
  45. 45.
    Gibson PG, Dolovich J, Denburg JA, et al. Chronic cough, eosinophilic bronchitis without asthma. Lancet 1989; I: 1346–8CrossRefGoogle Scholar
  46. 46.
    Carney IK, Gibson PG, Muree-Allen K, et al. A systematic evaluation of mechanisms in chronic cough. Am J Respir Crit Care Med 1997; 156: 211–6PubMedGoogle Scholar
  47. 47.
    Gibson PG, Hargreave FE, Girgis-Garbardo A, et al. Chronic cough with eosinophilic bronchitis: examination for variable airflow obstruction and response to corticosteroid. Clin Exp Allergy 1995; 25: 127–32PubMedCrossRefGoogle Scholar
  48. 48.
    Pizzichini MM, Pizzichini E, Parameswaran K, et al. Nonasthmatic chronic cough: no effect of treatment with an inhaled corticosteroid in patients without sputum eosinophilia. Can Respir J 1999; 6: 323–30PubMedGoogle Scholar
  49. 49.
    National Institutes of Health. Expert Panel Report II. Guidelines for the diagnosis and management of asthma. National Asthma Education and Prevention Program. Bethesda (WA), 1997Google Scholar
  50. 50.
    Jones SL, Kittelson J, Cowan JO, et al. The predictive value of exhaled oxide measurements in assessing changes in asthma control. Am J Respir Crit Care Med 2001; 164:738–43PubMedGoogle Scholar
  51. 51.
    Leuppi JD, Salome CM, Jenkins CR, et al. Predictive markers of asthma exacerbation during stepwise dose reduction of inhaled corticosteroids. Am J Respir Crit Care Med 2001; 163: 406–12PubMedGoogle Scholar
  52. 52.
    Barnes PJ, Kharitonov S. Exhaled nitric oxide: a new lung function test? Thorax 1996; 51: 233–7PubMedCrossRefGoogle Scholar
  53. 53.
    Hamid Q, Springall DR, Riveros-Mareno V, et al. Induction of nitric oxide synthetase in asthma. Lancet 1993; 342: 1510–3PubMedCrossRefGoogle Scholar
  54. 54.
    Ferreira HH, Madeiras MV, Lima CS. Inhibition of eosinophil chemotaxis by chronic blockade of nitric oxide synthetase. Eur J Pharmacol 1994; 358: 253–9CrossRefGoogle Scholar
  55. 55.
    Byrnes CA, Dinarevic S, Shinebourne EA, et al. Exhaled nitric oxide measurements in normal and asthmatic children. Paediatr Pulmonol 1997; 24: 312–8CrossRefGoogle Scholar
  56. 56.
    Wildhaber JH, Dore ND, Uhlig T, et al. Measurements of nitric oxide using the single breath technique with positive expiratory pressure in infants [abstract]. Am J Respir Crit Care Med 1998; 157: A469Google Scholar
  57. 57.
    Salome CM., Roberts AM, Brown NJ, et al. Exhaled nitric oxide in a population sample of young adults. Am J Respir Crit Care Med 1999; 159: 911–6PubMedGoogle Scholar
  58. 58.
    Gerlach H, Rossaint R, Pappert D, et al. Auto-inhalation of nitric oxide after endogenous synthesis in nasopharynx. Lancet 1994; 343: 518–9PubMedCrossRefGoogle Scholar
  59. 59.
    Kharitonov S, Alving K, Barnes PJ. Exhaled and nasal nitric oxide measurement: recommendations. Eur Respir J 1997; 10: 1683–93PubMedCrossRefGoogle Scholar
  60. 60.
    Silkoff PE. Recommendations for standardised procedures for the online and offline measurement of exhaled lower respiratory nitric oxide in adults and children -1999. Am J Respir Crit Care Med 1990; 160: 2104–17Google Scholar
  61. 61.
    Yates DH. Role of exhaled nitric oxide in asthma. Immunol Cell Biol 2001; 79: 178–90PubMedCrossRefGoogle Scholar
  62. 62.
    Massaro AF, Gaston B, Kita D, et al. Expired nitric oxide levels during treatment of acute asthma. Am J Respir Crit Care Med 1995; 152: 800–3PubMedGoogle Scholar
  63. 63.
    Kharitonov S, O’Connor BJ, Evans DJ, et al. Allergen induced late asthmatic reactions are associated with elevations of exhaled nitric oxide. Am J Respir Crit Care Med 1995; 151: 1894–9PubMedGoogle Scholar
  64. 64.
    Kharitonov S, Barnes PJ, O’Connor BJ. Reduction in exhaled nitric oxide after a single dose of nebulised budesonide in patients with asthma [abstract]. Am J Respir Crit Care Med 1996; 153: A799Google Scholar
  65. 65.
    Kharitonov S, Yates DH, Barnes PJ. Regular inhaled budesonide decreases nitric oxide concentration in the exhaled air of asthmatic patients. Am J Respir Crit Care Med 1996; 153: 454–7PubMedGoogle Scholar
  66. 66.
    Piacentini GL, Bodini A, Costella S, et al. Exhaled nitric oxide, serum ECP and airway responsiveness in mild asthmatic children. Eur Respir J 2000; 15: 839–43PubMedCrossRefGoogle Scholar
  67. 67.
    Leuppi J D, Salome CM, Jenkins CR, et al. Markers of airway inflammation and airway hyperresponsiveness in patients with well controlled asthma. Eur Respir J 2001; 18: 444–50PubMedCrossRefGoogle Scholar
  68. 68.
    Berlyne GS, Parameswaran K, Kamada D, et al. A comparison of exhaled nitric oxide and induced sputum as markers of airway inflammation. J Allergy Clin Immunol 2000; 106: 638–44PubMedCrossRefGoogle Scholar
  69. 69.
    Janson C, Herala M. Blood eosinophil count as a risk factor for relapse in acute asthma. Respir Med 1992; 86: 101–4PubMedCrossRefGoogle Scholar
  70. 70.
    Venge P. Serum measurements of eosinophil cationic protein [ECP] in bronchial asthma. Clin Exp Allergy 1993; 23Suppl. 2: 3–7PubMedCrossRefGoogle Scholar
  71. 71.
    Niimmi A, Amitani R, Suzuki K, et al. Serum measurement of eosinophil cationic protein. Clin Exp Allergy 1998; 28: 233–40CrossRefGoogle Scholar
  72. 72.
    Shields MD, Brown V, Stevenson C, et al. Serum eosinophilic cationic protein and blood eosinophil counts for the prediction of the presence of airways inflammation in children with wheezing. Clin Exp Allergy 1999; 29: 1382–9PubMedCrossRefGoogle Scholar
  73. 73.
    Wever AMJ, Wever-Hess J, Hensgens HE, et al. Serum eosinophil cationic protein [ECP] in chronic asthma: relationship to spirometry, flow-volume curves, PC20, and exacerbations. Respir Med 1994; 88: 613–21PubMedCrossRefGoogle Scholar
  74. 74.
    Ferguson AC, Vaughan R, Brown H, et al. Evaluation of serum eosinophil cationic protein as a marker of disease activity in chronic asthma. J Allergy Clin Immunol 1995; 95: 23–8PubMedCrossRefGoogle Scholar
  75. 75.
    Matsumoto H, Niimmi A, Minakuchi M, et al. Serum eosinophil cationic protein levels measured during exacerbation of asthma: characteristics of patients with low titres. Clin Exp Allergy 2001; 31: 637–43PubMedCrossRefGoogle Scholar
  76. 76.
    Lonnkvist K, Hellman C, Lundahl J, et al. Eosinophil markers in blood, serum and urine for monitoring the clinical course in childhood asthma: impact of budesonide treatment and withdrawal. J Allergy Clin Immunol 2001; 107: 812–7PubMedCrossRefGoogle Scholar
  77. 77.
    Pizzichini E, Pizzichini MM, Efthimiadis A, et al. Measuring airway inflammation in asthma: eosinophils and eosinophilic cationic protein in induced sputum compared with peripheral blood. J Allergy Clin Immunol 1997; 99: 539–44PubMedCrossRefGoogle Scholar
  78. 78.
    Sont JK, Willems LN, Bel EHJ, et al. Clinical control and histopathological outcome of asthma when using airway hyperesponsiveness as an additional guide to longterm treatment. Am J Respir Crit Care Med 1999; 159: 1043–51PubMedGoogle Scholar
  79. 79.
    in’t Veen JC, Smits HH, Hiemstra PS, et al. Lung function and sputum characteristics of patients with severe asthma during an induced exacerbation by double-blind steroid withdrawal. Am J Respir Crit Care Med 1999; 160: 93–9PubMedGoogle Scholar
  80. 80.
    Jayaram L, Parameswaran K, Sears M. Induced sputum cell counts: their usefulness in clinical practice. Eur Respir J 2000; 16: 150–8PubMedCrossRefGoogle Scholar
  81. 81.
    Brightling CE, Ward R, Goh KL, et al. Eosinophilic bronchitis is an important cause of chronic cough. Am J Respir Crit Care Med 1999; 160: 406–10PubMedGoogle Scholar
  82. 82.
    Parameswaran K, Anvari M, Efthimiadis A, et al. Lipid laden macrophages in induced sputum are markers of gastric oropharyngeal reflux and possible aspiration. Eur Respir J 2000; 16: 1119–22PubMedCrossRefGoogle Scholar
  83. 83.
    Wark PAB, Gibson PG, Fakes K. The role of induced sputum eosinophils in the assessment of asthma and chronic cough. Respirology 2000; 5: 51–7PubMedCrossRefGoogle Scholar

Copyright information

© Adis International Limited 2003

Authors and Affiliations

  1. 1.Research Division, Respiratory Cell and Molecular BiologySouthampton General HospitalSouthamptonUK
  2. 2.Department of Respiratory and Sleep Medicine, John Hunter HospitalThe University of Newcastle, and Hunter Medical Research InstituteNewcastleAustralia

Personalised recommendations