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Biomarkers Guided Treatment Strategies in Adult Patients with Asthma: Ready for the Clinical Field?

  • Zoi Tsilogianni
  • Polyxeni Ntontsi
  • Andriana I. Papaioannou
  • Petros Bakakos
  • Stelios Loukides
Review

Abstract

Asthma is a chronic inflammatory airways disorder mainly characterized by heterogeneity. In the more severe forms, a discordance often exists between symptoms and inflammation. Difficulty in managing asthma derives partly from the multiple phenotypes existing and our inability to recognize them. The use of non-invasive, with main representative the fraction of exhaled nitric oxide, or semi-invasive techniques such as induced sputum are effective tools that can help us to guide asthma treatment. In the latest years, several serum biomarkers related to asthmatic inflammation have been used for the better recognition of asthma sub-phenotypes to achieve optimization of therapy and disease outcome. In patients with mild–moderate asthma, as well as patients with more severe asthma, the use of blood eosinophils revealed an acceptable accuracy for the prediction of airway eosinophilia indicating that in future studies may facilitate both individualized treatment and management of asthma. None of the above techniques have been incorporated in clinical practice although sputum eosinophils can be used in patients with severe asthma particularly in specialized centers with great experience. Of great interest are blood eosinophils since current data support their role either as tool for treatment selections or/and as a biomarker of airway eosinophilia.

Keywords

Asthma Biomarkers Treatment Strategy Eosinophils Sputum 

Abbreviations

ACQ

Asthma control questionnaire

FeNO

Fraction of exhaled nitric oxide

ICS

Inhaled corticosteroids

LABA

Long-acting beta two-agonists

NOS

Nitric oxide synthase

Notes

Compliance with ethical standards

Conflict of interest

None of the authors have any conflicts to disclose.

References

  1. Agache IO (2013) From phenotypes to endotypes to asthma treatment. Curr Opin Allergy Clin Immunol 13:249–256CrossRefPubMedGoogle Scholar
  2. Alving K, Weitzberg E et al (1993) Increased amount of nitric oxide in exhaled air of asthmatics. Eur Respir J 6:1368–1370PubMedGoogle Scholar
  3. Bakakos P, Schleich F et al (2011) Induced sputum in asthma: from bench to bedside. Curr Med Chem 18:1415–1422CrossRefPubMedGoogle Scholar
  4. Bartoli ML, Bacci E et al (2004) Clinical assessment of asthma severity partially corresponds to sputum eosinophilic airway inflammation. Respir Med 98:184–193CrossRefPubMedGoogle Scholar
  5. Bateman ED, Boushey HA et al (2004) Can guideline-defined asthma control be achieved? The Gaining Optimal Asthma Control study. Am J Respir Crit Care Med 170:836–844CrossRefPubMedGoogle Scholar
  6. Bateman ED, Hurd SS et al (2008) Global strategy for asthma management and prevention: GINA executive summary. Eur Respir J 31:143–178CrossRefPubMedGoogle Scholar
  7. Bel EH, Wenzel SE et al (2014) Oral glucocorticoid-sparing effect of mepolizumab in eosinophilic asthma. N Engl J Med 371:1189–1197CrossRefPubMedGoogle Scholar
  8. Belda J, Leigh R et al (2000) Induced sputum cell counts in healthy adults. Am J Respir Crit Care Med 161(2 Pt 1):475–478CrossRefPubMedGoogle Scholar
  9. Bergeron C, Tulic MK et al (2007) Tools used to measure airway remodelling in research. Eur Respir J 29:596–604CrossRefPubMedGoogle Scholar
  10. Berry M, Morgan A et al (2007) Pathological features and inhaled corticosteroid response of eosinophilic and non-eosinophilic asthma. Thorax 62:1043–1049CrossRefPubMedPubMedCentralGoogle Scholar
  11. Biomarkers Definitions Working Group (2001) Biomarkers and surrogate endpoints: preferred definitions and conceptual framework. Clin Pharmacol Ther 69:89–95CrossRefGoogle Scholar
  12. Boulet LP, FitzGerald JM et al (2015) The revised 2014 GINA strategy report: opportunities for change. Curr Opin Pulm Med 21:1–7CrossRefPubMedGoogle Scholar
  13. Chlumsky J, Striz I et al (2006) Strategy aimed at reduction of sputum eosinophils decreases exacerbation rate in patients with asthma. J Int Med Res 34:129–139CrossRefPubMedGoogle Scholar
  14. Chung KF, Wenzel SE et al (2014) International ERS/ATS guidelines on definition, evaluation and treatment of severe asthma. Eur Respir J 43:343–373CrossRefPubMedGoogle Scholar
  15. Corren J, Lemanske RF et al (2011) Lebrikizumab treatment in adults with asthma. N Engl J Med 365:1088–1098CrossRefPubMedGoogle Scholar
  16. de Jongste JC, Carraro S et al (2009) Daily telemonitoring of exhaled nitric oxide and symptoms in the treatment of childhood asthma. Am J Respir Crit Care Med 179:93–97CrossRefPubMedGoogle Scholar
  17. Djukanovic R, Wilson SJ et al (2004) Effects of treatment with anti-immunoglobulin E antibody omalizumab on airway inflammation in allergic asthma. Am J Respir Crit Care Med 170:583–593CrossRefPubMedGoogle Scholar
  18. Dupont LJ, Demedts MG et al (2003) Prospective evaluation of the validity of exhaled nitric oxide for the diagnosis of asthma. Chest 123:751–756CrossRefPubMedGoogle Scholar
  19. Dweik RA, Boggs PB et al (2011) An official ATS clinical practice guideline: interpretation of exhaled nitric oxide levels (FENO) for clinical applications. Am J Respir Crit Care Med 184:602–615CrossRefPubMedPubMedCentralGoogle Scholar
  20. Gratziou C, Lignos M et al (1999) Influence of atopy on exhaled nitric oxide in patients with stable asthma and rhinitis. Eur Respir J 14:897–901CrossRefPubMedGoogle Scholar
  21. Green RH, Brightling CE et al (2002a) Asthma exacerbations and sputum eosinophil counts: a randomised controlled trial. Lancet 360:1715–1721CrossRefPubMedGoogle Scholar
  22. Green RH, Brightling CE et al (2002b) Analysis of induced sputum in adults with asthma: identification of subgroup with isolated sputum neutrophilia and poor response to inhaled corticosteroids. Thorax 57:875–879CrossRefPubMedPubMedCentralGoogle Scholar
  23. Guo FH, Comhair SA et al (2000) Molecular mechanisms of increased nitric oxide (NO) in asthma: evidence for transcriptional and post-translational regulation of NO synthesis. J Immunol 164:5970–5980CrossRefPubMedGoogle Scholar
  24. Haldar P, Pavord ID et al (2008) Cluster analysis and clinical asthma phenotypes. Am J Respir Crit Care Med 178:218–224CrossRefPubMedPubMedCentralGoogle Scholar
  25. Haldar P, Brightling CE et al (2009) Mepolizumab and exacerbations of refractory eosinophilic asthma. N Engl J Med 360:973–984CrossRefPubMedPubMedCentralGoogle Scholar
  26. Hamid Q, Song Y et al (1997) Inflammation of small airways in asthma. J Allergy Clin Immunol 100:44–51CrossRefPubMedGoogle Scholar
  27. Hamid QA, Wenzel SE et al (1999) Increased glucocorticoid receptor beta in airway cells of glucocorticoid-insensitive asthma. Am J Respir Crit Care Med 159(5 Pt 1):1600–1604CrossRefPubMedGoogle Scholar
  28. Hanania NA, Alpan O et al (2011) Omalizumab in severe allergic asthma inadequately controlled with standard therapy: a randomized trial. Ann Intern Med 154:573–582CrossRefPubMedGoogle Scholar
  29. Hanania NA, Wenzel S et al (2013) Exploring the effects of omalizumab in allergic asthma: an analysis of biomarkers in the EXTRA study. Am J Respir Crit Care Med 187:804–811CrossRefPubMedGoogle Scholar
  30. Hargreave FE, Nair P (2011) Point: is measuring sputum eosinophils useful in the management of severe asthma? Yes. Chest 139:1270–1273CrossRefPubMedGoogle Scholar
  31. Holgate S, Buhl R et al (2009) The use of omalizumab in the treatment of severe allergic asthma: a clinical experience update. Respir Med 103:1098–1113CrossRefPubMedGoogle Scholar
  32. Honkoop PJ, Loijmans RJ et al (2015) Symptom- and fraction of exhaled nitric oxide-driven strategies for asthma control: a cluster-randomized trial in primary care. J Allergy Clin Immunol 135(682–688):e11Google Scholar
  33. Jayaram L, Parameswaran K et al (2000) Induced sputum cell counts: their usefulness in clinical practice. Eur Respir J 16:150–158CrossRefPubMedGoogle Scholar
  34. Jayaram L, Pizzichini MM et al (2006) Determining asthma treatment by monitoring sputum cell counts: effect on exacerbations. Eur Respir J 27:483–494CrossRefPubMedGoogle Scholar
  35. Juniper EF, Bousquet J et al (2006) Identifying ‘well-controlled’ and ‘not well-controlled’ asthma using the asthma control questionnaire. Respir Med 100:616–621CrossRefPubMedGoogle Scholar
  36. Kallen B, Finnstrom O et al (2013) Association between preterm birth and intrauterine growth retardation and child asthma. Eur Respir J 41:671–676CrossRefPubMedGoogle Scholar
  37. Kharitonov SA, Barnes PJ (2001) Exhaled markers of pulmonary disease. Am J Respir Crit Care Med 163:1693–1722CrossRefPubMedGoogle Scholar
  38. Kharitonov SA, Yates D et al (1994) Increased nitric oxide in exhaled air of asthmatic patients. Lancet 343:133–135CrossRefPubMedGoogle Scholar
  39. Kostikas K, Papaioannou AI et al (2008) Portable exhaled nitric oxide as a screening tool for asthma in young adults during pollen season. Chest 133:906–913CrossRefPubMedGoogle Scholar
  40. Kraft M (2011) Asthma phenotypes and interleukin-13—moving closer to personalized medicine. N Engl J Med 365:1141–1144CrossRefPubMedPubMedCentralGoogle Scholar
  41. Louis R, Lau LC et al (2000) The relationship between airways inflammation and asthma severity. Am J Respir Crit Care Med 161:9–16CrossRefPubMedGoogle Scholar
  42. Loukides S, Kostikas K et al (2011) Non-invasive assessment of asthmatic inflammation: from bench to bedside. Curr Med Chem 18:1413–1414CrossRefPubMedGoogle Scholar
  43. Martin RJ, Szefler SJ et al (2007) The Predicting Response to Inhaled Corticosteroid Efficacy (PRICE) trial. J Allergy Clin Immunol 119:73–80CrossRefPubMedPubMedCentralGoogle Scholar
  44. Michils A, Baldassarre S et al (2008) Exhaled nitric oxide and asthma control: a longitudinal study in unselected patients. Eur Respir J 31:539–546CrossRefPubMedGoogle Scholar
  45. Michils A, Louis R et al (2009) Exhaled nitric oxide as a marker of asthma control in smoking patients. Eur Respir J 33:1295–1301CrossRefPubMedGoogle Scholar
  46. Murphy VE, Schatz M (2014) Asthma in pregnancy: a hit for two. Eur Respir Rev 23:64–68CrossRefPubMedGoogle Scholar
  47. Nair P, Pizzichini MM et al (2009) Mepolizumab for prednisone-dependent asthma with sputum eosinophilia. N Engl J Med 360:985–993CrossRefPubMedGoogle Scholar
  48. Ortega HG, Liu MC et al (2014) Mepolizumab treatment in patients with severe eosinophilic asthma. N Engl J Med 371:1198–1207CrossRefPubMedGoogle Scholar
  49. Papaioannou AI, Minas M et al (2009) Exhaled NO may predict loss of asthma control: the effect of concomitant allergic rhinitis. Eur Respir J 34:1006–1007CrossRefPubMedGoogle Scholar
  50. Petsky HL, Cates CJ et al (2012) A systematic review and meta-analysis: tailoring asthma treatment on eosinophilic markers (exhaled nitric oxide or sputum eosinophils). Thorax 67:199–208CrossRefPubMedGoogle Scholar
  51. Pijnenburg MW, Bakker EM et al (2005) Titrating steroids on exhaled nitric oxide in children with asthma: a randomized controlled trial. Am J Respir Crit Care Med 172:831–836CrossRefPubMedGoogle Scholar
  52. Pin I, Gibson PG et al (1992) Use of induced sputum cell counts to investigate airway inflammation in asthma. Thorax 47:25–29CrossRefPubMedPubMedCentralGoogle Scholar
  53. Powell H, Murphy VE et al (2011) Management of asthma in pregnancy guided by measurement of fraction of exhaled nitric oxide: a double-blind, randomised controlled trial. Lancet 378:983–990CrossRefPubMedGoogle Scholar
  54. Quaedvlieg V, Sele J et al (2009) Association between asthma control and bronchial hyperresponsiveness and airways inflammation: a cross-sectional study in daily practice. Clin Exp Allergy 39:1822–1829CrossRefPubMedGoogle Scholar
  55. Reddel HK, Bateman ED et al (2015) A summary of the new GINA strategy: a roadmap to asthma control. Eur Respir J 46:622–639CrossRefPubMedPubMedCentralGoogle Scholar
  56. Schleich FN, Seidel L et al (2010) Exhaled nitric oxide thresholds associated with a sputum eosinophil count ≥3% in a cohort of unselected patients with asthma. Thorax 65:1039–1044CrossRefPubMedGoogle Scholar
  57. Shaw DE, Berry MA et al (2007) The use of exhaled nitric oxide to guide asthma management: a randomized controlled trial. Am J Respir Crit Care Med 176:231–237CrossRefPubMedGoogle Scholar
  58. Simpson JL, Scott R et al (2006) Inflammatory subtypes in asthma: assessment and identification using induced sputum. Respirology 11:54–61CrossRefPubMedGoogle Scholar
  59. Smith AD, Cowan JO et al (2004) Diagnosing asthma: comparisons between exhaled nitric oxide measurements and conventional tests. Am J Respir Crit Care Med 169:473–478CrossRefPubMedGoogle Scholar
  60. Smith AD, Cowan JO et al (2005) Use of exhaled nitric oxide measurements to guide treatment in chronic asthma. N Engl J Med 352:2163–2173CrossRefPubMedGoogle Scholar
  61. Szefler SJ, Martin RJ et al (2002) Significant variability in response to inhaled corticosteroids for persistent asthma. J Allergy Clin Immunol 109:410–418CrossRefPubMedGoogle Scholar
  62. Szefler SJ, Mitchell H et al (2008) Management of asthma based on exhaled nitric oxide in addition to guideline-based treatment for inner-city adolescents and young adults: a randomised controlled trial. Lancet 372:1065–1072CrossRefPubMedPubMedCentralGoogle Scholar
  63. Tseliou E, Bessa V et al (2010) Exhaled nitric oxide and exhaled breath condensate pH in severe refractory asthma. Chest 138:107–113CrossRefPubMedGoogle Scholar
  64. Wagener AH, de Nijs SB et al (2015) External validation of blood eosinophils, FE(NO) and serum periostin as surrogates for sputum eosinophils in asthma. Thorax 70:115–120CrossRefPubMedGoogle Scholar
  65. Wenzel SE, Schwartz LB et al (1999) Evidence that severe asthma can be divided pathologically into two inflammatory subtypes with distinct physiologic and clinical characteristics. Am J Respir Crit Care Med 160:1001–1008CrossRefPubMedGoogle Scholar

Copyright information

© L. Hirszfeld Institute of Immunology and Experimental Therapy, Wroclaw, Poland 2016

Authors and Affiliations

  • Zoi Tsilogianni
    • 1
  • Polyxeni Ntontsi
    • 2
  • Andriana I. Papaioannou
    • 2
  • Petros Bakakos
    • 1
  • Stelios Loukides
    • 2
  1. 1.1st Respiratory Medicine Department, University of Athens Medical SchoolSotiria HospitalAthensGreece
  2. 2.2nd Respiratory Medicine Department, University of Athens Medical SchoolAttiko University HospitalAthensGreece

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