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Biomarkers in Severe Asthma

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Severe Asthma
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Abstract

Severe asthma is a heterogeneous disease with a variety of different phenotypes and endotypes. Biomarkers may facilitate the diagnosis and classification of severe asthma, predict efficacy of specific therapies, and assess medication response. Pulmonary function testing is an essential biomarker for the diagnosis and management of asthma. Recently, spirometric parameters reflecting small-airway obstruction have shown promise in the diagnosis and management of certain phenotypes of asthma. In addition, the presence of potential asthma biomarkers has been examined in a variety of biological samples including exhaled breath, blood, sputum, bronchoalveolar lavage fluid, bronchial brushings, bronchial biopsies, and urine. Biomarker candidates identified in these samples include fractional exhaled nitric oxide, eosinophils, neutrophils, IgE, cytokines, chemokines, and bioactive molecules. Despite the progress made in the identification of potential biomarkers for severe asthma, further studies are still needed to standardize collection methods, quantify measurement, and assess clinical significance of candidate biomarkers. Meanwhile, with the ongoing advancement in technologies related to proteomics, genomics, and metabolomics, the potential exists to discover more and more candidate biomarkers that will ultimately aid in the diagnosis and treatment of severe asthma.

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References

  1. The ENFUMOSA. cross-sectional European multicentre study of the clinical phenotype of chronic severe asthma. European Network for Understanding Mechanisms of Severe Asthma. Eur Respir J. 2003;22(3):470–7.

    Article  Google Scholar 

  2. Pride NB, Permutt S, Riley RL, Bromberger-Barnea B. Determinants of maximal expiratory flow from the lungs. J Appl Physiol. 1967;23(5):646–62.

    CAS  PubMed  Google Scholar 

  3. Mead J, Turner JM, Macklem PT, Little JB. Significance of the relationship between lung recoil and maximum expiratory flow. J Appl Physiol. 1967;22(1):95–108.

    CAS  PubMed  Google Scholar 

  4. Gelb AF, Zamel N. Unsuspected pseudophysiologic emphysema in chronic persistent asthma. Am J Respir Crit Care Med. 2000;162(5):1778–82.

    Article  CAS  PubMed  Google Scholar 

  5. Woolcock AJ, Read J. The static elastic properties of the lungs in asthma. Am Rev Respir Dis. 1968;98(5):788–94.

    CAS  PubMed  Google Scholar 

  6. Gelb AF, Schein A, Nussbaum E, Shinar CM, Aelony Y, Aharonian H, et al. Risk factors for near-fatal asthma. Chest. 2004;126(4):1138–46.

    Article  PubMed  Google Scholar 

  7. Sorkness RL, Bleecker ER, Busse WW, Calhoun WJ, Castro M, Chung KF, et al. Lung function in adults with stable but severe asthma: air trapping and incomplete reversal of obstruction with bronchodilation. J Appl Physiol. 2008;104(2):394–403.

    Article  PubMed  Google Scholar 

  8. Perez T, Chanez P, Dusser D, Devillier P. Prevalence and reversibility of lung hyperinflation in adult asthmatics with poorly controlled disease or significant dyspnea. Allergy. 2016;71(1):108–14.

    Article  CAS  PubMed  Google Scholar 

  9. Gibbons WJ, Sharma A, Lougheed D, Macklem PT. Detection of excessive bronchoconstriction in asthma. Am J Respir Crit Care Med. 1996;153(2):582–9.

    Article  CAS  PubMed  Google Scholar 

  10. Chapman DG, Berend N, Horlyck KR, King GG, Salome CM. Does increased baseline ventilation heterogeneity following chest wall strapping predispose to airway hyperresponsiveness? J Appl Physiol. 2012;113(1):25–30.

    Article  PubMed  Google Scholar 

  11. Kaminsky DA, Daud A, Chapman DG. Relationship between the baseline alveolar volume-to-total lung capacity ratio and airway responsiveness. Respirology. 2014;19(7):1046–51.

    Article  PubMed Central  PubMed  Google Scholar 

  12. Bourdin A, Paganin F, Prefaut C, Kieseler D, Godard P, Chanez P. Nitrogen washout slope in poorly controlled asthma. Allergy. 2006;61(1):85–9.

    Article  CAS  PubMed  Google Scholar 

  13. Porsbjerg C, Rasmussen L, Nolte H, Backer V. Association of airway hyperresponsiveness with reduced quality of life in patients with moderate to severe asthma. Ann Allergy Asthma Immunol. 2007;98(1):44–50.

    Article  PubMed  Google Scholar 

  14. Thamrin C, Nydegger R, Stern G, Chanez P, Wenzel SE, Watt RA, et al. Associations between fluctuations in lung function and asthma control in two populations with differing asthma severity. Thorax. 2011;66(12):1036–42.

    Article  PubMed  Google Scholar 

  15. Wenzel S. Physiologic and pathologic abnormalities in severe asthma. Clin Chest Med. 2006;27(1):29–40. v

    Article  PubMed  Google Scholar 

  16. Shi Y, Aledia AS, Galant SP, George SC. Peripheral airway impairment measured by oscillometry predicts loss of asthma control in children. J Allergy Clin Immunol. 2013;131(3):718–23.

    Article  PubMed  Google Scholar 

  17. Lutchen KR, Jensen A, Atileh H, Kaczka DW, Israel E, Suki B, et al. Airway constriction pattern is a central component of asthma severity: the role of deep inspirations. Am J Respir Crit Care Med. 2001;164(2):207–15.

    Article  CAS  PubMed  Google Scholar 

  18. Bates JH, Irvin CG, Farre R, Hantos Z. Oscillation mechanics of the respiratory system. Compr Physiol. 2011;1(3):1233–72.

    PubMed  Google Scholar 

  19. Sferrazza Papa GF, Pellegrino GM, Pellegrino R. Asthma and respiratory physiology: putting lung function into perspective. Respirology. 2014;19(7):960–9.

    Article  PubMed  Google Scholar 

  20. Alfieri V, Aiello M, Pisi R, Tzani P, Mariani E, Marangio E, et al. Small airway dysfunction is associated to excessive bronchoconstriction in asthmatic patients. Respir Res. 2014;15:86.

    Article  PubMed Central  PubMed  Google Scholar 

  21. Kelly VJ, Sands SA, Harris RS, Venegas JG, Brown NJ, Stuart-Andrews CR, et al. Respiratory system reactance is an independent determinant of asthma control. J Appl Physiol. 2013;115(9):1360–9.

    Article  CAS  PubMed  Google Scholar 

  22. 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(2):343–73.

    Article  CAS  PubMed  Google Scholar 

  23. Standards for the diagnosis and care of patients with chronic obstructive pulmonary disease (COPD) and asthma. This official statement of the American Thoracic Society was adopted by the ATS Board of Directors, November 1986. Am Rev Respir Dis 1987;136(1):225–44.

    Google Scholar 

  24. A plea to abandon asthma as a disease concept. Lancet. 2006;368(9537):705.

    Google Scholar 

  25. Haldar P, Pavord ID, Shaw DE, Berry MA, Thomas M, Brightling CE, et al. Cluster analysis and clinical asthma phenotypes. Am J Respir Crit Care Med. 2008;178(3):218–24.

    Article  PubMed Central  PubMed  Google Scholar 

  26. Moore WC, Meyers DA, Wenzel SE, Teague WG, Li H, Li X, et al. Identification of asthma phenotypes using cluster analysis in the Severe Asthma Research Program. Am J Respir Crit Care Med. 2010;181(4):315–23.

    Article  PubMed  Google Scholar 

  27. Fitzpatrick AM, Teague WG, Meyers DA, Peters SP, Li X, Li H, et al. Heterogeneity of severe asthma in childhood: confirmation by cluster analysis of children in the National Institutes of Health/National Heart, Lung, and Blood Institute Severe Asthma Research Program. J Allergy Clin Immunol. 2011;127(2):382–9 e1-13.

    Article  PubMed  Google Scholar 

  28. Schatz M, Hsu JW, Zeiger RS, Chen W, Dorenbaum A, Chipps BE, et al. Phenotypes determined by cluster analysis in severe or difficult-to-treat asthma. J Allergy Clin Immunol. 2014;133(6):1549–56.

    Article  PubMed  Google Scholar 

  29. Konstantellou E, Papaioannou AI, Loukides S, Patentalakis G, Papaporfyriou A, Hillas G, et al. Persistent airflow obstruction in patients with asthma: characteristics of a distinct clinical phenotype. Respir Med. 2015;109(11):1404–9.

    Article  PubMed  Google Scholar 

  30. Schatz M, Rosenwasser L. The allergic asthma phenotype. J Allergy Clin Immunol Pract. 2014;2(6):645–8. quiz 9

    Article  PubMed  Google Scholar 

  31. (GINA) GIfA. Diagnosis of diseases of chronic airflow limitation: asthma, COPD and Asthma-COPD Overlap Syndrome (ACOS). Global Strategy for Asthma Management and Prevention; 2014.

    Google Scholar 

  32. Gibson PG, McDonald VM. Asthma-COPD overlap 2015: now we are six. Thorax. 2015;70(7):683–91.

    Article  PubMed  Google Scholar 

  33. Finkelstein JA, Lozano P, Shulruff R, Inui TS, Soumerai SB, Ng M, et al. Self-reported physician practices for children with asthma: are national guidelines followed? Pediatrics. 2000;106(4 Suppl):886–96.

    CAS  PubMed  Google Scholar 

  34. (GINA) GIfA. Pocket guide for asthma management and prevention (A pocket guide for health professionals updated 2016); 2016.

    Google Scholar 

  35. Miller MR, Hankinson J, Brusasco V, Burgos F, Casaburi R, Coates A, et al. Standardisation of spirometry. Eur Respir J. 2005;26(2):319–38.

    Article  CAS  PubMed  Google Scholar 

  36. Expert panel Report 2: guidelines for the diagnosis and management of asthma (EPR-2 1997). NIH Publication No. 97-4051. Bethesda, MD: U.S. Department of Health and Human Services; National Institutes of Health; National Heart, Lung, and Blood Institutes; National Asthma Education and Prevention Program; 1997.

    Google Scholar 

  37. Bacharier LB, Strunk RC, Mauger D, White D, Lemanske RF Jr, Sorkness CA. Classifying asthma severity in children: mismatch between symptoms, medication use, and lung function. Am J Respir Crit Care Med. 2004;170(4):426–32.

    Article  PubMed  Google Scholar 

  38. Paull K, Covar R, Jain N, Gelfand EW, Spahn JD. Do NHLBI lung function criteria apply to children? A cross-sectional evaluation of childhood asthma at National Jewish Medical and Research Center, 1999-2002. Pediatr Pulmonol. 2005;39(4):311–7.

    Article  PubMed  Google Scholar 

  39. Strunk RC, Weiss ST, Yates KP, Tonascia J, Zeiger RS, Szefler SJ, et al. Mild to moderate asthma affects lung growth in children and adolescents. J Allergy Clin Immunol. 2006;118(5):1040–7.

    Article  PubMed  Google Scholar 

  40. Group TCAMPR. Long-term effects of budesonide or nedocromil in children with asthma. The Childhood Asthma Management Program Research Group. N Engl J Med. 2000;343(15):1054–63.

    Article  Google Scholar 

  41. Fitzpatrick AM, Gaston BM, Erzurum SC, Teague WG, National Institutes of Health/National Heart L, Blood Institute Severe Asthma Research P. Features of severe asthma in school-age children: atopy and increased exhaled nitric oxide. J Allergy Clin Immunol. 2006;118(6):1218–25.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  42. Simon MR, Chinchilli VM, Phillips BR, Sorkness CA, Lemanske RF Jr, Szefler SJ, et al. Forced expiratory flow between 25% and 75% of vital capacity and FEV1/forced vital capacity ratio in relation to clinical and physiological parameters in asthmatic children with normal FEV1 values. J Allergy Clin Immunol. 2010;126(3):527–34 e1-8.

    Article  PubMed Central  PubMed  Google Scholar 

  43. Perez T, Chanez P, Dusser D, Devillier P. Small airway impairment in moderate to severe asthmatics without significant proximal airway obstruction. Respir Med. 2013;107(11):1667–74.

    Article  PubMed  Google Scholar 

  44. Quanjer PH, Weiner DJ, Pretto JJ, Brazzale DJ, Boros PW. Measurement of FEF25-75% and FEF75% does not contribute to clinical decision making. Eur Respir J. 2014;43(4):1051–8.

    Article  PubMed  Google Scholar 

  45. Rao DR, Gaffin JM, Baxi SN, Sheehan WJ, Hoffman EB, Phipatanakul W. The utility of forced expiratory flow between 25% and 75% of vital capacity in predicting childhood asthma morbidity and severity. J Asthma. 2012;49(6):586–92.

    Article  PubMed Central  PubMed  Google Scholar 

  46. Riley CM, Wenzel SE, Castro M, Erzurum SC, Chung KF, Fitzpatrick AM, et al. Clinical implications of having reduced mid forced expiratory flow rates (FEF25-75), independently of FEV1, in adult patients with asthma. PLoS One. 2015;10(12):e0145476.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  47. Siroux V, Boudier A, Dolgopoloff M, Chanoine S, Bousquet J, Gormand F, et al. Forced midexpiratory flow between 25% and 75% of forced vital capacity is associated with long-term persistence of asthma and poor asthma outcomes. J Allergy Clin Immunol. 2016;137(6):1709–16. e6

    Article  PubMed  Google Scholar 

  48. Francisco B, Ner Z, Ge B, Hewett J, Konig P. Sensitivity of different spirometric tests for detecting airway obstruction in childhood asthma. J Asthma. 2015;52(5):505–11.

    Article  PubMed  Google Scholar 

  49. Mottram C. Ruppel’s manual of pulmonary function testing. 10th ed. Amsterdam: Elsevier; 2012.

    Google Scholar 

  50. Ignarro LJ, Buga GM, Wood KS, Byrns RE, Chaudhuri G. Endothelium-derived relaxing factor produced and released from artery and vein is nitric oxide. Proc Natl Acad Sci U S A. 1987;84(24):9265–9.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  51. Palmer RM, Ashton DS, Moncada S. Vascular endothelial cells synthesize nitric oxide from L-arginine. Nature. 1988;333(6174):664–6.

    Article  CAS  PubMed  Google Scholar 

  52. Dweik RA, Comhair SA, Gaston B, Thunnissen FB, Farver C, Thomassen MJ, et al. NO chemical events in the human airway during the immediate and late antigen-induced asthmatic response. Proc Natl Acad Sci U S A. 2001;98(5):2622–7.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  53. Ricciardolo FL. Multiple roles of nitric oxide in the airways. Thorax. 2003;58(2):175–82.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  54. Khatri SB, Hammel J, Kavuru MS, Erzurum SC, Dweik RA. Temporal association of nitric oxide levels and airflow in asthma after whole lung allergen challenge. J Appl Physiol. 2003;95(1):436–40. discussion 5

    Article  CAS  PubMed  Google Scholar 

  55. Khatri SB, Ozkan M, McCarthy K, Laskowski D, Hammel J, Dweik RA, et al. Alterations in exhaled gas profile during allergen-induced asthmatic response. Am J Respir Crit Care Med. 2001;164(10 Pt 1):1844–8.

    Article  CAS  PubMed  Google Scholar 

  56. Guo FH, De Raeve HR, Rice TW, Stuehr DJ, Thunnissen FB, Erzurum SC. Continuous nitric oxide synthesis by inducible nitric oxide synthase in normal human airway epithelium in vivo. Proc Natl Acad Sci U S A. 1995;92(17):7809–13.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  57. Guo FH, Erzurum SC. Characterization of inducible nitric oxide synthase expression in human airway epithelium. Environ Health Perspect. 1998;106(Suppl 5):1119–24.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  58. Guo FH, Uetani K, Haque SJ, Williams BR, Dweik RA, Thunnissen FB, et al. Interferon gamma and interleukin 4 stimulate prolonged expression of inducible nitric oxide synthase in human airway epithelium through synthesis of soluble mediators. J Clin Invest. 1997;100(4):829–38.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  59. Guo FH, Comhair SA, Zheng S, Dweik RA, Eissa NT, Thomassen MJ, et al. Molecular mechanisms of increased nitric oxide (NO) in asthma: evidence for transcriptional and post-translational regulation of NO synthesis. J Immunol. 2000;164(11):5970–80.

    Article  CAS  PubMed  Google Scholar 

  60. Alving K, Weitzberg E, Lundberg JM. Increased amount of nitric oxide in exhaled air of asthmatics. Eur Respir J. 1993;6(9):1368–70.

    CAS  PubMed  Google Scholar 

  61. Kharitonov SA, Yates D, Robbins RA, Logan-Sinclair R, Shinebourne EA, Barnes PJ. Increased nitric oxide in exhaled air of asthmatic patients. Lancet. 1994;343(8890):133–5.

    Article  CAS  PubMed  Google Scholar 

  62. Gaston B, Drazen J, Chee CBE, Wohl MEB, Stamler JS. Expired nitric oxide concentrations are elevated in patients with reactive airways disease. Endothelium. 1993;1:87–92.

    Google Scholar 

  63. 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(11):1506–11.

    Article  CAS  PubMed  Google Scholar 

  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(5):1322–8.

    Article  CAS  PubMed  Google Scholar 

  65. Dweik RA, Erzurum SC. Regulation of nitric oxide (NO) synthases and gas phase NO by oxygen. In: Marczin N, Kharitonov SA, Yacoub MH, Barnes PJ, editors. Disease markers in exhaled breath (lung biology in health and disease). New York: Marcel Dekker, Inc; 2003. p. 235–46.

    Google Scholar 

  66. Hansel TT, Kharitonov SA, Donnelly LE, Erin EM, Currie MG, Moore WM, et al. A selective inhibitor of inducible nitric oxide synthase inhibits exhaled breath nitric oxide in healthy volunteers and asthmatics. FASEB J. 2003;17(10):1298–300.

    CAS  PubMed  Google Scholar 

  67. 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(2):852–7.

    Article  CAS  PubMed  Google Scholar 

  68. Ricciardolo FL, Di Stefano A, Silvestri M, Van Schadewijk AM, Malerba M, Hiemstra PS, et al. Exhaled nitric oxide is related to bronchial eosinophilia and airway hyperresponsiveness to bradykinin in allergen-induced asthma exacerbation. Int J Immunopathol Pharmacol. 2012;25(1):175–82.

    Article  CAS  PubMed  Google Scholar 

  69. Covar RA, Szefler SJ, Martin RJ, Sundstrom DA, Silkoff PE, Murphy J, et al. Relations between exhaled nitric oxide and measures of disease activity among children with mild-to-moderate asthma. J Pediatr. 2003;142(5):469–75.

    Article  CAS  PubMed  Google Scholar 

  70. Smith AD, Cowan JO, Taylor DR. Exhaled nitric oxide levels in asthma: personal best versus reference values. J Allergy Clin Immunol. 2009;124(4):714–8. e4

    Article  CAS  PubMed  Google Scholar 

  71. Dweik RA, Boggs PB, Erzurum SC, Irvin CG, Leigh MW, Lundberg JO, et al. An official ATS clinical practice guideline: interpretation of exhaled nitric oxide levels (FENO) for clinical applications. Am J Respir Crit Care Med. 2011;184(5):602–15.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  72. Kotaniemi-Syrjanen A, Malmberg LP, Malmstrom K, Pelkonen AS, Makela MJ. Factors associated with elevated exhaled nitric oxide fraction in infants with recurrent respiratory symptoms. Eur Respir J. 2013;41(1):189–94.

    Article  CAS  PubMed  Google Scholar 

  73. 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(4):531–8.

    Article  CAS  PubMed  Google Scholar 

  74. Chien JW, Lin CY, Yang KD, Lin CH, Kao JK, Tsai YG. Increased IL-17A secreting CD4+ T cells, serum IL-17 levels and exhaled nitric oxide are correlated with childhood asthma severity. Clin Exp Allergy. 2013;43(9):1018–26.

    Article  CAS  PubMed  Google Scholar 

  75. Kawamatawong T, Siripongpun S, Rerkpattanapipat T. Role of eosinophilic inflammation and atopy in elderly asthmatic patients. Asia Pac Allergy. 2016;6(3):181–6.

    Article  PubMed Central  PubMed  Google Scholar 

  76. Dweik RA, Sorkness RL, Wenzel S, Hammel J, Curran-Everett D, Comhair SA, et al. Use of exhaled nitric oxide measurement to identify a reactive, at-risk phenotype among patients with asthma. Am J Respir Crit Care Med. 2010;181(10):1033–41.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  77. Amelink M, de Groot JC, de Nijs SB, Lutter R, Zwinderman AH, Sterk PJ, et al. Severe adult-onset asthma: a distinct phenotype. J Allergy Clin Immunol. 2013;132(2):336–41.

    Article  PubMed  Google Scholar 

  78. Bousquet J, Mantzouranis E, Cruz AA, Ait-Khaled N, Baena-Cagnani CE, Bleecker ER, et al. Uniform definition of asthma severity, control, and exacerbations: document presented for the World Health Organization Consultation on Severe Asthma. J Allergy Clin Immunol. 2010;126(5):926–38.

    Article  PubMed  Google Scholar 

  79. Lodrup Carlsen KC, Hedlin G, Bush A, Wennergren G, de Benedictis FM, De Jongste JC, et al. Assessment of problematic severe asthma in children. Eur Respir J. 2011;37(2):432–40.

    Article  CAS  PubMed  Google Scholar 

  80. de Andrade WC, Lasmar LM, Ricci Cde A, Camargos PA, Cruz AA. Phenotypes of severe asthma among children and adolescents in Brazil: a prospective study. BMC Pulm Med. 2015;15:36.

    Article  PubMed Central  PubMed  Google Scholar 

  81. Sharples J, Gupta A, Fleming L, Bossley CJ, Bracken-King M, Hall P, et al. Long-term effectiveness of a staged assessment for paediatric problematic severe asthma. Eur Respir J. 2012;40(1):264–7.

    Article  PubMed Central  PubMed  Google Scholar 

  82. Konradsen JR, Nordlund B, Lidegran M, Pedroletti C, Gronlund H, van Hage M, et al. Problematic severe asthma: a proposed approach to identifying children who are severely resistant to therapy. Pediatr Allergy Immunol. 2011;22(1 Pt 1):9–18.

    Article  PubMed  Google Scholar 

  83. Silkoff PE, Lent AM, Busacker AA, Katial RK, Balzar S, Strand M, et al. Exhaled nitric oxide identifies the persistent eosinophilic phenotype in severe refractory asthma. J Allergy Clin Immunol. 2005;116(6):1249–55.

    Article  CAS  PubMed  Google Scholar 

  84. Tseliou E, Bessa V, Hillas G, Delimpoura V, Papadaki G, Roussos C, et al. Exhaled nitric oxide and exhaled breath condensate pH in severe refractory asthma. Chest. 2010;138(1):107–13.

    Article  PubMed  Google Scholar 

  85. Michils A, Baldassarre S, Van Muylem A. Exhaled nitric oxide and asthma control: a longitudinal study in unselected patients. Eur Respir J. 2008;31(3):539–46.

    Article  CAS  PubMed  Google Scholar 

  86. 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(5):738–43.

    Article  CAS  PubMed  Google Scholar 

  87. 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(6):1492–9.

    Article  CAS  PubMed  Google Scholar 

  88. 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(2):265–71.

    Article  PubMed  CAS  Google Scholar 

  89. Brzozowska A, Majak P, Jerzynska J, Smejda K, Bobrowska-Korzeniowska M, Stelmach W, et al. Exhaled nitric oxide correlates with IL-2, MCP-1, PDGF-BB and TIMP-2 in exhaled breath condensate of children with refractory asthma. Postepy Dermatol Alergol. 2015;32(2):107–13.

    Article  PubMed Central  PubMed  Google Scholar 

  90. Gomersal T, Harnan S, Essat M, Tappenden P, Wong R, Lawson R, et al. A systematic review of fractional exhaled nitric oxide in the routine management of childhood asthma. Pediatr Pulmonol. 2016;51(3):316–28.

    Article  PubMed  Google Scholar 

  91. Pike K, Selby A, Price S, Warner J, Connett G, Legg J, et al. Exhaled nitric oxide monitoring does not reduce exacerbation frequency or inhaled corticosteroid dose in paediatric asthma: a randomised controlled trial. Clin Respir J. 2013;7(2):204–13.

    Article  CAS  PubMed  Google Scholar 

  92. Peirsman EJ, Carvelli TJ, Hage PY, Hanssens LS, Pattyn L, Raes MM, et al. Exhaled nitric oxide in childhood allergic asthma management: a randomised controlled trial. Pediatr Pulmonol. 2014;49(7):624–31.

    Article  PubMed  Google Scholar 

  93. Petsky HL, Li AM, Au CT, Kynaston JA, Turner C, Chang AB. Management based on exhaled nitric oxide levels adjusted for atopy reduces asthma exacerbations in children: a dual centre randomized controlled trial. Pediatr Pulmonol. 2015;50(6):535–43.

    Article  PubMed  Google Scholar 

  94. Shaw DE, Berry MA, Hargadon B, McKenna S, Shelley MJ, Green RH, et al. Association between neutrophilic airway inflammation and airflow limitation in adults with asthma. Chest. 2007;132(6):1871–5.

    Article  CAS  PubMed  Google Scholar 

  95. Szefler SJ, Mitchell H, Sorkness CA, Gergen PJ, O’Connor GT, Morgan WJ, et al. 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. 2008;372(9643):1065–72.

    Article  PubMed Central  PubMed  Google Scholar 

  96. Calhoun WJ, Ameredes BT, King TS, Icitovic N, Bleecker ER, Castro M, et al. Comparison of physician-, biomarker-, and symptom-based strategies for adjustment of inhaled corticosteroid therapy in adults with asthma: the BASALT randomized controlled trial. JAMA. 2012;308(10):987–97.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  97. Petsky HL, Cates CJ, Lasserson TJ, Li AM, Turner C, Kynaston JA, et al. A systematic review and meta-analysis: tailoring asthma treatment on eosinophilic markers (exhaled nitric oxide or sputum eosinophils). Thorax. 2012;67(3):199–208.

    Article  CAS  PubMed  Google Scholar 

  98. Essat M, Harnan S, Gomersall T, Tappenden P, Wong R, Pavord I, et al. Fractional exhaled nitric oxide for the management of asthma in adults: a systematic review. Eur Respir J. 2016;47(3):751–68.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  99. Malerba M, Ragnoli B, Radaeli A, Ricciardolo FLM. Long-term adjustment of stable asthma treatment with fractional exhaled nitric oxide and sputum eosinophils. Eur J Inflamm. 2012;10(3):383–92.

    Article  CAS  Google Scholar 

  100. Gibson PG. Using fractional exhaled nitric oxide to guide asthma therapy: design and methodological issues for ASthma TReatment ALgorithm studies. Clin Exp Allergy. 2009;39(4):478–90.

    Article  CAS  PubMed  Google Scholar 

  101. 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(4):877–83.e1.

    Article  CAS  PubMed  Google Scholar 

  102. Kharitonov SA, Yates DH, Barnes PJ. Inhaled glucocorticoids decrease nitric oxide in exhaled air of asthmatic patients. Am J Respir Crit Care Med. 1996;153(1):454–7.

    Article  CAS  PubMed  Google Scholar 

  103. Parulekar AD, Diamant Z, Hanania NA. Role of T2 inflammation biomarkers in severe asthma. Curr Opin Pulm Med. 2016;22(1):59–68.

    Article  CAS  PubMed  Google Scholar 

  104. Silkoff PE, Laviolette M, Singh D, FitzGerald JM, Kelsen S, Backer V, et al. Longitudinal stability of asthma characteristics and biomarkers from the Airways Disease Endotyping for Personalized Therapeutics (ADEPT) study. Respir Res. 2016;17:43.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  105. 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(3):433–8.

    Article  CAS  PubMed  Google Scholar 

  106. 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(11):895–900.

    Article  CAS  PubMed  Google Scholar 

  107. Thijs W, de Mutsert R, le Cessie S, Hiemstra PS, Rosendaal FR, Middeldorp S, et al. Reproducibility of exhaled nitric oxide measurements in overweight and obese adults. BMC Res Notes. 2014;7:775.

    Article  PubMed Central  PubMed  Google Scholar 

  108. Buchvald F, Eiberg H, Bisgaard H. Heterogeneity of FeNO response to inhaled steroid in asthmatic children. Clin Exp Allergy. 2003;33(12):1735–40.

    Article  CAS  PubMed  Google Scholar 

  109. Hanania NA, Wenzel S, Rosen 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(8):804–11.

    Article  CAS  PubMed  Google Scholar 

  110. Sorkness CA, Wildfire JJ, Calatroni A, Mitchell HE, Busse WW, O’Connor GT, et al. Reassessment of omalizumab-dosing strategies and pharmacodynamics in inner-city children and adolescents. J Allergy Clin Immunol Pract. 2013;1(2):163–71.

    Article  PubMed Central  PubMed  Google Scholar 

  111. Wenzel S, Ford L, Pearlman D, Spector S, Sher L, Skobieranda F, et al. Dupilumab in persistent asthma with elevated eosinophil levels. N Engl J Med. 2013;368(26):2455–66.

    Article  CAS  PubMed  Google Scholar 

  112. Luo J, Liu D, Liu CT. The efficacy and safety of antiinterleukin 13, a monoclonal antibody, in adult patients with asthma: a systematic review and meta-analysis. Medicine. 2016;95(6):e2556.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  113. American Thoracic S, European RS. 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(8):912–30.

    Article  Google Scholar 

  114. Olin AC, Bake B, Toren K. Fraction of exhaled nitric oxide at 50 mL/s: reference values for adult lifelong never-smokers. Chest. 2007;131(6):1852–6.

    Article  PubMed  Google Scholar 

  115. 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(5):1319–25.

    Article  PubMed  Google Scholar 

  116. Grob NM, Dweik RA. Exhaled nitric oxide in asthma. From diagnosis, to monitoring, to screening: are we there yet? Chest. 2008;133(4):837–9.

    Article  PubMed  Google Scholar 

  117. Buchvald F, Baraldi E, Carraro S, Gaston B, De Jongste J, Pijnenburg MW, et al. Measurements of exhaled nitric oxide in healthy subjects age 4 to 17 years. J Allergy Clin Immunol. 2005;115(6):1130–6.

    Article  CAS  PubMed  Google Scholar 

  118. 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.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  119. 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(3):238–42.

    Article  CAS  PubMed  Google Scholar 

  120. Dressel H, de la Motte D, Reichert J, Ochmann U, Petru R, Angerer P, et al. Exhaled nitric oxide: independent effects of atopy, smoking, respiratory tract infection, gender and height. Respir Med. 2008;102(7):962–9.

    Article  PubMed  Google Scholar 

  121. 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(1):169–75.

    Article  CAS  PubMed  Google Scholar 

  122. Wong GW, Liu EK, Leung TF, Yung E, Ko FW, Hui DS, et al. High levels and gender difference of exhaled nitric oxide in Chinese schoolchildren. Clin Exp Allergy. 2005;35(7):889–93.

    Article  CAS  PubMed  Google Scholar 

  123. Malmberg LP, Petays 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(7):635–42.

    Article  CAS  PubMed  Google Scholar 

  124. Jacinto T, Alving K, Correia R, Costa-Pereira A, Fonseca J. Setting reference values for exhaled nitric oxide: a systematic review. Clin Respir J. 2013;7(2):113–20.

    Article  CAS  PubMed  Google Scholar 

  125. Ludviksdottir D, Diamant Z, Alving K, Bjermer L, Malinovschi A. Clinical aspects of using exhaled NO in asthma diagnosis and management. Clin Respir J. 2012;6(4):193–207.

    Article  CAS  PubMed  Google Scholar 

  126. Saito J, Sato S, Fukuhara A, Sato Y, Nikaido T, Inokoshi Y, et al. Association of asthma education with asthma control evaluated by asthma control test, FEV1, and fractional exhaled nitric oxide. J Asthma. 2013;50(1):97–102.

    Article  CAS  PubMed  Google Scholar 

  127. Horvath I, Hunt J, Barnes PJ, Alving K, Antczak A, Baraldi E, et al. Exhaled breath condensate: methodological recommendations and unresolved questions. Eur Respir J. 2005;26(3):523–48.

    Article  CAS  PubMed  Google Scholar 

  128. Kietzmann D, Kahl R, Muller M, Burchardi H, Kettler D. Hydrogen peroxide in expired breath condensate of patients with acute respiratory failure and with ARDS. Intensive Care Med. 1993;19(2):78–81.

    Article  CAS  PubMed  Google Scholar 

  129. Effros RM, Hoagland KW, Bosbous M, Castillo D, Foss B, Dunning M, et al. Dilution of respiratory solutes in exhaled condensates. Am J Respir Crit Care Med. 2002;165(5):663–9.

    Article  PubMed  Google Scholar 

  130. Scheideler L, Manke HG, Schwulera U, Inacker O, Hammerle H. Detection of nonvolatile macromolecules in breath. A possible diagnostic tool? Am Rev Respir Dis. 1993;148(3):778–84.

    Article  CAS  PubMed  Google Scholar 

  131. Melo REPT, Solé D. <Exhaled breath temperature, a new biomarker in asthma control: a pilot study>. J Bras Pneumol. 2010;36(6):693–9.

    Article  PubMed  Google Scholar 

  132. Garcia G, Bergna M, Uribe E, Yanez A, Soriano JB. Increased exhaled breath temperature in subjects with uncontrolled asthma. Int J Tuberc Lung Dis. 2013;17(7):969–72.

    Article  CAS  PubMed  Google Scholar 

  133. Leonardi S, Cuppari C, Lanzafame A, Attardo D, Tardino L, Parisi G, et al. Exhaled breath temperature in asthmatic children. J Biol Regul Homeost Agents. 2015;29(2 Suppl 1):47–54.

    CAS  PubMed  Google Scholar 

  134. Piacentini GL, Peroni D, Crestani E, Zardini F, Bodini A, Costella S, Boner AL. Exhaled air temperature in asthma: methods and relationship with markers of disease. Clin Exp Allergy. 2007;37(3):415–9.

    Article  CAS  PubMed  Google Scholar 

  135. Paredi P, Kharitonov SA, Barnes PJ. Correlation of exhaled breath temperature with bronchial blood flow in asthma. Respir Res. 2005;6:15.

    Article  PubMed Central  PubMed  Google Scholar 

  136. Piacentini GLPD, Bodini A, Corradi M, Boner AL. Exhaled breath temperature as a marker of airway remodelling in asthma: a preliminary study. Allergy. 2008;63(4):484–5.

    Article  CAS  PubMed  Google Scholar 

  137. Crespo Lessmann A, Giner J, Torrego A, Mateus E, Torrejon M, Belda A, et al. Usefulness of the exhaled breath temperature plateau in asthma patients. Respiration. 2015;90(2):111–7.

    Article  CAS  PubMed  Google Scholar 

  138. Hamill L, Ferris K, Kapande K, McConaghy L, Douglas I, McGovern V, et al. Exhaled breath temperature measurement and asthma control in children prescribed inhaled corticosteroids: a cross sectional study. Pediatr Pulmonol. 2016;51(1):13–21.

    Article  PubMed  Google Scholar 

  139. Svensson H, Bjermer L, Tufvesson E. Exhaled breath temperature in asthmatics and controls after eucapnic voluntary hyperventilation and a methacholine challenge test. Respiration. 2014;87(2):149–57.

    Article  PubMed  Google Scholar 

  140. Vermeulen S, Barreto M, La Penna F, Prete A, Martella S, Biagiarelli F, et al. Exhaled breath temperature in children: reproducibility and influencing factors. J Asthma. 2014;51(7):743–50.

    Article  CAS  PubMed  Google Scholar 

  141. Barreto M, Piacentini G, Chiossi L, Ruggeri F, Caiazzo I, Campisano M, et al. Tidal-breathing measurement of exhaled breath temperature (EBT) in schoolchildren. Pediatr Pulmonol. 2014;49(12):1196–204.

    Article  CAS  PubMed  Google Scholar 

  142. Prince PBM, Boulet LP. A fast, simple, and inexpensive method to collect exhaled breath condensate for pH determination. Ann Allergy Asthma Immunol. 2006;97(5):622–7.

    Article  PubMed  Google Scholar 

  143. Paget-Brown AO, Ngamtrakulpanit L, Smith A, Bunyan D, Hom S, Nguyen A, et al. Normative data for pH of exhaled breath condensate. Chest. 2006;129(2):426–30.

    Article  PubMed  Google Scholar 

  144. Effros RM, Casaburi R, Porszasz J, Rehan V. Why conventional exhaled breath condensate pH studies cannot provide reliable estimates of airway acidification. Chest. 2011;140(4):1099.

    Article  PubMed Central  PubMed  Google Scholar 

  145. Hunt JF, Fang K, Malik R, Snyder A, Malhotra N, Platts-Mills TA, Gaston B. Endogenous airway acidification. Implications for asthma pathophysiology. Am J Respir Crit Care Med. 2000;161(3 Pt 1):694–9.

    Article  CAS  PubMed  Google Scholar 

  146. Antus B, Barta I, Kullmann T, Lazar Z, Valyon M, Horvath I, et al. Assessment of exhaled breath condensate pH in exacerbations of asthma and chronic obstructive pulmonary disease: a longitudinal study. Am J Respir Crit Care Med. 2010;182(12):1492–7.

    Article  PubMed  Google Scholar 

  147. Fitzpatrick AM, Holbrook JT, Wei CY, Brown MS, Wise RA, Teague WG, et al. Exhaled breath condensate pH does not discriminate asymptomatic gastroesophageal reflux or the response to lansoprazole treatment in children with poorly controlled asthma. J Allergy Clin Immunol Pract. 2014;2(5):579–86.e7.

    Article  PubMed Central  PubMed  Google Scholar 

  148. Bikov A, Galffy G, Tamasi L, Lazar Z, Losonczy G, Horvath I. Exhaled breath condensate pH is influenced by respiratory droplet dilution. J Breath Res. 2012;6(4):046002.

    Article  PubMed  CAS  Google Scholar 

  149. Liu L, Teague WG, Erzurum S, Fitzpatrick A, Mantri S, Dweik RA, et al. Determinants of exhaled breath condensate pH in a large population with asthma. Chest. 2011;139(2):328–36.

    Article  PubMed  Google Scholar 

  150. Leung TF, Li CY, Yung E, Liu EK, Lam CW, Wong GW. Clinical and technical factors affecting pH and other biomarkers in exhaled breath condensate. Pediatr Pulmonol. 2006;41(1):87–94.

    Article  PubMed  Google Scholar 

  151. von Jagwitz M, Pessler F, Akmatov M, Li J, Range U, Vogelberg C. Reduced breath condensate pH in asymptomatic children with prior wheezing as a risk factor for asthma. J Allergy Clin Immunol. 2011;128(1):50–5.

    Article  Google Scholar 

  152. Caffarelli C, Dascola CP, Peroni D, Rico S, Stringari G, Varini M, et al. Airway acidification in childhood asthma exacerbations. Allergy Asthma Proc. 2014;35(3):51–6.

    Article  PubMed  Google Scholar 

  153. Tomasiak-Lozowska MM, Zietkowski Z, Przeslaw K, Tomasiak M, Skiepko R, Bodzenta-Lukaszyk A. Inflammatory markers and acid-base equilibrium in exhaled breath condensate of stable and unstable asthma patients. Int Arch Allergy Immunol. 2012;159(2):121–9.

    Article  CAS  PubMed  Google Scholar 

  154. Kane B, Borrill Z, Southworth T, Woodcock A, Singh D. Reduced exhaled breath condensate pH in asthmatic smokers using inhaled corticosteroids. Respirology. 2009;14(3):419–23.

    Article  PubMed  Google Scholar 

  155. Davies KJ. Oxidative stress: the paradox of aerobic life. Biochem Soc Symp. 1995;61:1–31.

    Article  CAS  PubMed  Google Scholar 

  156. Conner EM, Grisham MB. Inflammation, free radicals, and antioxidants. Nutrition. 1996;12(4):274–7.

    Article  CAS  PubMed  Google Scholar 

  157. Jöbsis Q, Raatgeep HC, Hermans PW, de Jongste JC. Hydrogen peroxide in exhaled air is increased in stable asthmatic children. Eur Respir J. 1997;10(3):519–21.

    PubMed  Google Scholar 

  158. Antczak A, Nowak D, Shariati B, Król M, Piasecka G, Kurmanowska Z. Increased hydrogen peroxide and thiobarbituric acid-reactive products in expired breath condensate of asthmatic patients. Eur Respir J. 1997;10(6):1235–41.

    Article  CAS  PubMed  Google Scholar 

  159. Emelyanov A, Fedoseev G, Abulimity A, Rudinski K, Fedoulov A, Karabanov A, et al. Elevated concentrations of exhaled hydrogen peroxide in asthmatic patients. Chest. 2001;120(4):1136–9.

    Article  CAS  PubMed  Google Scholar 

  160. Loukides S, Bouros D, Papatheodorou G, Panagou P, Siafakas NM. The relationships among hydrogen peroxide in expired breath condensate, airway inflammation, and asthma severity. Chest. 2002;121(2):338–46.

    Article  CAS  PubMed  Google Scholar 

  161. Al-Obaidy AH, Al-Samarai AG. Exhaled breath condensate pH and hydrogen peroxide as non-invasive markers for asthma. Saudi Med J. 2007;28(12):1860–3.

    PubMed  Google Scholar 

  162. Caffarelli C, Calcinai E, Rinaldi L, Povesi Dascola C, Terracciano L, Corradi M. Hydrogen peroxide in exhaled breath condensate in asthmatic children during acute exacerbation and after treatment. Respiration. 2012;84(4):291–8.

    Article  CAS  PubMed  Google Scholar 

  163. Murata K, Fujimoto K, Kitaguchi Y, Horiuchi T, Kubo K, Honda T. Hydrogen peroxide content and pH of expired breath condensate from patients with asthma and COPD. COPD. 2014;11(1):81–7.

    Article  PubMed  Google Scholar 

  164. Warwick G, Thomas PS, Yates DH. Non-invasive biomarkers in exacerbations of obstructive lung disease. Respirology. 2013;18(5):874–84.

    Article  PubMed  Google Scholar 

  165. Trischler J, Merkel N, Konitzer S, Muller CM, Unverzagt S, Lex C. Fractionated breath condensate sampling: H(2)O(2) concentrations of the alveolar fraction may be related to asthma control in children. Respir Res. 2012;13:14.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  166. Al Obaidi AH, Al Samarai AM. Biochemical markers as a response guide for steroid therapy in asthma. J Asthma. 2008;45(5):425–8.

    Article  PubMed  CAS  Google Scholar 

  167. Teng Y, Sun P, Zhang J, Yu R, Bai J, Yao X, et al. Hydrogen peroxide in exhaled breath condensate in patients with asthma: a promising biomarker? Chest. 2011;140(1):108–16.

    Article  CAS  PubMed  Google Scholar 

  168. Robroeks CM, van Vliet D, Jobsis Q, Braekers R, Rijkers GT, Wodzig WK, et al. Prediction of asthma exacerbations in children: results of a one-year prospective study. Clin Exp Allergy. 2012;42(5):792–8.

    Article  CAS  PubMed  Google Scholar 

  169. Sood A, Qualls C, Seagrave J, McDonald J, Shohreh R, Chiavaroli A, et al. Effect of allergen inhalation on airway oxidant stress, using exhaled breath condensate 8-isoprostane, in mild asthma. J Asthma. 2013;50(5):449–56.

    Article  CAS  PubMed  Google Scholar 

  170. Koskela HO, Purokivi MK, Nieminen RM, Moilanen E. Asthmatic cough and airway oxidative stress. Respir Physiol Neurobiol. 2012;181(3):346–50.

    Article  CAS  PubMed  Google Scholar 

  171. Montuschi P, Corradi M, Ciabattoni G, Nightingale J, Kharitonov SA, Barnes PJ. Increased 8-isoprostane, a marker of oxidative stress, in exhaled condensate of asthma patients. Am J Respir Crit Care Med. 1999;160(1):216–20.

    Article  CAS  PubMed  Google Scholar 

  172. Baraldi E, Ghiro L, Piovan V, Carraro S, Ciabattoni G, Barnes PJ, et al. Increased exhaled 8-isoprostane in childhood asthma. Chest. 2003;124(1):25–31.

    Article  CAS  PubMed  Google Scholar 

  173. Mondino C, Ciabattoni G, Koch P, Pistelli R, Trove A, Barnes PJ, et al. Effects of inhaled corticosteroids on exhaled leukotrienes and prostanoids in asthmatic children. J Allergy Clin Immunol. 2004;114(4):761–7.

    Article  CAS  PubMed  Google Scholar 

  174. Zanconato S, Carraro S, Corradi M, Alinovi R, Pasquale MF, Piacentini G, et al. Leukotrienes and 8-isoprostane in exhaled breath condensate of children with stable and unstable asthma. J Allergy Clin Immunol. 2004;113(2):257–63.

    Article  CAS  PubMed  Google Scholar 

  175. Shahid SK, Kharitonov SA, Wilson NM, Bush A, Barnes PJ. Exhaled 8-isoprostane in childhood asthma. Respir Res. 2005;6:79.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  176. Samitas K, Chorianopoulos D, Vittorakis S, Zervas E, Economidou E, Papatheodorou G, et al. Exhaled cysteinyl-leukotrienes and 8-isoprostane in patients with asthma and their relation to clinical severity. Respir Med. 2009;103(5):750–6.

    Article  PubMed  Google Scholar 

  177. Caballero Balanzá S, Martorell Aragonés A, Cerdá Mir JC, Belda Ramírez J, Navarro Iváñez R, Navarro Soriano A, et al. Leukotriene B4 and 8-isoprostane in exhaled breath condensate of children with episodic and persistent asthma. J Investig Allergol Clin Immunol. 2010;20(3):237–43.

    PubMed  Google Scholar 

  178. Hasan RA, O’Brien E, Mancuso P. Lipoxin A(4) and 8-isoprostane in the exhaled breath condensate of children hospitalized for status asthmaticus. Pediatr Crit Med. 2012;13(2):141–5.

    Article  Google Scholar 

  179. Carraro S, Cogo PE, Isak I, Simonato M, Corradi M, Carnielli VP, et al. EIA and GC/MS analysis of 8-isoprostane in EBC of children with problematic asthma. Eur Respir J. 2010;35(6):1364–9.

    Article  CAS  PubMed  Google Scholar 

  180. Keskin O, Balaban S, Keskin M, Kucukosmanoglu E, Gogebakan B, Ozkars MY, et al. Relationship between exhaled leukotriene and 8-isoprostane levels and asthma severity, asthma control level, and asthma control test score. Allergol Immunopathol. 2014;42(3):191–7.

    Article  CAS  Google Scholar 

  181. Brussino L, Badiu I, Sciascia S, Bugiani M, Heffler E, Guida G, et al. Oxidative stress and airway inflammation after allergen challenge evaluated by exhaled breath condensate analysis. Clin Exp Allergy. 2010;40(11):1642–7.

    Article  CAS  PubMed  Google Scholar 

  182. Piotrowski WJ, Majewski S, Marczak J, Kurmanowska Z, Gorski P, Antczak A. Exhaled breath 8-isoprostane as a marker of asthma severity. Arch Med Sci. 2012;8(3):515–20.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  183. Keskin O, Uluca U, Keskin M, Gogebakan B, Kucukosmanoglu E, Ozkars MY, et al. The efficacy of single-high dose inhaled corticosteroid versus oral prednisone treatment on exhaled leukotriene and 8-isoprostane levels in mild to moderate asthmatic children with asthma exacerbation. Allergol Immunopathol. 2016;44(2):138–48.

    Article  CAS  Google Scholar 

  184. Liu J, Thomas PS. Exhaled breath condensate as a method of sampling airway nitric oxide and other markers of inflammation. Med Sci Monit. 2005;11(8):MT53–62.

    CAS  PubMed  Google Scholar 

  185. Ganas K, Loukides S, Papatheodorou G, Panagou P, Kalogeropoulos N. Total nitrite/nitrate in expired breath condensate of patients with asthma. Respir Med. 2001;95(8):649–54.

    Article  CAS  PubMed  Google Scholar 

  186. Corradi M, Pesci A, Casana R, Alinovi R, Goldoni M, Vettori MV, et al. Nitrate in exhaled breath condensate of patients with different airway diseases. Nitric Oxide. 2003;8(1):26–30.

    Article  CAS  PubMed  Google Scholar 

  187. Ratnawati, Morton J, Henry RL, Thomas PS. Exhaled breath condensate nitrite/nitrate and pH in relation to pediatric asthma control and exhaled nitric oxide. Pediatr Pulmonol. 2006;41(10):929–36.

    Article  CAS  PubMed  Google Scholar 

  188. Zetterquist W, Marteus H, Hedlin G, Alving K. Increased exhaled nitrite in children with allergic asthma is not related to nitric oxide formation. Clin Respir J. 2008;2(3):166–74.

    Article  CAS  PubMed  Google Scholar 

  189. Bouzigon E, Monier F, Boussaha M, Le Moual N, Huyvaert H, Matran R, et al. Associations between nitric oxide synthase genes and exhaled NO-related phenotypes according to asthma status. PLoS One. 2012;7(5):e36672.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  190. Hauswirth DW, Sundy JS, Mervin-Blake S, Fernandez CA, Patch KB, Alexander KM, et al. Normative values for exhaled breath condensate pH and its relationship to exhaled nitric oxide in healthy African Americans. J Allergy Clin Immunol. 2008;122(1):101–6.

    Article  CAS  PubMed  Google Scholar 

  191. Rihak V, Zatloukal P, Chladkova J, Zimulova A, Havlinova Z, Chladek J. Nitrite in exhaled breath condensate as a marker of nitrossative stress in the airways of patients with asthma, COPD, and idiopathic pulmonary fibrosis. J Clin Lab Anal. 2010;24(5):317–22.

    Article  CAS  PubMed  Google Scholar 

  192. Malinovschi A, Pizzimenti S, Sciascia S, Heffler E, Badiu I, Rolla G. Exhaled breath condensate nitrates, but not nitrites or FENO, relate to asthma control. Respir Med. 2011;105(7):1007–13.

    Article  PubMed  Google Scholar 

  193. Scott JA, North ML, Rafii M, Huang H, Pencharz P, Subbarao P, et al. Asymmetric dimethylarginine is increased in asthma. Am J Respir Crit Care Med. 2011;184(7):779–85.

    Article  CAS  PubMed  Google Scholar 

  194. Carraro S, Giordano G, Piacentini G, Kantar A, Moser S, Cesca L, et al. Asymmetric dimethylarginine in exhaled breath condensate and serum of children with asthma. Chest. 2013;144(2):405–10.

    Article  CAS  PubMed  Google Scholar 

  195. Samuelsson B, Granstrom E, Green K, Hamberg M, Hammarstrom S. Prostaglandins. Annu Rev Biochem. 1975;44:669–95.

    Article  CAS  PubMed  Google Scholar 

  196. Montuschi P, Barnes PJ. Analysis of exhaled breath condensate for monitoring airway inflammation. Trends Pharmacol Sci. 2002;23(5):232–7.

    Article  CAS  PubMed  Google Scholar 

  197. Montuschi P, Barnes PJ. Exhaled leukotrienes and prostaglandins in asthma. J Allergy Clin Immunol. 2002;109(4):615–20.

    Article  CAS  PubMed  Google Scholar 

  198. Samuelsson B. Leukotrienes: mediators of immediate hypersensitivity reactions and inflammation. Science. 1983;220(4597):568–75.

    Article  CAS  PubMed  Google Scholar 

  199. Montuschi P, Sala A, Dahlen S-E, Folco G. Pharmacological modulation of the leukotriene pathway in allergic airway disease. Drug Discov Today. 2007;12:404.

    Article  CAS  PubMed  Google Scholar 

  200. Wardlaw AJ, Hay H, Cromwell O, Collins JV, Kay AB. Leukotrienes, LTC4 and LTB4, in bronchoalveolar lavage in bronchial asthma and other respiratory diseases. J Allergy Clin Immunol. 1989;84(1):19–26.

    Article  CAS  PubMed  Google Scholar 

  201. Claesson HE, Odlander B, Jakobsson PJ. Leukotriene B4 in the immune system. Int J Immunopharmacol. 1992;14(3):441–9.

    Article  CAS  PubMed  Google Scholar 

  202. Hallstrand TS, Henderson WR Jr. An update on the role of leukotrienes in asthma. Curr Opin Allergy Clin Immunol. 2010;10(1):60–6.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  203. Holgate ST, Peters-Golden M, Panettieri RA, Henderson WR Jr. Roles of cysteinyl leukotrienes in airway inflammation, smooth muscle function, and remodeling. J Allergy Clin Immunol. 2003;111(1 Suppl):S18–34. discussion S-6

    Article  CAS  PubMed  Google Scholar 

  204. Ono E, Mita H, Taniguchi M, Higashi N, Tsuburai T, Hasegawa M, et al. Increase in inflammatory mediator concentrations in exhaled breath condensate after allergen inhalation. J Allergy Clin Immunol. 2008;122(4):768–73.e1.

    Article  CAS  PubMed  Google Scholar 

  205. Antczak A, Montuschi P, Kharitonov S, Gorski P, Barnes PJ. Increased exhaled cysteinyl-leukotrienes and 8-isoprostane in aspirin-induced asthma. Am J Respir Crit Care Med. 2002;166(3):301–6.

    Article  PubMed  Google Scholar 

  206. Montuschi P, Mondino C, Koch P, Barnes PJ, Ciabattoni G. Effects of a leukotriene receptor antagonist on exhaled leukotriene E4 and prostanoids in children with asthma. J Allergy Clin Immunol. 2006;118(2):347–53.

    Article  CAS  PubMed  Google Scholar 

  207. Kielbasa B, Moeller A, Sanak M, Hamacher J, Hutterli M, Cmiel A, et al. Eicosanoids in exhaled breath condensates in the assessment of childhood asthma. Pediatr Allergy Immunol. 2008;19(7):660–9.

    PubMed  Google Scholar 

  208. Hanazawa T, Kharitonov SA, Barnes PJ. Increased nitrotyrosine in exhaled breath condensate of patients with asthma. Am J Respir Crit Care Med. 2000;162(4 Pt 1):1273–6.

    Article  CAS  PubMed  Google Scholar 

  209. Cap P, Chladek J, Pehal F, Maly M, Petru V, Barnes PJ, et al. Gas chromatography/mass spectrometry analysis of exhaled leukotrienes in asthmatic patients. Thorax. 2004;59(6):465–70.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  210. Baraldi E, Carraro S, Alinovi R, Pesci A, Ghiro L, Bodini A, et al. Cysteinyl leukotrienes and 8-isoprostane in exhaled breath condensate of children with asthma exacerbations. Thorax. 2003;58(6):505–9.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  211. Laberge S, El Bassam S. Cytokines, structural cells of the lungs and airway inflammation. Paediatr Respir Rev. 2004;5(Suppl A):S41–5.

    Article  PubMed  Google Scholar 

  212. Shahid SK, Kharitonov SA, Wilson NM, Bush A, Barnes PJ. Increased interleukin-4 and decreased interferon-gamma in exhaled breath condensate of children with asthma. Am J Respir Crit Care Med. 2002;165(9):1290–3.

    Article  PubMed  Google Scholar 

  213. Carpagnano GE, Resta O, Ventura MT, Amoruso AC, Di Gioia G, Giliberti T, et al. Airway inflammation in subjects with gastro-oesophageal reflux and gastro-oesophageal reflux-related asthma. J Intern Med. 2006;259(3):323–31.

    Article  CAS  PubMed  Google Scholar 

  214. Robroeks CM, van de Kant KD, Jobsis Q, Hendriks HJ, van Gent R, Wouters EF, et al. Exhaled nitric oxide and biomarkers in exhaled breath condensate indicate the presence, severity and control of childhood asthma. Clin Exp Allergy. 2007;37(9):1303–11.

    Article  CAS  PubMed  Google Scholar 

  215. Profita M, La Grutta S, Carpagnano E, Riccobono L, Di Giorgi R, Bonanno A, et al. Noninvasive methods for the detection of upper and lower airway inflammation in atopic children. J Allergy Clin Immunol. 2006;118(5):1068–74.

    Article  PubMed  Google Scholar 

  216. Carpagnano GE, Foschino Barbaro MP, Cagnazzo M, Di Gioia G, Giliberti T, Di Matteo C, et al. Use of exhaled breath condensate in the study of airway inflammation after hypertonic saline solution challenge. Chest. 2005;128(5):3159–66.

    Article  PubMed  Google Scholar 

  217. Matsunaga K, Yanagisawa S, Ichikawa T, Ueshima K, Akamatsu K, Hirano T, et al. Airway cytokine expression measured by means of protein array in exhaled breath condensate: correlation with physiologic properties in asthmatic patients. J Allergy Clin Immunol. 2006;118(1):84–90.

    Article  CAS  PubMed  Google Scholar 

  218. Ojoo JC, Mulrennan SA, Kastelik JA, Morice AH, Redington AE. Exhaled breath condensate pH and exhaled nitric oxide in allergic asthma and in cystic fibrosis. Thorax. 2005;60(1):22–6.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  219. Gluck J, Rymarczyk B, Kasprzak M, Rogala B. Increased levels of interleukin-33 and thymic stromal lymphopoietin in exhaled breath condensate in chronic bronchial asthma. Int Arch Allergy Immunol. 2016;169(1):51–6.

    Article  PubMed  CAS  Google Scholar 

  220. Zietkowski Z, Skiepko R, Tomasiak MM, Bodzenta-Lukaszyk A. Endothelin-1 in exhaled breath condensate of stable and unstable asthma patients. Respir Med. 2008;102(3):470–4.

    Article  CAS  PubMed  Google Scholar 

  221. Zietkowski Z, Tomasiak MM, Skiepko R, Bodzenta-Lukaszyk A. RANTES in exhaled breath condensate of stable and unstable asthma patients. Respir Med. 2008;102(8):1198–202.

    Article  CAS  PubMed  Google Scholar 

  222. Zietkowski Z, Tomasiak-Lozowska MM, Skiepko R, Zietkowska E, Bodzenta-Lukaszyk A. Eotaxin-1 in exhaled breath condensate of stable and unstable asthma patients. Respir Res. 2010;11:110.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  223. Wu D, Zhou J, Bi H, Li L, Gao W, Huang M, et al. CCL11 as a potential diagnostic marker for asthma? J Asthma. 2014;51(8):847–54.

    Article  CAS  PubMed  Google Scholar 

  224. Huszar E, Vass G, Vizi E, Csoma Z, Barat E, Molnar Vilagos G, et al. Adenosine in exhaled breath condensate in healthy volunteers and in patients with asthma. Eur Respir J. 2002;20(6):1393–8.

    Article  CAS  PubMed  Google Scholar 

  225. Greenwald R, Fitzpatrick AM, Gaston B, Marozkina NV, Erzurum S, Teague WG. Breath formate is a marker of airway S-nitrosothiol depletion in severe asthma. PLoS One. 2010;5(7):e11919.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  226. Simpson JL, Scott RJ, Boyle MJ, Gibson PG. Differential proteolytic enzyme activity in eosinophilic and neutrophilic asthma. Am J Respir Crit Care Med. 2005;172(5):559–65.

    Article  PubMed  Google Scholar 

  227. Corradi M, Folesani G, Andreoli R, Manini P, Bodini A, Piacentini G, et al. Aldehydes and glutathione in exhaled breath condensate of children with asthma exacerbation. Am J Respir Crit Care Med. 2003;167(3):395–9.

    Article  PubMed  Google Scholar 

  228. Zietkowski Z, Tomasiak-Lozowska MM, Skiepko R, Mroczko B, Szmitkowski M, Bodzenta-Lukaszyk A. High-sensitivity C-reactive protein in the exhaled breath condensate and serum in stable and unstable asthma. Respir Med. 2009;103(3):379–85.

    Article  PubMed  Google Scholar 

  229. Grob NM, Aytekin M, Dweik RA. Biomarkers in exhaled breath condensate: a review of collection, processing and analysis. J Breath Res. 2008;2(3):037004.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  230. Bloemen K, Van Den Heuvel R, Govarts E, Hooyberghs J, Nelen V, Witters E, et al. A new approach to study exhaled proteins as potential biomarkers for asthma. Clin Exp Allergy. 2011;41(3):346–56.

    Article  CAS  PubMed  Google Scholar 

  231. Bartoli ML, Novelli F, Costa F, Malagrino L, Melosini L, Bacci E, et al. Malondialdehyde in exhaled breath condensate as a marker of oxidative stress in different pulmonary diseases. Mediat Inflamm. 2011;2011:891752.

    Article  CAS  Google Scholar 

  232. Motta A, Paris D, D’Amato M, Melck D, Calabrese C, Vitale C, et al. NMR metabolomic analysis of exhaled breath condensate of asthmatic patients at two different temperatures. J Proteome Res. 2014;13(12):6107–20.

    Article  CAS  PubMed  Google Scholar 

  233. Klaassen EM, van de Kant KD, Jobsis Q, Penders J, van Schooten FJ, Quaak M, et al. Integrative genomic analysis identifies a role for intercellular adhesion molecule 1 in childhood asthma. Pediatr Allergy Immunol. 2014;25(2):166–72.

    Article  PubMed  Google Scholar 

  234. Miekisch W, Schubert JK, Noeldge-Schomburg GF. Diagnostic potential of breath analysis—focus on volatile organic compounds. Clin Chim Acta. 2004;347(1–2):25–39.

    Article  CAS  PubMed  Google Scholar 

  235. Buszewski B, Kesy M, Ligor T, Amann A. Human exhaled air analytics: biomarkers of diseases. Biomedical Chromatogr. 2007;21(6):553–66.

    Article  CAS  Google Scholar 

  236. van de Kant KD, van der Sande LJ, Jobsis Q, van Schayck OC, Dompeling E. Clinical use of exhaled volatile organic compounds in pulmonary diseases: a systematic review. Respir Res. 2012;13:117.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  237. Olopade CO, Zakkar M, Swedler WI, Rubinstein I. Exhaled pentane levels in acute asthma. Chest. 1997;111(4):862–5.

    Article  CAS  PubMed  Google Scholar 

  238. Caldeira M, Perestrelo R, Barros AS, Bilelo MJ, Morete A, Camara JS, et al. Allergic asthma exhaled breath metabolome: a challenge for comprehensive two-dimensional gas chromatography. J Chromatogr A. 2012;1254:87–97.

    Article  CAS  PubMed  Google Scholar 

  239. Smolinska A, Klaassen EM, Dallinga JW, van de Kant KD, Jobsis Q, Moonen EJ, et al. Profiling of volatile organic compounds in exhaled breath as a strategy to find early predictive signatures of asthma in children. PLoS One. 2014;9(4):e95668.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  240. Dragonieri S, Schot R, Mertens BJ, Le Cessie S, Gauw SA, Spanevello A, et al. An electronic nose in the discrimination of patients with asthma and controls. J Allergy Clin Immunol. 2007;120(4):856–62.

    Article  PubMed  Google Scholar 

  241. Paredi P, Kharitonov SA, Barnes PJ. Elevation of exhaled ethane concentration in asthma. Am J Respir Crit Care Med. 2000;162(4 Pt 1):1450–4.

    Article  CAS  PubMed  Google Scholar 

  242. Fens N, Zwinderman AH, van der Schee MP, de Nijs SB, Dijkers E, Roldaan AC, et al. Exhaled breath profiling enables discrimination of chronic obstructive pulmonary disease and asthma. Am J Respir Crit Care Med. 2009;180(11):1076–82.

    Article  CAS  PubMed  Google Scholar 

  243. Timms C, Thomas PS, Yates DH. Detection of gastro-oesophageal reflux disease (GORD) in patients with obstructive lung disease using exhaled breath profiling. J Breath Res. 2012;6(1):016003.

    Article  PubMed  Google Scholar 

  244. Delfino RJ, Gong H, Linn WS, Hu Y, Pellizzari ED. Respiratory symptoms and peak expiratory flow in children with asthma in relation to volatile organic compounds in exhaled breath and ambient air. J Expo Anal Environ Epidemiol. 2003;13(5):348–63.

    Article  CAS  PubMed  Google Scholar 

  245. Robroeks CM, van Berkel JJ, Jobsis Q, van Schooten FJ, Dallinga JW, Wouters EF, et al. Exhaled volatile organic compounds predict exacerbations of childhood asthma in a 1-year prospective study. Eur Respir J. 2013;42(1):98–106.

    Article  CAS  PubMed  Google Scholar 

  246. van der Schee MP, Palmay R, Cowan JO, Taylor DR. Predicting steroid responsiveness in patients with asthma using exhaled breath profiling. Clin Exp Allergy. 2013;43(11):1217–25.

    Article  PubMed  CAS  Google Scholar 

  247. Sly PD, Boner AL, Bjorksten B, Bush A, Custovic A, Eigenmann PA, et al. Early identification of atopy in the prediction of persistent asthma in children. Lancet. 2008;372(9643):1100–6.

    Article  PubMed Central  PubMed  Google Scholar 

  248. Simpson A, Tan VY, Winn J, Svensen M, Bishop CM, Heckerman DE, et al. Beyond atopy: multiple patterns of sensitization in relation to asthma in a birth cohort study. Am J Respir Crit Care Med. 2010;181(11):1200–6.

    Article  PubMed  Google Scholar 

  249. Stoltz DJ, Jackson DJ, Evans MD, Gangnon RE, Tisler CJ, Gern JE, et al. Specific patterns of allergic sensitization in early childhood and asthma & rhinitis risk. Clin Exp Allergy. 2013;43(2):233–41.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  250. Bousquet J, Wenzel S, Holgate S, Lumry W, Freeman P, Fox H. Predicting response to omalizumab, an anti-IgE antibody, in patients with allergic asthma. Chest. 2004;125(4):1378–86.

    Article  CAS  PubMed  Google Scholar 

  251. Wahn U, Martin C, Freeman P, Blogg M, Jimenez P. Relationship between pretreatment specific IgE and the response to omalizumab therapy. Allergy. 2009;64(12):1780–7.

    Article  CAS  PubMed  Google Scholar 

  252. Szefler SJ, Wenzel S, Brown R, Erzurum SC, Fahy JV, Hamilton RG, et al. Asthma outcomes: biomarkers. J Allergy Clin Immunol. 2012;129(3 Suppl):S9–23.

    Article  PubMed Central  PubMed  Google Scholar 

  253. Peters MC, Mekonnen ZK, Yuan S, Bhakta NR, Woodruff PG, Fahy JV. Measures of gene expression in sputum cells can identify TH2-high and TH2-low subtypes of asthma. J Allergy Clin Immunol. 2014;133(2):388–94.

    Article  CAS  PubMed  Google Scholar 

  254. Tran TN, Khatry DB, Ke X, Ward CK, Gossage D. High blood eosinophil count is associated with more frequent asthma attacks in asthma patients. Ann Allergy Asthma Immunol. 2014;113(1):19–24.

    Article  PubMed  Google Scholar 

  255. Ulrik CS, Frederiksen J. Mortality and markers of risk of asthma death among 1,075 outpatients with asthma. Chest. 1995;108(1):10–5.

    Article  CAS  PubMed  Google Scholar 

  256. Malinovschi A, Fonseca JA, Jacinto T, Alving K, Janson C. Exhaled nitric oxide levels and blood eosinophil counts independently associate with wheeze and asthma events in National Health and Nutrition Examination Survey subjects. J Allergy Clin Immunol. 2013;132(4):821–7 e1-5.

    Article  CAS  PubMed  Google Scholar 

  257. Ulrik CS. Peripheral eosinophil counts as a marker of disease activity in intrinsic and extrinsic asthma. Clin Exp Allergy. 1995;25(9):820–7.

    Article  CAS  PubMed  Google Scholar 

  258. Taylor KJ, Luksza AR. Peripheral blood eosinophil counts and bronchial responsiveness. Thorax. 1987;42(6):452–6.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  259. 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(2):233–42.

    Article  CAS  PubMed  Google Scholar 

  260. Kupczyk M, Haque S, Middelveld RJ, Dahlen B, Dahlen SE, Investigators B. Phenotypic predictors of response to oral glucocorticosteroids in severe asthma. Respir Med. 2013;107(10):1521–30.

    Article  PubMed  Google Scholar 

  261. Castro M, Wenzel SE, Bleecker ER, Pizzichini E, Kuna P, Busse WW, et al. Benralizumab, an anti-interleukin 5 receptor alpha monoclonal antibody, versus placebo for uncontrolled eosinophilic asthma: a phase 2b randomised dose-ranging study. Lancet Respir Med. 2014;2(11):879–90.

    Article  CAS  PubMed  Google Scholar 

  262. Ortega HG, Liu MC, Pavord ID, Brusselle GG, FitzGerald JM, Chetta A, et al. Mepolizumab treatment in patients with severe eosinophilic asthma. N Engl J Med. 2014;371(13):1198–207.

    Article  PubMed  CAS  Google Scholar 

  263. Pavord ID, Korn S, Howarth P, Bleecker ER, Buhl R, Keene ON, et al. Mepolizumab for severe eosinophilic asthma (DREAM): a multicentre, double-blind, placebo-controlled trial. Lancet. 2012;380(9842):651–9.

    Article  CAS  PubMed  Google Scholar 

  264. Bel EH, Wenzel SE, Thompson PJ, Prazma CM, Keene ON, Yancey SW, et al. Oral glucocorticoid-sparing effect of mepolizumab in eosinophilic asthma. N Engl J Med. 2014;371(13):1189–97.

    Article  PubMed  CAS  Google Scholar 

  265. Nair P, Pizzichini MM, Kjarsgaard M, Inman MD, Efthimiadis A, Pizzichini E, et al. Mepolizumab for prednisone-dependent asthma with sputum eosinophilia. N Engl J Med. 2009;360(10):985–93.

    Article  CAS  PubMed  Google Scholar 

  266. Castro M, Mathur S, Hargreave F, Boulet LP, Xie F, Young J, et al. Reslizumab for poorly controlled, eosinophilic asthma: a randomized, placebo-controlled study. Am J Respir Crit Care Med. 2011;184(10):1125–32.

    Article  CAS  PubMed  Google Scholar 

  267. Busse W, Spector S, Rosén K, Wang Y, Alpan O. High eosinophil count: a potential biomarker for assessing successful omalizumab treatment effects. J Allergy Clin Immunol. 2013;132(2):485–6.e11.

    Article  PubMed  Google Scholar 

  268. Haldar P, Brightling CE, Hargadon B, Gupta S, Monteiro W, Sousa A, et al. Mepolizumab and exacerbations of refractory eosinophilic asthma. N Engl J Med. 2009;360(10):973–84.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  269. Leckie MJ, ten Brinke A, Khan J, Diamant Z, O’Connor BJ, Walls CM, et al. Effects of an interleukin-5 blocking monoclonal antibody on eosinophils, airway hyper-responsiveness, and the late asthmatic response. Lancet. 2000;356(9248):2144–8.

    Article  CAS  PubMed  Google Scholar 

  270. Gauthier M, Ray A, Wenzel SE. Evolving concepts of asthma. Am J Respir Crit Care Med. 2015;192(6):660–8.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  271. Takayama G, Arima K, Kanaji T, Toda S, Tanaka H, Shoji S, et al. Periostin: a novel component of subepithelial fibrosis of bronchial asthma downstream of IL-4 and IL-13 signals. J Allergy Clin Immunol. 2006;118(1):98–104.

    Article  CAS  PubMed  Google Scholar 

  272. Sidhu SS, Yuan S, Innes AL, Kerr S, Woodruff PG, Hou L, et al. Roles of epithelial cell-derived periostin in TGF-beta activation, collagen production, and collagen gel elasticity in asthma. Proc Natl Acad Sci U S A. 2010;107(32):14170–5.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  273. Woodruff PG, Boushey HA, Dolganov GM, Barker CS, Yang YH, Donnelly S, et al. Genome-wide profiling identifies epithelial cell genes associated with asthma and with treatment response to corticosteroids. Proc Natl Acad Sci U S A. 2007;104(40):15858–63.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  274. Yuyama N, Davies DE, Akaiwa M, Matsui K, Hamasaki Y, Suminami Y, et al. Analysis of novel disease-related genes in bronchial asthma. Cytokine. 2002;19(6):287–96.

    Article  CAS  PubMed  Google Scholar 

  275. Lopez-Guisa JM, Powers C, File D, Cochrane E, Jimenez N, Debley JS. Airway epithelial cells from asthmatic children differentially express proremodeling factors. J Allergy Clin Immunol. 2012;129(4):990–7. e6

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  276. Blanchard C, Mingler MK, McBride M, Putnam PE, Collins MH, Chang G, et al. Periostin facilitates eosinophil tissue infiltration in allergic lung and esophageal responses. Mucosal Immunol. 2008;1(4):289–96.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  277. Conway SJ, Izuhara K, Kudo Y, Litvin J, Markwald R, Ouyang G, et al. The role of periostin in tissue remodeling across health and disease. Cell Mol Life Sci. 2014;71(7):1279–88.

    Article  CAS  PubMed  Google Scholar 

  278. Jia G, Erickson RW, Choy DF, Mosesova S, Wu LC, Solberg OD, et al. Periostin is a systemic biomarker of eosinophilic airway inflammation in asthmatic patients. J Allergy Clin Immunol. 2012;130(3):647–54. e10

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  279. Kanemitsu Y, Matsumoto H, Izuhara K, Tohda Y, Kita H, Horiguchi T, et al. Increased periostin associates with greater airflow limitation in patients receiving inhaled corticosteroids. J Allergy Clin Immunol. 2013;132(2):305–12. e3

    Article  CAS  PubMed  Google Scholar 

  280. Hanania NA, Noonan M, Corren J, Korenblat P, Zheng Y, Fischer SK, et al. Lebrikizumab in moderate-to-severe asthma: pooled data from two randomised placebo-controlled studies. Thorax. 2015;70(8):748–56.

    Article  PubMed Central  PubMed  Google Scholar 

  281. Corren J, Lemanske RF, Hanania NA, Korenblat PE, Parsey MV, Arron JR, et al. Lebrikizumab treatment in adults with asthma. N Engl J Med. 2011;365(12):1088–98.

    Article  CAS  PubMed  Google Scholar 

  282. Masuoka M, Shiraishi H, Ohta S, Suzuki S, Arima K, Aoki S, et al. Periostin promotes chronic allergic inflammation in response to Th2 cytokines. J Clin Invest. 2012;122(7):2590–600.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  283. Matsumoto H. Serum periostin: a novel biomarker for asthma management. Allergol Int. 2014;63(2):153–60.

    Article  CAS  PubMed  Google Scholar 

  284. Izuhara K, Matsumoto H, Ohta S, Ono J, Arima K, Ogawa M. Recent developments regarding periostin in bronchial asthma. Allergol Int. 2015;64(Suppl):S3–10.

    Article  PubMed  Google Scholar 

  285. Bobolea I, Barranco P, Del Pozo V, Romero D, Sanz V, Lopez-Carrasco V, et al. Sputum periostin in patients with different severe asthma phenotypes. Allergy. 2015;70(5):540–6.

    Article  CAS  PubMed  Google Scholar 

  286. Gorska K, Maskey-Warzechowska M, Nejman-Gryz P, Korczynski P, Prochorec-Sobieszek M, Krenke R. Comparative study of periostin expression in different respiratory samples in patients with asthma and chronic obstructive pulmonary disease. Pol Arch Med Wewn. 2016;126(3):124–37.

    PubMed  Google Scholar 

  287. Patil SP, Wisnivesky JP, Busse PJ, Halm EA, Li XM. Detection of immunological biomarkers correlated with asthma control and quality of life measurements in sera from chronic asthmatic patients. Ann Allergy Asthma Immunol. 2011;106(3):205–13.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  288. Saad-El-Din Bessa S, Abo El-Magd GH, Mabrouk MM. Serum chemokines RANTES and monocyte chemoattractant protein-1 in Egyptian patients with atopic asthma: relationship to disease severity. Arch Med Res. 2012;43(1):36–41.

    Article  CAS  PubMed  Google Scholar 

  289. Chambers ES, Nanzer AM, Pfeffer PE, Richards DF, Timms PM, Martineau AR, et al. Distinct endotypes of steroid-resistant asthma characterized by IL-17A(high) and IFN-gamma(high) immunophenotypes: potential benefits of calcitriol. J Allergy Clin Immunol. 2015;136(3):628–37. e4

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  290. Ciprandi G, Cuppari C, Salpietro AM, Tosca MA, Rigoli L, Grasso L, et al. Serum IL-23 strongly and inversely correlates with FEV1 in asthmatic children. Int Arch Allergy Immunol. 2012;159(2):183–6.

    Article  CAS  PubMed  Google Scholar 

  291. Sziksz E, Kozma GT, Pallinger E, Komlosi ZI, Adori C, Kovacs L, et al. Galectin-9 in allergic airway inflammation and hyper-responsiveness in mice. Int Arch Allergy Immunol. 2010;151(4):308–17.

    Article  CAS  PubMed  Google Scholar 

  292. Niki T, Tsutsui S, Hirose S, Aradono S, Sugimoto Y, Takeshita K, et al. Galectin-9 is a high affinity IgE-binding lectin with anti-allergic effect by blocking IgE-antigen complex formation. J Biol Chem. 2009;284(47):32344–52.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  293. Katoh S, Shimizu H, Obase Y, Oomizu S, Niki T, Ikeda M, et al. Preventive effect of galectin-9 on double-stranded RNA-induced airway hyperresponsiveness in an exacerbation model of mite antigen-induced asthma in mice. Exp Lung Res. 2013;39(10):453–62.

    Article  CAS  PubMed  Google Scholar 

  294. Hsu DK, Zuberi RI, Liu FT. Biochemical and biophysical characterization of human recombinant IgE-binding protein, an S-type animal lectin. J Biol Chem. 1992;267(20):14167–74.

    CAS  PubMed  Google Scholar 

  295. Di Lella S, Sundblad V, Cerliani JP, Guardia CM, Estrin DA, Vasta GR, et al. When galectins recognize glycans: from biochemistry to physiology and back again. Biochemistry. 2011;50(37):7842–57.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  296. Newlaczyl AU, Yu LG. Galectin-3—a jack-of-all-trades in cancer. Cancer Lett. 2011;313(2):123–8.

    Article  CAS  PubMed  Google Scholar 

  297. Mauri P, Riccio AM, Rossi R, Di Silvestre D, Benazzi L, De Ferrari L, et al. Proteomics of bronchial biopsies: galectin-3 as a predictive biomarker of airway remodelling modulation in omalizumab-treated severe asthma patients. Immunol Lett. 2014;162(1 Pt A):2–10.

    Article  CAS  PubMed  Google Scholar 

  298. Mosca T, Menezes MC, Dionigi PC, Stirbulov R, Forte WC. C3 and C4 complement system components as biomarkers in the intermittent atopic asthma diagnosis. J Pediatr. 2011;87(6):512–6.

    Google Scholar 

  299. Tang H, Fang Z, Sun Y, Li B, Shi Z, Chen J, et al. YKL-40 in asthmatic patients, and its correlations with exacerbation, eosinophils and immunoglobulin E. Eur Respir J. 2010;35(4):757–60.

    Article  CAS  PubMed  Google Scholar 

  300. Specjalski K, Jassem E. YKL-40 protein is a marker of asthma. J Asthma. 2011;48(8):767–72.

    Article  CAS  PubMed  Google Scholar 

  301. Ezzat MH, Imam SS, Shaheen KY, Elbrhami EM. Serum OX40 ligand levels in asthmatic children: a potential biomarker of severity and persistence. Allergy Asthma Proc. 2011;32(4):313–8.

    Article  CAS  PubMed  Google Scholar 

  302. Tanju A, Cekmez F, Aydinoz S, Karademir F, Suleymanoglu S, Gocmen I. Association between clinical severity of childhood asthma and serum leptin levels. Indian J Pediatr. 2011;78(3):291–5.

    Article  PubMed  Google Scholar 

  303. Nishioka T, Uchida K, Meno K, Ishii T, Aoki T, Imada Y, et al. Alpha-1-antitrypsin and complement component C7 are involved in asthma exacerbation. Proteomics Clin Appl. 2008;2(1):46–54.

    Article  CAS  PubMed  Google Scholar 

  304. Rhim T, Choi YS, Nam BY, Uh ST, Park JS, Kim YH, et al. Plasma protein profiles in early asthmatic responses to inhalation allergen challenge. Allergy. 2009;64(1):47–54.

    Article  CAS  PubMed  Google Scholar 

  305. Singh A, Cohen Freue GV, Oosthuizen JL, Kam SH, Ruan J, Takhar MK, et al. Plasma proteomics can discriminate isolated early from dual responses in asthmatic individuals undergoing an allergen inhalation challenge. Proteomics Clin Appl. 2012;6(9–10):476–85.

    Article  CAS  PubMed  Google Scholar 

  306. Izbicka E, Streeper RT, Michalek JE, Louden CL, Diaz A 3rd, Campos DR. Plasma biomarkers distinguish non-small cell lung cancer from asthma and differ in men and women. Cancer Genomics Proteomics. 2012;9(1):27–35.

    CAS  PubMed  Google Scholar 

  307. Verrills NM, Irwin JA, He XY, Wood LG, Powell H, Simpson JL, et al. Identification of novel diagnostic biomarkers for asthma and chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2011;183(12):1633–43.

    Article  CAS  PubMed  Google Scholar 

  308. Araújo L, Moreira A, Palmares C, Beltrão M, Fonseca J, Delgado L. Induced sputum in children: success determinants, safety, and cell profiles. J Investig Allergol Clin Immunol. 2011;21(3):216–21.

    PubMed  Google Scholar 

  309. Dasgupta A, Nair P. When are biomarkers useful in the management of airway diseases? Pol Arch Med Wewn. 2013;123(4):183–8.

    PubMed  Google Scholar 

  310. Efthimiadis A, Spanevello A, Hamid Q, Kelly MM, Linden M, Louis R, et al. Methods of sputum processing for cell counts, immunocytochemistry and in situ hybridisation. Eur Respir J Suppl. 2002;37:19s–23s.

    CAS  PubMed  Google Scholar 

  311. Gershman NH, Wong HH, Liu JT, Mahlmeister MJ, Fahy JV. Comparison of two methods of collecting induced sputum in asthmatic subjects. Eur Respir J. 1996;9(12):2448–53.

    Article  CAS  PubMed  Google Scholar 

  312. Pin I, Gibson PG, Kolendowicz R, Girgis-Gabardo A, Denburg JA, Hargreave FE, et al. Use of induced sputum cell counts to investigate airway inflammation in asthma. Thorax. 1992;47(1):25–9.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  313. Pizzichini E, Pizzichini MM, Efthimiadis A, Hargreave FE, Dolovich J. Measurement of inflammatory indices in induced sputum: effects of selection of sputum to minimize salivary contamination. Eur Respir J. 1996;9(6):1174–80.

    Article  CAS  PubMed  Google Scholar 

  314. Fireman E, Toledano B, Buchner N, Stark M, Schwarz Y. Simplified detection of eosinophils in induced sputum. Inflamm Res. 2011;60(8):745–50.

    Article  CAS  PubMed  Google Scholar 

  315. Goncalves J, Pizzichini E, Pizzichini MM, Steidle LJ, Rocha CC, Ferreira SC, et al. Reliability of a rapid hematology stain for sputum cytology. J Bras Pneumol. 2014;40(3):250–8.

    Article  PubMed Central  PubMed  Google Scholar 

  316. Wenzel SE, Schwartz LB, Langmack EL, Halliday JL, Trudeau JB, Gibbs RL, 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(3):1001–8.

    Article  CAS  PubMed  Google Scholar 

  317. Simpson JL, Scott R, Boyle MJ, Gibson PG. Inflammatory subtypes in asthma: assessment and identification using induced sputum. Respirology. 2006;11(1):54–61.

    Article  PubMed  Google Scholar 

  318. Reddel HK, Taylor DR, Bateman ED, Boulet LP, Boushey HA, Busse WW, et al. An official American Thoracic Society/European Respiratory Society statement: asthma control and exacerbations: standardizing endpoints for clinical asthma trials and clinical practice. Am J Respir Crit Care Med. 2009;180(1):59–99.

    Article  PubMed  Google Scholar 

  319. Belda J, Leigh R, Parameswaran K, O’Byrne PM, Sears MR, Hargreave FE. Induced sputum cell counts in healthy adults. Am J Respir Crit Care Med. 2000;161(2 Pt 1):475–8.

    Article  CAS  PubMed  Google Scholar 

  320. Louis R, Sele J, Henket M, Cataldo D, Bettiol J, Seiden L, et al. Sputum eosinophil count in a large population of patients with mild to moderate steroid-naive asthma: distribution and relationship with methacholine bronchial hyperresponsiveness. Allergy. 2002;57(10):907–12.

    Article  CAS  PubMed  Google Scholar 

  321. in’t Veen JC, Smits HH, Hiemstra PS, Zwinderman AE, Sterk PJ, Bel EH. 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(1):93–9.

    Article  PubMed  Google Scholar 

  322. Hastie AT, Moore WC, Meyers DA, Vestal PL, Li H, Peters SP, et al. Analyses of asthma severity phenotypes and inflammatory proteins in subjects stratified by sputum granulocytes. J Allergy Clin Immunol. 2010;125(5):1028–36. e13

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  323. Jatakanon A, Lim S, Barnes PJ. Changes in sputum eosinophils predict loss of asthma control. Am J Respir Crit Care Med. 2000;161(1):64–72.

    Article  CAS  PubMed  Google Scholar 

  324. Woodruff PG, Khashayar R, Lazarus SC, Janson S, Avila P, Boushey HA, et al. Relationship between airway inflammation, hyperresponsiveness, and obstruction in asthma. J Allergy Clin Immunol. 2001;108(5):753–8.

    Article  CAS  PubMed  Google Scholar 

  325. Berry M, Morgan A, Shaw DE, Parker D, Green R, Brightling C, et al. Pathological features and inhaled corticosteroid response of eosinophilic and non-eosinophilic asthma. Thorax. 2007;62(12):1043–9.

    Article  PubMed Central  PubMed  Google Scholar 

  326. 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(10):875–9.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  327. Green RH, Brightling CE, McKenna S, Hargadon B, Parker D, Bradding P, et al. Asthma exacerbations and sputum eosinophil counts: a randomised controlled trial. Lancet. 2002;360(9347):1715–21.

    Article  PubMed  Google Scholar 

  328. van Rensen EL, Straathof KC, Veselic-Charvat MA, Zwinderman AH, Bel EH, Sterk PJ. Effect of inhaled steroids on airway hyperresponsiveness, sputum eosinophils, and exhaled nitric oxide levels in patients with asthma. Thorax. 1999;54(5):403–8.

    Article  PubMed Central  PubMed  Google Scholar 

  329. Pizzichini MM, Pizzichini E, Clelland L, Efthimiadis A, Mahony J, Dolovich J, et al. Sputum in severe exacerbations of asthma: kinetics of inflammatory indices after prednisone treatment. Am J Respir Crit Care Med. 1997;155(5):1501–8.

    Article  CAS  PubMed  Google Scholar 

  330. Leuppi JD, Salome CM, Jenkins CR, Anderson SD, Xuan W, Marks GB, et al. Predictive markers of asthma exacerbation during stepwise dose reduction of inhaled corticosteroids. Am J Respir Crit Care Med. 2001;163(2):406–12.

    Article  CAS  PubMed  Google Scholar 

  331. Deykin A, Lazarus SC, Fahy JV, Wechsler ME, Boushey HA, Chinchilli VM, et al. Sputum eosinophil counts predict asthma control after discontinuation of inhaled corticosteroids. J Allergy Clin Immunol. 2005;115(4):720–7.

    Article  CAS  PubMed  Google Scholar 

  332. Flood-Page P, Swenson C, Faiferman I, Matthews J, Williams M, Brannick L, et al. A study to evaluate safety and efficacy of mepolizumab in patients with moderate persistent asthma. Am J Respir Crit Care Med. 2007;176(11):1062–71.

    Article  CAS  PubMed  Google Scholar 

  333. Moore WC, Hastie AT, Li X, Li H, Busse WW, Jarjour NN, et al. Sputum neutrophil counts are associated with more severe asthma phenotypes using cluster analysis. J Allergy Clin Immunol. 2014;133(6):1557–63.e5.

    Article  PubMed  Google Scholar 

  334. Wenzel SE, Szefler SJ, Leung DY, Sloan SI, Rex MD, Martin RJ. Bronchoscopic evaluation of severe asthma. Persistent inflammation associated with high dose glucocorticoids. Am J Respir Crit Care Med. 1997;156(3 Pt 1):737–43.

    Article  CAS  PubMed  Google Scholar 

  335. Choi JS, Jang AS, Park JS, Park SW, Paik SH, Park JS, et al. Role of neutrophils in persistent airway obstruction due to refractory asthma. Respirology. 2012;17(2):322–9.

    Article  PubMed  Google Scholar 

  336. Schleich FN, Manise M, Sele J, Henket M, Seidel L, Louis R. Distribution of sputum cellular phenotype in a large asthma cohort: predicting factors for eosinophilic vs neutrophilic inflammation. BMC Pulm Med. 2013;13:11.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  337. Cowan DC, Cowan JO, Palmay R, Williamson A, Taylor DR. Effects of steroid therapy on inflammatory cell subtypes in asthma. Thorax. 2010;65(5):384–90.

    Article  PubMed  Google Scholar 

  338. Nguyen LT, Lim S, Oates T, Chung KF. Increase in airway neutrophils after oral but not inhaled corticosteroid therapy in mild asthma. Respir Med. 2005;99(2):200–7.

    Article  PubMed  Google Scholar 

  339. Shannon J, Ernst P, Yamauchi Y, Olivenstein R, Lemiere C, Foley S, et al. Differences in airway cytokine profile in severe asthma compared to moderate asthma. Chest. 2008;133(2):420–6.

    Article  CAS  PubMed  Google Scholar 

  340. McKinley L, Alcorn JF, Peterson A, Dupont RB, Kapadia S, Logar A, et al. TH17 cells mediate steroid-resistant airway inflammation and airway hyperresponsiveness in mice. J Immunol. 2008;181(6):4089–97.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  341. Al-Ramli W, Prefontaine D, Chouiali F, Martin JG, Olivenstein R, Lemiere C, et al. T(H)17-associated cytokines (IL-17A and IL-17F) in severe asthma. J Allergy Clin Immunol. 2009;123(5):1185–7.

    Article  CAS  PubMed  Google Scholar 

  342. Lajoie S, Lewkowich IP, Suzuki Y, Clark JR, Sproles AA, Dienger K, et al. Complement-mediated regulation of the IL-17A axis is a central genetic determinant of the severity of experimental allergic asthma. Nat Immunol. 2010;11(10):928–35.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  343. Hastie AT, Moore WC, Li H, Rector BM, Ortega VE, Pascual RM, et al. Biomarker surrogates do not accurately predict sputum eosinophil and neutrophil percentages in asthmatic subjects. J Allergy Clin Immunol. 2013;132(1):72–80.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  344. Bakakos P, Schleich F, Alchanatis M, Louis R. Induced sputum in asthma: from bench to bedside. Curr Med Chem. 2011;18(10):1415–22.

    Article  CAS  PubMed  Google Scholar 

  345. Koh GC, Shek LP, Goh DY, Van Bever H, Koh DS. Eosinophil cationic protein: is it useful in asthma? A systematic review. Respir Med. 2007;101(4):696–705.

    Article  PubMed  Google Scholar 

  346. Kim CK, Callaway Z, Fletcher R, Koh YY. Eosinophil-derived neurotoxin in childhood asthma: correlation with disease severity. J Asthma. 2010;47(5):568–73.

    Article  CAS  PubMed  Google Scholar 

  347. Pavord ID, Bafadhel M. Exhaled nitric oxide and blood eosinophilia: independent markers of preventable risk. J Allergy Clin Immunol. 2013;132(4):828–9.

    Article  CAS  PubMed  Google Scholar 

  348. Jia CE, Zhang HP, Lv Y, Liang R, Jiang YQ, Powell H, et al. The Asthma Control Test and Asthma Control Questionnaire for assessing asthma control: systematic review and meta-analysis. J Allergy Clin Immunol. 2013;131(3):695–703.

    Article  PubMed  Google Scholar 

  349. Mostafa GA, Reda SM, Abd El-Aziz MM, Ahmed SA. Sputum neurokinin A in Egyptian asthmatic children and adolescents: relation to exacerbation severity. Allergy. 2008;63(9):1244–7.

    Article  CAS  PubMed  Google Scholar 

  350. Yamaguchi M, Niimi A, Matsumoto H, Ueda T, Takemura M, Matsuoka H, et al. Sputum levels of transforming growth factor-beta1 in asthma: relation to clinical and computed tomography findings. J Investig Allergol Clin Immunol. 2008;18(3):202–6.

    CAS  PubMed  Google Scholar 

  351. Mattos W, Lim S, Russell R, Jatakanon A, Chung KF, Barnes PJ. Matrix metalloproteinase-9 expression in asthma: effect of asthma severity, allergen challenge, and inhaled corticosteroids. Chest. 2002;122(5):1543–52.

    Article  CAS  PubMed  Google Scholar 

  352. Saito J, Zhang Q, Hui C, Macedo P, Gibeon D, Menzies-Gow A, et al. Sputum hydrogen sulfide as a novel biomarker of obstructive neutrophilic asthma. J Allergy Clin Immunol. 2013;131(1):232–4 e1-3.

    Article  CAS  PubMed  Google Scholar 

  353. Brickey WJ, Alexis NE, Hernandez ML, Reed W, Ting JP, Peden DB. Sputum inflammatory cells from patients with allergic rhinitis and asthma have decreased inflammasome gene expression. J Allergy Clin Immunol. 2011;128(4):900–3.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  354. Alexis NE, Soukup J, Nierkens S, Becker S. Association between airway hyperreactivity and bronchial macrophage dysfunction in individuals with mild asthma. Am J Physiol Lung Cell Mol Physiol. 2001;280(2):L369–75.

    CAS  PubMed  Google Scholar 

  355. Alexis NE, Brickey WJ, Lay JC, Wang Y, Roubey RA, Ting JP, et al. Development of an inhaled endotoxin challenge protocol for characterizing evoked cell surface phenotype and genomic responses of airway cells in allergic individuals. Ann Allergy Asthma Immunol. 2008;100(3):206–15.

    Article  CAS  PubMed  Google Scholar 

  356. Loughlin CE, Esther CR Jr, Lazarowski ER, Alexis NE, Peden DB. Neutrophilic inflammation is associated with altered airway hydration in stable asthmatics. Respir Med. 2010;104(1):29–33.

    Article  PubMed  Google Scholar 

  357. Brightling CE, Symon FA, Birring SS, Bradding P, Pavord ID, Wardlaw AJ. TH2 cytokine expression in bronchoalveolar lavage fluid T lymphocytes and bronchial submucosa is a feature of asthma and eosinophilic bronchitis. J Allergy Clin Immunol. 2002;110(6):899–905.

    Article  CAS  PubMed  Google Scholar 

  358. Alexis NE, Hu SC, Zeman K, Alter T, Bennett WD. Induced sputum derives from the central airways: confirmation using a radiolabeled aerosol bolus delivery technique. Am J Respir Crit Care Med. 2001;164(10 Pt 1):1964–70.

    Article  CAS  PubMed  Google Scholar 

  359. Alexis N, Soukup J, Ghio A, Becker S. Sputum phagocytes from healthy individuals are functional and activated: a flow cytometric comparison with cells in bronchoalveolar lavage and peripheral blood. Clin Immunol. 2000;97(1):21–32.

    Article  CAS  PubMed  Google Scholar 

  360. Goleva E, Jackson LP, Harris JK, Robertson CE, Sutherland ER, Hall CF, et al. The effects of airway microbiome on corticosteroid responsiveness in asthma. Am J Respir Crit Care Med. 2013;188(10):1193–201.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  361. Esnault S, Kelly EA, Schwantes EA, Liu LY, DeLain LP, Hauer JA, et al. Identification of genes expressed by human airway eosinophils after an in vivo allergen challenge. PLoS One. 2013;8(7):e67560.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  362. Vargas JE, Porto BN, Puga R, Stein RT, Pitrez PM. Identifying a biomarker network for corticosteroid resistance in asthma from bronchoalveolar lavage samples. Mol Biol Rep. 2016;43(7):697–710.

    Article  CAS  PubMed  Google Scholar 

  363. Park SW, Lee EH, Lee EJ, Kim HJ, Bae DJ, Han S, et al. Apolipoprotein A1 potentiates lipoxin A4 synthesis and recovery of allergen-induced disrupted tight junctions in the airway epithelium. Clin Exp Allergy. 2013;43(8):914–27.

    Article  CAS  PubMed  Google Scholar 

  364. Sampson AP. The leukotrienes: mediators of chronic inflammation in asthma. Clin Exp Allergy. 1996;26(9):995–1004.

    Article  CAS  PubMed  Google Scholar 

  365. Montuschi P, Peters-Golden ML. Leukotriene modifiers for asthma treatment. Clin Exp Allergy. 2010;40(12):1732–41.

    Article  CAS  PubMed  Google Scholar 

  366. Montuschi P, Santini G, Valente S, Mondino C, Macagno F, Cattani P, et al. Liquid chromatography-mass spectrometry measurement of leukotrienes in asthma and other respiratory diseases. J Chromatogr B. 2014;964:12–25.

    Article  CAS  Google Scholar 

  367. Severien C, Artlich A, Jonas S, Becher G. Urinary excretion of leukotriene E4 and eosinophil protein X in children with atopic asthma. Eur Respir J. 2000;16(4):588–92.

    Article  CAS  PubMed  Google Scholar 

  368. Suzuki N, Hishinuma T, Abe F, Omata K, Ito S, Sugiyama M, et al. Difference in urinary LTE4 and 11-dehydro-TXB2 excretion in asthmatic patients. Prostaglandins Other Lipid Mediat. 2000;62(4):395–403.

    Article  CAS  PubMed  Google Scholar 

  369. Aggarwal S, Moodley YP, Thompson PJ, Misso NL. Prostaglandin E2 and cysteinyl leukotriene concentrations in sputum: association with asthma severity and eosinophilic inflammation. Clin Exp Allergy. 2010;40(1):85–93.

    CAS  PubMed  Google Scholar 

  370. Marmarinos A, Saxoni-Papageorgiou P, Cassimos D, Manoussakis E, Tsentidis C, Doxara A, et al. Urinary leukotriene E4 levels in atopic and non-atopic preschool children with recurrent episodic (viral) wheezing: a potential marker? J Asthma. 2015;52(6):554–9.

    Article  PubMed  CAS  Google Scholar 

  371. Morales M, Flores C, Pino K, Angulo J, Lopez-Lastra M, Castro-Rodriguez JA. Urinary leukotriene and Bcl I polymorphism of glucocorticoid receptor gene in preschoolers with recurrent wheezing and high risk of asthma. Allergol Immunopathol. 2016;44(1):59–65.

    Article  CAS  Google Scholar 

  372. Chiu CY, Tsai MH, Yao TC, Tu YL, Hua MC, Yeh KW, et al. Urinary LTE4 levels as a diagnostic marker for IgE-mediated asthma in preschool children: a birth cohort study. PLoS One. 2014;9(12):e115216.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  373. Higashi N, Mita H, Ono E, Fukutomi Y, Yamaguchi H, Kajiwara K, et al. Profile of eicosanoid generation in aspirin-intolerant asthma and anaphylaxis assessed by new biomarkers. J Allergy Clin Immunol. 2010;125(5):1084–91. e6

    Article  CAS  PubMed  Google Scholar 

  374. O’Shaughnessy KM, Wellings R, Gillies B, Fuller RW. Differential effects of fluticasone propionate on allergen-evoked bronchoconstriction and increased urinary leukotriene E4 excretion. Am Rev Respir Dis. 1993;147(6 Pt 1):1472–6.

    Article  PubMed  Google Scholar 

  375. Liu MC, Dube LM, Lancaster J. Acute and chronic effects of a 5-lipoxygenase inhibitor in asthma: a 6-month randomized multicenter trial. Zileuton Study Group. J Allergy Clin Immunol. 1996;98(5 Pt 1):859–71.

    Article  CAS  PubMed  Google Scholar 

  376. Thomson NC, Chaudhuri R, Spears M, Messow CM, Jelinsky S, Miele G, et al. Arachidonic acid metabolites and enzyme transcripts in asthma are altered by cigarette smoking. Allergy. 2014;69(4):527–36.

    Article  CAS  PubMed  Google Scholar 

  377. Rabinovitch N, Reisdorph N, Silveira L, Gelfand EW. Urinary leukotriene E(4) levels identify children with tobacco smoke exposure at risk for asthma exacerbation. J Allergy Clin Immunol. 2011;128(2):323–7.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  378. Murray JJ, Tonnel AB, Brash AR, Roberts LJ 2nd, Gosset P, Workman R, et al. Release of prostaglandin D2 into human airways during acute antigen challenge. N Engl J Med. 1986;315(13):800–4.

    Article  CAS  PubMed  Google Scholar 

  379. O’Sullivan S, Dahlen B, Dahlen SE, Kumlin M. Increased urinary excretion of the prostaglandin D2 metabolite 9 alpha, 11 beta-prostaglandin F2 after aspirin challenge supports mast cell activation in aspirin-induced airway obstruction. J Allergy Clin Immunol. 1996;98(2):421–32.

    Article  PubMed  Google Scholar 

  380. Nagakura T, Obata T, Shichijo K, Matsuda S, Sigimoto H, Yamashita K, et al. GC/MS analysis of urinary excretion of 9alpha,11beta-PGF2 in acute and exercise-induced asthma in children. Clin Exp Allergy. 1998;28(2):181–6.

    Article  CAS  PubMed  Google Scholar 

  381. Misso NL, Aggarwal S, Phelps S, Beard R, Thompson PJ. Urinary leukotriene E4 and 9 alpha, 11 beta-prostaglandin F concentrations in mild, moderate and severe asthma, and in healthy subjects. Clin Exp Allergy. 2004;34(4):624–31.

    Article  CAS  PubMed  Google Scholar 

  382. Reimert CM, Minuva U, Kharazmi A, Bendtzen K. Eosinophil protein X/eosinophil derived neurotoxin (EPX/EDN). Detection by enzyme-linked immunosorbent assay and purification from normal human urine. J Immunol Methods. 1991;141(1):97–104.

    Article  CAS  PubMed  Google Scholar 

  383. Klonoff-Cohen H, Polavarapu M. Eosinophil protein X and childhood asthma: a systematic review and meta-analysis. Immun Inflamm Dis. 2016;4(2):114–34.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  384. Khalil Kalaajieh W, Hoilat R. Asthma attack severity and urinary concentration of eosinophil X protein in children. Allergol Immunopathol. 2002;30(4):225–31.

    Article  Google Scholar 

  385. Nuijsink M, Hop WC, Sterk PJ, Duiverman EJ, De Jongste JC. Urinary eosinophil protein X in childhood asthma: relation with changes in disease control and eosinophilic airway inflammation. Mediat Inflamm. 2013;2013:532619.

    Article  CAS  Google Scholar 

  386. Wu W, Chen Y, d’Avignon A, Hazen SL. 3-Bromotyrosine and 3,5-dibromotyrosine are major products of protein oxidation by eosinophil peroxidase: potential markers for eosinophil-dependent tissue injury in vivo. Biochemistry. 1999;38(12):3538–48.

    Article  CAS  PubMed  Google Scholar 

  387. Wu W, Samoszuk MK, Comhair SA, Thomassen MJ, Farver CF, Dweik RA, et al. Eosinophils generate brominating oxidants in allergen-induced asthma. J Clin Invest. 2000;105(10):1455–63.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  388. Wedes SH, Wu W, Comhair SA, McDowell KM, DiDonato JA, Erzurum SC, et al. Urinary bromotyrosine measures asthma control and predicts asthma exacerbations in children. J Pediatr. 2011;159(2):248–55.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

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Li, W., Glaum, M.C. (2018). Biomarkers in Severe Asthma. In: Lee, Y., Kim, S., Cho, S. (eds) Severe Asthma. Springer, Singapore. https://doi.org/10.1007/978-981-10-1998-2_4

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