Advertisement

Practical Considerations in the Management of Eosinophilic Asthma

  • Anurag Bhalla
  • Parameswaran NairEmail author
Chapter
  • 436 Downloads
Part of the Respiratory Medicine book series (RM)

Abstract

“Eosinophilic asthma” is a new terminology that has come to be used to describe an old concept of patients with asthma whose symptoms and severity are predominantly driven by the eosinophil. Quantitative sputum cytometry is the most validated and sensitive test for diagnosis of eosinophilic asthma. Other biomarkers, including blood eosinophils, immunoglobulin (Ig) E, fraction of exhaled nitric oxide (FeNO), and periostin, have also been used as surrogates for airway eosinophilia. Corticosteroids, inhaled and systemic, are mainstay of treatment and are most effective when they are titrated guided by sputum eosinophil percent. Recent approval of monoclonal antibodies directed against key mediators of type 2 inflammation, notably IgE, interleukin (IL)-5, IL-4, and IL-13, have added to the arsenal of treatment options available for patients with severe asthma. Anti-alarmin (including thymic stromal lymphopoietin (TSLP) and IL-33) and anti-chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTh2) therapies are currently under evaluation.

Keywords

Eosinophilic asthma Endotype Sputum eosinophils Blood eosinophils FeNO Omalizumab Mepolizumab Reslizumab Benralizumab Dupilumab 

Notes

Disclosure Statement

P. Nair is supported by the Frederick E. Hargreave Teva Innovation Chair in Airway Diseases. In the past 2 years, he has received consultancy and lecture fees from Astra-Zeneca, Sanofi, Teva, Novartis, Theravance, Knopp, Merck, GlaxoSmithKline, and Roche and research support from GlaxoSmithKline, AstraZeneca, and Novartis; and his institution has received research support from Roche, Teva, Sanofi, Boehringer Ingelheim, AstraZeneca, and Novartis. A. Bhalla does not have any conflicts to declare.

References

  1. 1.
    Hargreave FE, Nair P. The definition and diagnosis of asthma. Clin Exp Allergy. 2009;39(11):1652–8.PubMedCrossRefPubMedCentralGoogle Scholar
  2. 2.
    D’Silva L, Hassan N, Wang HY, Kjarsgaard M, Efthimiadis A, Hargreave FE, et al. Heterogeneity of bronchitis in airway diseases in tertiary care clinical practice. Can Respir J. 2011;18(3):144–8.PubMedPubMedCentralCrossRefGoogle Scholar
  3. 3.
    Brown HM. Treatment of chronic asthma with prednisolone; significance of eosinophils in the sputum. Lancet (London, England). 1958;2(7059):1245–7.CrossRefGoogle Scholar
  4. 4.
    Kay AB, Phipps S, Robinson DS. A role for eosinophils in airway remodelling in asthma. Trends Immunol. 2004;25(9):477–82.PubMedCrossRefPubMedCentralGoogle Scholar
  5. 5.
    ten Brinke A, Zwinderman AH, Sterk PJ, Rabe KF, Bel EH. Factors associated with persistent airflow limitation in severe asthma. Am J Respir Crit Care Med. 2001;164(5):744–8.PubMedCrossRefPubMedCentralGoogle Scholar
  6. 6.
    Schleich FN, Chevremont A, Paulus V, Henket M, Manise M, Seidel L, et al. Importance of concomitant local and systemic eosinophilia in uncontrolled asthma. Eur Respir J. 2014;44(1):97–108.PubMedCrossRefPubMedCentralGoogle Scholar
  7. 7.
    Nair P, Dasgupta A, Brightling CE, Chung KF. How to diagnose and phenotype asthma. Clin Chest Med. 2012;33(3):445–57.PubMedCrossRefPubMedCentralGoogle Scholar
  8. 8.
    Wenzel SE. Asthma: defining of the persistent adult phenotypes. Lancet (London, England). 2006;368(9537):804–13.CrossRefGoogle Scholar
  9. 9.
    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.CrossRefGoogle Scholar
  10. 10.
    van Veen IH, Ten Brinke A, Gauw SA, Sterk PJ, Rabe KF, Bel EH. Consistency of sputum eosinophilia in difficult-to-treat asthma: a 5-year follow-up study. J Allergy Clin Immunol. 2009;124(3):615–7, 7.e1-2.PubMedPubMedCentralCrossRefGoogle Scholar
  11. 11.
    McGrath KW, Icitovic N, Boushey HA, Lazarus SC, Sutherland ER, Chinchilli VM, et al. A large subgroup of mild-to-moderate asthma is persistently noneosinophilic. Am J Respir Crit Care Med. 2012;185(6):612–9.PubMedPubMedCentralCrossRefGoogle Scholar
  12. 12.
    Juniper EF, O’Byrne PM, Guyatt GH, Ferrie PJ, King DR. Development and validation of a questionnaire to measure asthma control. Eur Respir J. 1999;14(4):902–7.PubMedCrossRefPubMedCentralGoogle Scholar
  13. 13.
    Juniper EF, Bousquet J, Abetz L, Bateman ED. Identifying ‘well-controlled’ and ‘not well-controlled’ asthma using the asthma control questionnaire. Respir Med. 2006;100(4):616–21.PubMedCrossRefPubMedCentralGoogle Scholar
  14. 14.
    Nathan RA, Sorkness CA, Kosinski M, Schatz M, Li JT, Marcus P, et al. Development of the asthma control test: a survey for assessing asthma control. J Allergy Clin Immunol. 2004;113(1):59–65.PubMedCrossRefPubMedCentralGoogle Scholar
  15. 15.
    Koolen BB, Pijnenburg MW, Brackel HJ, Landstra AM, van den Berg NJ, Merkus PJ, et al. Comparing Global Initiative For Asthma (GINA) criteria with the Childhood Asthma Control Test (C-ACT) and Asthma Control Test (ACT). Eur Respir J. 2011;38(3):561–6.PubMedCrossRefPubMedCentralGoogle Scholar
  16. 16.
    Radhakrishna N, Tay TR, Hore-Lacy F, Hoy R, Dabscheck E, Hew M. Profile of difficult to treat asthma patients referred for systematic assessment. Respir Med. 2016;117:166–73.PubMedCrossRefPubMedCentralGoogle Scholar
  17. 17.
    Tay TR, Radhakrishna N, Hore-Lacy F, Smith C, Hoy R, Dabscheck E, et al. Comorbidities in difficult asthma are independent risk factors for frequent exacerbations, poor control and diminished quality of life. Respirology (Carlton, VIC). 2016;21(8):1384–90.CrossRefGoogle Scholar
  18. 18.
    Gamble J, Stevenson M, McClean E, Heaney LG. The prevalence of nonadherence in difficult asthma. Am J Respir Crit Care Med. 2009;180(9):817–22.PubMedPubMedCentralCrossRefGoogle Scholar
  19. 19.
    Murphy AC, Proeschal A, Brightling CE, Wardlaw AJ, Pavord I, Bradding P, et al. The relationship between clinical outcomes and medication adherence in difficult-to-control asthma. Thorax. 2012;67(8):751–3.PubMedPubMedCentralCrossRefGoogle Scholar
  20. 20.
    Williams LK, Peterson EL, Wells K, Ahmedani BK, Kumar R, Burchard EG, et al. Quantifying the proportion of severe asthma exacerbations attributable to inhaled corticosteroid nonadherence. J Allergy Clin Immunol. 2011;128(6):1185–91.e2.PubMedPubMedCentralCrossRefGoogle Scholar
  21. 21.
    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.CrossRefGoogle Scholar
  22. 22.
    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.PubMedPubMedCentralCrossRefGoogle Scholar
  23. 23.
    Pizzichini MM, Popov TA, Efthimiadis A, Hussack P, Evans S, Pizzichini E, et al. Spontaneous and induced sputum to measure indices of airway inflammation in asthma. Am J Respir Crit Care Med. 1996;154(4Pt 1):866–9.PubMedCrossRefPubMedCentralGoogle Scholar
  24. 24.
    Vlachos-Mayer H, Leigh R, Sharon RF, Hussack P, Hargreave FE. Success and safety of sputum induction in the clinical setting. Eur Respir J. 2000;16(5):997–1000.PubMedCrossRefPubMedCentralGoogle Scholar
  25. 25.
    Popov TA, Pizzichini MM, Pizzichini E, Kolendowicz R, Punthakee Z, Dolovich J, et al. Some technical factors influencing the induction of sputum for cell analysis. Eur Respir J. 1995;8(4):559–65.PubMedPubMedCentralGoogle Scholar
  26. 26.
    Kelly MM, Efthimiadis A, Hargreave FE. Induced sputum: selection method. Methods Mol Med. 2001;56:77–91.PubMedPubMedCentralGoogle Scholar
  27. 27.
    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.PubMedCrossRefPubMedCentralGoogle Scholar
  28. 28.
    Spanevello A, Confalonieri M, Sulotto F, Romano F, Balzano G, Migliori GB, et al. Induced sputum cellularity. Reference values and distribution in normal volunteers. Am J Respir Crit Care Med. 2000;162(3 Pt 1):1172–4.PubMedCrossRefPubMedCentralGoogle Scholar
  29. 29.
    Nair P. What is an “eosinophilic phenotype” of asthma? J Allergy Clin Immunol. 2013;132(1):81–3.PubMedCrossRefPubMedCentralGoogle Scholar
  30. 30.
    Jayaram L, Pizzichini MM, Cook RJ, Boulet LP, Lemiere C, Pizzichini E, et al. Determining asthma treatment by monitoring sputum cell counts: effect on exacerbations. Eur Respir J. 2006;27(3):483–94.PubMedCrossRefPubMedCentralGoogle Scholar
  31. 31.
    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 (London, England). 2002;360(9347):1715–21.CrossRefGoogle Scholar
  32. 32.
    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.PubMedCrossRefGoogle Scholar
  33. 33.
    Persson C. Primary lysis of eosinophils in severe desquamative asthma. Clin Exp Allergy. 2014;44(2):173–83.PubMedCrossRefGoogle Scholar
  34. 34.
    Parameswaran K, Anvari M, Efthimiadis A, Kamada D, Hargreave FE, Allen CJ. Lipid-laden macrophages in induced sputum are a marker of oropharyngeal reflux and possible gastric aspiration. Eur Respir J. 2000;16(6):1119–22.PubMedCrossRefGoogle Scholar
  35. 35.
    Leigh R, Sharon RF, Efthimiadis A, Hargreave FE, Kitching AD. Diagnosis of left-ventricular dysfunction from induced sputum examination. Lancet (London, England). 1999;354(9181):833–4.CrossRefGoogle Scholar
  36. 36.
    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.PubMedCrossRefGoogle Scholar
  37. 37.
    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.PubMedPubMedCentralCrossRefGoogle Scholar
  38. 38.
    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 (London, England). 2012;380(9842):651–9.CrossRefGoogle Scholar
  39. 39.
    Sehmi R, Lim HF, Mukherjee M, Huang C, Radford K, Newbold P, et al. Benralizumab attenuates airway eosinophilia in prednisone-dependent asthma. J Allergy Clin Immunol. 2018;141(4):1529–32.e8.PubMedCrossRefGoogle Scholar
  40. 40.
    Wagener AH, de Nijs SB, Lutter R, Sousa AR, Weersink EJ, Bel EH, et al. External validation of blood eosinophils, FE(NO) and serum periostin as surrogates for sputum eosinophils in asthma. Thorax. 2015;70(2):115–20.PubMedPubMedCentralCrossRefGoogle Scholar
  41. 41.
    Belda J, Parameswaran K, Lemiere C, Kamada D, O’Byrne PM, Hargreave FE. Predictors of loss of asthma control induced by corticosteroid withdrawal. Can Respir J. 2006;13(3):129–33.PubMedPubMedCentralCrossRefGoogle Scholar
  42. 42.
    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.PubMedCrossRefPubMedCentralGoogle Scholar
  43. 43.
    Wark PA, McDonald VM, Gibson PG. Adjusting prednisone using blood eosinophils reduces exacerbations and improves asthma control in difficult patients with asthma. Respirology (Carlton, VIC). 2015;20(8):1282–4.CrossRefGoogle Scholar
  44. 44.
    Brightling CE, Green RH, Pavord ID. Biomarkers predicting response to corticosteroid therapy in asthma. Treat Respir Med. 2005;4(5):309–16.PubMedCrossRefPubMedCentralGoogle Scholar
  45. 45.
    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.CrossRefGoogle Scholar
  46. 46.
    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.PubMedCrossRefGoogle Scholar
  47. 47.
    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.PubMedCrossRefGoogle Scholar
  48. 48.
    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.PubMedCrossRefPubMedCentralGoogle Scholar
  49. 49.
    FitzGerald JM, Bleecker ER, Nair P, Korn S, Ohta K, Lommatzsch M, et al. Benralizumab, an anti-interleukin-5 receptor alpha monoclonal antibody, as add-on treatment for patients with severe, uncontrolled, eosinophilic asthma (CALIMA): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet (London, England). 2016;388(10056):2128–41.CrossRefGoogle Scholar
  50. 50.
    Nair P, Wenzel S, Rabe KF, Bourdin A, Lugogo NL, Kuna P, et al. Oral glucocorticoid-sparing effect of Benralizumab in severe asthma. N Engl J Med. 2017;376(25):2448–58.CrossRefGoogle Scholar
  51. 51.
    Bjermer L, Lemiere C, Maspero J, Weiss S, Zangrilli J, Germinaro M. Reslizumab for inadequately controlled asthma with elevated blood eosinophil levels: a randomized phase 3 study. Chest. 2016;150(4):789–98.PubMedCrossRefGoogle Scholar
  52. 52.
    Castro M, Zangrilli J, Wechsler ME, Bateman ED, Brusselle GG, Bardin P, et al. Reslizumab for inadequately controlled asthma with elevated blood eosinophil counts: results from two multicentre, parallel, double-blind, randomised, placebo-controlled, phase 3 trials. Lancet Respir Med. 2015;3(5):355–66.PubMedCrossRefGoogle Scholar
  53. 53.
    Ortega HG, Yancey SW, Mayer B, Gunsoy NB, Keene ON, Bleecker ER, et al. Severe eosinophilic asthma treated with mepolizumab stratified by baseline eosinophil thresholds: a secondary analysis of the DREAM and MENSA studies. Lancet Respir Med. 2016;4(7):549–56.PubMedCrossRefPubMedCentralGoogle Scholar
  54. 54.
    Price D, Wilson AM, Chisholm A, Rigazio A, Burden A, Thomas M, et al. Predicting frequent asthma exacerbations using blood eosinophil count and other patient data routinely available in clinical practice. J Asthma Allergy. 2016;9:1–12.PubMedPubMedCentralCrossRefGoogle Scholar
  55. 55.
    Zhang XY, Simpson JL, Powell H, Yang IA, Upham JW, Reynolds PN, et al. Full blood count parameters for the detection of asthma inflammatory phenotypes. Clin Exp Allergy. 2014;44(9):1137–45.CrossRefGoogle Scholar
  56. 56.
    Fowler SJ, Tavernier G, Niven R. High blood eosinophil counts predict sputum eosinophilia in patients with severe asthma. J Allergy Clin Immunol. 2015;135(3):822–4.e2.PubMedCrossRefGoogle Scholar
  57. 57.
    Pizzichini MM, Pizzichini E, Clelland L, Efthimiadis A, Pavord I, Dolovich J, et al. Prednisone-dependent asthma: inflammatory indices in induced sputum. Eur Respir J. 1999;13(1):15–21.PubMedCrossRefGoogle Scholar
  58. 58.
    Mukherjee M, Nair P. Blood or sputum eosinophils to guide asthma therapy? Lancet Respir Med. 2015;3(11):824–5.PubMedCrossRefGoogle Scholar
  59. 59.
    Sehmi R, Smith SG, Kjarsgaard M, Radford K, Boulet LP, Lemiere C, et al. Role of local eosinophilopoietic processes in the development of airway eosinophilia in prednisone-dependent severe asthma. Clin Exp Allergy. 2016;46(6):793–802.PubMedCrossRefPubMedCentralGoogle Scholar
  60. 60.
    Smith SG, Chen R, Kjarsgaard M, Huang C, Oliveria JP, O'Byrne PM, et al. Increased numbers of activated group 2 innate lymphoid cells in the airways of patients with severe asthma and persistent airway eosinophilia. J Allergy Clin Immunol. 2016;137(1):75–86.e8.PubMedCrossRefPubMedCentralGoogle Scholar
  61. 61.
    Mukherjee M, Bulir DC, Radford K, Kjarsgaard M, Huang CM, Jacobsen EA, et al. Sputum autoantibodies in patients with severe eosinophilic asthma. J Allergy Clin Immunol. 2017;141(4):1269–79.PubMedCrossRefPubMedCentralGoogle Scholar
  62. 62.
    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.PubMedPubMedCentralCrossRefGoogle Scholar
  63. 63.
    Jatakanon A, Lim S, Kharitonov SA, Chung KF, Barnes PJ. Correlation between exhaled nitric oxide, sputum eosinophils, and methacholine responsiveness in patients with mild asthma. Thorax. 1998;53(2):91–5.PubMedPubMedCentralCrossRefGoogle Scholar
  64. 64.
    Gibson PG, Henry RL, Thomas P. Noninvasive assessment of airway inflammation in children: induced sputum, exhaled nitric oxide, and breath condensate. Eur Respir J. 2000;16(5):1008–15.PubMedPubMedCentralGoogle Scholar
  65. 65.
    Mattes J, Storm van’s Gravesande K, Reining U, Alving K, Ihorst G, Henschen M, et al. NO in exhaled air is correlated with markers of eosinophilic airway inflammation in corticosteroid-dependent childhood asthma. Eur Respir J. 1999;13(6):1391–5.PubMedPubMedCentralGoogle Scholar
  66. 66.
    Silvestri M, Spallarossa D, Frangova Yourukova V, Battistini E, Fregonese B, Rossi GA. Orally exhaled nitric oxide levels are related to the degree of blood eosinophilia in atopic children with mild-intermittent asthma. Eur Respir J. 1999;13(2):321–6.PubMedCrossRefPubMedCentralGoogle Scholar
  67. 67.
    Lim S, Jatakanon A, John M, Gilbey T, O’Connor BJ, Chung KF, et al. Effect of inhaled budesonide on lung function and airway inflammation. Assessment by various inflammatory markers in mild asthma. Am J Respir Crit Care Med. 1999;159(1):22–30.PubMedCrossRefPubMedCentralGoogle Scholar
  68. 68.
    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.PubMedCrossRefPubMedCentralGoogle Scholar
  69. 69.
    Smith AD, Cowan JO, Brassett KP, Filsell S, McLachlan C, Monti-Sheehan G, et al. Exhaled nitric oxide: a predictor of steroid response. Am J Respir Crit Care Med. 2005;172(4):453–9.PubMedCrossRefPubMedCentralGoogle Scholar
  70. 70.
    Smith AD, Cowan JO, Brassett KP, Herbison GP, Taylor DR. Use of exhaled nitric oxide measurements to guide treatment in chronic asthma. N Engl J Med. 2005;352(21):2163–73.PubMedCrossRefPubMedCentralGoogle Scholar
  71. 71.
    Massaro AF, Gaston B, Kita D, Fanta C, Stamler JS, Drazen JM. Expired nitric oxide levels during treatment of acute asthma. Am J Respir Crit Care Med. 1995;152(2):800–3.PubMedCrossRefPubMedCentralGoogle Scholar
  72. 72.
    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.PubMedPubMedCentralCrossRefGoogle Scholar
  73. 73.
    Kharitonov SA, Wells AU, O’Connor BJ, Cole PJ, Hansell DM, Logan-Sinclair RB, et al. Elevated levels of exhaled nitric oxide in bronchiectasis. Am J Respir Crit Care Med. 1995;151(6):1889–93.PubMedCrossRefPubMedCentralGoogle Scholar
  74. 74.
    Henriksen AH, Sue-Chu M, Holmen TL, Langhammer A, Bjermer L. Exhaled and nasal NO levels in allergic rhinitis: relation to sensitization, pollen season and bronchial hyperresponsiveness. Eur Respir J. 1999;13(2):301–6.PubMedCrossRefPubMedCentralGoogle Scholar
  75. 75.
    Silkoff PE, Caramori M, Tremblay L, McClean P, Chaparro C, Kesten S, et al. Exhaled nitric oxide in human lung transplantation. A noninvasive marker of acute rejection. Am J Respir Crit Care Med. 1998;157(6Pt 1):1822–8.PubMedCrossRefPubMedCentralGoogle Scholar
  76. 76.
    Nair P, Kjarsgaard M, Armstrong S, Efthimiadis A, O’Byrne PM, Hargreave FE. Nitric oxide in exhaled breath is poorly correlated to sputum eosinophils in patients with prednisone-dependent asthma. J Allergy Clin Immunol. 2010;126(2):404–6.PubMedCrossRefPubMedCentralGoogle Scholar
  77. 77.
    Lemiere C, Ernst P, Olivenstein R, Yamauchi Y, Govindaraju K, Ludwig MS, et al. Airway inflammation assessed by invasive and noninvasive means in severe asthma: eosinophilic and noneosinophilic phenotypes. J Allergy Clin Immunol. 2006;118(5):1033–9.CrossRefGoogle Scholar
  78. 78.
    Hanania NA, Alpan O, Hamilos DL, Condemi JJ, Reyes-Rivera I, Zhu J, et al. Omalizumab in severe allergic asthma inadequately controlled with standard therapy: a randomized trial. Ann Intern Med. 2011;154(9):573–82.CrossRefGoogle Scholar
  79. 79.
    Wenzel S, Castro M, Corren J, Maspero J, Wang L, Zhang B, et al. Dupilumab efficacy and safety in adults with uncontrolled persistent asthma despite use of medium-to-high-dose inhaled corticosteroids plus a long-acting beta2 agonist: a randomised double-blind placebo-controlled pivotal phase 2b dose-ranging trial. Lancet (London, England). 2016;388(10039):31–44.CrossRefGoogle Scholar
  80. 80.
    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.PubMedCrossRefPubMedCentralGoogle Scholar
  81. 81.
    Galli SJ, Tsai M. IgE and mast cells in allergic disease. Nat Med. 2012;18(5):693–704.PubMedPubMedCentralCrossRefGoogle Scholar
  82. 82.
    Humbert M, Beasley R, Ayres J, Slavin R, Hebert J, Bousquet J, et al. Benefits of omalizumab as add-on therapy in patients with severe persistent asthma who are inadequately controlled despite best available therapy (GINA 2002 step 4 treatment): INNOVATE. Allergy. 2005;60(3):309–16.PubMedCrossRefPubMedCentralGoogle Scholar
  83. 83.
    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.PubMedPubMedCentralCrossRefGoogle Scholar
  84. 84.
    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.PubMedCrossRefPubMedCentralGoogle Scholar
  85. 85.
    Hanania NA, Korenblat P, Chapman KR, Bateman ED, Kopecky P, Paggiaro P, et al. Efficacy and safety of lebrikizumab in patients with uncontrolled asthma (LAVOLTA I and LAVOLTA II): replicate, phase 3, randomised, double-blind, placebo-controlled trials. Lancet Respir Med. 2016;4(10):781–96.PubMedCrossRefPubMedCentralGoogle Scholar
  86. 86.
    Carpagnano GE, Scioscia G, Lacedonia D, Soccio P, Lepore G, Saetta M, et al. Looking for airways periostin in severe asthma: could it be useful for clustering type 2 endotype? Chest. 2018;154(5):1083–90.PubMedCrossRefPubMedCentralGoogle Scholar
  87. 87.
    Woolnough K, Wardlaw AJ. Eosinophilia in pulmonary disorders. Immunol Allergy Clin N Am. 2015;35(3):477–92.CrossRefGoogle Scholar
  88. 88.
    Curtis C, Ogbogu PU. Evaluation and differential diagnosis of persistent marked eosinophilia. Immunol Allergy Clin N Am. 2015;35(3):387–402.CrossRefGoogle Scholar
  89. 89.
    Aziz-Ur-Rehman A, Dasgupta A, Kjarsgaard M, Hargreave FE, Nair P. Sputum cell counts to manage prednisone-dependent asthma: effects on FEV1 and eosinophilic exacerbations. Allergy Asthma Clin Immunol. 2017;13:17.PubMedPubMedCentralCrossRefGoogle Scholar
  90. 90.
    Kelly MM, Leigh R, Jayaram L, Goldsmith CH, Parameswaran K, Hargreave FE. Eosinophilic bronchitis in asthma: a model for establishing dose-response and relative potency of inhaled corticosteroids. J Allergy Clin Immunol. 2006;117(5):989–94.PubMedCrossRefPubMedCentralGoogle Scholar
  91. 91.
    Nair P. Update on clinical inflammometry for the management of airway diseases. Can Respir J. 2013;20(2):117–20.PubMedPubMedCentralCrossRefGoogle Scholar
  92. 92.
    Malo JL, Cartier A, Merland N, Ghezzo H, Burek A, Morris J, et al. Four-times-a-day dosing frequency is better than a twice-a-day regimen in subjects requiring a high-dose inhaled steroid, budesonide, to control moderate to severe asthma. Am Rev Respir Dis. 1989;140(3):624–8.PubMedCrossRefPubMedCentralGoogle Scholar
  93. 93.
    Liu D, Ahmet A, Ward L, Krishnamoorthy P, Mandelcorn ED, Leigh R, et al. A practical guide to the monitoring and management of the complications of systemic corticosteroid therapy. Allergy Asthma Clin Immunol. 2013;9(1):30.PubMedPubMedCentralCrossRefGoogle Scholar
  94. 94.
    Global Initiative for Asthma. Global strategy for asthma management and prevention, 2017. Available from: www.ginasthma.org.
  95. 95.
    FitzGerald JM, Lemiere C, Lougheed MD, Ducharme FM, Dell SD, Ramsey C, et al. Recognition and management of severe asthma: a Canadian Thoracic Society position statement. Can J Respir Crit Care Sleep Med. 2017;1(4):199–221.CrossRefGoogle Scholar
  96. 96.
    Jabbal S, Lipworth BJ. Blood eosinophils: the forgotten man of inhaled steroid dose titration. Clin Exp Allergy. 2018;48(1):93–5.PubMedCrossRefPubMedCentralGoogle Scholar
  97. 97.
    Evans PM, O’Connor BJ, Fuller RW, Barnes PJ, Chung KF. Effect of inhaled corticosteroids on peripheral blood eosinophil counts and density profiles in asthma. J Allergy Clin Immunol. 1993;91(2):643–50.PubMedCrossRefPubMedCentralGoogle Scholar
  98. 98.
    Kew KM, Karner C, Mindus SM, Ferrara G. Combination formoterol and budesonide as maintenance and reliever therapy versus combination inhaler maintenance for chronic asthma in adults and children. Cochrane Database Syst Rev. 2013;12:CD009019.Google Scholar
  99. 99.
    Sindi A, Todd DC, Nair P. Antiinflammatory effects of long-acting beta2-agonists in patients with asthma: a systematic review and metaanalysis. Chest. 2009;136(1):145–54.PubMedCrossRefPubMedCentralGoogle Scholar
  100. 100.
    Kerstjens HA, Moroni-Zentgraf P, Tashkin DP, Dahl R, Paggiaro P, Vandewalker M, et al. Tiotropium improves lung function, exacerbation rate, and asthma control, independent of baseline characteristics including age, degree of airway obstruction, and allergic status. Respir Med. 2016;117:198–206.PubMedCrossRefPubMedCentralGoogle Scholar
  101. 101.
    Casale TB, Bateman ED, Vandewalker M, Virchow JC, Schmidt H, Engel M, et al. Tiotropium Respimat add-on is efficacious in symptomatic asthma, independent of T2 phenotype. J Allergy Clin Immunol Pract. 2018;6(3):923–35.e9.PubMedCrossRefPubMedCentralGoogle Scholar
  102. 102.
    Gibson PG, Yang IA, Upham JW, Reynolds PN, Hodge S, James AL, et al. Effect of azithromycin on asthma exacerbations and quality of life in adults with persistent uncontrolled asthma (AMAZES): a randomised, double-blind, placebo-controlled trial. Lancet (London, England). 2017;390(10095):659–68.CrossRefGoogle Scholar
  103. 103.
    Pizzichini E, Leff JA, Reiss TF, Hendeles L, Boulet LP, Wei LX, et al. Montelukast reduces airway eosinophilic inflammation in asthma: a randomized, controlled trial. Eur Respir J. 1999;14(1):12–8.PubMedCrossRefPubMedCentralGoogle Scholar
  104. 104.
    Minoguchi K, Kohno Y, Minoguchi H, Kihara N, Sano Y, Yasuhara H, et al. Reduction of eosinophilic inflammation in the airways of patients with asthma using montelukast. Chest. 2002;121(3):732–8.PubMedCrossRefPubMedCentralGoogle Scholar
  105. 105.
    Jayaram L, Pizzichini E, Lemiere C, Man SF, Cartier A, Hargreave FE, et al. Steroid naive eosinophilic asthma: anti-inflammatory effects of fluticasone and montelukast. Thorax. 2005;60(2):100–5.PubMedPubMedCentralCrossRefGoogle Scholar
  106. 106.
    Jayaram L, Duong M, Pizzichini MM, Pizzichini E, Kamada D, Efthimiadis A, et al. Failure of montelukast to reduce sputum eosinophilia in high-dose corticosteroid-dependent asthma. Eur Respir J. 2005;25(1):41–6.PubMedCrossRefPubMedCentralGoogle Scholar
  107. 107.
    Chauhan BF, Ducharme FM. Addition to inhaled corticosteroids of long-acting beta2-agonists versus anti-leukotrienes for chronic asthma. Cochrane Database Syst Rev. 2014;1:CD003137.Google Scholar
  108. 108.
    Bardin P, Kanniess F, Gauvreau G, Bredenbroker D, Rabe KF. Roflumilast for asthma: efficacy findings in mechanism of action studies. Pulm Pharmacol Ther. 2015;35(Suppl):S4–10.PubMedCrossRefPubMedCentralGoogle Scholar
  109. 109.
    Nair P. Anti-interleukin-5 monoclonal antibody to treat severe eosinophilic asthma. N Engl J Med. 2014;371(13):1249–51.PubMedCrossRefPubMedCentralGoogle Scholar
  110. 110.
    McGregor MC, Krings JG, Nair P, Castro M. Role of biologics in asthma. Am J Respir Crit Care Med. 2019;199(4):433–45.PubMedCrossRefPubMedCentralGoogle Scholar
  111. 111.
    Busse WW, Morgan WJ, Gergen PJ, Mitchell HE, Gern JE, Liu AH, et al. Randomized trial of omalizumab (anti-IgE) for asthma in inner-city children. N Engl J Med. 2011;364(11):1005–15.PubMedPubMedCentralCrossRefGoogle Scholar
  112. 112.
    de Llano LP, Vennera Mdel C, Alvarez FJ, Medina JF, Borderias L, Pellicer C, et al. Effects of omalizumab in non-atopic asthma: results from a Spanish multicenter registry. J Asthma. 2013;50(3):296–301.PubMedCrossRefPubMedCentralGoogle Scholar
  113. 113.
    Garcia G, Magnan A, Chiron R, Contin-Bordes C, Berger P, Taille C, et al. A proof-of-concept, randomized, controlled trial of omalizumab in patients with severe, difficult-to-control, nonatopic asthma. Chest. 2013;144(2):411–9.PubMedCrossRefPubMedCentralGoogle Scholar
  114. 114.
    Pillai P, Chan YC, Wu SY, Ohm-Laursen L, Thomas C, Durham SR, et al. Omalizumab reduces bronchial mucosal IgE and improves lung function in non-atopic asthma. Eur Respir J. 2016;48(6):1593–601.PubMedCrossRefPubMedCentralGoogle Scholar
  115. 115.
    Khatri S, Moore W, Gibson PG, Leigh R, Bourdin A, Maspero J, et al. Assessment of the long-term safety of mepolizumab and durability of clinical response in patients with severe eosinophilic asthma. J Allergy Clin Immunol. 2018;Google Scholar
  116. 116.
    Mukherjee M, Cherukat J, Javkar T, Al-Hayyan H, Rezaee N, Kjarsgaard M, Radford K, LaVigne N, Halbecki J, Dvorkin-Gheva A, Nair P. High failure rate of anti-IL-5 therapies in prednisone-dependent asthma is associated with airway autoimmune responses. ATS international conference; Dallas, USA2019.Google Scholar
  117. 117.
    Mukherjee M, Lim HF, Thomas S, Miller D, Kjarsgaard M, Tan B, et al. Airway autoimmune responses in severe eosinophilic asthma following low-dose Mepolizumab therapy. Allergy Asthma Clin Immunol. 2017;13(2)  https://doi.org/10.1186/s13223-016-0174-5.
  118. 118.
    Murphy K, Jacobs J, Bjermer L, Fahrenholz JM, Shalit Y, Garin M, et al. Long-term safety and efficacy of Reslizumab in patients with eosinophilic asthma. J Allergy Clin Immunol Pract. 2017;5(6):1572–81.e3.PubMedCrossRefGoogle Scholar
  119. 119.
    Busse WW, Bleecker ER, FitzGerald JM, Ferguson GT, Barker P, Sproule S, et al. Long-term safety and efficacy of benralizumab in patients with severe, uncontrolled asthma: 1-year results from the BORA phase 3 extension trial. Lancet Respir Med. 2019;7(1):46–59.PubMedCrossRefPubMedCentralGoogle Scholar
  120. 120.
    Bateman ED, Djukanovic R, Castro M, Canvin J, Germinaro M, Noble R, et al. Predicting responders to Reslizumab after 16 weeks of treatment using an algorithm derived from clinical studies of severe eosinophilic asthma patients. Am J Respir Crit Care Med. 2018;199(4):489–95.CrossRefGoogle Scholar
  121. 121.
    Kolbeck R, Kozhich A, Koike M, Peng L, Andersson CK, Damschroder MM, et al. MEDI-563, a humanized anti-IL-5 receptor alpha mAb with enhanced antibody-dependent cell-mediated cytotoxicity function. J Allergy Clin Immunol. 2010;125(6):1344–53.e2.PubMedCrossRefPubMedCentralGoogle Scholar
  122. 122.
    Castro M, Corren J, Pavord ID, Maspero J, Wenzel S, Rabe KF, et al. Dupilumab efficacy and safety in moderate-to-severe uncontrolled asthma. N Engl J Med. 2018;378(26):2486–96.CrossRefGoogle Scholar
  123. 123.
    Rabe KF, Nair P, Brusselle G, Maspero JF, Castro M, Sher L, et al. Efficacy and safety of Dupilumab in glucocorticoid-dependent severe asthma. N Engl J Med. 2018;378(26):2475–85.CrossRefGoogle Scholar
  124. 124.
    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.PubMedPubMedCentralCrossRefGoogle Scholar
  125. 125.
    Piper E, Brightling C, Niven R, Oh C, Faggioni R, Poon K, et al. A phase II placebo-controlled study of tralokinumab in moderate-to-severe asthma. Eur Respir J. 2013;41(2):330–8.PubMedCrossRefPubMedCentralGoogle Scholar
  126. 126.
    Panettieri RA Jr, Sjobring U, Peterffy A, Wessman P, Bowen K, Piper E, et al. Tralokinumab for severe, uncontrolled asthma (STRATOS 1 and STRATOS 2): two randomised, double-blind, placebo-controlled, phase 3 clinical trials. Lancet Respir Med. 2018;6(7):511–25.PubMedCrossRefPubMedCentralGoogle Scholar
  127. 127.
    Russell RJ, Chachi L, FitzGerald JM, Backer V, Olivenstein R, Titlestad IL, et al. Effect of tralokinumab, an interleukin-13 neutralising monoclonal antibody, on eosinophilic airway inflammation in uncontrolled moderate-to-severe asthma (MESOS): a multicentre, double-blind, randomised, placebo-controlled phase 2 trial. Lancet Respir Med. 2018;6(7):499–510.PubMedCrossRefPubMedCentralGoogle Scholar
  128. 128.
    Busse WW, Brusselle GG, Korn S, Kuna P, Magnan A, Cohen D, et al. Tralokinumab did not demonstrate oral corticosteroid-sparing effects in severe asthma. Eur Respir J. 2019;53(2)PubMedCrossRefPubMedCentralGoogle Scholar
  129. 129.
    Brightling CE, Saha S, Hollins F. Interleukin-13: prospects for new treatments. Clin Exp Allergy. 2010;40(1):42–9.PubMedPubMedCentralGoogle Scholar
  130. 130.
    Kaur D, Gomez E, Doe C, Berair R, Woodman L, Saunders R, et al. IL-33 drives airway hyper-responsiveness through IL-13-mediated mast cell: airway smooth muscle crosstalk. Allergy. 2015;70(5):556–67.PubMedPubMedCentralCrossRefGoogle Scholar
  131. 131.
    Nair P, O’Byrne PM. The interleukin-13 paradox in asthma: effective biology, ineffective biologicals. Eur Respir J. 2019;53(2):1802250.  https://doi.org/10.1183/13993003.02250-2018.PubMedCrossRefGoogle Scholar
  132. 132.
    Gauvreau GM, O’Byrne PM, Boulet LP, Wang Y, Cockcroft D, Bigler J, et al. Effects of an anti-TSLP antibody on allergen-induced asthmatic responses. N Engl J Med. 2014;370(22):2102–10.PubMedCrossRefPubMedCentralGoogle Scholar
  133. 133.
    Corren J, Parnes JR, Wang L, Mo M, Roseti SL, Griffiths JM, et al. Tezepelumab in adults with uncontrolled asthma. N Engl J Med. 2017;377(10):936–46.CrossRefGoogle Scholar
  134. 134.
    Lee HY, Rhee CK, Kang JY, Byun JH, Choi JY, Kim SJ, et al. Blockade of IL-33/ST2 ameliorates airway inflammation in a murine model of allergic asthma. Exp Lung Res. 2014;40(2):66–76.PubMedCrossRefGoogle Scholar
  135. 135.
    Gonem S, Berair R, Singapuri A, Hartley R, Laurencin MFM, Bacher G, et al. Fevipiprant, a prostaglandin D2 receptor 2 antagonist, in patients with persistent eosinophilic asthma: a single-centre, randomised, double-blind, parallel-group, placebo-controlled trial. Lancet Respir Med. 2016;4(9):699–707.PubMedCrossRefGoogle Scholar
  136. 136.
    Busse W, Chupp G, Nagase H, Albers FC, Doyle S, Shen Q, et al. Anti-IL-5 treatments in patients with severe asthma by blood eosinophil thresholds: indirect treatment comparison. J Allergy Clin Immunol. 2018;143(1):190–200.e20.PubMedCrossRefGoogle Scholar
  137. 137.
    Casale TB, Luskin AT, Busse W, Zeiger RS, Trzaskoma B, Yang M, et al. Omalizumab effectiveness by biomarker status in patients with asthma: evidence from PROSPERO, a prospective real-world study. J Allergy Clin Immunol Pract. 2018;7(1):156–164.e1.PubMedCrossRefGoogle Scholar
  138. 138.
    Bourdin A, Husereau D, Molinari N, Golam S, Siddiqui MK, Lindner L, et al. Matching-adjusted indirect comparison of Benralizumab versus Interleukin-5 inhibitors: systematic review. Eur Respir J. 2018;52(5):1801393.  https://doi.org/10.1183/13993003.01393-2018.PubMedCrossRefGoogle Scholar
  139. 139.
    Mukherjee M, Aleman Paramo F, Kjarsgaard M, Salter B, Nair G, LaVigne N, et al. Weight-adjusted intravenous Reslizumab in severe asthma with inadequate response to fixed-dose subcutaneous Mepolizumab. Am J Respir Crit Care Med. 2018;197(1):38–46.PubMedCrossRefPubMedCentralGoogle Scholar
  140. 140.
    Svenningsen S, Nair P. Asthma Endotypes and an overview of targeted therapy for asthma. Front Med. 2017;4:158.CrossRefGoogle Scholar
  141. 141.
    Buhl R, Humbert M, Bjermer L, Chanez P, Heaney LG, Pavord I, et al. Severe eosinophilic asthma: a roadmap to consensus. Eur Respir J. 2017;49(5):1700634.  https://doi.org/10.1183/13993003.00634-2017.PubMedCrossRefGoogle Scholar
  142. 142.
    Corren J, Weinstein S, Janka L, Zangrilli J, Garin M. Phase 3 study of Reslizumab in patients with poorly controlled asthma: effects across a broad range of eosinophil counts. Chest. 2016;150(4):799–810.PubMedCrossRefPubMedCentralGoogle Scholar
  143. 143.
    Bleecker ER, FitzGerald JM, Chanez P, Papi A, Weinstein SF, Barker P, et al. Efficacy and safety of benralizumab for patients with severe asthma uncontrolled with high-dosage inhaled corticosteroids and long-acting beta2-agonists (SIROCCO): a randomised, multicentre, placebo-controlled phase 3 trial. Lancet (London, England). 2016;388(10056):2115–27.CrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2020

Authors and Affiliations

  1. 1.Division of RespirologyFirestone Institute for Respiratory Health, St Joseph’s Healthcare, McMaster UniversityHamiltonCanada

Personalised recommendations