Eosinophilic airway inflammation: Role in asthma and chronic obstructive pulmonary disease

Therapeutic Advances in Chronic Disease

Volumn 7, Issue 1, 2016, Pages 34-51

  George, Leena ^a   Brightling, Christopher E ^b  

^a UNIVERSITY OF LEICESTER   (United Kingdom)

^b UNIVERSITY HOSPITALS OF LEICESTER NHS TRUST   (United Kingdom)

Author keywords

ACOS; Anti CRTh2; Anti IL 13; Anti IL4R; Anti IL5; Asthma; Biomarker; COPD; Corticosteroid; Eosinophil

Indexed keywords

ARRY 502; AZD3778; BENRALIZUMAB; BI 671800; CORTICOSTEROID; DUPILUMAB; FEVIPIPRANT; GW76694; IMMUNOMODULATING AGENT; INTERLEUKIN 13; INTERLEUKIN 3; INTERLEUKIN 4; INTERLEUKIN 5; LEBRIKIZUMAB; LENZILUMAB; LEUKOTRIENE RECEPTOR BLOCKING AGENT; MEPOLIZUMAB; OC000459; OMALIZUMAB; RESLIZUMAB; THEOPHYLLINE; TPI ASM8; TRALOKINUMAB; TRANSCRIPTION FACTOR RUNX2; UNCLASSIFIED DRUG; VIDUPIPRANT;

ASTHMA; BRONCHOSCOPY; BRONCHUS BIOPSY; CHRONIC OBSTRUCTIVE LUNG DISEASE; DISEASE EXACERBATION; EOSINOPHILIA; HUMAN; LEUKOCYTE DIFFERENTIAL COUNT; LUNG LAVAGE; MORBIDITY; MORTALITY; PHASE 2 CLINICAL TRIAL (TOPIC); PHASE 3 CLINICAL TRIAL (TOPIC); PRIORITY JOURNAL; RANDOMIZED CONTROLLED TRIAL (TOPIC); RESPIRATORY TRACT INFLAMMATION; REVIEW; SPUTUM ANALYSIS; TREATMENT OUTCOME;

EID: 84953439931     PISSN: 20406223     EISSN: 20406231     Source Type: Journal    
DOI: 10.1177/2040622315609251     Document Type: Review

References (145)

1. Amelink M. Nijs S. Groot J. Tilburg P. Spiegel P. Krouwels F. et al. (2013) Three phenotypes of adult-onset asthma. Allergy 68: 674–680.
2. Ayars G. Altman L. Gleich G. Loegering D. Baker C. (1985) Eosinophil-and eosinophil granule-mediated pneumocyte injury. J Allergy Clin Immunol 76: 595–604.
3. Bafadhel M. McKenna S. Terry S. Mistry V. Pancholi M. Venge P. et al. (2012) Blood eosinophils to direct corticosteroid treatment of exacerbations of chronic obstructive pulmonary disease: a randomized placebo-controlled trial. Am J Respir Crit Care Med 186: 48–55.
4. Bafadhel M. McKenna S. Terry S. Mistry V. Reid C. Haldar P. et al. (2011) Acute exacerbations of chronic obstructive pulmonary disease: identification of biologic clusters and their biomarkers. Am J Respir Crit Care Med 184: 662–671.
5. Bardin P. Thompson P. Luckey A. Yarranton G. Molfino N. (2013) A randomized placebo-controlled safety and pharmacodynamic study of KB002, a chimeric antiGMCSF monoclonal antibody, in patients with asthma. Am J Respir Crit Care Med 187: A3867.
6. Barnes P. (2006) Theophylline for COPD. Thorax 61: 742–744.
7. Barnes P. Adcock I. Ito K. (2005) Histone acetylation and deacetylation: importance in inflammatory lung diseases. Eur Respir J 25: 552–563.
8. Barnes N. Laviolette M. Allen D. Flood-Page P. Hargreave F. Corris P. et al. (2007) Effects of montelukast compared to double dose budesonide on airway inflammation and asthma control. Respir Med 101: 1652–1658.
9. Barnes N. Pavord I. Chuchalin A. Bell J. Hunter M. Lewis T. et al. (2012) A randomized, double-blind, placebo-controlled study of the CRTH 2 antagonist OC 000459 in moderate persistent asthma. Clin Exp Allergy 42: 38–48.
10. Bel E. Ortega H. Pavord I. (2014) Glucocorticoids and mepolizumab in eosinophilic asthma. N Engl J Med 371: 2434.
11. Berry M. Shaw D. Green R. Brightling C. Wardlaw A. Pavord I. (2005) The use of exhaled nitric oxide concentration to identify eosinophilic airway inflammation: an observational study in adults with asthma. Clin Exp Allergy 35: 1175–1179.
12. Boorsma M. Lutter R. van de Pol M. Out T. Jansen H. Jonkers R. (2007) Repeatability of inflammatory parameters in induced sputum of COPD patients. J Chron Obstruct Pulmon Dis 4: 321–329.
13. Brightling C. (2013) Biomarkers that predict and guide therapy for exacerbations of chronic obstructive pulmonary disease. Ann Am Thorac Soc 10: S214–S219.
14. Brightling C. Bleecker E. Panettieri R. Bafadhel M. She D. Ward C. et al. (2014) Benralizumab for chronic obstructive pulmonary disease and sputum eosinophilia: a randomised, double-blind, placebo-controlled, phase 2a study. Lancet Respir Med 2: 891–901.
15. Brightling C. Bradding P. Symon F. Holgate S. Wardlaw A. Pavord I. (2002) Mast-cell infiltration of airway smooth muscle in asthma. N Engl J Med 346: 1699–1705.
16. Brightling C. McKenna S. Hargadon B. Birring S. Green R. Siva R. et al. (2005) Sputum eosinophilia and the short term response to inhaled mometasone in chronic obstructive pulmonary disease. Thorax 60: 193–198.
17. Brightling C. Monteiro W. Ward R. Parker D. Morgan M. Wardlaw A. et al. (2000) Sputum eosinophilia and short-term response to prednisolone in chronic obstructive pulmonary disease: a randomised controlled trial. Lancet 356: 1480–1485.
18. Brightling C. Saha S. Hollins F. (2010) Interleukin-13: prospects for new treatments. Clin Exp Allergy 40: 42–49.
19. Brightling C. Symon F. Birring S. Bradding P. Wardlaw A. Pavord I. (2003) Comparison of airway immunopathology of eosinophilic bronchitis and asthma. Thorax 58: 528–532.
20. Brown H. (1958) Treatment of chronic asthma with prednisolone significance of eosinophils in the sputum. Lancet 272: 1245–1247.
21. Burrowes K. Doel T. Brightling C. (2014) Computational modeling of the obstructive lung diseases asthma and COPD. J Transl Med 12(Suppl. 2): S5.
22. Busse W. Wenzel S. Meltzer E. Kerwin E. Liu M. Zhang N. et al. (2013) Safety and efficacy of prostaglandin D 2 receptor antagonist AMG 853 in asthmatic patients. J Allergy Clin Immunol 131: 339–345.
23. Castro M. Mathur S. Hargreave F. Boulet L. Xie F. Young J. et al. (2011) Reslizumab for poorly controlled, eosinophilic asthma: a randomized, placebo-controlled study. Am J Respir Crit Care Med 184: 1125–1132.
24. Castro M. Wenzel S. Bleecker E. Pizzichini E. Kuna P. Busse W. et al. (2014) Benralizumab, an anti-interleukin 5 receptor α monoclonal antibody, versus placebo for uncontrolled eosinophilic asthma: a phase 2b randomised dose-ranging study. Lancet Respir Med 2: 879–890.
25. Castro M. Zangrilli J. Wechsler M. Bateman E. Brusselle G. Bardin P. et al. (2015) 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 3: 355–366.
26. Chauhan B. Ducharme F. (2012) Anti-leukotriene agents compared to inhaled corticosteroids in the management of recurrent and / or chronic asthma in adults and children. Cochrane Database Syst Rev 5: CD002314.
27. Corren J. Lemanske R. Jr. Hanania N. Korenblat P. Parsey M. Arron J. et al. (2011) Lebrikizumab treatment in adults with asthma. N Engl J Med 365: 1088–1098.
28. Corren J. Weinstein J. Janka L. O'Brien C. Zangrilli J. (2014) A randomised phase 3 study of reslizumab efficacy in relation to blood eosinophil levels in patients with moderate to severe asthma. Eur Respir J 44(Suppl. 58): 4673.
29. Davoine F. Lacy P. (2014) Eosinophil cytokines, chemokines, and growth factors: emerging roles in immunity. Front Immunol 5: 570.
30. Denburg J. (1998) The origins of basophils and eosinophils in allergic inflammation. J Allergy Clin Immunol 102: S74–S76.
31. Desai D. Brightling C. (2009) Cytokine and anti-cytokine therapy in asthma: ready for the clinic? Clin Exp Immunol 158: 10–19.
32. Desai D. Newby C. Symon F. Haldar P. Shah S. Gupta S. et al. (2013) Elevated sputum interleukin-5 and submucosal eosinophilia in obese individuals with severe asthma. Am J Respir Crit Care Med 188: 657–663.
33. Djukanović R. Wilson J. Britten K. Wilson S. Walls A. Roche W. et al. (1992) Effect of an inhaled corticosteroid on airway inflammation and symptoms in asthma. Am Rev Respir Dis 145: 669–674.
34. Djukanović R. Wilson S. Kraft M. Jarjour N. Steel M. Chung K. et al. (2004) Effects of treatment with anti-immunoglobulin E antibody omalizumab on airway inflammation in allergic asthma. Am J Respir Crit Care Med 170: 583–593.
35. Douwes J. Gibson P. Pekkanen J. Pearce N. (2002) Non-eosinophilic asthma: importance and possible mechanisms. Thorax 57: 643–648.
36. Ducharme F. Lasserson T. Cates C. (2011) Addition to inhaled corticosteroids of long-acting beta2-agonists versus anti-leukotrienes for chronic asthma. Cochrane Database Syst Rev 5: CD003137.
37. Edwards S. von Maltzahn R. Naya I. Harrison T. (2010) Budesonide / formoterol for maintenance and reliever therapy of asthma: a meta analysis of randomised controlled trials. Int J Clin Pract 64: 619–627.
38. Eltboli O. Bafadhel M. Hollins F. Wright A. Hargadon B. Kulkarni N. et al. (2014) COPD exacerbation severity and frequency is associated with impaired macrophage efferocytosis of eosinophils. BMC Pulm Med 14: 112.
39. Eltboli O. Brightling C. (2013) Eosinophils as diagnostic tools in chronic lung disease. Expert Rev Respir Med 7: 33–42.
40. Eltboli O. Mistry V. Barker B. Brightling C. (2015) Relationship between blood and bronchial submucosal eosinophilia and reticular basement membrane thickening in chronic obstructive pulmonary disease. Respirology 20: 667–670.
41. Erzurum S. Leff J. Cochran J. Ackerson L. Szefler S. Martin R. et al. (1991) Lack of benefit of methotrexate in severe, steroid-dependent asthma: a double-blind, placebo-controlled study. Ann Intern Med 114: 353–360.
42. Fitzgerald M. Snape S. Febbraro S. Banyard A. Patnell C. Ruparelia B. et al. (2013) The safety, PK, PD profile of AD3680, a potent and selective CRTH 2 antagonist in healthy volunteers and partly controlled atopic asthmatic subjects. C-23 Novel therapeutic in asthma. ATS Conference Proceedings, Pennsylvania, 21 May 2013. Abstract A3874.
43. Flood-Page P. Menzies-Gow A. Phipps S. Ying S. Wangoo A. Ludwig M. et al. (2003) Anti-IL-5 treatment reduces deposition of ECM proteins in the bronchial subepithelial basement membrane of mild atopic asthmatics. J Clin Invest 112: 1029–1036.
44. Flood-Page P. Swenson C. Faiferman I. Matthews J. Williams M. Brannick L. et al. (2007) A study to evaluate safety and efficacy of mepolizumab in patients with moderate persistent asthma. Am J Respir Crit Care Med 176: 1062–1071.
45. Ford P. Durham A. Russell R. Gordon F. Adcock I. Barnes P. (2010) Treatment effects of low-dose theophylline combined with an inhaled corticosteroid in COPD. Chest 137: 1338–1344.
46. Frigas E. Motojima S. Gleich G. (1991) The eosinophilic injury to the mucosa of the airways in the pathogenesis of bronchial asthma. Eur Respir J Suppl 13: 123s–135s.
47. Fukuda T. Fukushima Y. Numao T. Ando N. Arima M. Nakajima H. et al. (1996) Role of interleukin-4 and vascular cell adhesion molecule-1 in selective eosinophil migration into the airways in allergic asthma. Am J Respir Cell Mol Biol 14: 84–94.
48. Fulkerson P. Rothenberg M. (2013) Targeting eosinophils in allergy, inflammation and beyond. Nat Rev Drug Discov 12: 117–129.
49. Gauvreau G. Pageau R. Séguin R. Carballo D. Gauthier J. D'Anjou H. et al. (2011)Dose response effects of TPI ASM 8 in asthmatic after allergen. Allergy 66: 1242–1248.
50. Ghazi A. Trikha A. Calhoun W. (2012) Benralizumab–a humanized m Ab to IL-5α with enhanced antibody-dependent cell-mediated cytotoxicity–a novel approach for the treatment of asthma. Expert Opin Biol Ther 12: 113–118.
51. Ghebre M. Bafadhel M. Desai D. Cohen S. Newbold P. Rapley L. et al. (2015) Biological clustering supports both “Dutch” and “British” hypotheses of asthma and chronic obstructive pulmonary disease. J Allergy Clin Immunol 135: 63–72.
52. Gibson P. Denburg J. Dolovich J. Ramsdale E. Hargreave F. (1989) Chronic cough: eosinophilic bronchitis without asthma. Lancet 333: 1346–1348.
53. Gibson P. Hargreave F. Girgis-Gabardo A. Morris M. Denburg J. Dolovich J. (1995) Chronic cough with eosinophilic bronchitis: examination for variable airflow obstruction and response to corticosteroid. Clin Exp Allergy 25: 127–132.
54. Gonem S. Berair R. Singapuri A. Hartley R. Laurencin M. Bacher G. et al. (2014) Late-breaking abstract: phase 2a randomized placebo-controlled trial of the oral prostaglandin D 2 receptor (DP2/CRTh2) antagonist QAW 039 in eosinophilic asthma. Eur Respir J 44(Suppl. 58): 2908.
55. Green R. Brightling C. McKenna S. Hargadon B. Neale N. Parker D. et al. (2006) Comparison of asthma treatment given in addition to inhaled corticosteroids on airway inflammation and responsiveness. Eur Respir J 27: 1144–1151.
56. Green R. Brightling C. McKenna S. Hargadon B. Parker D. Bradding P. et al. (2002 a) Asthma exacerbations and sputum eosinophil counts: a randomised controlled trial. Lancet 360: 1715–1721.
57. Green R. Brightling C. Woltmann G. Parker D. Wardlaw A. Pavord I. (2002 b) Analysis of induced sputum in adults with asthma: identification of subgroup with isolated sputum neutrophilia and poor response to inhaled corticosteroids. Thorax 57: 875–879.
58. Greiff L. Ahlström-Emanuelsson C. Bahl A. Bengtsson T. Dahlström K. Erjefält J. et al. (2010) Effects of dual CCR 3 and H-1 antagnonist on symptoms and eosinophilic inflammation in allergic rhinitis. Respir Res 11: 17.
59. Haldar P. Brightling C. Hargadon B. Gupta S. Monteiro W. Sousa A. et al. (2009) Mepolizumab and exacerbations of refractory eosinophilic asthma. N Engl J Med 360: 973–984.
60. Haldar P. Brightling C. Singapuri A. Hargadon B. Gupta S. Monteiro W. et al. (2014) Outcomes after cessation of mepolizumab therapy in severe eosinophilic asthma: a 12-month follow-up analysis. J Allergy Clin Immunol 133: 921.
61. Haldar P. Pavord I. Shaw D. Berry M. Thomas M. Brightling C. et al. (2008) Cluster analysis and clinical asthma phenotypes. Am J Respir Crit Care Med 178: 218–224.
62. Hall I. Sarno M. Disse B. Atis S. Bateman E. Finnigan H. (2012) Efficacy and safety of BI 671800, an oral CRTH 2 antagonist, as add on therapy in poorly controlled asthma patients prescribed an inhaled corticosteroid. Eur Respir J 40(Suppl. 56): abstract 2551.
63. Hallstrand T. Henderson W. Jr. (2010) An update on the role of leukotrienes in asthma. Curr Opin Allergy Clin Immunol 10: 60–66.
64. Hanania N. (2014) Efficacy and safety of lebrikizumab in severe uncontrolled asthma: results from the lute and verse phase II randomized, double-blind, placebo-controlled trials. J Allergy Clin Immunol 133: AB402.
65. Hanania N. Wenzel S. Rosén K. Hsieh H. Mosesova S. Choy D. et al. (2013) Exploring the effects of omalizumab in allergic asthma: an analysis of biomarkers in the EXTRA study. Am J Respir Crit Care Med 187: 804–811.
66. Heitzer M. Wolf I. Sanchez E. Witchel S. de Franco D. (2007) Glucocorticoid receptor physiology. Rev Endocr Metab Disord 8: 321–330.
67. Hirai H. Tanaka K. Yoshie O. Ogawa K. Kenmotsu K. Takamori Y. et al. (2001) Prostaglandin D2 selectively induces chemotaxis in T helper type 2 cells, eosinophils, and basophils via seven-transmembrane receptor CRTH2. J Exp Med 193: 255–261.
68. Humbles A. Lloyd C. McMillan S. Friend D. Xanthou G. McKenna E. et al. (2004) A critical role for eosinophils in allergic airways remodeling. Science 305: 1776–1779.
69. Ito K. Yamamura S. Essilfie-Quaye S. Cosio B. Ito M. Barnes P. et al. (2006) Histone deacetylase 2-mediated deacetylation of the glucocorticoid receptor enables NF-kappaB suppression. J Exp Med 203: 7–13.
70. Jatakanon A. Lim S. Barnes P. (2000) Changes in sputum eosinophils predict loss of asthma control. Am J Respir Crit Care Med 161: 64–72.
71. Jayaram L. Pizzichini M. Cook R. Boulet L. Lemiere C. Pizzichini E. et al. (2006) Determining asthma treatment by monitoring sputum cell counts: effect on exacerbations. Eur Respir J 27: 483–494.
72. Jayaram L. Pizzichini E. Lemiere C. Man S. Cartier A. Hargreave F. et al. (2005) Steroid naive eosinophilic asthma: anti-inflammatory effects of fluticasone and montelukast. Thorax 60: 100–105.
73. Jia G. Erickson R. Choy D. Mosesova S. Wu L. Solberg O. et al. (2012) Periostin is a systemic biomarker of eosinophilic airway inflammation in asthmatic patients. J Allergy Clin Immunol 130: 647–654.
74. KaloBios (2014) KaloBios Reports Top-Line Data for Phase 2 Study of KB 003 in Severe Asthma. Available at: http://ir.kalobios.com/releasedetail.cfm?ReleaseID=821931 (accessed July 2015).
75. Kay A. (2014) The early history of the eosinophil. Clin Exp Allergy 45: 575–582.
76. Kay A. Phipps S. Robinson D. (2004) A role for eosinophils in airway remodelling in asthma. Trends Immunol 25: 477–482.
77. Keatings V. Evans D. O'Connor B. Barnes P. (1997) Cellular profiles in asthmatic airways: a comparison of induced sputum, bronchial washings, and bronchoalveolar lavage fluid. Thorax 52: 372–374.
78. Krinner E. Raum T. Petsch S. Bruckmaier S. Schuster I. Petersen L. et al. (2007) A human monoclonal IgG 1 potently neutralizing the pro-inflammatory cytokine GM-CSF. Mol Immunol 44: 916–925.
79. Krug N. Gupta A. Badorrek D. Mueller M. Casper A. Pivovarova A. et al. (2012) CRTH 2 antagonist, BI 671800 (BI), reduces nasal symptoms and inhibits nasal cytokines and eosinophils in SAR patients exposed to grass pollen in an environmental challenge chamber (ECC). Am J Resp Crit Care Med 185: A4185.
80. Kulkarni N. Hollins F. Sutcliffe A. Saunders R. Shah S. Siddiqui S. et al. (2010) Eosinophil protein in airway macrophages: a novel biomarker of eosinophilic inflammation in patients with asthma. J Allergy Clin Immunol 126: 61–69.
81. Laviolette M. Gossage D. Gauvreau G. Leigh R. Olivenstein R. Katial R. et al. (2013) Effects of benralizumab on airway eosinophils in asthmatic patients with sputum eosinophilia. J Allergy Clin Immunol 132: 1086–1096.
82. Leckie M. Brinke A. Khan J. Diamant Z. O'Connor B. Walls C. et al. (2000) Effects of an interleukin-5 blocking monoclonal antibody on eosinophils, airway hyper-responsiveness, and the late asthmatic response. Lancet 356: 2144–2148.
83. Leigh R. Pizzichini M. Morris M. Maltais F. Hargreave F. Pizzichini E. (2006) Stable COPD: predicting benefit from high-dose inhaled corticosteroid treatment. Eur Respir J 27: 964–971.
84. Lewis R. Soter N. Diamond P. Austen K. Oates J. Roberts L. 2nd. (1982) Prostaglandin D 2 generation after activation of rat and human mast cells with anti-Ig E. J Immunol 129: 1627–1631.
85. Lim S. Jatakanon A. Gordon D. Macdonald C. Chung K. Barnes P. (2000) Comparison of high dose inhaled steroids, low dose inhaled steroids plus low dose theophylline, and low dose inhaled steroids alone in chronic asthma in general practice. Thorax 55: 837–841.
86. Lim S. Tomita K. Carramori G. Jatakanon A. Oliver B. Keller A. et al. (2001) Low-dose theophylline reduces eosinophilic inflammation but not exhaled nitric oxide in mild asthma. Am J Respir Crit Care Med 164: 273–276.
87. Loymans R. Gemperli A. Cohen J. Rubinstein S. Sterk P. Reddel H. et al. (2014) Comparative effectiveness of long term drug treatment strategies to prevent asthma exacerbations: network meta-analysis. BMJ 348: g3009.
88. Luijk B. Lindemans C. Kanters D. van der Heijde R. Bertics P. Lammers J. et al. (2005) Gradual increase in priming of human eosinophils during extravasation from peripheral blood to the airways in response to allergen challenge. J Allergy Clin Immunol 115: 997–1003.
89. Maestrelli P. Saetta M. Di Stefano A. Calcagni P. Turato G. Ruggieri M. et al. (1995) Comparison of leukocyte counts in sputum, bronchial biopsies, and bronchoalveolar lavage. Am J Respir Crit Care Med 152: 1926–1931.
90. McGrath K. Icitovic N. Boushey H. Lazarus S. Sutherland E. Chinchilli V. et al. (2012) A large subgroup of mild-to-moderate asthma is persistently noneosinophilic. Am J Respir Crit Care Med 185: 612–619.
91. Mesquita-Santos F. Vieira-de-Abreu A. Calheiros A. Figueiredo I. Castro-Faria-Neto H. Weller P. et al. (2006) Cutting edge: prostaglandin D 2 enhances leukotriene C 4 synthesis by eosinophils during allergic inflammation: synergistic in vivo role of endogenous eotaxin. J Immunol 176: 1326–1330.
92. Molfino N. Bardin P. Thompson P. Lucky A. Yarranton G. (2013) A randomised placebo controlled safety and pharmacodynamic study of KB002, a Chimeric anti GM-CSF monoclonal antibody, in patients with asthma. Am J Respir Crit Care Med 187: A3867.
93. Moqbel R. Levi-Schaffer F. Kay A. (1994) Cytokine generation by eosinophils. J Allergy Clin Immunol 94: 1183–1188.
94. Mutalithas K. Guillen C. Day C. Brightling C. Pavord I. Wardlaw A. (2010) CRTH 2 expression on T cells in asthma. Clin Exp Immunol 161: 34–40.
95. Nagata K. Hirai H. Tanaka K. Ogawa K. Aso T. Sugamura K. et al. (1999) CRTH2, an orphan receptor of T-helper-2-cells, is expressed on basophils and eosinophils and responds to mast cell-derived factor (s). FEBS Lett 459: 195–199.
96. Navarro S. Aleu J. Jimenez M. Boix E. Cuchillo C. Nogues M. (2008) The cytotoxicity of eosinophil cationic protein / ribonuclease 3 on eukaryotic cell lines takes place through its aggregation on the cell membrane. Cell Mol Life Sci 65: 324–337.
97. Neighbour H. Boulet L. Lemiere C. Sehmi R. Leigh R. Sousa A. et al. (2014) Safety and efficacy of an oral CCR 3 antagonist in patients with asthma and eosinophilic bronchitis: a randomized, placebo-controlled clinical trial. Clin Exp Allergy 44: 508–516.
98. Newby C. Agbetile J. Hargadon B. Monteiro W. Green R. Pavord I. et al. (2014 a) Lung function decline and variable airway inflammatory pattern: longitudinal analysis of severe asthma. J Allergy Clin Immunol 134: 287–294.
99. Newby C. Heaney L. Menzies-Gow A. Niven R. Mansur A. Bucknall C. et al. (2014 b) Statistical cluster analysis of the British Thoracic Society Severe refractory Asthma Registry: clinical outcomes and phenotype stability. PloS ONE 9: e102987.
100. Normansell R. Walker S. Milan S. Walters E. Nair P. (2014) Omalizumab for asthma in adults and children. Cochrane Database Syst Rev 1: CD003559.
101. Ortega H. Liu M. Pavord I. Brusselle G. FitzGerald J. Chetta A. et al. (2014) Mepolizumab treatment in patients with severe eosinophilic asthma. N Engl J Med 371: 1198–1207.
102. Patel K. (1998) Eosinophil tethering to interleukin-4-activated endothelial cells requires both P-selectin and vascular cell adhesion molecule-1. Blood 92: 3904–3911.
103. Pavord I. Korn S. Howarth P. Bleecker E. Buhl R. Keene O. et al. (2012) Mepolizumab for severe eosinophilic asthma (DREAM): a multicentre, double-blind, placebo-controlled trial. Lancet 380: 651–659.
104. Pavord I. Pizzichini M. Pizzichini E. Hargreave F. (1997) The use of induced sputum to investigate airway inflammation. Thorax 52: 498–501.
105. Pavord I. Woodcock A. Parker D. Rice L. and SOLTA Study Group. (2007) Salmeterol plus fluticasone propionate versus fluticasone propionate plus montelukast: a randomised controlled trial investigating the effects on airway inflammation in asthma. Respir Res 8: 67.
106. Pease J. Horuk R. (2014) Recent progress in the development of antagonists to the chemokine receptors CCR 3 and CCR4. Expert Opin Drug Discov 9: 467–483.
107. Pettipher R. Perkins M. Collins L. Baillet M. Lewis T. Steiner J. et al. (2014) The potent & selective CRTH 2 antagonist OC 000459 is effective in the treatment of eosinophilic asthma when given once daily. J Allergy Clin Immunol 133: AB3.
108. Pettipher R. Whittaker M. (2012) Update on the development of antagonists of chemoattractant receptor-homologous molecule expressed on Th 2 cells (CRTH2). From lead optimization to clinical proof-of-concept in asthma and allergic rhinitis. J Med Chem 55: 2915–2931.
109. Piper E. Brightling C. Niven R. Oh C. Faggioni R. Poon K. et al. (2013) A phase II placebo-controlled study of tralokinumab in moderate-to-severe asthma. Eur Respir J 41: 330–338.
110. Pizzichini E. Leff J. Reiss T. Hendeles L. Boulet L. Wei L. et al. (1999) Montelukast reduces airway eosinophilic inflammation in asthma: a randomized, controlled trial. Eur Respir J 14: 12–18.
111. Pizzichini E. Pizzichini M. Efthimiadis A. Evans S. Morris M. Squillace D. et al. (1996) Indices of airway inflammation in induced sputum: reproducibility and validity of cell and fluid-phase measurements. Am J Respir Crit Care Med 154: 308–317.
112. Pizzichini E. Pizzichini M. Gibson P. Parameswaran K. Gleich G. Berman L. et al. (1998) Sputum eosinophilia predicts benefit from prednisone in smokers with chronic obstructive bronchitis. Am J Respir Crit Care Med 158: 1511–1517.
113. Reddel H. Taylor D. Bateman E. Boulet L. Boushey H. Busse W. et al. (2009) 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 180: 59–99.
114. Rosenberg H. Phipps S. Foster P. (2007) Eosinophil trafficking in allergy and asthma. J Allergy Clin Immunol 119: 1303–1310.
115. Rutgers S. Timens W. Kaufmann H. van der Mark T. Koeter G. Postma D. (2000) Comparison of induced sputum with bronchial wash, bronchoalveolar lavage and bronchial biopsies in COPD. Eur Respir J 15: 109–115.
116. Saetta M. Di Stefano A. Maestrelli P. Turato G. Ruggieri M. Roggeri A. et al. (1994) Airway eosinophilia in chronic bronchitis during exacerbations. Am J Respir Crit Care Med 150: 1646–1652.
117. Saha S. Berry M. Parker D. Siddiqui S. Morgan A. May R. et al. (2008) Increased sputum and bronchial biopsy IL-13 expression in severe asthma. J Allergy Clin Immunol 121: 685–691.
118. Sakula A. (1986) Charcot–Leyden crystals and Curschmann spirals in asthmatic sputum. Thorax 41: 503–507.
119. Schleich F. Manise M. Sele J. Henket M. Seidel L. Louis R. (2013) Distribution of sputum cellular phenotype in a large asthma cohort: predicting factors for eosinophilic vs neutrophilic inflammation. BMC Pulm Med 13: 11.
120. Sethi S. Murphy T. (2008) Infection in the pathogenesis and course of chronic obstructive pulmonary disease. N Engl J Med 359: 2355–2365.
121. She D. Ranade K. Piper E. Brightling C. (2014) Efficacy and safety Of tralokinumab, an anti-Il-13 monoclonal antibody, in a phase 2b study of uncontrolled severe Asthma. Am J Respir Crit Care Med 189: A6670.
122. Siddiqui S. Mistry V. Doe C. Roach K. Morgan A. Wardlaw A. et al. (2008) Airway hyperresponsiveness is dissociated from airway wall structural remodeling. J Allergy Clin Immunol 122: 335–341.
123. Singh D. Kolsum U. Brightling C. Locantore N. Agusti A. Tal-Singer R. et al. (2014) Eosinophilic inflammation in COPD: prevalence and clinical characteristics. Eur Respir J 44: 1697–1700.
124. Siva R. Green R. Brightling C. Shelley M. Hargadon B. McKenna S. et al. (2007) Eosinophilic airway inflammation and exacerbations of COPD: a randomised controlled trial. Eur Respir J 29: 906–913.
125. Smit J. Lukacs N. (2006) A closer look at chemokines and their role in asthmatic responses. Eur J Pharmacol 533: 277–288.
126. Stanescu D. Sanna A. Veriter C. Kostianev S. Calcagni P. Fabbri L. et al. (1996) Airways obstruction, chronic expectoration, and rapid decline of FEV 1 in smokers are associated with increased levels of sputum neutrophils. Thorax 51: 267–271.
127. Subramanian R. Jindal A. Viswambhar V. Babu A. (2015) The study of efficacy, tolerability and safety of theophylline given along with formoterol plus budesonide in COPD. J Clin Diagn Res 9: OC10–OC13.
128. Sugimoto H. Shichijo M. Iino T. Manabe Y. Watanabe A. Shimazaki M. et al. (2003) An orally bioavailable small molecule antagonist of CRTH2, ramatroban (BAY u3405), inhibits prostaglandin D2-induced eosinophil migration in vitro. J Pharmacol Exp Ther 305: 347–352.
129. Sutherland R. Tetzlaff K. Nivens C. Tsukayama M. Guerreros A. Manuel R. et al. (2012) Efficacy and safety of BI671800, an oral CRTH 2 antagnoist in controller naïve patients with poorly controlled asthma. Eur Respir J 40(Suppl. 56): 3084.
130. Sweeney J. Brightling C. Menzies-Gow A. Niven R. Patterson C. Heaney L. et al. (2012) Clinical management and outcome of refractory asthma in the UK from the British Thoracic Society Difficult Asthma Registry. Thorax 67: 754–756.
131. Symon F. Lawrence M. Williamson M. Walsh G. Watson S. Wardlaw A. (1996) Functional and structural characterization of the eosinophil P-selectin ligand. J Immunol 157: 1711–1719.
132. Teper A. Wang L. Pirozzi G. Radin A. Graham N. Castro M. et al. (2014) ACQ 5 improvement with dupilumab in patients with persistent asthma and elevated eosinophil levels: responder analysis from a 12-week proof-of-concept placebo-controlled trial. Am J Respir Crit Care Med 189: A1323.
133. Ultsch M. Bevers J. Nakamura G. Vandlen R. Kelley R. Wu L. et al. (2013) Structural basis of signaling blockade by anti-IL-13 antibody lebrikizumab. J Mol Biol 425: 1330–1339.
134. Wagener A. de Nijs S. Lutter R. Sousa A. Weersink E. Bel E. et al. (2015) External validation of blood eosinophils, FENO and serum periostin as surrogates for sputum eosinophils in asthma. Thorax 70: 115–120.
135. Wardlaw A. (1999) Molecular basis for selective eosinophil trafficking in asthma: a multistep paradigm. J Allergy Clin Immunol 104: 917–926.
136. Wardlaw A. Silverman M. Siva R. Pavord I. Green R. (2005) Multi-dimensional phenotyping: towards a new taxonomy for airway disease. Clin Exp Allergy 35: 1254–1262.
137. Wenzel S. Ford L. Pearlman D. Spector S. Sher L. Skobieranda F. et al. (2013) Dupilumab in persistent asthma with elevated eosinophil levels. N Engl J Med 368: 2455–2466.
138. Wenzel S. Hopkins R. Saunders M. Chantry D. Anderson L. Aitchison R. et al. (2014) Safety and efficacy of ARRY-502, a potent, selective, oral CRTh 2 antagonist, in patients with mild to moderate Th2-driven asthma. J Allergy Clin Immunol 133: AB4.
139. Woltmann G. McNulty C. Dewson G. Symon F. Wardlaw A. (2000) Interleukin-13 induces PSGL-1/P-selectin-dependent adhesion of eosinophils, but not neutrophils, to human umbilical vein endothelial cells under flow. Blood 95: 3146–3152.
140. Woodruff P. Boushey H. Dolganov G. Barker C. Yang Y. Donnelly S. et al. (2007) Genome-wide profiling identifies epithelial cell genes associated with asthma and with treatment response to corticosteroids. Proc Natl Acad Sci USA 104: 15858–15863.
141. Woodruff P. Modrek B. Choy D. Jia G. Abbas A. Ellwanger A. et al. (2009) T-helper type 2–driven inflammation defines major subphenotypes of asthma. Am J Respir Crit Care Med 180: 388–395.
142. Yang I. Clarke M. Sim E. Fong K. (2012) Inhaled corticosteroids for stable chronic obstructive pulmonary disease. Cochrane Database Syst Rev 7: CD002991.
143. Ying S. Robinson D. Meng Q. Rottman J. Kennedy R. Ringler D. et al. (1997) Enhanced expression of eotaxin and CCR 3 mRNA and protein in atopic asthma. Association with airway hyperresponsiveness and predominant co-localization of eotaxin mRNA to bronchial epithelial and endothelial cells. Eur J Immunol 27: 3507–3516.
144. Zietkowski Z. Bodzenta-Lukaszyk A. Tomasiak M. Skiepko R. Szmitkowski M. (2006) Comparison of exhaled nitric oxide measurement with conventional tests in steroid-naive asthma patients. J Investig Allergol Clin Immunol 16: 239–246.
145. ZuWallack R. Mahler D. Reilly D. Church N. Emmett A. Rickard K. et al. (2001) Salmeterol plus theophylline combination therapy in the treatment of COPD. Chest 119: 1661–1670.