Addressing corticosteroid insensitivity in adults with asthma

Expert Review of Respiratory Medicine

Volumn 10, Issue 2, 2016, Pages 137-156

  Thomson, Neil C ^a  

^a UNIVERSITY OF GLASGOW   (United Kingdom)

Author keywords

Adherence; asthma; biological agents; biomarkers; cigarette smoking; corticosteroid insensitivity; corticosteroid resistance; corticosteroids; small molecule drugs

Indexed keywords

ALLERGEN; BRODALUMAB; CIGARETTE SMOKE; CORTICOSTEROID; GLUCOCORTICOID RECEPTOR; HISTONE DEACETYLASE 2; HYDROXYMETHYLGLUTARYL COENZYME A REDUCTASE INHIBITOR; IMMUNOGLOBULIN E RECEPTOR; IMMUNOGLOBULIN ENHANCER BINDING PROTEIN; LEUKOTRIENE RECEPTOR BLOCKING AGENT; MACROLIDE; PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR GAMMA AGONIST; PHOSPHATIDYLINOSITOL 3 KINASE INHIBITOR; PHOSPHODIESTERASE III INHIBITOR; PHOSPHODIESTERASE IV INHIBITOR; PROTEIN KINASE INHIBITOR; THEOPHYLLINE; TRANSCRIPTION FACTOR;

ASTHMA; BINDING AFFINITY; BODY MASS; CLINICAL TRIAL (TOPIC); CORTICOSTEROID THERAPY; DIAGNOSTIC ERROR; GENETIC VARIABILITY; HEREDITY; HISTONE ACETYLATION; HUMAN; INHALER; LOW DRUG DOSE; LUNG FUNCTION; NONHUMAN; RACE DIFFERENCE; RANDOMIZED CONTROLLED TRIAL (TOPIC); REVIEW; SMOKING CESSATION; TREATMENT REFUSAL; TREATMENT RESPONSE; VITAMIN D DEFICIENCY; VITAMIN SUPPLEMENTATION;

EID: 84957659212     PISSN: 17476348     EISSN: 17476356     Source Type: Journal    
DOI: 10.1586/17476348.2016.1133304     Document Type: Review

References (165)

1. GINA Report. Global strategy for asthma management and prevention 2014. [cited 2015 Oct 11]. Available from: http://www.ginasthma.com
2. British guideline on the management of asthma. A national clinical guideline. Thorax. 2014;1-180. [cited 2015 Oct 11]. Available from: www.sign.ac.uk
3. Adams N, Bestall J, Jones P, et al. Fluticasone at different doses for chronic asthma in adults and children. Cochrane Database Systematic Rev. 2008;4Art. No.: CD003534doi:10.1002/14651858.CD003534.pub3
4. Bateman ED, Boushey HA, Bousquet J, et al. Can guideline-defined asthma control be achieved? The gaining optimal asthma control study. Am J Respir Crit Care Med. 2004;170(8):836-844
5. Travers J, Marsh S, Williams M, et al. External validity of randomised controlled trials in asthma: to whom do the results of the trials apply? Thorax. 2007;62(3):219-223
6. Malmstrom K, Rodriguez-Gomez G, Guerra J, et al. Oral montelukast, inhaled beclomethasone, and placebo for chronic asthma. A randomized, controlled trial. Montelukast/Beclomethasone Study Group. Ann Intern Med. 1999;130(6):487-495
7. Colice GL, Stampone P, Leung DYM, et al. Oral corticosteroids in poorly controlled asthma. J Allergy Clin Immunol. 2005;115(1):200-201
8. Szefler SJ, Martin RJ. Lessons learned from variation in response to therapy in clinical trials. J Allergy Clin Immunol. 2010;125(2):285-4
9. Lipworth BJ. Systemic adverse effects of inhaled corticosteroid therapy: A systematic review and meta-analysis. Arch Intern Med. 1999;159(9):941-955
10. Lapi F, Kezouh A, Suissa S, et al. The use of inhaled corticosteroids and the risk of adrenal insufficiency. Eur Respir J. 2013;42(1):79-86
11. Ernst P, Suissa S. Systemic effects of inhaled corticosteroids. Curr Opin Pulm Med. 2012;18(1):85-89
12. Clemmer GL, Wu AC, Rosner B, et al. Measuring the corticosteroid responsiveness endophenotype in asthmatic patients. J Allergy Clin Immunol. 2015;136(2):274-81.e8
13. Woodruff PG, Modrek B, Choy DF, et al. T-helper Type 2-driven Inflammation Defines Major Subphenotypes of Asthma. Am J Respir Crit Care Med. 2009;180(5):388-395
14. Cowan DC, Taylor DR, Peterson LE, et al. Biomarker-based asthma phenotypes of corticosteroid response. J Allergy Clin Immunol. 2015;135:877-83
15. Kelly MM, King EM, Rider CF, et al. Corticosteroid-induced gene expression in allergen-challenged asthmatic subjects taking inhaled budesonide. Br J Pharmacol. 2012;165(6):1737-1747
16. Van Der Schee MP, Palmay R, Cowan JO, et al. Predicting steroid responsiveness in patients with asthma using exhaled breath profiling. Clin Exp Allergy. 2013;43 (11):1217-1225
17. Livingston E, Chaudhuri R, McMahon AD, et al. Systemic sensitivity to corticosteroids in smokers with asthma. Eur Respir J. 2007;29(1):64-71
18. Maranville JC, Baxter SS, Torres JM, et al. Inter-ethnic differences in lymphocyte sensitivity to glucocorticoids reflect variation in transcriptional response. Pharmacogenomics. 2013;13(2):121-129
19. Chun E, Lee H-S, Bang B-R, et al. Dexamethasoneinduced FKBP51 expression in peripheral blood mononuclear cells could play a role in predicting the response of asthmatics to treatment with corticosteroids. J Clin Immunol. 2011;31(1):122-127
20. Goleva E, Jackson LP, Gleason M, et al. Usefulness of PBMCs to predict clinical response to corticosteroids in asthmatic patients. J Allergy Clin Immunol. 2012;129 (3):687-693
21. The Childhood Asthma Management Program Research G. 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):1054-1063
22. Tantisira KG, Hwang ES, Raby BA, et al. TBX21: A functional variant predicts improvement in asthma with the use of inhaled corticosteroids. Proc Natl Acad Sci U S A. 2004;101(52):18099-18104
23. Tantisira K, Lake S, Silverman E, et al. Corticosteroid pharmacogenetics: association of sequence variants in CRHR1 with improved lung function in asthmatics treated with inhaled corticosteroids. Hum Mol Genet. 2004;13:1353-1359
24. Tantisira KG, Silverman ES, Mariani TJ, et al. FCER2: A pharmacogenetic basis for severe exacerbations in children with asthma. J Allergy Clin Immunol. 2007;120 (6):1285-1291
25. Tantisira KG, Lasky-Su J, Harada M, et al Genomewide Association between GLCCI1 and Response to Glucocorticoid Therapy in Asthma. N Eng J Med. 2011;365(13):1173-1183
26. Tantisira KG, Damask A, Szefler SJ, et al. Genome-wide Association Identifies the T Gene as a Novel Asthma Pharmacogenetic Locus. Am J Respir Crit Care Med. 2012;185(12):1286-1291
27. Wang Y, Tong C,Wang Z, et al. Pharmacodynamic genomewide association study identifies new responsive loci for glucocorticoid intervention in asthma. Pharmacogenomics J. 2015;15(5):422-429
28. Sharma S, Kho AT, Chhabra D, et al. Glucocorticoid genes and the developmental origins of asthma susceptibility and treatment response. Am J Respir Cell Mol Biol. 2015;52(5):543-553
29. Chalmers GW, Macleod KJ, Little SA, et al. Influence of cigarette smoking on inhaled corticosteroid treatment in mild asthma. Thorax. 2002;57(3):226-230
30. Lazarus SC, Chinchilli VM, Rollings NJ, et al. Smoking affects response to inhaled corticosteroids or leukotriene receptor antagonists in asthma. Am J Respir Crit Care Med. 2007;175(8):783-790
31. Chaudhuri R, Livingston E, McMahon AD, et al. Cigarette smoking impairs the therapeutic response to oral corticosteroids in chronic asthma. Am J Respir Crit Care Med. 2003;168(11):1308-1311
32. Polosa R, Thomson NC. Smoking and asthma: dangerous liaisons. Eur Respir J. 2013;41(3):716-726
33. Tomlinson JEM, McMahon AD, Chaudhuri R, et al. Efficacy of low and high dose inhaled corticosteroid in smokers versus non-smokers with mild asthma. Thorax. 2005;60 (4):282-287
34. Telenga E, Kerstjens H, Ten Hacken N, et al. van den Berge M. Inflammation and corticosteroid responsiveness in ex-, current-and never-smoking asthmatics. BMC Pulm Med. 2013;13(1):58
35. Dijkstra A, Vonk JM, Jongepier H, et al. Lung function decline in asthma: association with inhaled corticosteroids, smoking and sex. Thorax. 2006;61(2):105-110
36. Lange P, Scharling H, Ulrik CS, et al. Inhaled corticosteroids and decline of lung function in community residents with asthma. Thorax. 2006;61(2):100-104
37. O'Byrne PM, Lamm CJ, Busse WW, et al. The effects of inhaled budesonide on lung function in smokers and nonsmokers with mild persistent asthma. Chest. 2009;136(6):1514-1520
38. Cohen RT, Raby BA, Van Steen K, et al. In utero smoke exposure and impaired response to inhaled corticosteroids in children with asthma. J Allergy Clin Immunol. 2010;126(3):491-497
39. Nimmagadda S, Szefler S, Spahn J, et al. Allergen exposure decreases glucocorticoid receptor binding affinity and steroid responsiveness in atopic asthmatics. Am J Respir Crit Care Med. 1997;155:87-93
40. Larsson S, Hansson L, Greiff L, et al Natural allergen exposure does not diminish the sensitivity of cytokine production to glucocorticoids in blood cells of seasonal allergic asthma and rhinitis patients. Resp Med. 2002;96:927-933
41. Castanhinha S, Sherburn R, Walker S, et al. Pediatric severe asthma with fungal sensitization is mediated by steroid-resistant IL-33. J Allergy Clin Immunol. 2015;136 (2):312-22.e7
42. Li L-B, Goleva E, Hall CF, et al. Superantigen-induced corticosteroid resistance of human T cells occurs through activation of the mitogen-activated protein kinase kinase/extracellular signal-regulated kinase (MEK-ERK) pathway. J Allergy Clin Immunol. 2004;114(5):1059-1069
43. Fakhri S, Tulic M, Christodoulopoulos P, et al. Microbial superantigens induce glucocorticoid receptor beta and steroid resistance in a nasal explant model. Laryngoscope. 2004;114:887-892
44. Goleva E, Jackson LP, Harris JK, et al. The effects of airway microbiome on corticosteroid responsiveness in asthma. Am J Respir Crit Care Med. 2013;188(10):1193-1201
45. Goleva E, Hauk PJ, Hall CF, et al. Corticosteroid-resistant asthma is associated with classical antimicrobial activation of airway macrophages. J Allergy Clin Immunol. 2008;122(3):550-9
46. Hadebe S, Kirstein F, Fierens K, et al Microbial ligand costimulation drives neutrophilic steroid-refractory asthma. PLoS ONE. 2015;10(8):e0134219
47. Ducharme FM, Lemire C, Noya FJD, et al. Preemptive use of high-dose fluticasone for virus-induced wheezing in young children. N Eng J Med. 2009;360(4):339-353
48. Papi A, Contoli M, Adcock IM, et al. Rhinovirus infection causes steroid resistance in airway epithelium through nuclear factor ?B and c-Jun N-terminal kinase activation. J Allergy Clin Immunol. 2013;132(5):1075-1085
49. Footitt J, Mallia P, Durham AL, et al. Oxidative and nitrosative stress and histone deacetylase-2 activity in exacerbations of chronic obstructive pulmonary disease. Chest. 2015; doi:10.1378/chest.14-2637Epub ahead of print
50. McSharry C, Spears M, Chaudhuri R, et al. Increased sputum endotoxin levels are associated with an impaired lung function response to oral steroids in asthmatic patients. J Allergy Clin Immunol. 2014;134 (5):1068-1075
51. Sutherland ER, Goleva E, Jackson LP, et al. Vitamin D levels, lung function, and steroid response in adult asthma. Am J Respir Crit Care Med. 2010;181(7):699-704
52. Pavord I, Brightling C, Woltmann G, et al. Non-eosinophilic corticosteroid unresponsive asthma. Lancet. 1999;353:2213-2214
53. McGrath KW, Icitovic N, Boushey HA, et al. A large subgroup of mild-to-moderate asthma is persistently noneosinophilic. Am J Respir Crit Care Med. 2012;185(6):612-619
54. Chung EH, Jia Y, Ohnishi H, et al. LeukotrieneB4 receptor 1 is differentially expressed on peripheral T cells of steroid-sensitive and-resistant asthmatics. Ann Allergy Asthma Immunol. 2014;112(3):211-216.e1
55. Bourdin A, Kleis S, Chakra M, et al. Limited short-term steroid responsiveness is associated with thickening of bronchial basement membrane in severe asthma. Chest. 2012;141(6):1504-1511
56. Heaney LG, Horne R. Non-adherence in difficult asthma: time to take it seriously. Thorax. 2012;67(3):268-270
57. Williams LK, Peterson EL, Wells K, et al. Quantifying the proportion of severe asthma exacerbations attributable to inhaled corticosteroid nonadherence. J Allergy Clin Immunol. 2011;128(6):1185-1191
58. Gamble J, Stevenson M, McClean E, et al. The prevalence of nonadherence in difficult asthma. Am J Respir Crit Care Med. 2009;180(9):817-822
59. Haczku A, Panettieri RA Jr. Social stress and asthma: The role of corticosteroid insensitivity. J Allergy Clin Immunol. 2010;125(3):550-558
60. Federico MJ, Covar RA, Brown EE, et al. Racial differences in T-lymphocyte response to glucocorticoids. Chest. 2005;127(2):571-578
61. Dunn RM, Lehman E, Chinchilli VM, et al. Impact of age and sex on response to asthma therapy. Am J Respir Crit Care Med. 2015;192:551-558
62. Wechsler ME, Castro M, Lehman E, et al. Impact of race on asthma treatment failures in the Asthma Clinical Research Network. Am J Respir Crit Care Med. 2011;184 (11):1247-1253
63. Gould W, Peterson EL, Karungi G, et al. Factors predicting inhaled corticosteroid responsiveness in African American patients with asthma. J Allergy Clin Immunol. 2010;126(6):1131-1138
64. Boulet L-P, Franssen E. Influence of obesity on response to fluticasone with or without salmeterol in moderate asthma. Respir Med. 2007;101(11):2240-2247
65. Sutherland ER, Lehman EB, Teodorescu M, et al. Body mass index and phenotype in subjects with mild-to-moderate persistent asthma. J Allergy Clin Immunol. 2009;123 (6):1328-34.e1
66. Sutherland ER, Goleva E, Strand M, et al. Body mass and glucocorticoid response in asthma. Am J Respir Crit Care Med. 2008;178(7):682-687
67. Fingleton J, Travers J, Williams M, et al. Treatment responsiveness of phenotypes of symptomatic airways obstruction in adults. J Allergy Clin Immunol. 2015;136 (3):601-609
68. Invernizzi G, Ruprecht A, Marco C, et al. Inhaled steroid/tobacco smoke particle interactions: a new light on steroid resistance. Resp Res. 2009;10(1):48
69. Stott EJ, Chan WL, Mills KH, et al. Preliminary report: protection of cynomolgus macaques against simian immunodeficiency virus by fixed infected-cell vaccine. Lancet. 1990;336(8730):1538-1541
70. Barnes PJ. Glucocorticosteroids: current and future directions. Br J Pharmol. 2011;163(1):29-43
71. Clark AR, Belvisi MG. Maps and legends: the quest for dissociated ligands of the glucocorticoid receptor. Pharmacol Ther. 2012;134(1):54-67
72. Boardman C, Chachi L, Gavrila A, et al. Mechanisms of glucocorticoid action and insensitivity in airways disease. Pulm Pharmacol Ther. 2014;29(2):129-143
73. Barnes PJ. Corticosteroid resistance in patients with asthma and chronic obstructive pulmonary disease. J Allergy Clin Immunol. 2013;131(3):636-645
74. Keenan CR, Radojicic D, Li M, et al. Heterogeneity in mechanisms influencing glucocorticoid sensitivity: the need for a systems biology approach to treatment of glucocorticoid-resistant inflammation. Pharmacol Ther. 2015;150:81-93
75. Vazquez-Tello A, Semlali A, Chakir J, et al. Induction of glucocorticoid receptor-beta expression in epithelial cells of asthmatic airways by T-helper type 17 cytokines. Clin Exp Allergy. 2010;40(9):1312-1322
76. Livingston E, Darroch C, Chaudhuri R, et al. Glucocorticoid receptor alpha:beta ratio in blood mononuclear cells is reduced in cigarette smokers. J Allergy Clin Immunol. 2004;114:1475-1478
77. Goleva E, Li L-B, Eves PT, et al. Increased glucocorticoid receptor beta alters steroid response in glucocorticoidinsensitive asthma. Am J Respir Crit Care Med. 2006;173 (6):607-616
78. Butler CA, McQuaid S, Taggart CC, et al. Glucocorticoid receptor ? and histone deacetylase 1 and 2 expression in the airways of severe asthma. Thorax. 2012; 67(5):392-398
79. Sutherland ER, Goleva E, King TS, et al Cluster analysis of obesity and asthma phenotypes. PLoS ONE. 2012;7(5): e36631
80. Kobayashi Y, Mercado N, Barnes PJ, et al. Defects of protein phosphatase 2A causes corticosteroid insensitivity in severe asthma. PLoS ONE. 2011;6(12):e27627
81. Bhavsar P, Hew M, Khorasani N, et al. Relative corticosteroid insensitivity of alveolar macrophages in severe asthma compared with non-severe asthma. Thorax. 2008;63(9):784-790
82. Li JJ, Wang W, Baines KJ, et al. IL-27/IFN-? induce MyD88-dependent steroid-resistant airway hyperresponsiveness by inhibiting glucocorticoid signaling in macrophages. J Immunol. 2010;185(7):4401-4409
83. Li JJ, Tay HL, Maltby S, et al. MicroRNA-9 regulates steroid-resistant airway hyperresponsiveness by reducing protein phosphatase 2A activity. J Allergy Clin Immunol. 2015;136(2):462-473
84. Cornejo S, Tantisira K, Raby BA, et al. Nuclear bioavailability of the glucocorticoid receptor in a pediatric asthma cohort with variable corticosteroid responsiveness. Pediatr Res. 2015;78:505-512. doi:10.1038/pr.2015. [Epub ahead of print]
85. Hakonarson H, Bjornsdottir US, Halapi E, et al. Profiling of genes expressed in peripheral blood mononuclear cells predicts glucocorticoid sensitivity in asthma patients. Proc Natl Acad Sci U S A. 2005;102(41):14789-14794
86. Loke T-K, Mallett KH, Ratoff J, et al. Systemic glucocorticoid reduces bronchial mucosal activation of activator protein 1 components in glucocorticoid-sensitive but not glucocorticoid-resistant asthmatic patients. J Allergy Clin Immunol. 2006;118(2):368-375
87. Ito K, Caramori G, Lim S, et al. Expression and activity of histone deacetylases in human asthmatic airways. Am J Respir Crit Care Med. 2002;166(3):392-396
88. Hew M, Bhavsar P, Torrego A, et al. Relative corticosteroid insensitivity of peripheral blood mononuclear cells in severe asthma. Am J Respir Crit Care Med. 2006;174 (2):134-141
89. Cosío BG, Mann B, Ito K, et al. Histone acetylase and deacetylase activity in alveolar macrophages and blood mononocytes in asthma. Am J Respir Crit Care Med. 2004;170(2):141-147
90. Ito K, Lim S, Caramori G, et al. Cigarette smoking reduces histone deacetylase 2 expression, enhances cytokine expression, and inhibits glucocorticoid actions in alveolar macrophages. FASEB J. 2001;15(6):1110-1112
91. Cosio BG, Tsaprouni L, Ito K, et al. Theophylline restores histone deacetylase activity and steroid responses in COPD macrophages. J Exp Med. 2004;200:689-695
92. Hawrylowicz C, Richards D, Loke T-K, et al. A defect in corticosteroid-induced IL-10 production in T lymphocytes from corticosteroid-resistant asthmatic patients. J Allergy Clin Immunol. 2002;109(2):369-370
93. Dejager L, Dendoncker K, Eggermont M, et al. Neutralizing TNF[alpha] restores glucocorticoid sensitivity in a mouse model of neutrophilic airway inflammation. Mucosal Immunol. 2015; doi:10.1038/ mi.2015.12Epub ahead of print
94. Bel EH, Sousa A, Fleming L, et al. Diagnosis and definition of severe refractory asthma: an international consensus statement from the Innovative Medicine Initiative (IMI). Thorax. 2011;66(10):910-917
95. Schlender A, Alperin PE, Grossman HL, et al. Modeling the impact of increased adherence to asthma therapy. PLoS ONE. 2012;7(12):e51139
96. Chaudhuri R, Livingston E, McMahon AD, et al. Effects of smoking cessation on lung function and airway inflammation in smokers with asthma. Am J Respir Crit Care Med. 2006;174(2):127-133
97. Zhang Y, Leung DYM, Goleva E. Anti-inflammatory and corticosteroid-enhancing actions of vitamin D in monocytes of patients with steroid-resistant and those with steroid-sensitive asthma. J Allergy Clin Immunol. 2014;133(6):1744-52
98. Nanzer AM, Chambers ES, Ryanna K, et al. Enhanced production of IL-17A in patients with severe asthma is inhibited by 1?,25-dihydroxyvitamin D3 in a glucocorticoid-independent fashion. J Allergy Clin Immunol. 2013;132(2):297-304
99. Xystrakis E, Kusumakar S, Boswell S, et al. Reversing the defective induction of IL-10-secreting regulatory T cells in glucocorticoid-resistant asthma patients. J Clin Invest. 2006;116(1):146-155
100. Nanzer AM, Chambers ES, Ryanna K, et al. The effects of calcitriol treatment in glucocorticoid-resistant asthma. J Allergy Clin Immunol. 2014;133(6):1755-7
101. Chambers ES, Nanzer AM, Pfeffer PE, et al. Distinct endotypes of steroid-resistant asthma characterized by IL-17A (high) and IFN-?(high) immunophenotypes: Potential benefits of calcitriol. J Allergy Clin Immunol. 2015;136 (3):628-637
102. Castro M, King TS, Kunselman SJ, et al. Effect of vitamin D3 on asthma treatment failures in adults with symptomatic asthma and lower vitamin d levels: the VIDA randomized clinical trial. JAMA. 2014;311(20): 2083-2091
103. Martineau AR, Hanifa Y, Witt KD, et al. Double-blind randomised controlled trial of vitamin D3 supplementation for the prevention of acute respiratory infection in older adults and their carers (ViDiFlu). Thorax. 2015;70 (10):953-960
104. Groot JC, Van Roon ENH, Storm H, et al. Vitamin D reduces eosinophilic airway inflammation in nonatopic asthma. J Allergy Clin Immunol. 2015;135(3):670-5
105. Roche N, Postma DS, Colice G, et al. Differential effects of inhaled corticosteroids in smokers/ex-smokers and nonsmokers with asthma. Am J Respir Crit Care Med. 2015;191(8):960-964
106. Kobayashi Y, Mercado N, Miller-Larsson A, et al. Increased corticosteroid sensitivity by a long acting ?2 agonist formoterol via ?2 adrenoceptor independent protein phosphatase 2A activation. Pulm Pharm Therap. 2012;25(3):201-207
107. Rossios C, To Y, Osoata G, et al. Corticosteroid insensitivity is reversed by formoterol via phosphoinositide-3-kinase inhibition. Br J Pharmacol. 2012;167(4):775-786
108. Manetsch M, Ramsay EE, King EM, et al. Corticosteroids and ?2-agonists upregulate mitogen-activated protein kinase phosphatase 1: in vitro mechanisms. Br J Pharmacol. 2012;166(7):2049-2059
109. To Y, Ito K, Kizawa Y, et al. Targeting phosphoinositide-3-kinase-delta with theophylline reverses corticosteroid insensitivity in chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2010;182(7):897-904
110. Spears M, Donnelly I, Jolly L, et al. Effect of low-dose theophylline plus beclometasone on lung function in smokers with asthma: a pilot study. Eur Respir J. 2009;33(5):1010-1017
111. Price D, Popov TA, Bjermer L, et al. Effect of montelukast for treatment of asthma in cigarette smokers. J Allergy Clin Immunol. 2013;131(3):763-771
112. Normansell R, Walker S, Milan SJ, et al. Omalizumab for asthma in adults and children. Cochrane Database of Systematic Reviews. 2014;1Art. No.: CD003559doi:10.1002/ 14651858.CD003559.pub4
113. Ortega HG, Liu MC, Pavord ID, et al. Mepolizumab treatment in patients with severe eosinophilic asthma. New England J Med. 2014;371(13):1198-1207
114. Bel EH, Wenzel SE, Thompson PJ, et al. Oral glucocorticoid-sparing effect of mepolizumab in eosinophilic asthma. New England J Med. 2014;371(13):1189-1197
115. Cameron EJ, McSharry C, Chaudhuri R, et al. Long-term macrolide treatment of chronic inflammatory airway diseases: risks, benefits and future developments. Clin Exp Allergy. 2012;42(9):1302-1312
116. Kobayashi Y, Wada H, Rossios C, et al. A novel macrolide solithromycin exerts superior anti-inflammatory effect via NF-?B inhibition. J Pharmacol Exp Ther. 2013;345 (1):76-84
117. Kobayashi Y, Wada H, Rossios C, et al. A novel macrolide/ fluoroketolide, solithromycin (CEM-101), reverses corticosteroid insensitivity via phosphoinositide 3-kinase pathway inhibition. Br J Pharmacol. 2013;169 (5):1024-1034
118. Essilfie A-T, Horvat JC, Kim RY, et al. Macrolide therapy suppresses key features of experimental steroid-sensitive and steroid-insensitive asthma. Thorax. 2015;70 (5):458-467
119. Cameron EJ, Chaudhuri R, Mair F, et al. Randomised controlled trial of azithromycin in smokers with asthma. Eur Respir J. 2013;42(5):1412-1415
120. Brusselle GG, VanderStichele C, Jordens P, et al. Azithromycin for prevention of exacerbations in severe asthma (AZISAST): a multicentre randomised doubleblind placebo-controlled trial. Thorax. 2013;68(4):322-329
121. Balloy V, Deveaux A, Lebeaux D, et al. Azithromycin analogue CSY0073 attenuates lung inflammation induced by LPS challenge. Br J Pharmacol. 2014;171 (7):1783-1794
122. Bhavsar P, Khorasani N, Hew M, et al. Effect of p38 MAPK inhibition on corticosteroid suppression of cytokine release in severe asthma. Eur Respir J. 2010;35 (4):750-756
123. Guntur VP, Reinero CR. The potential use of tyrosine kinase inhibitors in severe asthma. Curr Opin Allergy Clin Immunol. 2012;12(1):68-75
124. Chung KF. p38 mitogen-activated protein kinase pathways in asthma and COPD. Chest. 2011;139 (6):1470-1479
125. Mercado N, Hakim A, Kobayashi Y, et al Restoration of corticosteroid sensitivity by p38 mitogen activated protein kinase inhibition in peripheral blood mononuclear cells from severe asthma. PLoS ONE. 2012;7(7):e41582
126. Khorasani N, Baker J, Johnson M, et al. Reversal of corticosteroid insensitivity by p38 MAPK inhibition in peripheral blood mononuclear cells from COPD. Int J Chron Obstruct Pulmon Dis. 2015;10:283-291
127. Rhee CK, Kim JW, Park CK, et al. Effect of imatinib on airway smooth muscle thickening in a murine model of chronic asthma. Int Arch Allergy Immunol. 2011;155 (3):243-251
128. Humbert M, Blay F, Garcia G, et al. Masitinib, a c-kit/ PDGF receptor tyrosine kinase inhibitor, improves disease control in severe corticosteroid-dependent asthmatics. Allergy. 2009;64(8):1194-1201
129. Marwick JA, Caramori G, Casolari P, et al. A role for phosphoinositol 3-kinase delta in the impairment of glucocorticoid responsiveness in patients with chronic obstructive pulmonary disease. J Allergy Clin Immunol. 2010;125(5):1146-1153
130. Ito K, Caramori G, Adcock IM. Therapeutic potential of phosphatidylinositol 3-kinase inhibitors in inflammatory respiratory disease. J Pharmacol Exp Ther. 2007;321(1):1-8
131. Doukas J, Eide L, Stebbins K, et al. Aerosolized phosphoinositide 3-kinase gamma/delta inhibitor TG100-115 [3-[2,4-diamino-6-(3-hydroxyphenyl)pteridin-7-yl]phenol] as a therapeutic candidate for asthma and chronic obstructive pulmonary disease. J Pharmacol Exp Ther. 2009;328(3):758-765
132. Mercado N, To Y, Ito K, et al. Nortriptyline reverses corticosteroid insensitivity by inhibition of phosphoinositide-3-kinase-delta. J Pharmacol Exp Ther. 2011;337:465-470
133. Schuliga M. NF-kappaB signaling in chronic inflammatory airway disease. Biomolecules. 2015;5(3):1266-1283
134. Page CP, Spina D. Selective PDE inhibitors as novel treatments for respiratory diseases. Curr Opin Pharmacol. 2012;12(3):275-286
135. Milara J, Lluch J, Almudever P, et al. Roflumilast N-oxide reverses corticosteroid resistance in neutrophils from patients with chronic obstructive pulmonary disease. J Allergy Clin Immunol. 2014;134(2):314-322
136. Chapman RW, House A, Richard J, et al Pharmacology of a potent and selective inhibitor of PDE4 for inhaled administration. Eur J Pharmacol. 2010;643(2-3):274-281
137. Singh D, Petavy F, Macdonald A, et al. The inhaled phosphodiesterase 4 inhibitor GSK256066 reduces allergen challenge responses in asthma. Resp Res. 2010;11(1):26
138. Moretto N, Caruso P, Bosco R, et al. CHF6001 I: a novel highly potent and selective phosphodiesterase 4 inhibitor with robust anti-inflammatory activity and suitable for topical pulmonary administration. J Pharmacol Exp Ther. 2015;352(3):559-567
139. Watz H, Mistry S, Lazaar A. investigators. I. Safety and tolerability of the inhaled phosphodiesterase 4 inhibitor GSK256066 in moderate COPD. Pulm Pharmacol Ther. 2013;26(5):588-595
140. Milara J, Navarro A, Almudéver P, et al. Oxidative stressinduced glucocorticoid resistance is prevented by dual PDE3/PDE4 inhibition in human alveolar macrophages. Clin Exp Allergy. 2011;41(4):535-546
141. Franciosi LG, Diamant Z, Banner KH, et al. Efficacy and safety of RPL554, a dual PDE3 and PDE4 inhibitor, in healthy volunteers and in patients with asthma or chronic obstructive pulmonary disease: findings from four clinical trials. Lancet Respir Med. 2013;1(9):714-727
142. Spears M, McSharry C, Thomson NC. Peroxisome proliferator-activated receptor-gamma agonists as potential anti-inflammatory agents in asthma and chronic obstructive pulmonary disease. Clin Exp Allergy. 2006;36 (12):1494-1504
143. Lea S, Plumb J, Metcalfe H, et al. The effect of peroxisome proliferator-activated receptor-? ligands on in vitro and in vivo models of COPD. Eur Respir J. 2014;43 (2):409-420
144. Spears M, Donnelly I, Jolly L, et al. Bronchodilatory effect of the PPAR-gamma agonist rosiglitazone in smokers with asthma. Clin Pharmacol Ther. 2009;86(1):49-53
145. Hothersall E, McSharry C, Thomson NC. Potential therapeutic role for statins in respiratory disease. Thorax. 2006;61(8):729-734
146. Yeganeh B, Wiechec E, Ande S, et al. Targeting the mevalonate cascade as a new therapeutic approach in heart disease, cancer and pulmonary disease. Pharmacol Ther. 2014;143(1):87-110
147. McKay A, Leung BP, McInnes IB, et al. A novel antiinflammatory role of simvastatin in a murine model of allergic asthma. J Immunol. 2004;172(5):2903-2908
148. Lee J-H, Lee D-S, Kim E-K, et al. Simvastatin inhibits cigarette smoking-induced emphysema and pulmonary hypertension in rat lungs. Am J Respir Crit Care Med. 2005;172(8):987-993
149. Samson K, Minoguchi K, Tanaka A, et al. Inhibitory effects of fluvastatin on cytokine and chemokine production by peripheral blood mononuclear cells in patients with allergic asthma. Clin Exp Allergy. 2006;36(4):475-482
150. Maneechotesuwan K, Ekjiratrakul W, Kasetsinsombat K, et al. Statins enhance the anti-inflammatory effects of inhaled corticosteroids in asthmatic patients through increased induction of indoleamine 2, 3-dioxygenase. J Allergy Clin Immunol. 2010;126(4):754-762
151. Braganza G, Chaudhuri R, McSharry C, et al Effects of shortterm treatment with atorvastatin in smokers with asthma-A randomized controlled trial. BMC Pulm Med. 2011;11:16
152. Thomson NC, Charron CE, Chaudhuri R, et al. Atorvastatin in combination with inhaled beclometasone modulates inflammatory sputum mediators in smokers with asthma. Pulm Pharmacol Ther. 2015;31:1-8
153. Maneechotesuwan K, Kasetsinsombat K, Wongkajornsilp A, et al. Decreased indoleamine 2,3-dioxygenase activity and IL-10/IL-17A ratio in patients with COPD. Thorax. 2013;68(4):330-337
154. Glasser SW, Senft P, Maxfield MD, et al. Genetic replacement of surfactant protein-C reduces respiratory syncytial virus induced lung injury. Respir Res. 2013;14(1):137
155. Nair P, Gaga M, Zervas E, et al. Safety and efficacy of a CXCR2 antagonist in patients with severe asthma and sputum neutrophils: a randomized, placebocontrolled clinical trial. Clin Exp Allergy. 2012;42 (7):1097-1103
156. Rennard SI, Dale DC, Donohue JF, et al. CXCR2 antagonist MK-7123-A phase 2 proof-of-concept trial for chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2015;191(9):1001-1011
157. Chaudhuri R, Norris V, Kelly K, et al. Effects of a FLAP inhibitor, GSK2190915, in asthmatics with high sputum neutrophils. Pulm Pharmacol Ther. 2014;27(1):62-69
158. Chesné J, Braza F, Mahay G, et al. IL-17 in severe asthma. where do we stand?. Am J Respir Crit Care Med. 2014;190 (10):1094-1101
159. Busse WW, Holgate S, Kerwin E, et al. Randomized, double-blind, placebo-controlled study of brodalumab, a human anti-IL-17 receptor monoclonal antibody, in moderate to severe asthma. Am J Respir Crit Care Med. 2013;188(11):1294-1302
160. Wenzel SE, Barnes PJ, Bleecker ER, et al. A randomized, double-blind, placebo-controlled study of tumor necrosis factor-alpha blockade in severe persistent asthma. Am J Respir Crit Care Med. 2009;179(7):549-558
161. Holgate ST, Noonan M, Chanez P, et al. Efficacy and safety of etanercept in moderate-to-severe asthma: a randomised, controlled trial. Eur Respir J. 2011;37(6):1352-1359
162. Jarjour NN, Erzurum SC, Bleecker ER, et al. Severe asthma: lessons learned from the national heart, lung, and blood institute severe asthma research program. Am J Respir Crit Care Med. 2012;185(4):356-362
163. The ENFUMOSA Study Group. 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):470-477
164. Shaw DE, Sousa AR, Fowler SJ, et al. Clinical and inflammatory characteristics of the European U-BIOPRED adult severe asthma cohort. Eur Respir J. 2015;46(5):1308-1321
165. Heaney LG, Djukanovic R, Woodcock A, et al. Research in progress: medical research council United Kingdom refractory asthma stratification programme (RASP-UK). Thorax. 2015; doi:10.1136/thoraxjnl-2015-207326 [Epub ahead of print]